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J A Cook

Publications and source records attributed to J A Cook.

At least 73 records · Page 4Linked to original sources
PubMed1998

The cytotoxicity of nitroxyl: possible implications for the pathophysiological role of NO.

In addition to the broad repertoire of regulatory functions nitric oxide (NO) serves in mammalian physiology, the L-arginine:NO pathway is also involved in numerous pathophysiological mechanisms. While NO itself may actually protect cells from the toxicity of reactive oxygen radicals in some cases, it has been suggested that reactive nitrogen oxide species formed from nitric oxide synthase (NOS) can be cytotoxic. In addition to NO, the one electron reduction product NO- has been proposed to be formed from NOS. We investigated the potential cytotoxic role of nitroxyl (NO-), using the nitroxyl donor Angelis's salt, (AS; sodium trioxodinitrate, Na2N2O3) as the source of NO-. As was found to be cytotoxic to Chinese hamster V79 lung fibroblast cells over a concentration range of 2-4 mM. The presence of equimolar ferricyanide (Fe(III)-(CN6)3-), which converts NO- to NO, afforded dramatic protection against AS-mediated cytotoxicity. Treatment of V79 cells with L-buthionine sulfoximine to reduce intracellular glutathione markedly enhanced AS cytotoxicity, which suggests that GSH is critical for cellular protection against the toxicity of NO-. Further experiments showed that low molecular weight transition metal complexes associated with the formation of reactive oxygen species are not involved in AS-mediated cytotoxicity since metal chelators had no effect. However, under aerobic conditions, AS was more toxic than under hypoxic conditions, suggesting that oxygen dramatically enhanced AS-mediated cytotoxicity. At a molecular level, AS exposure resulted in DNA double strand breaks in whole cells, and this effect was completely prevented by coincubation of cells with ferricyanide or Tempol. The data in this study suggest that nitroxyl may contribute to the cytotoxicity associated with an enhanced expression of the L-arginine:NO pathway under different biological conditions.

Animals↗
PubMed1998

Pharmacokinetics and pharmacodynamics of CI-992 following intravenous and oral administration to cynomolgus monkeys.

The purpose of this study was to characterize CI-992 pharmacokinetics and pharmacokinetics/pharmacodynamics (PK/PD) in sodium deplete monkeys. Panels of monkeys were administered CI-992 as a 1 h intravenous infusions (0.1 and 1 mg kg-1) or as single oral doses (0, 10, 50, and 100 mg kg-1). Mean arterial blood pressure (MABP) was monitored and serial blood samples were collected up to 24 h postdose. Plasma CI-992 concentrations were quantitated by radioimmunoassay. Pharmacokinetic parameters were calculated by noncompartmental methods. PK/PD relationships were assessed by standard methods. Oral bioavailability of CI-992 in the monkeys was < 2%; steady-state volume of distribution was 0.67 L kg-1; clearance was 10.4 mL min-1 kg-1. Following oral administration, tmax generally occurred 6-9 h postadministration; plasma CI-992 concentrations increased with increasing dose between 10 and 50 mg kg-1, but did not change appreciably from 50 to 100 mg kg-1. After intravenous administration, change in MABP was correlated with plasma CI-992 concentration through an effect compartment model in which the maximum achievable effect was a 22 mm Hg decrease in MABP; the steady-state concentration which produced half the maximum effect was 11 ng mL-1. Following the 10 mg kg-1 oral dose the maximum decrease in MABP was 19.1 mm Hg; higher doses did not produce greater maximum response but increased the duration of action. In contrast to observations following intravenous administration, a trend for decreasing MABP with increasing plasma CI-992 was not apparent following oral CI-992 administration.

Administration, Oral↗
PubMed1998

Endotoxin activation of mitogen-activated protein kinase in THP-1 cells; diminished activation following endotoxin desensitization.

The signal transduction events occurring in monocytes in response to endotoxin (LPS) stimulation are incompletely delineated, although pertussis toxin (PT)-sensitive G proteins and the mitogen-activated protein kinase (MAPK) cascade have been implicated. Cellular desensitization in response to 18-h pre-exposure to 1 microgram/mL LPS alters signal transduction pathways of cellular activation and decreases production of certain inflammatory mediators such as thromboxane (Tx)B2, the stable metabolite of TxA2. We hypothesized that LPS stimulation of the human monocyte cell line THP-1 occurs via MAPK activation, and that LPS desensitization, induced by pre-exposure to LPS, is associated with altered signaling through the MAPK cascade. Involvement of a specific MAPK, ERK, in LPS-stimulated TxB2 production was further tested using a specific MAPK cascade inhibitor, PD98059 (PD). PD inhibited LPS and phorbol myristate acetate (PMA)-stimulated ERK activation as demonstrated by immunoblots using anti-activated ERK antibodies. PD significantly inhibited LPS and PMA-stimulated TxB2 synthesis to non-detectable levels, suggesting an involvement of MAPK in LPS-stimulated activation. Because PT-sensitive G proteins mediate LPS-stimulated signal transduction, their role in MAPK activation was tested. Pretreatment with PT inhibited basal and LPS-stimulated, but not PMA-stimulated ERK activation. Activation of ERK after LPS desensitization was also assessed. LPS pre-exposure resulted in a profound decrease in LPS-stimulated activation of ERK, but did not affect PMA activation of ERK. These data implicate the involvement of the MAPK cascade in LPS-stimulated activation of THP-1 cells and suggest coupling of Gi proteins and MAPKs in LPS-stimulated events. LPS desensitization is associated with decreased MAPK activation, but does not impair MAPK activation by PMA. Thus, LPS desensitization appears to selectively alter signal transduction upstream of ERK.

Carcinogens↗
PubMed1998

The molecular phylogenetics of tuco-tucos (genus Ctenomys, Rodentia: Octodontidae) suggests an early burst of speciation.

Variation in the nucleotide sequence of the entire mitochondrial cytochrome b gene (1140 bp) was examined for 27 individuals representing 13 species of South American rodents of the genera Ctenomys, Octodontomys, Tympanoctomys, and Spalacopus. Representatives of the family Echimyidae, Euryzygomatomys and Mesomys, were used as outgroups to test the monophyly of the Octodontinae and Ctenomyinae. Relationships among species of tuco-tucos (genus Ctenomys) were also examined including representatives of the three described subgenera and the two sperm morphs. Reciprocal monophyly of the Octodontinae and Ctenomyinae is strongly supported. Several basal relationships among species of the genus Ctenomys are poorly resolved, suggesting the possibility of a hard polytomy due to a rapid and potentially simultaneous radiation early in the history of the genus. In other cases, clades within the Ctenomyinae previously identified on the basis of allozymes, chromosomes, parasites, or skull morphology were supported. Calibrations based on the fossil record suggest that the mitochondrial cytochrome b of these caviomorphs has evolved at a rapid rate, comparable to those proposed for Mus-Rattus, and three to four times higher than ungulate rates.

Animals↗
PubMed1998

Professional-led versus family-led support groups: exploring the differences.

Support groups often help families cope more effectively with relatives' mental illnesses. This study examines the differences between support groups led by professionals and those led by family members, focusing specifically on group participation benefits and group content. Results indicate that participants of both professional and family-led groups reported that the groups provided them with needed information about mental illness and its treatment and that the groups improved their relationships with their ill relatives. Professional-led groups placed a greater emphasis on the relatives' problems and coping with emotions, and family-led groups placed a greater emphasis on advocacy. Suggestions are provided regarding increased collaboration between professional and family-led support groups.

Adaptation, Psychological↗
PubMed1998

Use of the Trolox assay to estimate the antioxidant content of seventeen edible wild plants of Niger.

Although wild edible plants of the western Sahel and other parts of sub-Saharan Africa are consumed to some extent at all times of the year, greater amounts are consumed when cereal harvests are insufficient to support the populations living in these areas. The purpose of this study was to use a recently reported Trolox-based assay to measure the total antioxidant capacity of aqueous extracts of 17 plants that we gathered from southern Niger. The antioxidant contents of the aqueous extracts were compared to those of spinach and potato. Of the 17 plants, 11 had a greater antioxidant content than spinach and 14 had a greater antioxidant content than potato. The leaves of Tapinanthus globiferus had the greatest antioxidant content, and the fruit of Parinari macrophylla had the lowest. In general, leaves contained more antioxidants than either fruits or seeds. The total antioxidant capacity of the aqueous extracts was relatively high, indicating that the wild plants of the western Sahel may contain substantial amounts of water-soluble flavonoid glycosides, which are potent antioxidants and have been shown to have anticancer properties.

Antioxidants↗
PubMed1998

'Mouth-feeding' in monkeys after sensorimotor system lesions: an analysis based upon the Denny-Brown collection.

Utilizing the Denny-Brown collection, we investigated an unusual feeding behavior exhibited by monkeys after sequential pre- and post-central gyrus lesions. The behavior involves ingestion of food by placing the lips directly over the food object, i.e., 'mouth-feeding.' Interestingly, this behavior persists long after recovery of the ability to hand-feed. In all of the cases within the collection and in descriptions of mouth-feeding found in the literature, mouth-feeding occurs only after bilateral lesions. We suggest that the co-existence of mouth- and hand-feeding behavior in animals with pre- and post-central gyrus lesions results partly from the sparing of corticospinal projections arising outside these gyri, e.g., the cingulate region, thereby preserving to a certain extent discrete use of the forelimbs.

Animals↗
PubMed1998

Neurogenic acceleration of osteoarthritis.

The nervous system has a variety of mechanisms whereby it can potentially initiate or accelerate joint disease. Whether these potential mechanisms are clinically significant factors in the etiology of osteoarthritis remains uncertain. However, 11 papers published in the past year provide further support for the view that these mechanisms are important in the pathogenesis of the disease.

Animals↗
PubMed1998

Intravenous delivery of 5'-iododeoxyuridine during hyperfractionated radiotherapy for locally advanced head and neck cancers: results of a pilot study.

OBJECTIVES: Locally advanced cancers of the head and neck require aggressive treatment, often with limited effectiveness and significant toxicity and morbidity. This pilot study was designed to assess tolerance using combined hyperfractionated radiotherapy and the halogenated pyrimidine radiosensitizer 5'-iododeoxyuridine (IdUrd). STUDY DESIGN: This was a prospective single-arm study open to patients with advanced head and neck cancers that had a poor chance of control with conventional radiation therapy. Patients were treated with hyperfractionated radiation therapy at standard doses in combination with an IdUrd infusion and observed for tumor response and normal tissue tolerances. METHODS: Radiation therapy was delivered in fractions of 1.2 Gy or 1.5 Gy twice daily to a total dose in the range of 70 to 76 Gy. IdUrd was delivered as an intravenous infusion (1000 mg/m2 per day) for a maximum of 14 days at the beginning and then again during the middle of the radiotherapy. RESULTS: Twelve patients with advanced squamous cell lesions were enrolled and 11 were observed to have complete clinical remissions. Seven patients remained clinically free of local disease at the time of death or most recent follow-up. Acute toxicities, usually hematologic or mucosal, were severe and all patients required treatment modifications and considerable supportive care. CONCLUSIONS: Although a high rate of response was achieved using this regimen, the toxicities are prohibitive. The kinetic profile of IdUrd incorporation suggests the need for future studies using repetitive short courses of IdUrd.

Adult↗
PubMed1998

Increased prostacyclin and PGE2 stimulated cAMP production by macrophages from endotoxin-tolerant rats.

Sublethal administration of lipopolysaccharide (LPS) renders rats tolerant to multiple lethal stimuli. Tolerant macrophages exhibit differential alterations in LPS-stimulated cytokine and inflammatory mediator release. Increased cAMP levels stimulated by PGE2 or prostacyclin (PGI2) result in differential effects on LPS-induced cytokine release and protect against the pathophysiological changes of endotoxemia. In the present studies, we sought to determine whether PGE2- and PGI2-stimulated cAMP levels are altered in tolerant macrophages. Incubation of macrophages with cicaprost or 11-deoxy-PGE1 in the presence of phosphodiesterase inhibitors resulted in significantly higher (2.5- to 6.5-fold) cAMP concentrations in tolerant macrophages compared with control. In contrast, isoproterenol-stimulated cAMP levels were not significantly different between control and tolerant cells. Also, incubation of tolerant macrophages with LPS did not result in significantly elevated cAMP levels. Prostacyclin (IP) receptor mRNA levels were significantly increased in tolerant cells compared with controls, whereas [3H]PGE2 binding and PGE2 EP4 receptor mRNA levels were not significantly changed. These studies suggest that LPS tolerance induces selective alterations in eicosanoid regulation of cAMP formation.

Adenylyl Cyclases↗
PubMed1998

Development of functional electron paramagnetic resonance imaging.

The potential use of electron paramagnetic resonance imaging (EPRI) to obtain physiological information noninvasively is reviewed. EPR, a spectroscopic technique similar to nuclear magnetic resonance (NMR), is useful in detecting and characterizing free radical species. The ability to obtain information about tissue redox and oxygen status using nontoxic free radical spin probes is presented. The capability to encode this information spatially using magnetic field gradients, similar to magnetic resonance imaging (MRI), gives this technique the ability to overlay functional information of tissue with anatomic information. The noninvasive and quantitative nature of EPRI makes it a potentially useful technique for obtaining physiological information from tumors. The requirements for the magnetic field strengths are approximately 600 times lower than that for proton MRI at an identical frequency, making this a low-cost diagnostic tool.

Journal Article↗
PubMed1998

Interaction of gemcitabine with paclitaxel and cisplatin in human tumor cell lines.

We have used clonogenic survival assays and flow cytometry of human lung A549, breast MCF7 and pancreas adenocarcinoma P-SW cell lines to examine the effects of gemcitabine (2'-deoxy-2', 2'-difluorocytidine) in combination with cisplatin, paclitaxel or radiation. Additive cell killing was observed for all cell lines when they were treated with cisplatin for 1 h followed by varying concentrations of gemcitabine for 24 h. Likewise, additive cell killing was noted in all cell lines when treated with gemcitabine for 24 h followed by varying doses of radiation. When A549 cells were exposed to gemcitabine for 24 h followed by a 1 h exposure to cisplatin, synergistic effects were noted. Using the latter regimen, MCF7 cells demonstrated additive cell kill, while the P-SW cells showed a more complex relationship with additive killing below 50 nM gemcitabine and less than additive effect above 50 nM gemcitabine. All three cell lines were also tested with various gemcitabine/paclitaxel combinations. When gemcitabine and paclitaxel were incubated concurrently, gemcitabine antagonized the cell kill produced by paclitaxel. All cell lines showed less than additive killing when either gemcitabine incubation preceded the paclitaxel incubation or the paclitaxel incubation preceded the gemcitabine incubation. Our results show that gemcitabine acts as a radiation sensitizer to increase the effects of radiation. Likewise, we demonstrate that the only uniformly beneficial drug combination schedule in all three cell lines was when cisplatin incubation preceded gemcitabine incubation. The gemcitabine/paclitaxel combinations were much more disturbing with respect to potential clinical trials. Our results would caution any planned clinical trials combining paclitaxel with gemcitabine to be reconsidered because of the potential for less than additive and even antagonistic effects of the combination.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Trachoma.

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Global Health↗
PubMed1998

Endotoxin tolerance alters macrophage membrane regulatory G proteins.

Administration of sublethal doses of endotoxin (LPS) or tumor necrosis factor-alpha (TNF alpha) renders rats tolerant to supralethal doses of LPS. Peritoneal macrophages from tolerant rats are refractory to LPS induced arachidonic acid (AA) metabolism and cytokine production in vivo, and exhibit reduced membrane GTPase activity and GTP gamma S binding. Since LPS stimulated AA metabolism is mediated by Gi alpha proteins, we sought to determine whether Gi alpha and/or other G proteins are reduced in LPS tolerance. Rats were rendered tolerant by two daily sublethal doses of Salmonella enteritidis LPS, 100 micrograms/kg and 500 micrograms/kg administered intraperitoneally. Animals were allowed to rest for 72 hours. Alternatively, tolerance to LPS was induced by sublethal administration of human recombinant TNF alpha (10 micrograms/kg) intraperitoneally 24 hrs before the experiments. Macrophage membrane G protein content was determined by immunoblot analysis with specific antisera to Gi1,2 alpha, Gi3 alpha, Gs alpha and the G protein beta subunits (G beta). Membrane G proteins were differentially decreased in tolerant macrophages. In macrophages from rats rendered tolerant by sublethal doses of LPS, Gi3 alpha was reduced the most to 48 +/- 8% of control (n = 3, P < 0.05) and this reduction was significant compared to those of other G proteins. Gi1,2 alpha and G beta were reduced to 73 +/- 5% (n = 3, P < 0.05) and 65 +/- 4% (n = 3, P < 0.05) of control respectively. Gs alpha(L) and Gs alpha(H) were also reduced to 61 +/- 5% (n = 3, P < 0.05) and 68 +/- 3% (n = 3, P < 0.05) of control, respectively. In contrast, only Gi3 alpha was reduced in macrophage membranes from rats pretreated with TNF alpha. Gi3 alpha was reduced to 57 +/- 11% of control (n = 4, P < 0.05) whereas Gi1,2 alpha and G beta were not significantly affected. These results demonstrate selective changes in tolerant macrophage membrane G proteins and suggest a potential role for Gi3 alpha in mediating LPS tolerance. The molecular mechanisms underlying these changes and their significance in LPS tolerance merit further investigation.

Animals↗
PubMed1998

The role of nitric oxide chemistry in cancer treatment.

Over the last decade the role of nitric oxide (NO) in various disease states has become apparent. In cancer, NO plays a variety of roles which are at times contradictory. On one hand, NO is involved in different etiological mechanisms as well as promoting tumor growth. Yet, NO derived from leukocytes plays a seminal role in their tumoricidal activity. In cancer treatment, NO also has diverse effects. Whereas in vitro, NO can enhance the cytotoxic efficacy of some chemotherapeutic agents as well as radiation, NO donors can provide whole body protection against these same agents. This manuscript will discuss some mechanisms involved with NO and cancer treatment modalities and the potential application of these findings to cancer therapy.

Animals↗
PubMed1997

Qualitative and quantitative analysis of DNA fragmentation using digital imaging.

Apoptosis is an important and common pathway of cellular death. Differentiation from cellular necrosis and quantitation of apoptosis within the milieu of necrosis are analytical challenges. We describe the use of the RIT120 digital imaging software package for quantitative and qualitative analysis of apoptotic DNA ladders induced by a variety of agents, such as serum, tumor necrosis factor-alpha, transforming growth factor-beta1, and nitric oxide. Autoradiographs of DNA ladders are densitometrically scanned to yield a set of curves with peaks corresponding to specific DNA fragments, thereby allowing quantitative subtraction of concurrent DNA degradation from necrotic death. Integration of the areas specifically under the peaks yields a quantitative measure of apoptosis. We provide a useful, rapid, and objective means to quantitate apoptosis, using relatively inexpensive hardware and software.

Animals↗