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C Newton

Publications and source records attributed to C Newton.

At least 37 records · Page 2Linked to original sources
PubMed1998

The role of macrophages in THC-induced alteration of the cytokine network.

Delta-9-tetrahydrocannabinol (THC) has been shown to decrease Th1 responses (cell mediated immunity) while increasing Th2 responses (humoral immunity), both in vitro and in vivo. The addition of THC to murine splenocytes stimulated for 72 hrs with pokeweed mitogen (PWM) increased the detection of IL-4 and IL-10, cytokines associated with Th2 responses, and decreased IFN-gamma, IL-15 and IL-12, cytokines associated with Th1 responses. To investigate the cellular molecular basis for these effects of THC, cell depletion studies were performed. Removal of macrophages from the cell cultures eliminated the increase in IL-4 activity. This effect was observed when the macrophages were depleted during the first few hours but not after 24 hrs. Thus, it appears that the macrophages were producing an early factor responsible for the IL-4 increase. To examine the direct effect of THC on macrophages, peritoneal macrophages were cultured with various stimulators in the presence of THC. It was found that THC suppressed IL-12, IL-15 and IL-6 and increased IL-1 alpha, IL-1 beta, and TNF alpha in all of the stimulated cultures. IL-12 and IL-15 are known to induce IFN gamma production from T cells and NK cells and to be involved in the induction a Th1 response, while IL-1 is considered a growth factor for Th2 cells. Thus, the effects of THC on macrophages reflects the basic observation that THC decreases Th1 responses and increases Th2 responses. The data obtained adds to the understanding of the THC-induced Th1/Th2 shift, but the mechanisms still must be determined. However, the results of these studies do suggest that, in addition to lymphocytes, THC affects macrophages in splenocyte cultures and that the macrophages are involved in the alternation of the cytokines. Furthermore, the data demonstrate the diversity of the immunomodulatory effects THC exerts.

Adjuvants, Immunologic↗
PubMed1998

Cannabinoid receptors and the cytokine network.

Splenocyte cultures from BALB/c mice were treated with THC and mitogen and shown to produce less Th1 cytokine, IFN gamma, and more Th2 cytokines, IL-4 and IL-10. This suggested that drug treatment caused a shift in the development of Th1 and Th2 cells. In studies designed to look at molecular mechanisms, the CBI antagonist, SR141716A, did not attenuate the THC enhancement of IL-4 production, but pertussis toxin attenuated the drug effect and the CB2 agonist, JWH-051, increased IL-4 production similar to THC. These results suggest that cannabinoids may increase Th2 development and IL-4 production in cultured immune cells through the activity of the CB2 receptor subtype. Studies are currently in progress to further define the molecular and cellular mechanisms involved.

Adjuvants, Immunologic↗
PubMed1998

Fibromyalgia and women's pursuit of personal goals: a daily process analysis.

For 30 days, 50 women with primary fibromyalgia syndrome reported daily progress and effort toward a health-fitness and a social-interpersonal goal and the extent to which their pain and fatigue hindered their accomplishment. They also carried palmtop computers to assess their sleep and their pain, fatigue, and positive and negative mood throughout the day. Analyses of the person-day data set showed that on days during which pain or fatigue increased from morning to evening, participants perceived their goal progress to be more attenuated by pain and fatigue. Unrestorative sleep the night before predicted the following day's effort and progress toward accomplishing health-fitness goals, but not social-interpersonal goals. Finally, participants who reported more progress toward social-interpersonal goals on a given day were more likely to evidence improvements in positive mood across the day, regardless of any changes in pain or fatigue that day.

Adaptation, Psychological↗
PubMed1998

Immunologic response and pathophysiology of Legionella infection.

Legionella pneumophila, the causative agent of legionnaires' disease, is a gram-negative pleomorphic bacillus and fastidious in its growth in artificial medium. These bacteria grow readily intracellularly, including growth in macrophages and other phagocytic cells. Humoral antibodies develop readily to these bacteria not only in infected patients, but also in persons who have had subclinical exposure. High-levels of serum antibodies may also occur in individuals who recover from infection. However, cell-mediated immunity based on lymphocytes reacting with the organisms and cytokines produced by such lymphocytes are important in resistance. Vaccines prepared from killed Legionella or their components readily induce cell-mediated immunity. Immune resistance to disease depends on lymphocyte-based immunity, activating cytokine formation, some of which activate macrophages to resist infection. Resistance to Legionella infection by experimental animals such as mice correlates with activation of macrophages, which can inhibit replication of the bacteria. Much recent experimental work has involved studies using inbred animals, including inbred mice genetically resistant to Legionella versus mice genetically susceptible. Detailed studies show that regulation of macrophage resistance versus susceptibility to infection is mediated by specific genetic mechanisms. Induction of cytokines by Legionella can activate immune cells, especially helper T cells. Th 1 type helper cells that produce type 1 class cytokines, such as interferon gamma and interleukin-2 (IL-2), are known to be important in cellular immunity to Legionella as well as to other opportunistic intracellular bacteria. In contrast, Th 2 type helper cells, which secrete type 2 class cytokines such as IL-4, IL-5, and IL-6, activate B lymphocytes to produce humoral antibodies important in resistance to extracellular bacteria which secrete toxins and extracellular factors as compared to intracellular bacteria such as Legionella. Although Legionella, similar to other ubiquitous opportunistic pathogens, can cause serious infection in immunocompromised individuals, these bacteria have many distinguishing characteristics, such as very rapid replication in macrophages from susceptible individuals. However, activated macrophages restrict the growth of these bacteria. Infection by Legionella, if recognized clinically, can be readily treated with appropriate antibiotics. Currently, many studies are in progress concerning the mechanism of pathogenicity and assessment of the molecular biologic mechanisms of protective immune responses to this bacterium, which causes serious infection in immunocompromised individuals.

Cytokines↗
PubMed1997

The elimination of primer-dimer accumulation in PCR.

We attempted to produce primer-dimers (PDs) from a variety of primers with differing types and extents of complementarity. Where PDs were produced they were cloned and sequenced. We were unable to produce detectable PDs either with individual primers alone or with similar sequence primers even if they had 3'complementarity. These observations led to the hypothesis that a system could be developed whereby the accumulation of PDs in a PCR may be eliminated. We demonstrate a method for the general suppression of PD formation that uses a sequence of additional nucleotides (a Tail) at the 5' ends of amplimers. Tailed amplimers are present at low concentration and only participate during early cycles of PCR. In subsequent PCR cycles, amplification is achieved using a single primer that has the same sequence as that of the Tail portion of the early cycle primers, here we refer to this as a Tag. When products are small, as with PDs, there is a high local concentration of complementary sequences derived from the Tail. This favours the annealing of the complementary ends of a single strand produced by tailed primer interactions and gives rise to 'pan-handle' structures. The formation of these outcompetes the annealing of further Tag primers thereby preventing the accumulation of non-specific PD products. This aids the design of large multiplex reactions and provides a means of detecting specific amplicons directly in the reaction vessel by using an intercalating dye.

Base Sequence↗
PubMed1997

Evaluation of an alternative traffic light change anticipation system.

A driving simulator was used to study the efficacy of an alternative signal phasing program. The new Traffic Light Change Anticipation System (TLCAS) utilizes a flashing amber in conjunction with a solid green indication to warn drivers of the impending onset of the solid amber indication. This new program was expected to provide drivers with additional information with which to make safe stopping or crossing decisions, and reduce behaviour associated with increased accident rates at signalized intersections. Additionally, a new measure of first response variability was introduced to evaluate the effect of the new program on driver behavior. The results indicated that the new system has the ability to reduce the number of red light violations. Of the 1148 target intersections, 43 violations were recorded for the regular program compared to 9 for the TLCAS program. The severity of decelerations was also impacted. The regular program displayed average maximum decelerations of 3.1 m/sec2 compared to 2.5 m/sec2 for the TLCAS program. However, the TLCAS program showed an increased variability in first response five times larger than the regular program. This finding, in conjunction with traditional measures, indicates that the new system performs comparably to an increased amber duration by increasing the potential for conflicting decisions between successive drivers approaching an intersection. Altogether, the results suggest that this alternative signal phasing program would not improve intersection safety. The findings also suggest that further study of the longitudinal behavior after the introduction of a TLCAS program may be warranted. Specifically, future studies should examine whether subjects engage in appropriate adaptive changes when confronted with a solid amber period warning after becoming familiar with the TLCAS.

Accidents, Traffic↗
PubMed1997

Differential immunologic modulatory effects of tetrahydrocannabinol as a function of age.

Tetrahydrocannabinol (THC) the major psychoactive component of marijuana, differentially modulates the immune response of lymphoid cells from young and old mice. This effect was previously shown when cells from mice of different ages were treated with THC in vitro. In the present study THC was given in vivo to mice of different ages. Lymphoid cells from the young and old mice had different immunologic potential in terms of ability to produce cytokines following stimulation with either Con A or anti-CD3 antibody. IL-4 and IL-10 production was consistently up-regulated in spleen cell cultures from the older animals. In addition, in vivo administration of THC up-regulated the proliferative response of lymphoid cells from young adult mice. Such enhancement was not evident for cells from older animals. Although the proliferative response of spleen cells in the old mice tended to be suppressed, statistical significance was not evident possibly because of marked variation of the responses of cells from the older mice. Since marijuana is used by persons of a wide range of ages, aging should be an important variable that must be considered when assessing the immunomodilatory effect of this drug.

Adjuvants, Immunologic↗
PubMed1997

Psychoactive cannabinoids increase mortality and alter acute phase cytokine responses in mice sublethally infected with Legionella pneumophila.

Marijuana contains both psychoactive and nonpsychoactive cannabinoids which have varying effects on the immune response system. Previous studies with delta-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, showed that this substance augmented the susceptibility of mice to infection with the opportunistic pathogen Legionella pneumophila. The present study compared the enhancement of Legionella-induced mortality in mice due to two other major of marijuana components, cannabinol and cannabidiol, as well as the synthetic psychoactive cannabinoid CP 55,940. Inbred BALB/c mice, relatively resistant to infection with Legionella, were given the marijuana component 1 day before and 1 day after a sublethal intravenous infection with Legionella. Unlike the effect of THC, an 8 mg/kg dose of either cannabinol or cannabidiol did not affect mortality of the mice sublethally infected with Legionella. Mice given a 16 mg/kg dose of these components of marijuana, however, showed a slight to moderately increased mortality following the sublethal infection with Legionella. In contrast, a dose of 6 mg/kg of the synthetic psychoactive cannabinoid CP 55,940 given 1 day before and 1 day after infection with Legionella resulted in about 50% of the animals dying, the same level of augmentation of lethality induced by THC. Liver, spleen, and lung tissues were removed from the surviving mice 24 hr after the second THC injection and tested for the presence of viable Legionella using a standard CFU assay. The mice injected with THC before and after infection showed significantly higher levels of bacteria in their lung than mice that were not given any cannabinoid but were infected sublethally with the Legionella. Mice injected with the other cannabinoids, including the synthetic cannabinoid, showed a much smaller increase in the number of Legionella in their lung when infected with Legionella and treated with the drug. The number of bacteria recovered from the kidney and liver of the mice regardless of treatment with a cannabinoid, including with THC, did not show significant changes. RNA isolated from the spleen of the THC- and Legionella-treated animals was examined to determine at the molecular level whether acute phase pro-inflammatory cytokines (i.e., IL-1, IL-6 and TNF-alpha) were altered following drug treatment and infection, since previous studies had shown there were increased serum levels of these cytokines in the mice. It was found that the mRNA levels for IL-1 remained generally constant regardless of whether the infected animals were treated with a cannabinoid. However, the mRNA level for IL-6 was markedly increased following treatment of the infected animals with THC, suggesting the possible involvement of this pro-inflammatory cytokine in increased mortality. The mRNA level for TNF-alpha was generally low and not significantly altered in the drug treated animals. Mice given other cannabinoids, including cannabinol and cannabidiol, as well as the synthetic CP 55,940, showed no significant change in the level of mRNA for any of the cytokines tested.

Acute-Phase Proteins↗
PubMed1997

Management skills in an era of shifting paradigms.

Managers have vital roles in balancing clinical practice and business-related outcomes. Skills in recruiting and retaining a diversified staff, along with a broad perspective of health care and political savvy, are essential in implementing changes, negotiating, collaborating, conducting meetings, and managing workloads. Demystifying the myths related to management is a crucial step when the paradigm shifts and requires changing roles.

Financial Management↗
PubMed1996

Memory complaints associated with the use of gonadotropin-releasing hormone agonists: a preliminary study.

OBJECTIVES: To study the effect of GnRH agonist (GnRH-a) treatment on memory and to assess the role of psychological factors. DESIGN: A randomized prospective study. SETTING: An academic teaching hospital. PARTICIPANTS: Women with endometriosis and infertility or endometriosis alone. MAIN OUTCOME MEASURES: Memory Observation Questionnaire, Profile of Mood States, Health Concerns scale, a weekly diary of adverse effects. RESULTS: Perceived memory functioning decreased during GnRH-a administration and by the final week of treatment 44% of women reported moderate to marked impairment in comparison to community norms. Prospective memory was most affected and withdrawal of GnRH-a treatment resulted in a return to normal memory functioning. Impairment was not related to excessive health concerns or mood changes and was uncorrelated with other adverse effects. CONCLUSIONS: Memory disruption may be a more common side effect of GnRH-a treatment than currently is recognized. Problems were temporary and more likely a result of rapid estrogen depletion than a consequence of mood, somatic distress, or personality factors.

Adult↗
PubMed1995

Indicators of life-threatening malaria in African children.

BACKGROUND: About 90 percent of the deaths from malaria are in African children, but criteria to guide the recognition and management of severe malaria have not been validated in them. METHODS: We conducted a prospective study of all children admitted to the pediatric ward of a Kenyan district hospital with a primary diagnosis of malaria. We calculated the frequency and mortality rate for each of the clinical and laboratory criteria in the current World Health Organization (WHO) definition of severe malaria, and then used logistic-regression analysis to identify the variables with the greatest prognostic value. RESULTS: We studied 1844 children (mean age, 26.4 months) with a primary diagnosis of malaria. Not included were 18 children who died on arrival and 4 who died of other causes. The mortality rate was 3.5 percent (95 percent confidence interval, 2.7 to 4.3 percent), and 84 percent of the deaths occurred within 24 hours of admission. Logistic-regression analysis identified four key prognostic indicators: impaired consciousness (relative risk, 3.3; 95 percent confidence interval, 1.6 to 7.0), respiratory distress (relative risk, 3.9; 95 percent confidence interval, 2.0 to 7.7), hypoglycemia (relative risk, 3.3; 95 percent confidence interval, 1.6 to 6.7), and jaundice (relative risk, 2.6; 95 percent confidence interval, 1.1 to 6.3). Of the 64 children who died, 54 were among those with impaired consciousness (n = 336; case fatality rate, 11.9 percent) or respiratory distress (n = 251; case fatality rate, 13.9 percent), or both. Hence, this simple bedside index identified 84.4 percent of the fatal cases, as compared with the 79.7 percent identified by the current WHO criteria. CONCLUSIONS: In African children with malaria, the presence of impaired consciousness or respiratory distress can identify those at high risk for death.

Anemia↗
PubMed1995

LPS inhibits the intracellular growth of Legionella pneumophila in thioglycolate elicited murine peritoneal macrophages by iron-dependent, tryptophan-independent, oxygen-independent, and arginine-independent mechanisms.

Thioglycolate-elicited murine macrophages from genetically susceptible A/J mice activated with lipopolysaccharide (LPS) and infected with Legionella pneumophila in vitro evince marked inhibition of intracellular growth of this bacterium. The mechanism of inhibition by LPS-activated macrophages in terms of replication of this intracellular pathogen is unclear. LPS activation of murine macrophages induced a downshift in transferrin receptor (TfR) expression and reduction in cellular iron content, and this was correlated with augmented intracellular growth of Legionella in the cells. When LPS-stimulated macrophages were first saturated with iron, partial reversion of L. pneumophila growth restriction was observed. However, an excess of exogenous L-tryptophan (Trp) did not reverse this growth inhibition, nor did supplementation of the macrophage culture medium with both iron and Trp. The antilegionella activity of the macrophages induced by LPS activation was independent of reactive oxygen intermediates (ROI), since the scavengers catalase, superoxide dismutase, mannitol, and thiourea had no effect on growth restriction. Likewise, notwithstanding the ability of LPS-activated macrophages to synthesize reactive nitrogen intermediates (RNI), which was inhibited by L-arginine analogs NG-monomethyl-L-arginine and L-aminoguanidine), as well as by incubation in arginine-free medium, their ability to inhibit the intracellular replication of L. pneumophila was not affected. Thus, we conclude that LPS-activated macrophages inhibit the intracellular growth of L. pneumophila partially by iron-dependent, Trp-independent, and ROI- and RNI-independent mechanisms. We also suggest that additional unknown mechanisms are involved, since complete reversion was not obtained.

Animals↗
PubMed1995

Spatial learning impairment in mice infected with Legionella pneumophila or administered exogenous interleukin-1-beta.

The effect of interleukin-1 beta (IL 1 beta) on spatial learning was examined. In one experiment, C57BL/6 mice were given daily injections (100 ng/mouse) of recombinant murine IL1 beta prior to training on the Morris water maze. In another experiment, mice were infected with a sublethal dose of a gram-negative bacterium (Legionella pneumophila; Lp). Mice rendered ill by the infection were given either anti-IL1 beta antibodies (100 micrograms/mouse) or saline and then trained on the water maze. Results indicated that (1) exogenous IL1 beta blocked acquisition of spatial learning, (2) Lp infection attenuated learning on this task, and (3) neutralizing circulating IL1 beta in Lp-infected mice normalized learning despite the continuation of the illness. The data indicate that cognitive impairment may be a component of cytokine-mediated sickness behavior.

Animals↗
PubMed1995

Marijuana, receptors and immunomodulation.

THC, the major psychoactive component of marijuana, has been shown both in humans and experimental animals to have immunomodulatory properties. For example, marijuana smokers may show impaired immunological functions, including deficiency of blood leukocyte blastogenesis to mitogens. Detailed studies with mice have shown that animals given THC can show marked immunomodulation, including suppression of antibody formation, deficient cytokine production, etc. However, recent studies have also shown that lymphoid cells evince enhanced production or release or IL1, but suppression of IL2 and interferon production. Such lymphoid cells treated in vitro with THC also show suppressed blastogenesis to antigens and mitogens, suppressed NK activity, etc. In contrast, it has recently been shown that THC can enhance production or release of pro-inflammatory cytokines. This includes release of these cytokines from macrophages, including augmented release of IL1, TNF alpha, and IL6 activity. Susceptibility of mice to infection with opportunistic organisms such as L. pneumophila has been found and this increased susceptibility can be modulated by THC. A toxic shock-like death to Legionella has been induced by THC treatment given one day before and one day after infection. Receptors to THC have been detected in the brain as well as in peripheral tissues, including lymphoid cells. Thus, immunomodulation induced by THC may be related to receptor effects as well as unrelated to such receptors. It is clear that THC and other cannabinoids are excellent tools for studying the mechanisms of immune modulation, especially altered susceptibility to microbial infection.

Adjuvants, Immunologic↗
PubMed1995

IL-1 beta and TNF alpha modulate delta 9-tetrahydrocannabinol-induced catalepsy in mice.

The role of the proinflammatory cytokines interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha) in THC-induced catalepsy in mice was examined. Recombinant IL-1 beta (400 ng/mouse, IV) and TNF alpha (500 ng/mouse, IV) were effective in potentiating the cataleptic effect of low-dose THC (10 micrograms/mouse, IV). Recombinant IL-1 alpha and IL-6 did not potentiate catalepsy at any dose tested. Anti-IL-1 beta and anti-TNF alpha antibodies were effective in attenuating high-dose (75 micrograms/mouse) THC-induced catalepsy. Antibodies to IL-1 alpha and IL-6 had no effect on catalepsy. Early onset catalepsy (10 min postinjection) was potentiated by exogenous recombinant IL-1 beta and TNF alpha but only later catalepsy (2 h postinjection) was attenuated by antibodies to endogenous IL-1 beta or TNF alpha. This divergence of the cytokine effect suggests that these substances regulate, by different mechanisms, the early and late THC-induced cataleptic response.

Animals↗