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Biomedical subjects

S Cook

Publications and source records attributed to S Cook.

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

A Phase I-II study of 96-hour infusional topotecan and paclitaxel for patients with recurrent Müllerian tumors.

BACKGROUND: Topotecan and paclitaxel are schedule dependent chemotherapeutic agents with activity against ovarian carcinoma. A Phase I-II study in which both drugs were administered concurrently by 96-hour, continuous, intravenous infusion was performed to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy of the combination. METHODS: Women with ovarian or primary peritoneal carcinoma and documented recurrent disease were eligible for the study. The dose of topotecan was escalated from 1.6 mg/m(2) while maintaining the paclitaxel dose constant at 100 mg/m(2). Plasma concentrations of both drugs were monitored daily during the first cycle of therapy. RESULTS: Forty-five patients with a median age of 54 years (range, 42-70 years) received 181 cycles of therapy. Five patients were recruited to each of four dose levels (topotecan 1.6 mg/m(2), 2.0 mg/m(2), 2.8 mg/m(2), and 3.6 mg/m(2)), and an additional 25 patients were treated at the MTD (Phase II). Neutropenia and thrombocytopenia became dose limiting toxicities (DLT) at the fourth dose level. Emesis, mucositis, peripheral neuropathy, diarrhea, and alopecia were mild. Twenty patients (44%) had line-related occlusion, thrombosis, or infection. The mean values (+/- standard deviation) of the apparent steady-state plasma concentrations at the Phase II doses were 2.3 nM +/- 0.5 nM for topotecan lactone, 5.6 nM +/- 2.1 nM for total topotecan, and 40.1 nM +/- 16.8 nM for paclitaxel. There were seven partial responses (Phase II) contributing to an objective response rate of 28% and a median survival time of 11.7 months (range, 0.6-20.1 months). CONCLUSIONS: Topotecan at a dose of 2.8 mg/m(2) and paclitaxel at a dose of 100 mg/m(2) administered by concurrent, 96-hour, continuous intravenous infusions shows activity against tumors of Müllerian origin.

Adult↗
PubMed2001

Proliferating oligodendrocytes are present in both active and chronic inactive multiple sclerosis plaques.

The proliferation marker Ki-67 labels cell nuclei in the G(1), S, M, and G(2) phases of the cell cycle. We used Ki-67 immunohistochemistry to quantify proliferating glial cells in brain tissue sections from twenty-four patients, comprised of multiple sclerosis, normal brains, and other neurological disease controls. Glial proliferation was greatly increased in MS lesions when compared with control brain white matter. Both actively demyelinating/early remyelinating plaques and chronic inactive plaques of long standing often displayed large numbers of glial cells in the proliferative cycle. The bulk of these proliferating cells were of oligodendroglial lineage in the MS plaques. Ki-67 positive macrophage/microglial lineage cells were largely restricted to acute lesions. The finding of increased numbers of proliferating oligodendroglia in most MS plaques, regardless of disease duration or activity state, indicates that the MS brain is capable of recruiting unexpectedly large numbers of new oligodendrocytes over long periods of time. The factors within the MS plaque microenvironment that provoke new oligodendrocyte generation and their subsequent loss still need to be identified.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2001

Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase.

BACKGROUND: Insulin resistance and arterial hypertension are related, but the underlying mechanism is unknown. Endothelial nitric oxide synthase (eNOS) is expressed in skeletal muscle, where it may govern metabolic processes, and in the vascular endothelium, where it regulates arterial pressure. METHODS AND RESULTS: To study the role of eNOS in the control of the metabolic action of insulin, we assessed insulin sensitivity in conscious mice with disruption of the gene encoding for eNOS. eNOS(-/-) mice were hypertensive and had fasting hyperinsulinemia, hyperlipidemia, and a 40% lower insulin-stimulated glucose uptake than control mice. Insulin resistance in eNOS(-/-) mice was related specifically to impaired NO synthesis, because in equally hypertensive 1-kidney/1-clip mice (a model of renovascular hypertension), insulin-stimulated glucose uptake was normal. CONCLUSIONS: These results indicate that eNOS is important for the control not only of arterial pressure but also of glucose and lipid homeostasis. A single gene defect, eNOS deficiency, may represent the link between metabolic and cardiovascular disease.

Animals↗
PubMed2001

Optimizing effectiveness of laser tympanic membrane fenestration in chronic otitis media with effusion. Clinical and technical considerations.

OBJECTIVE: To describe the patient, disease and clinical characteristics that optimize the effectiveness of laser tympanic membrane fenestration (LTMF) to treat chronic otitis media with effusion (OME). SETTING: Four pediatric otolaryngology tertiary referral centers. IRB approved; participation by informed consent. METHODS: An observational clinical effectiveness trial was conducted in 164 ears (94 children), who had chronic OME. All patients were candidates for insertion of pressure equalization tubes (PETs) but agreed to undergo LTMF instead. Clinical and audiologic follow-up are reported at 90 days after LTMF. OUTCOME MEASURES: Clinical effectiveness was defined as an effusion free middle ear at otoscopy with A or C1 tympanogram and normal hearing. RESULTS: At 90 days, 66% of the 95 evaluable ears were effusion free, all with normal hearing. Children younger than 4 years (P<0.04), who had shorter durations of effusion (P<0.009), and who experienced longer duration of fenestration patency (FP) (P<0.009) correlated to improved outcomes. CONCLUSIONS: The use of LTMF to create 2--3 weeks of middle ear ventilation in patients with chronic OME (middle ear effusion (MEE) for 3 months or greater) is effective in 66% of 95 (58%) of ears evaluable at 90 days follow-up. This study provides basic information needed to optimize the use of LTMF today and enhance research efforts in the future.

Child↗
PubMed2001

Evidence for the neural crest origin of turtle plastron bones.

The migrating cranial neural crest cells of birds, fish, and mammals have been shown to form the membranous bones of the cranium and face. These findings have been extrapolated to suggest that all the dermal bones of the vertebrate exoskeleton are derived from the neural crest ectomesenchyme. However, only one group of extant animals, the Chelonians, has an extensive bony exoskeleton in the trunk. We have previously shown that the autapomorphic carapacial and plastron bones of the turtle shell arise from dermal intramembranous ossification. Here, we show that the bones of the plastron stain positively for HNK-1 and PDGFRalpha and are therefore most likely of neural crest origin. This extends the hypothesis of the neural crest origin of the exoskeleton to include the turtle plastron.

Animals↗
PubMed2001

Effect of photosensitizer riboflavin on the fate of 2,4,6-trinitrotoluene in a freshwater environment.

The effect of riboflavin (1 microM) on the fate of TNT (20 mg/l) in a natural water environment was studied. The relative contribution of photolysis, microbial assemblages and freshwater matrix to TNT degradation was examined. The rates, extent and products of TNT and riboflavin transformation were compared under different experimental conditions. It was found that riboflavin significantly enhanced the degradation of TNT in natural water environment. Thus it is a potentially useful photosensitizing agent for the treatment of TNT-contaminated surface water. Furthermore, in the presence of riboflavin, two new intermediates with max. absorption wavelength of 230 nm were found, demonstrating that transformation of TNT in the presence of riboflavin undergoes different pathways.

Biodegradation, Environmental↗
PubMed2001

Evaluation of the athlete who 'goes to ground'

The athlete represents the healthiest segment of our society. Yet, there are still reports of sudden death occurring while on the athletic field. Any athlete who 'goes to ground' temporarily (syncope) warrants an immediate investigation. The differential diagnosis of syncope is wide-ranging. However, if a cardiac cause is the underlying etiology of an athlete with syncope, and that athlete participates and has another syncopal episode the likelihood of resuscitation may be quite low. This article reviews the most common causes of sudden death in athletes (hypertrophic cardiomyopathy, anomalous coronary arteries, arrhythmogenic right ventricular cardiomyopathy, myocarditis, and dilated cardiomyopathy). Important attention will be centered on the pathophysiology of each abnormality and how it contributes to symptoms of syncope and sudden death. Also, the ideal evaluation of each will be reviewed. Recommendations regarding eligibility for competition in sports with each underlying abnormality will be reviewed. In addition, this article will review the evaluation of children and young adults who wish to participate in athletics.

Journal Article↗
PubMed2001

Threading of a glycosylated protein loop through a protein hole: implications for combination of human chorionic gonadotropin subunits.

Chorionic gonadotropin (hCG) is a heterodimeric placental glycoprotein hormone essential for human reproduction. Twenty hCG beta-subunit residues, termed the seatbelt, are wrapped around alpha-subunit loop 2 (alpha 2) and their positions "latched" by a disulfide formed by cysteines at the end of the seatbelt (Cys 110) and in the beta-subunit core (Cys 26). This unique arrangement explains the stability of the heterodimer but raises questions as to how the two subunits combine. The seatbelt is latched in the free beta-subunit. If the seatbelt remained latched during the process of subunit combination, formation of the heterodimer would require alpha 2 and its attached oligosaccharide to be threaded through a small beta-subunit hole. The subunits are known to combine during oxidizing conditions in vitro, and studies described here tested the idea that this requires transient disruption of the latch disulfide, possibly as a consequence of the thioredoxin activity reported in hCG. We observed that alkylating agents did not modify either cysteine in the latch disulfide (Cys 26 or Cys 110) during heterodimer formation in several oxidizing conditions and had minimal influence on these cysteines during combination in the presence of mild reductants (1--3 mM beta-mercaptoethanol). Reducing agents appeared to accelerate subunit combination by disrupting a disulfide (Cys 93--Cys 100) that forms a loop within the seatbelt, thereby increasing the size of the beta-subunit hole. We propose a mechanism for hCG assembly in vitro that depends on movements of alpha 2 and the seatbelt and suggest that the process of glycoprotein hormone subunit combination may be useful for studying the movements of loops during protein folding.

Alkylating Agents↗
PubMed2001

Earwitness testimony: effects of exposure and attention on the face overshadowing effect.

Two experiments tested memory for a once-heard voice. Experiment 1 showed that hearing an unknown voice utter the same sentence three times improved recognition of the voice a week later compared with hearing only a single utterance of the sentence, but instructions to attend to the voice did not. The impairment caused by seeing the speaker's face during the original utterance (the Face Overshadowing Effect--FOE) occurred only with the single utterance and was unaffected by instructions. It was concluded that length of utterance without increase in speech variety aids voice recognition, and that the FOE is not due to voluntary attention to face rather than voice, but may be due to involuntary attention to the initial exposure of the face. Experiment 2 investigated whether exposure to the face before the onset of speech reduced the FOE. Such an effect was observed and it was concluded that the FOE is due to involuntary preference for processing face information in order to aid later recognition of the individual, while speech is processed primarily for meaning. Absence of an FOE on memory for the words uttered was consistent with this interpretation.

Adolescent↗
PubMed2001

Barriers to providing diabetes care in community health centers.

OBJECTIVE: We aimed to identify barriers to improving care for individuals with diabetes in community health centers. These findings are important because many such patients, as in most other practice settings, receive care that does not meet evidence-based standards. RESEARCH DESIGN AND METHODS: In 42 Midwestern health centers, we surveyed 389 health providers and administrators about the barriers they faced delivering diabetes care. We report on home blood glucose monitoring, HbA1c tests, dilated eye examinations, foot examinations, diet, and exercise, all of which are a subset of the larger clinical practice recommendations of the American Diabetes Association (ADA). RESULTS: Among the 279 (72%) respondents, providers perceived that patients were significantly less likely than providers to believe that key processes of care were important (overall mean on 30-point scale: providers 26.8, patients 18.2, P = 0.0001). Providers were more confident in their ability to instruct patients on diet and exercise than on their ability to help them make changes in these areas. Ratings of the importance of access to care and finances as barriers varied widely; however, >25% of the providers and administrators agreed that significant barriers included affordability of home blood glucose monitoring, HbA1c testing, dilated eye examination, and special diets; nonproximity of ophthalmologist; forgetting to order eye examinations and to examine patients' feet; time required to teach home blood glucose monitoring; and language or cultural barriers. CONCLUSIONS: Providers in health centers indicate a need to enhance behavioral change in diabetic patients. In addition, better health care delivery systems and reforms that improve the affordability, accessibility, and efficiency of care are also likely to help health centers meet ADA standards of care.

Blood Glucose Self-Monitoring↗
PubMed2000

Shedding of somatic angiotensin-converting enzyme (ACE) is inefficient compared with testis ACE despite cleavage at identical stalk sites.

The somatic and testis isoforms of angiotensin-converting enzyme (ACE) are both C-terminally anchored ectoproteins that are shed by an unidentified secretase. Although testis and somatic ACE both share the same stalk and membrane domains the latter was reported to be shed inefficiently compared with testis ACE, and this was ascribed to cleavage at an alternative site [Beldent, Michaud, Bonnefoy, Chauvet and Corvol (1995) J. Biol. Chem. 270, 28962-28969]. These differences constitute a useful model system of the regulation and substrate preferences of the ACE secretase, and hence we investigated this further. In transfected Chinese hamster ovary cells, human somatic ACE (hsACE) was indeed shed less efficiently than human testis ACE, and shedding of somatic ACE responded poorly to phorbol ester activation. However, using several analytical techniques, we found no evidence that the somatic ACE cleavage site differed from that characterized in testis ACE. First, anti-peptide antibodies raised to specific sequences on either side of the reported cleavage site (Arg(1137)/Leu(1138)) clearly recognized soluble porcine somatic ACE, indicating that cleavage was C-terminal to Arg(1137). Second, a competitive ELISA gave superimposable curves for porcine plasma ACE, secretase-cleaved porcine somatic ACE (eACE), and trypsin-cleaved ACE, suggesting similar C-terminal sequences. Third, mass-spectral analyses of digests of released soluble hsACE or of eACE enabled precise assignments of the C-termini, in each case to Arg(1203). These data indicated that soluble human and porcine somatic ACE, whether generated in vivo or in vitro, have C-termini consistent with cleavage at a single site, the Arg(1203)/Ser(1204) bond, identical with the Arg(627)/Ser(628) site in testis ACE. In conclusion, the inefficient release of somatic ACE is not due to cleavage at an alternative stalk site, but instead supports the hypothesis that the testis ACE ectodomain contains a motif that activates shedding, which is occluded by the additional domain found in somatic ACE.

Amino Acid Sequence↗
PubMed2000

Reoperation after primary posterior instrumentation and fusion for idiopathic scoliosis. Toward defining late operative site pain of unknown cause.

STUDY DESIGN: Retrospective case series. OBJECTIVES: To determine the frequency and categorize the indications for reoperation in three implant systems (Harrington, Cotrel-Dubousset [C-D], and Isola). To define late operative site pain (LOSP) of no apparent cause as an indication for implant removal and determine the success of implant removal in relieving LOSP. SUMMARY OF BACKGROUND DATA: Late operative site pain of no apparent cause has been discussed briefly in the literature but has not been investigated as a major indication for implant removal. METHODS: One hundred eighty-two of 190 consecutive patients with idiopathic scoliosis (96%) who underwent primary surgery between January 1, 1981, and December 31, 1992, by one surgeon in one hospital, with use of Harrington, C-D, or Isola instrumentation were studied an average of 9 years after surgery to determine the indications for and frequency of reoperation. RESULTS: The overall frequency of reoperation for all instrumentation types combined was 19%: Harrington, 19%; C-D, 24%; and Isola, 14%. By 6 years' follow-up the cumulative risk of reoperation by Kaplan-Meier analysis was Harrington, 14%; C-D, 21%; and Isola, 14%. (statistically nonsignificant difference). The most frequent indication for reoperation was LOSP of no apparent cause: 8% (14 patients) for all instrumentation types combined. The average interval between the initial operation and reoperation for LOSP was 46 months (range, 20-97 months). The frequency of each implant type was Harrington, 6%; C-D, 12%; and Isola, 6%. By 6 years' follow-up, the cumulative Kaplan-Meier risk for reoperation due to LOSP was Harrington, 5%; C-D, 13%; and Isola, 8% (statistically non-significant difference). Of the 14 patients who had instrumentation removal for LOSP, 10 (71%) had successful relief of pain after implant removal. CONCLUSIONS: Occurring regardless of implant type, LOSP of no apparent cause after posterior instrumentation of scoliosis is a distinct clinical entity and is relieved by implant removal in most patients.

Adolescent↗
PubMed2000

Getting better all the time: improving preference scores reflect increases in the strength of filial imprinting.

In the investigation of the neural mechanisms of filial imprinting, neurochemical measures are often correlated with preference score (PS): approach activity to the training stimulus/total approach in a test. In a previous study, domestic chicks, Gallus gallus domesticus, that had a PS under 65% were classed as 'poor learners' and those with a PS greater than 65% were called 'good learners'. We tested the effects of continued imprinting training in chicks from these two categories. After exposure to an imprinting stimulus for 30 min on day 1 after hatching, preferences were tested and then the chicks were exposed to the same stimulus for either 90 min, 3 h or 4 h on the next day, followed by a second preference test. In all these experiments there was a significant improvement in mean PS in the 'poor learners' between the first and second test, such that these chicks acquired a significant mean preference for the training stimulus. There was no such improvement in chicks that did not receive further training on day 2. When absolute approach was analysed, there was no significant difference between 'poor learners' and 'good learners' at the second test, after 4 h of retraining. Overall, mean preference scores increased with length of training. These results suggest that 'poor learners' are better characterized as 'slow learners', and that their initially low PS is not caused by, for example, a lack of motivation to express a preference. Preference scores reflect the strength of learning during imprinting. Copyright 2000 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed2000

Efficacy and hematologic toxicity of salvage chemotherapy following stem cell-supported high-dose chemotherapy in women with recurrent ovarian cancer.

OBJECTIVE: The objective of this study was to determine the efficacy and hematologic toxicity of salvage chemotherapy in patients with recurrent ovarian cancer following high-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT). METHODS: A retrospective analysis of 19 Massachusetts General Hospital case records of women with relapsed ovarian cancer following PBSCT was conducted. RESULTS: Between February 1996 and September 1998, 24 women with ovarian cancer were treated with PBSCT. Nine patients were treated with an upfront PBSCT regimen to consolidate first-line chemotherapy and 15 patients were treated with PBSCT after a median of two lines (range: 1-3) of prior chemotherapy. Sixteen patients presented with relapsed disease at a median of 230 days post-PBSCT and 3 patients had persistent disease through high-dose chemotherapy. Each of these 19 patients has been treated with salvage chemotherapy following PBSCT. Patients received one of six different first-line salvage chemotherapy regimens. Sixteen of nineteen patients are alive a median of 383 days (range: 156-868) after relapse following PBSCT. Three patients died of progressive disease at a median of 284 days (range: 224-648) after post-PBSCT relapse. Six patients achieved a complete response, four patients had a partial response, three patients had stable disease, and six patients had progressive disease in response to first-line salvage chemotherapy. Seven patients experienced grade III/IV neutropenia, and three patients experienced grade III/IV thrombocytopenia. CONCLUSIONS: We conclude that in a patient population selected for chemotherapy sensitive and low-volume disease prior to PBSCT, patients with recurrent tumor appear to respond to salvage chemotherapy, and associated hematologic toxicity is acceptable and manageable.

Adult↗