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Biomedical subjects

J A Cook

Publications and source records attributed to J A Cook.

At least 37 records · Page 2Linked to original sources
PubMed1994

Adrenal medulla and Parkinson's disease.

Parkinson's disease has been described as a multisystem disorder that includes alterations in the function of the autonomic nervous system. The activity of the adrenal medulla in this disease has not been thoroughly investigated. Previous reports are reviewed that demonstrate that the adrenal medullae of parkinsonian patients are compromised, having a decreased content of all catecholamines and several neuropeptides. An animal model was used to investigate whether the observations made in human patients were related to extended treatment with antiparkinsonian medications or were a natural concomitant of the disease. Administration of L-dopa and/or carbidopa to C57BL mice for 4-16 weeks had no significant effect on the level of any of the adrenal medullary catecholamines. Treatment with MPTP 4-16 weeks prior to sacrifice did not deplete adrenal medullary catecholamines in these animals, thus not fully mimicking Parkinson's disease in this animal model. The only significant effect was an interaction between group (MPTP or control) and treatment with antiparkinsonian medications; L-dopa, in the absence and presence of carbidopa, had opposite effects in the two groups. Based primarily on the lack of effect of antiparkinsonian medications on adrenal medullary catecholamines, it was concluded that the adrenal medullary depletion observed in human patients was a peripheral concomitant of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Changes in radiation survival curve parameters in human tumor and rodent cells exposed to paclitaxel (Taxol).

PURPOSE: Late G2 and M are the most radiosensitive phases of the cell cycle. Cells exposed to paclitaxel develop a cell cycle arrest in G2/M. These studies were performed to assess the in vitro radiosensitization properties of paclitaxel in human tumor and rodent cell lines. METHODS AND MATERIALS: The effect of paclitaxel on the radiation sensitivity of human breast (MCF-7), lung (A549), ovary (OVG-1) adenocarcinoma and Chinese hamster lung fibroblast V79 cells was determined with clonogenic assays. DNA flow cytometry studies were performed to define the cell cycle characteristics of the cells during irradiation. Survival curve parameters for all cell lines were determined with the use of a computer program which represents cell survival after radiation by a linear-quadratic model. RESULTS: All cell lines developed a G2/M block after exposure to paclitaxel for 24 h. However, the degree of radiosensitization produced by paclitaxel varied among the cell lines. The maximal sensitizer enhancement ratio (SER) of paclitaxel was 1.8 in MCF-7 cells, 1.6 in OVG-1 cells, and 1.7 in V79 cells. However, no concentration of paclitaxel was able to enhance the radiation sensitivity of A549 cells. Paclitaxel increased the linear (alpha) component of the radiation survival curves in all cell lines. The quadratic (beta) component was unaffected by paclitaxel in the rodent cells. High concentrations of paclitaxel (> or = 1000 nM) increased beta slightly in the human cell lines but there was considerable variation in the effect of paclitaxel on beta. The cells which were sensitized to radiation by paclitaxel had a relatively small baseline alpha component, while A549 cells had a large alpha component. CONCLUSION: We conclude that paclitaxel is a modest radiosensitizer in some, but not all, human tumor cells. Paclitaxel appears to cause radiosensitization mainly by increasing the alpha component of radiation survival curves. Cells that normally have a relatively small alpha component should exhibit the most radiosensitization in response to paclitaxel while cells with a large alpha component should show little or no radiosensitization after paclitaxel treatment. Because the greatest effect of paclitaxel is on the linear component of radiation survival curves, these results indicate that paclitaxel may be an effective radiation sensitizer in many human tumors treated at clinically relevant radiation doses of 2 Gy or less.

Animals↗
PubMed1994

In vitro studies of Taxol as a radiation sensitizer in human tumor cells.

BACKGROUND: Cells exposed to paclitaxel (Taxol) develop a cell cycle arrest in G2/M. It has long been recognized that late G2 and M are the most radiosensitive phases of the cell cycle. PURPOSE: These studies were performed to assess the in vitro radiosensitization properties of paclitaxel in human tumor cell lines. METHODS: The effect of paclitaxel at concentrations ranging from 0 to 10,000 nM on the radiation sensitivity (from 0 to as much as 10 Gy in certain experiments) of human breast (MCF-7), lung (A549), ovary (OVG-1), and pancreas (PC-Sh) adenocarcinoma cells was determined using clonogenic assays. DNA flow cytometry studies were performed to define the cell cycle characteristics of populations of cells that had been treated for 6-72 hours with 0, 100, 1000, or 10,000 nM paclitaxel. RESULTS: All cell lines developed a G2/M block after exposure to 100-10,000 nM paclitaxel for 24 hours. However, the degree of radiosensitization produced by paclitaxel varied among the cell lines. The sensitizer enhancement ratio (SER) of paclitaxel at 10% survival was 1.8 in MCF-7 cells and 1.6 in OVG-1 cells. However, paclitaxel at any concentration was unable to enhance the radiation sensitivity of A549 cells. PC-Sh cells demonstrated a complex and inconsistent radiosensitization response to paclitaxel. At 10% survival, an SER of 1.5 was observed in PC-Sh cells. However, at 1% survival, no radiosensitization was observed in PC-Sh cells. Maneuvers that prevented paclitaxel from producing a G2/M block, including coincident treatment with cycloheximide or treatment of cells in plateau phase of growth, completely abrogated the radiosensitization afforded by paclitaxel in MCF-7 cells. CONCLUSIONS: Paclitaxel is a modest radiosensitizer in some, but not all, human tumor cells. The degree of radiosensitization that we have observed with paclitaxel is similar to what has been found with other chemotherapeutic agents. The absence of radiosensitization by paclitaxel in MCF-7 cells grown to plateau phase or treated with cycloheximide implies that the development of a G2/M block is a necessary condition for paclitaxel radiosensitization. However, the inability of paclitaxel to radiosensitize A549 cells despite the presence of a G2/M block in those cells demonstrates that a G2/M block is not a sufficient condition for paclitaxel radiosensitization. IMPLICATIONS: Paclitaxel can radiosensitize to a modest degree some, but not all, human cell lines by a mechanism that requires the production of a G2/M cell cycle block. Additional studies are needed to define more clearly the mechanism by which paclitaxel radiosensitizes cells.

Cell Cycle↗
PubMed1994

The influence of Cremophor EL on the cell cycle effects of paclitaxel (Taxol) in human tumor cell lines.

We have performed DNA flow analysis, mitotic index studies, time-lapse photography, and paclitaxel uptake studies of human tumor cell lines exposed to paclitaxel. DNA flow analysis demonstrated that cells began accumulating in G2/M within 6 hrs of exposure to paclitaxel; by 12 hrs over 50% of cells accumulated in G2/M at all concentrations tested. After 24 hrs of exposure to 10 nM paclitaxel, cells underwent non-uniform mitotic division resulting in multinucleated cells. Of cells treated with 30 nM to 1000 nM paclitaxel, 75% to 85% remained blocked in G2/M for up to 72 hrs. Although a large proportion of cells treated with higher concentrations of paclitaxel (10,000 nM) was blocked in G2/M, a significant proportion (10% to 40%) of these cells was also in G1. Cells exposed to lower concentrations of paclitaxel (10 nM to 1000 nM) in medium containing 0.135% (v/v) Cremophor EL also had a relatively large proportion in G1. Mitotic index studies demonstrated that the paclitaxel-induced G2/M block was initially a mitotic block and that cells remained in mitosis for up to 24 hrs. With additional time of exposure to paclitaxel, mitotic index and time-lapse studies indicated that cells attempted to complete mitosis; however, cytokinesis was inhibited and cells became multinucleated. Time-lapse photography revealed that paclitaxel markedly prolonged the time in mitosis from 0.5 hr to 15 hr. High levels of Cremophor EL (0.135% v/v) markedly reduced the number of cells in mitosis but did not alter the mitotic delay induced by paclitaxel. 3H-paclitaxel uptake studies revealed that high concentrations of Cremophor EL did reduce the rate of uptake of paclitaxel into cells but had little effect on total paclitaxel accumulation. These results confirm that paclitaxel has striking effects on the cell cycle and show that high concentrations of Cremophor EL are capable of inducing a cell cycle block distinct from the mitotic block seen with paclitaxel. These results also demonstrate that cells exposed to paclitaxel for longer than 24 hours attempt to complete mitosis but the process of cytokinesis is inhibited. Together with cytotoxicity data, these results indicate that entry into and exit out of mitosis are prerequisites for paclitaxel cytotoxicity.

Adenocarcinoma↗
PubMed1994

Pharmacokinetic properties of nitroxide-labeled albumin in mice.

We have conjugated bovine serum albumin (BSA) with a pyrrolidinyl nitroxide and report on the in vivo pharmacokinetic properties of this conjugate in mice. In vivo EPR measurements of nitroxide were obtained after intravenous injection of 30 mg of labeled BSA by analysis of the nitroxide signal from the tails of mice. Following in vivo nitroxide measurements, the animals were sacrificed by exsanguination and organs were removed for determination of nitroxide levels. The level of nitroxide as determined by in vivo measurements declined exponentially with time and had a half-life (t1/2) of 7 hours. Blood nitroxide levels also declined exponentially with time with an initial t1/2 of 70 minutes and a terminal t1/2 of 10 hours. Nitroxide concentration varied among different organs; no nitroxide was detected within brain whereas lung had high concentrations of nitroxide. Liver and kidney both had relatively low levels of oxidized nitroxide, though total nitroxide (reduced plus oxidized) accumulated in the kidneys with time. Nitroxide-labeled BSA was well tolerated by the mice, is relatively stable, and is mainly confined to the intravascular space. Nitroxide-labeled albumin may be useful as a contrast agent for MRI or EPR imaging.

Animals↗
PubMed1994

Using concept mapping to develop a conceptual framework of staff's views of a supported employment program for individuals with severe mental illness.

This article describes the use of concept mapping to develop a pictorial multivariate conceptual framework of staff views of a program of supported employment (SE) for individuals with severe mental illness. The SE program involves extended individualized supported employment for clients through a mobile job support worker (MJSW) who maintains contact with the client after job placement and supports the client in various ways. All 14 staff members of a psychiatric rehabilitation agency with assignments associated with the SE program. They brainstormed a large number of specific program activity statements (N = 96), sorted and rated the statements, and interpreted the map that was produced through multidimensional scaling and hierarchical cluster analysis. The resulting map enabled identification of 4 issues that should be included in any theory of SE programs--the specific activity sequences that characterize the program itself; the pattern of local program evolution; the definition of program staff roles; and the influence of key contextual factors such as the client's family or the program's administrative structure. The implications of concept mapping methodology for theory development and program evaluation are considered.

Community Mental Health Services↗
PubMed1994

Age and family burden among parents of offspring with severe mental illness.

Family burden reported by parents of offspring with severe mental illness was examined to determine whether burden increases with age. Older parents were troubled by cognitive dimensions of burden, while younger parents were distressed by their offspring's behavior, suggesting that interventions should vary according to parents' age as well as developmental stage of their child's illness.

Activities of Daily Living↗
PubMed1994

Efficacy of tumor necrosis factor alpha and eicosanoid inhibitors in experimental models of neonatal sepsis.

The potential role of tumor necrosis factor alpha (TNF alpha) and eicosanoids in the pathogenesis of experimental neonatal sepsis models was investigated. Lethality was induced in neonatal rats by administration of heat killed group B streptococci (GBS, 7 mg kg-1 intracardially) or Salmonella enteritidis endotoxin (0.35 mg kg-1 intracardially). The relative efficacy of six compounds with putative TNF alpha and eicosanoid inhibitory actions were tested. These were: ibuprofen (3 and 20 mg kg-1), a cyclo-oxygenase inhibitor; CGS85515 (30 mg kg-1), a lipoxygenase inhibitor; LY203647 (30 mg kg-1), a leukotriene D4 receptor antagonist; pentoxifylline (10, 50 and 100 mg kg-1), a TNF inhibitor; cloricromene (2 and 10 mg kg-1), a thromboxane A2 synthetase inhibitor with TNF alpha inhibitory actions; and SKF86002 (2.5, 5, 10 and 20 mg kg-1), a dual cyclo-oxygenase/lipoxygenase inhibitor with TNF alpha inhibitory activity. Pentoxifylline, cloricromene and SKF86002, when given intraperitoneally 2 h before challenge, produced 45, 52 and 61% reductions, respectively, in plasma levels of TNF alpha at 2.5 h post-injection with killed GBS (P < 0.05). On the contrary, pretreatment with ibuprofen, CGS85515 or LY203647 did not significantly affect TNF alpha levels. All compounds significantly attenuated the lethality by killed GBS and S. enteritidis endotoxin. These data suggest that TNF alpha and eicosanoids contribute to the pathogenesis of shock induced by killed GBS and endotoxemia.

Acetophenones↗
PubMed1994

Beneficial effects of interleukin-6 in neonatal mouse models of group B streptococcal disease.

Previous studies have shown that tumor necrosis factor alpha (TNF-alpha) plays a pathophysiologic role in sepsis induced in rat pups by group B streptococci (GBS). In this model, TNF-alpha is also partially responsible for the induction of interleukin-6 (IL-6). The present study was undertaken to investigate the role of IL-6 in neonatal BALB/c mice infected with type III GBS. The effect of anti-IL-6 monoclonal antibodies and recombinant IL-6 on lethality and TNF-alpha production was investigated. In mouse pups infected with GBS strain COH1, plasma IL-6 reached levels of 3,067 +/- 955 and 1,923 +/- 891 U/ml when measured at 22 and 48 h, respectively (P < 0.05 compared with uninfected controls). Pretreatment with 25 micrograms of anti-IL-6 antibodies totally prevented the increase in circulating IL-6 bioactivity at both 22 and 48 h after infection (P < 0.05). Treatment with anti-IL-6 also induced a moderate decrease in survival time of mice infected with lethal doses of strains COH1 and COH31, as evidenced by increased lethality (P < 0.05) at 24 to 48 h but not at 96 h. Mouse recombinant IL-6 (12,500 U) given 6 h before challenge with strains COH1 and COH31 consistently increased survival time, as evidenced by decreased (P < 0.05) lethality at 48 to 72 h but not at 96 h. The effects of IL-6 pretreatment were dose dependent, since no protection was observed with doses lower than 12,500 U. In addition, no effects on lethality were noted when IL-6 was given at the time of challenge or at later times. TNF-alpha elevations (P < 0.05 compared with uninfected controls) were measured at 12, 22, and 48 h after challenge with strain COH1 (68 +/- 28, 233 +/- 98, and 98 +/- 34 U, respectively). Pretreatment with IL-6 significantly (P < 0.05) decreased plasma TNF-alpha levels at 12 and 22 h, with 55 and 69% inhibitions, respectively. Anti-IL-6 had an opposite effect, as evidenced by a 145% increase (P < 0.05) in TNF-alpha levels at 48 h after challenge. Collectively, our data are compatible with the hypothesis that IL-6 is involved in negative feedback regulation of plasma TNF-alpha levels in experimental GBS sepsis. In this model, IL-6 pretreatment can increase survival time. Future studies will be needed to investigate the mechanisms underlying this effect.

Animals↗
PubMed1994

Endotoxin tolerance is associated with decreased prostaglandin H synthases-1 and -2.

Lipopolysaccharide (LPS) induces macrophage protein and eicosanoid synthesis. Previous studies have shown that LPS induction of eicosanoid metabolism is transcription dependent and that prostaglandin (PG) H synthase is the committed step in the conversion of arachidonic acid (AA) to thromboxane (Tx) B2. LPS tolerance induced by sublethal in vivo injections of LPS renders rats resistant to LPS in vivo and macrophages refractory to LPS-stimulated eicosanoid synthesis in vitro. This study examined potential activity and content changes in constitutive and mitogen inducible PGH synthase in LPS-stimulated control and tolerant macrophages. TxB2 levels were measured to evaluate basal PGH synthase activity and stimulation by Salmonella enteritidis LPS (50 micrograms/ml), calcium ionophore A-23187, and AA. All tolerant macrophage groups demonstrated decreased TxB2 synthesis. TxB2 synthesis stimulated by AA in tolerant cells was decreased by 70% (P < 0.05) compared with control macrophages. In subsequent studies changes in PGH synthase content were examined in rat peritoneal macrophages from tolerant and control rats incubated with and without LPS. Immunoblot analysis of PGH synthase-1 (constitutive) demonstrated no increase in cells stimulated with LPS compared with basal but was diminished by 62 +/- 9% (n = 4, P < 0.05) in tolerant macrophages compared with control cells. Immunoblot analysis of PGH synthase-2 (mitogen inducible) demonstrated induction in response to LPS that was maximal between 12 and 24 h. PGH synthase-2 was also induced in tolerant macrophages in response to LPS but was less than in control cells. The results demonstrate that endotoxin tolerance is associated with reduced activity and content of PGH synthase-1 and a decreased LPS induction of PGH synthase-2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Endotoxin tolerance: effects on lethality and macrophage thromboxane (B2) and interleukin 6 production.

The effects of endotoxin pretreatment on induction of in vivo tolerance to endotoxin lethality, and on in vitro stimulated peritoneal macrophage mediators, thromboxane (TX)B2 and interleukin 6 (IL-6) were investigated. Rats were given i.p. injections of S. enteritidis endotoxin on days 1 (100 micrograms/kg) and 2 (500 micrograms/kg), respectively. After 5 days, or after 2-8 weeks of initial pretreatment, either endotoxin-induced mortality was assessed, or peritoneal cells were harvested for the in vitro studies. Endotoxin tolerant rats were resistant (p < .05) to endotoxin lethality for 2 weeks after initial induction of tolerance. In vitro studies with peritoneal macrophages demonstrated that endotoxin or monophosphoryl lipid A stimulated (p < .05) TXB2 production. However, peritoneal cells harvested from endotoxin tolerant rats exhibited suppressed (*p < .05) TXB2 production to both stimuli which persisted for at least 8 weeks. Endotoxin stimulated (p < .05) in vitro levels of IL-6 in control cells, but in contrast to the suppressed TXB2 production in tolerance, also stimulated (p < .05) in vitro IL-6 in the endotoxin tolerant group. Paradoxically, lipid A did not induce IL-6 production in either group. These composite observations suggest that during endotoxin tolerance neither in vitro peritoneal macrophage TXB2 nor IL-6 synthesis temporally correlate with in vivo resistance to lethality.

Animals↗
PubMed1994

Cholinergic manipulations and passive avoidance in the rat: effects on acquisition and recall.

A review of the literature concerning cholinergic manipulations and passive avoidance reveals that state-dependency is usually not controlled adequately, nor is acquisition of the passive avoidance task ascertained before retention is tested. These problems make interpretation of results difficult. We report three experiments on 129 rats, controlling both of these factors, in which scopolamine and pilocarpine impaired both acquisition and retention of a passive avoidance response. Lesions of the nucleus basalis magnocellularis had no effect on this task. The results suggest that an optimal level of central cholinergic activity exists for learning and memory, and that deviations from this optimal level impair acquisition and retention.

Acetylcholine↗
PubMed1994

Cycloheximide inhibits the cytotoxicity of paclitaxel (Taxol).

Treatment of human breast (MCF-7) and lung (A549) adenocarcinoma cell lines with 10 micrograms/ml cycloheximide provided substantial protection from paclitaxel-induced cytotoxicity. Addition of cycloheximide to cells at 0, 6, 12 or 18 h into a 24 h exposure to paclitaxel resulted in cytotoxicity similar to that found in cells treated with paclitaxel alone for only 0, 6, 12 or 18 h, respectively. DNA flow cytometry showed that paclitaxel blocked cells in G2/M. Mitotic index studies demonstrated that paclitaxel arrested cells in mitosis and that prolonged exposure to paclitaxel resulted in the development of multiple micronuclei. Concurrent incubation of cells in cycloheximide prevented the development of a G2/M block, mitotic arrest and micronuclei formation. The addition of cycloheximide to cells at 6 or 12 h into a 24 h exposure to paclitaxel reduced the degree of G2/M block to that produced by incubation of cells in paclitaxel alone for only 6 or 12 h. Mitotic index studies confirmed that cells treated with cycloheximide during paclitaxel exposure had a marked reduction in the percentage of cells in mitosis. However, the percentage of paclitaxel-treated cells which had multiple micronuclei was increased in cells treated with cycloheximide. These results indicate that entry into mitosis is a prerequisite for paclitaxel-induced cytotoxicity and that cycloheximide reduces cytotoxicity due to paclitaxel by preventing cells from entering mitosis. However, once cells have entered mitosis in the presence of paclitaxel, protein synthesis is not required for the development of multiple micronuclei and cytotoxicity.

Adenocarcinoma↗
PubMed1994

Sequence dependence of paclitaxel (Taxol) combined with cisplatin or alkylators in human cancer cells.

Clinical trials combining paclitaxel with other active chemotherapy agents are currently underway. In vitro preclinical studies may assist in the selection of appropriate drug combinations or sequences for clinical investigation. We have used clonogenic cell survival assays and DNA flow cytometry to examine the effect of paclitaxel combined with melphalan, thiotepa, or cisplatin on the survival and cell-cycle parameters of human lung A549 and breast MCF-7 adenocarcinoma cells. A549 and MCF-7 cells were incubated with paclitaxel for 24 h, followed by a 1 h exposure to cisplatin, melphalan, or thiotepa. Both cell types were also incubated with cisplatin or an alkylator for 1 h followed by a 24 h paclitaxel exposure. When the paclitaxel exposure preceded either melphalan, thiotepa, or cisplatin, the cytotoxicity was additive for both cell lines tested. When cisplatin or alkylator exposure was given prior to the paclitaxel, cytotoxicity was also additive in MCF-7 cells. However, cisplatin or alkylators were antagonistic to paclitaxel cytotoxicity when they preceded the paclitaxel exposure in A549 cells (e.g., 2% survival with 100 nM paclitaxel vs. 7% survival with cisplatin and paclitaxel). Cell-cycle analysis revealed that exposure to 100 nM paclitaxel for 24 h blocked a majority of the cells into the G2/M phase (> or = 80% for A549 cells, 60-65% for MCF-7 cells). However, exposure to alkylators before incubation in paclitaxel reduced the proportion of A549 but not MCF-7 cells in G2/M--e.g., exposure to 30 micrograms/ml cisplatin prior to paclitaxel exposure caused only 25% of A549 and 55% of MCF-7 cells to block in G2/M.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1994

Nocturnal intermittent peritoneal dialysis.

Automated methods of peritoneal dialysis have developed as alternative methods of treatment to CAPD. We review our experience of 47 patients treated with nocturnal intermittent peritoneal dialysis (NIPD). Patients receive a nocturnal exchange of 15-25 litres of dialysate with the peritoneum left dry during the day. If biochemical control is inadequate, 1 litre of dialysate is left in during the day. Indications for NIPD included social reasons and CAPD failure due to poor ultrafiltration or problems related to raised intra-abdominal pressure. Some features of biochemical control were less good with NIPD compared with CAPD with higher phosphate (2.18 mmol/l versus 1.83 mmol/l, P < 0.001); creatinine (1256 mumol/l versus 1085 mumol/l, P < 0.001); and potassium (4.92 mmol/l versus 4.64 mmol/l, P = 0.056) in patients changing between CAPD and NIPD. Overall peritonitis rate on NIPD was one episode per 47.1 months compared with a rate of one episode per 17.5 months for patients commencing CAPD over the same period. Conversion from CAPD to NIPD was successful in all six cases for problems related to raised intra-abdominal pressure on CAPD and in six of nine patients transferred due to poor ultrafiltration. NIPD is a useful form of treatment and we believe that the increased cost is offset by the reduced peritonitis rate.

Adult↗