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Biomedical subjects

J A Cook

Publications and source records attributed to J A Cook.

At least 55 records · Page 3Linked to original sources
PubMed1999

Disorders of proprioceptive responses in monkeys after cerebellar lesions: an analysis using the Denny-Brown Collection.

We used the Denny-Brown Research Collection to study in detail the reflex responses of monkeys after ablation of the anterior lobe, posterior lobe or the entire cerebellum. The Collection includes written, film and histological records, and photographs of the brain at autopsy. Large cerebellar ablations severely suppress proprioceptive responses, thereby significantly impairing the capacity to stand, walk, and hop. Cutaneous reflexes are also impaired, although more selectively, permitting expression of normally suppressed responses such as magnet reactions and tactile avoiding responses. Enhancement (release) of responses to truncal cutaneous stimulation, along with suppression of opposing proprioceptive responses, leads to postures of persistent flexion. Large cerebellar lesions also interfere with reflex responses mediated by visual and vestibular systems. More limited cerebellar ablations have similar, but less severe effects.

Animals↗
PubMed1999

Induction of nitric oxide production in infiltrating leukocytes following in vivo irradiation of tumor-bearing mice.

Nitric oxide (NO) has been implicated both in regression and progression of tumors due to its production by both tumor cells and infiltrating leukocytes. Ionizing radiation causes the regression of tumors, and can augment the production of NO by macrophages in vitro. We examined the cellular and systemic production of NO in mice in which radiation-resistant RIF-1 fibrosarcoma cells were implanted subcutaneously and were then either irradiated or sham-treated at the tumor site. Ten days following implantation of the tumors, CD45- tumor cells and CD45+ leukocytes were derived from resected tumors immediately after irradiation with 60 Gy, a dose previously reported to reduce tumor growth. Leukocytes from tumors of irradiated hosts produced spontaneously up to four-fold more NO than did either leukocytes from unirradiated mice or CD45- tumor cells from either unirradiated or irradiated mice. Between days 10-14 following tumor implantation, serum NO2-/NO3- increased in both irradiated and unirradiated mice to an equal extent, culminating in levels higher than those of non-tumor-bearing mice. Though NO production is elevated in macrophages treated with 1-10 Gy of radiation in vitro, higher doses may be required by tumor-infiltrating macrophages in vivo and thus may indicate that tumor-infiltrating macrophages are deactivated.

Animals↗
PubMed1999

High-speed data acquisition system and receiver configurations for time-domain radiofrequency electron paramagnetic resonance spectroscopy and imaging.

Design strategies, system configuration, and operation of a dual-channel data acquisition system for a radiofrequency (RF) time-domain electron paramagnetic resonance (EPR) spectrometer/imager operating at 300 MHz are described. This system wasconfigured to incorporate high-speed analog-to-digital conversion (ADC) and summation capabilities with both internal and external triggering via GPIB interface. The sampling rate of the ADC is programmable up to a maximum of 1 GS/s when operating in a dual-channel mode or 2 GS/s when the EPR data are collected in a single-channel mode. By using high-speed flash ADCs, a pipelined 8-bit adder, and a 24-bit accumulator, a repetition rate of 230 kHz is realized to sum FIDs of 4096 points. The record length is programmable up to a maximum of 8K points and a large number of FIDs (2(24)) can be summed without overflow before the data can be transferred to a host computer via GPIB interface for further processing. The data acquisition system can operate in a two-channel (quadrature) receiver mode for the conventional mixing to baseband. For detection using the single-channel mode, the resonance signals around the center frequency of 300 MHz were mixed with a synchronized local oscillator of appropriate frequency leading to an intermediate frequency (IF) which is sampled at a rate of 2 GS/s. Comparison of quadrature-mode and an IF-mode operation for EPR detection is presented by studying the FID signal intensity across a bandwidth of 10 MHz and as a function of transmit RF power. Imaging of large-sized phantoms accommodated in appropriately sized resonators indicates that IF-mode operation can be used to obtain distortion-free images in resonators of size 50 mm diameter and 50 mm length.

Data Collection↗
PubMed1999

Cytochrome b phylogeny of North American hares and jackrabbits (Lepus, lagomorpha) and the effects of saturation in outgroup taxa.

Jackrabbits and hares, members of the genus Lepus, comprise over half of the species within the family Leporidae (Lagomorpha). Despite their ecological importance, potential economic impact, and worldwide distribution, the evolution of hares and jackrabbits has been poorly studied. We provide an initial phylogenetic framework for jackrabbits and hares so that explicit hypotheses about their evolution can be developed and tested. To this end, we have collected DNA sequence data from a 702-bp region of the mitochondrial cytochrome b gene and reconstructed the evolutionary history (via parsimony, neighbor joining, and maximum likelihood) of 11 species of Lepus, focusing on North American taxa. Due to problems of saturation, induced by multiple substitutions, at synonymous coding positions between the ingroup taxa and the outgroups (Oryctolagus and Sylvilagus), both rooted and unrooted trees were examined. Variation in tree topologies generated by different reconstruction methods was observed in analyses including the outgroups, but not in the analyses of unrooted ingroup networks. Apparently, substitutional saturation hindered the analyses when outgroups were considered. The trees based on the cytochrome b data indicate that the taxonomic status of some species needs to be reassessed and that species of Lepus within North America do not form a monophyletic entity.

Animals↗
PubMed1999

Stumbling corrective responses in healthy human subjects to rapid reversal of treadmill direction.

The kinematics of stumbling and recovery induced by a rapidly reversing treadmill is described for eight healthy adults. Stability was achieved in approximately 400 ms following treadmill reversal (initiated at heel-strike) and the ensuing stumble. It appeared to be accomplished primarily by rapid flexion of the thigh and knee of the stance limb, which prevented damage to the knee joint and lowered the trunk, and by extension of the contralateral joints (swing limb), which contacted the ground presumably to deliver an impulsive thrust to counter the backward lean of the trunk. The movements of the ankle also contributed to the recovery from the stumble, but its movements were markedly more variable among the subjects than those of the thigh and knee. The observed kinematics to some extent resembled a crossed-extension reflex, which may have been triggered by muscle, joint, cutaneous or vestibular afferents. These data should provide a baseline by which to compare groups in which recovery from stumbling is known to be deficient (e.g., the elderly).

Accidental Falls↗
PubMed1999

Visual localization in dyslexia.

Individuals with specific reading disability (SRD) may exhibit visual psychophysical abnormalities that include prolonged visual persistence, decreased luminance contrast sensitivity, lower flicker fusion thresholds, abnormal metacontrast masking, and lower motion detection sensitivity. These abnormalities could result from impairment of the magnocellular division of the visual afferent pathway to the cortex. The authors predicted that an impairment of this pathway would also cause abnormalities in ability to localize visual stimuli. This prediction was tested in 2 experiments. Results of both experiments showed that adults who reported a history of SRD and who currently had lower reading performance were less able than non-SRD participants to report the locations of small visual stimuli that were briefly flashed at positions similar to the ends of lines of text.

Adult↗
PubMed1999

The effect of patient-focused redesign on midlevel nurse managers' role responsibilities and work environment.

OBJECTIVE: The authors determine the effect of patient-focused redesign on midlevel nurse managers' role responsibilities and perceptions of work environment. BACKGROUND: Patient-focused redesign models have been initiated in a number of hospitals over the past 10 years. Few studies of the impact of these models on nurse leaders' roles and work responsibilities have been conducted. METHODS: Nine midlevel nurse managers were interviewed about their redesigned leadership roles and the challenges they experienced in implementing patient-focused redesign. RESULTS: Several themes emerged from the data. These themes focused on role change, ambiguity, position power, and environmental uncertainty and turbulence. Each of the nurse managers described feelings of frustration, disconnectedness, and inadequacy and spoke of how difficult it was to be the central figure in the eye of the storm. They noted that previously successful administrative strategies were not producing the same effect as in the past. CONCLUSION: This study provides beginning information about the magnitude of the impact of organizational redesign on midlevel nurse managers. Midlevel managers in this study struggled to keep up with the demands of the change and their own recognition of the importance of remaining committed to the uncertain goals of the institution. They were frustrated by their perceived inability to fix the situation and to meet the multiple needs of the staff. Nonetheless, they supported senior executives and attempted reasonable solutions to the problem.

Humans↗
PubMed1999

Managed-care research, Part 1: Defining the domain.

New research opportunities are arising in response to the changes associated with care delivery provided in managed-care environments. A review of the managed-care literature suggests five characteristics that are associated with the care delivery models currently in place. Each of these components needs investigation to determine which of them contribute to cost reductions and care delivery outcomes seen.

Community Participation↗
PubMed1999

Managed-care research, Part 2: Researching the domain.

A review of research pertaining to managed care suggests that little information is known about the impact of the components of managed care on care delivery outcomes. Characteristics of managed-care systems rarely are considered, resulting in uncertainty and confusion about which of the domain components of managed care have contributed to the outcomes seen. In part 1 (JONA November 1999) of this two-part series, we described how the shift to managed care has affected healthcare organizations and healthcare providers. We also identified several research questions relevant to the five domain components of managed care. In this article, we review the research literature concerning managed care and identify where research deficiencies exist within the domain.

Community Participation↗
PubMed1999

The effect of a tyrosine kinase inhibitor on endotoxin mortality and splenocyte mediator production in the neonatal rat.

Tyrosine kinases mediate cellular signal transduction to endotoxin. A class of tyrosine kinase inhibitors, the tyrphostins, have been shown to protect mice from endotoxin-induced lethality. Neonatal rats and mice have been shown to be uniquely susceptible to lethal endotoxic shock. In our study, the effect of a lipophilic tyrphostin, AG 556, on endotoxin-induced neonatal and adult mortality and in vitro neonatal splenic cell thromboxane (TxB2), tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) production were examined. Neonatal rats (<24 h old) were administered tyrphostin (100 microg subcutaneous) 2 h before an approximate LD50 dose of Salmonella enteritidis endotoxin (.024 mg/kg/intracardiac). There was a significant decrease in mortality in the animals pretreated with 100 microg of tyrphostin (29% mortality in the treated group, n = 41 versus 53% in the vehicle control group, n = 40; p < .05). Also in adult rats tyrphostin (5 mg/kg intraperitoneal) 2 h before endotoxin (10 mg/kg intravenous) significantly improved survival (50% drug treated versus 84% in control, n = 12/group; p < .05). Adherent neonatal splenic cell mediator production of TxB2, TNF-alpha, and NO (measured by nitrite) in tyrphostin pretreated splenic cells were compared with endotoxin-stimulated splenic cells in vitro. The studies (n = 4) demonstrate an increase (p < .05) in the production of TxB2, TNF-alpha, and NO in the endotoxin- (10 microg/mL) stimulated adherent splenic cells compared with basal. Tyrphostin pretreatment (10, 20, 50 microM) produced a dose-dependent decrease (p < .05) in endotoxin-stimulated TxB2 and TNF-alpha production. NO production was not significantly reduced. In conclusion, tryphostin appears to have a protective effect on mortality in both adult and neonatal rat endotoxic shock. Tyrphostin decreased specific mediator production in stimulated neonatal cells. Thus, inhibition of signal transduction pathways of endotoxin activation by tyrosine kinase inhibition may provide an effective approach to treat endotoxic shock in the neonate.

Animals↗
PubMed1999

Tolerance to LPS decreases macrophage G protein content.

The effects of tolerizing doses of LPS on mRNA and protein levels of three different G protein subunits were investigated to understand the mechanism(s) responsible for the reduction in Gialpha protein content in LPS tolerance. Tolerance was induced in rats using Salmonella enteritidis LPS (intraperitoneal route) with a single dose of 100 microg/kg. Peritoneal macrophages were harvested 6 and 24 h later. In some studies, a second dose of LPS 500 microg/kg was given on the following day, and peritoneal macrophages were harvested 5 days after the first injection. Macrophage RNA or a crude membrane fraction was prepared from macrophages, and the mRNA level or the protein content for Gialpha3, Gialpha2, and Gsalpha was analyzed using Northern or Western blots, respectively. Compared with the control levels, the message for Gialpha3 was reduced (p < .025) at 6 and 24 h and 5 day time periods after LPS treatment. The Gialpha2 mRNA was increased relative to the control levels (p < .05) at 6 h and 5 days after LPS treatment, respectively, and Gsalpha message was not significantly changed. The half-life of Gialpha3 mRNA was not significantly different in control versus tolerant macrophages. The Gialpha3 mRNA and membrane protein were not significantly changed by incubation with LPS for intervals up to 6 h in vitro. Macrophage membrane Gialpha3 and Gialpha1 and 2 protein content from tolerant rats were reduced compared with the controls at 6 and 24 h, respectively (p < .05). These studies are consistent with our previous observations of selective changes in macrophage Gialpha protein content in LPS tolerance and raise the possibility that this may affect signal transduction events in these cells.

Animals↗
PubMed1999

Protective effect of tyrphostin AG-556 on shock induced by endotoxin or gram positive bacteria.

The effects of tyrphostin AG-556 (TYR), a tyrosine kinase inhibitor, were evaluated on shock induced by lipopolysaccharide (LPS) or group B streptococcus (GBS) in rats. Mortality and mean survival time were monitored. Plasma 6-keto prostaglandin F1alpha (6-keto PGF1alpha) was also measured at four hours after LPS injection. The effects of TYR on the production of 6-keto PGF1alpha thromboxane B2(TXB2) and nitrite (NO) from LPS or GBS stimulated in vitro peritoneal rat macrophage were also examined. Salmonella enteritidis LPS (12 mg/kg, i.v. ) (n=6) produced severe shock (100% mortality). Simultaneous treatment with TYR (n=6) significantly (p < 0.01) extended mean survival time and 33% of rats survived. Plasma 6-keto PGF1alpha concentrations were increased in LPS controls, whereas TYR (5 mg/kg) significantly (p < 0.05) decreased the production. Animals treated with GBS/D-galactosamine (n=9) also exhibited shock with 100% lethality and TYR again prolonged survival time (p < 0.05) with 55% of the animals surviving. To evaluate direct effects of TYR on mediator production induced by LPS or GBS, rat macrophages were stimulated with heat-killed GBS or LPS with or without TYR. Supernatants were collected at 24 h for determination of TXB2, 6-keto PGF1alpha and NO. All mediators measured were significantly increased (p < 0.05) with LPS or GBS. TYR inhibited (p < 0.05) the production of all mediators from macrophages induced by LPS or GBS. The decrease in eicosanoids was associated with a reduction of the content of cyclooxygenase-2 (COX-2) as determined by western blotting. Collectively, these results suggest that TYR ameliorates toxic shock induced by LPS or gram positive bacteria. This protection is associated with suppression of macrophage mediator production.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Isolation and characterization of a hantavirus from Lemmus sibiricus: evidence for host switch during hantavirus evolution.

A novel hantavirus, first detected in Siberian lemmings (Lemmus sibiricus) collected near the Topografov River in the Taymyr Peninsula, Siberia (A. Plyusnin et al., Lancet 347:1835-1836, 1996), was isolated in Vero E6 cells and in laboratory-bred Norwegian lemmings (Lemmus lemmus). The virus, named Topografov virus (TOP), was most closely related to Khabarovsk virus (KBR) and Puumala viruses (PUU). In a cross focus reduction neutralization test, anti-TOP Lemmus antisera showed titers at least fourfold higher with TOP than with other hantaviruses; however, a rabbit anti-KBR antiserum neutralized TOP and KBR at the same titer. The TOP M segment showed 77% nucleotide and 88% amino acid identity with KBR and 76% nucleotide and 82% amino acid identity with PUU. However, the homology between TOP and the KBR S segment was disproportionately higher: 88% at the nucleotide level and 96% at the amino acid level. The 3' noncoding regions of KBR and the TOP S and M segments were alignable except for 113- and 58-nucleotide deletions in KBR. The phylogenetic relationships of TOP, KBR, and PUU and their respective rodent carriers suggest that an exceptional host switch took place during the evolution of these viruses; while TOP and KBR are monophyletic, the respective rodent host species are only distantly related.

Animals↗
PubMed1999

A multidrug-resistant breast cancer cell line induced by weekly exposure to doxorubicin.

Attempts to study drug resistance in vitro have focused on continuous exposure of cell lines to cytotoxic agents that results in marked resistance. In an effort to examine drug resistance in an environment that is more typical of a clinical setting, monolayered human breast cancer cells (MCF-7) were exposed weekly for one hour to doxorubicin at a concentration that is achieved in vivo (0.1 microg/ml). After 20 weeks, the treated cell line (C20) was found to be resistant to doxorubicin by a factor of 2.0-2.5 at the 10 and 1% cell survival level compared to parent MCF-7 cells. Additionally, cross resistance to other chemotherapeutic agents including etoposide, vincristine, cisplatin, and mitomycin C was observed. Similar to other models of in vitro drug resistance, no modification of radiosensitivity was observed in C20 cells. The p170 glycoprotein was not overexpressed on C20 cells as assessed by the anti-p170 glycoprotein monoclonal antibody C219 staining nor was mRNA for the mdr-1 or MRP gene overexpressed. In addition, the mdr-blocking agent verapamil had no effect on the level of resistance encountered in tissue culture. C20 cells did not differ from the parent cell line with respect to cell cycle distribution, doubling time, GSH, GSH peroxidase, GSH reductase or GSH transferase levels. After a one-hour exposure to doxorubicin, lower intracellular doxorubicin levels were found in C20 cells compared to the parent line which provides at least a partial explanation for resistance, although the mechanism for this is unclear. Although the magnitude of resistance observed in the C20 cell line is low compared to other in vitro models of drug resistance, the modest level of drug resistance is probably sufficient to explain drug resistance seen clinically. The model of non-mdr mediated drug resistance presented may be a more relevant model for the evaluation of drug resistance in vitro.

Antineoplastic Agents↗
PubMed1999

Principles of chemoradiation: theoretical and practical considerations.

Chemotherapy agents known to enhance the effects of radiation in preclinical studies have been used concurrently with radiotherapy in numerous clinical trials with the prospect of further enhancing radiation-induced local tumor control. While some success in several tumor histologies has been achieved using this approach, a major concern has been enhancement in normal tissue toxicity. This brief review addresses both theoretical and practical issues with respect to chemoradiation clinical trials. Recommendations for clinical trials are provided that, if implemented, can increase our understanding of basic mechanisms (in patients) and provide a more rational approach for future trials.

Animals↗
PubMed1998

Redox generation of nitric oxide to radiosensitize hypoxic cells.

PURPOSE: Previous studies have shown that nitric oxide (NO) delivered from NO donor agents sensitizes hypoxic cells to ionizing radiation. In the present study, nitroxyl (NO-), a potential precursor to endogenous NO production, was evaluated for hypoxic cell radiosensitization, either alone or in combination with electron acceptor agents. METHODS AND MATERIALS: Radiation survival curves of Chinese hamster V79 lung fibroblasts under aerobic and hypoxic conditions were assessed by clonogenic assay. Hypoxia induction was achieved by metabolism-mediated oxygen depletion in dense cell suspensions. Cells were treated with NO- produced from the nitroxyl donor Angeli's salt (AS, Na2N2O3, sodium trioxodinitrate), in the absence or presence of electron acceptor agents, ferricyanide, or tempol. NO concentrations resulting from the combination of AS and ferricyanide or tempol were measured under hypoxic conditions using an NO-sensitive electrode. RESULTS: Treatment of V79 cells under hypoxic conditions with AS alone did not result in radiosensitization; however, the combination of AS with ferricyanide or tempol resulted in significant hypoxic radiosensitization with SERs of 2.5 and 2.1, respectively. Neither AS alone nor AS in combination with ferricyanide or tempol influenced aerobic radiosensitivity. The presence of NO generated under hypoxic conditions from the combination of AS with ferricyanide or tempol was confirmed using an NO-sensitive electrode. CONCLUSION: Combining NO- generated from AS with electron acceptors results in NO generation and substantial hypoxic cell radiosensitization. NO- derived from donor agents or endogenously produced in tumors, combined with electron acceptors, may provide an important strategy for radiosensitizing hypoxic cells and warrants in vivo evaluation.

Animals↗