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Biomedical subjects

J G Cannon

Publications and source records attributed to J G Cannon.

At least 19 recordsLinked to original sources
PubMed2001

Influence of barometric pressure on interleukin-1 beta secretion.

Monocytes and macrophages are activated by various environmental challenges, including microorganisms, radiation, and pollutants. These cells release cytokines, such as interleukin (IL)-1 beta, that mediate physiological adaptations to stress. This study sought to define further the role of IL-1 beta in general adaptation to environmental stress by testing the hypothesis that high altitude (20,000 ft, 6,096 m) would stimulate IL-1 beta secretion from isolated human blood mononuclear cells. Cells from six young men (aged 22--26 yr) were divided into separate cultures incubated in either standard ambient conditions or in one of three test conditions, hypobaric hypoxia (simulating 20,000 ft), hypobaric normoxia (20,000 ft, O(2) supplemented), and normobaric hypoxia (10% O(2)). This design allowed differentiation between pressure-related vs. oxygen-related effects. Each subject made multiple blood donations in order that cells from all subjects were tested in all conditions. Contrary to the hypothesis, IL-1 beta secretion was not induced at simulated altitude in basal cell cultures. In lipopolysaccharide-stimulated cell cultures, exposure to altitude inhibited IL-1 beta secretion by approximately 40%, and the inhibition was due to the change in pressure (P = 0.039) rather than the change in oxygen. Secretion of other factors (IL-1 receptor antagonist and soluble IL-1 receptor type II) was not inhibited. Although these results are in opposition to the original hypothesis, they provide insight regarding adaptations necessary for hematopoiesis in response to high altitude and also provide a cellular rationale for the mountain sanatoriums of the 19th and early 20th centuries.

Adult↗
PubMed2000

Glucocorticoid sensitivity of interleukin-1 agonist and antagonist secretion: the effects of age and gender.

Interleukin-1 (IL-1) is a primary mediator of inflammation that is regulated, in part, by the hypothalamic-pituitary-adrenal axis. The purpose of this study was to determine if gender- or age-related differences exist in the sensitivity of IL-1-producing cells to hydrocortisone. Peripheral blood mononuclear cells (PBMC) isolated from men and women (21-77 yr old) were incubated with hydrocortisone (0, 50, 100, 500, or 1,000 ng/ml) with or without lipopolysaccharide (LPS). Secretion of IL-1beta and IL-1 receptor antagonist was inhibited in a dose-dependent manner (P = 0.001) without age- or gender-related differences. Hydrocortisone decreased soluble IL-1 receptor type II (sIL-1RII) secretion by unstimulated cells (P = 0. 0001), but it increased secretion by LPS-stimulated cells (P = 0. 0001) in all groups. Unstimulated cell supernatants from men contained greater concentrations of sIL-1RII than the supernatants from women (P = 0.011). Compared with men, PBMCs from women were less responsive to hydrocortisone inhibition of sIL-1RII secretion, regardless of age (P = 0.001), and compared with the follicular phase, sIL-1RII secretion was lower in the luteal phase of the menstrual cycle (P < 0.05). These data indicate that basal secretion and glucocorticoid modulation of sIL-1RII secretion by cultured PBMCs are gender dependent. Moreover, glucocorticoid influences on sIL-1RII secretion depend on the presence or absence of gram-negative bacterial toxins.

Adult↗
PubMed2000

Macrophage migration inhibitory factor antagonizes hydrocortisone-induced increases in cytosolic IkappaBalpha.

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine secreted by several cell types, including mononuclear and pituitary cells. It has also been shown to counteract cortisol-induced inhibition of inflammatory cytokine secretion. The purpose of this study was to determine whether MIF antagonized the effect of hydrocortisone on the NF-kappaB/IkappaB signal transduction pathway in lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells. Physiological doses of hydrocortisone (50-200 ng/ml) diminished both the LPS-stimulated decrease in cytosolic IkappaBalpha levels and the subsequent increase in nuclear NF-kappaB DNA binding. In the presence of both LPS and hydrocortisone, 1 ng/ml of MIF antagonized the effects of hydrocortisone, resulting in decreased cytosolic IkappaBalpha levels (P < 0.05) and increased nuclear NF-kappaB DNA binding (P < 0.05). In the absence of hydrocortisone, MIF had no effect on LPS-induced decreases in IkappaBalpha. In the absence of LPS, MIF inhibited hydrocortisone-induced increases in IkappaBalpha (P = 0.03). Thus the mechanism by which MIF antagonizes the effect of hydrocortisone on the NF-kB/IkappaB signal transduction pathway is through inhibiting the ability of hydrocortisone to increase cytosolic IkappaBalpha.

Adult↗
PubMed2000

Influence of hormone replacement therapy and aspirin on temperature regulation in postmenopausal women.

Postmenopausal women receiving estrogen-replacement therapy (ERT) regulate body temperature (T(b)) at a lower level than women not receiving hormone replacement therapy (untreated) and women using estrogen plus progesterone therapy (E + P), but it is not clear if reproductive hormones alter T(b) by directly acting on central thermoregulatory centers or indirectly via a secondary mediator(s). The purpose of the present investigation was to examine the possible involvement of pyrogenic cytokines and cyclooxygenase (COX) products (e.g., prostaglandins) in the regulation of T(b) in three groups of postmenopausal women (8 ERT, 7 E + P, and 8 untreated). We measured ex vivo secretion of cytokine agonists [tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta and -6] and modifiers (IL-2 soluble receptor, IL-1 receptor antagonist, soluble TNF receptor type I, soluble TNF receptor type II, soluble IL-6 receptor, and soluble glycoprotein 130) from peripheral blood mononuclear cells and thermoregulatory responses at rest and during 1 h of passive whole body heating in the postmenopausal women before and after 3 days of placebo or aspirin (50 mg. day(-1). kg(-1)). With and without aspirin, the ERT group had a lower baseline rectal temperature (T(re); 0.44 degrees C, P < 0.004) and a reduced T(b) threshold for cutaneous vasodilation (0.29 degrees C and 0.38 degrees C, P < 0.01) compared with the untreated and E + P groups, respectively. In the placebo condition, waking morning oral temperature (T(or)) correlated with ex vivo secretion of the proteins associated with IL-6 bioactivity. Aspirin caused significant reductions in waking T(or) in the E + P group and in baseline T(re) in the untreated group. However, the difference in thermoregulation brought about by steroid hormone treatment could not be explained by these relatively modest apparent influences by cytokines and COX products. Therefore, the altered thermoregulation induced by reproductive steroid therapy appears to occur via a mechanism distinct from a classic infection-induced fever.

Aged↗
PubMed1999

Construction of mutant strains of Neisseria gonorrhoeae lacking new antibiotic resistance markers using a two gene cassette with positive and negative selection.

The pathogenesis of infections caused by Neisseria gonorrhoeae, the causative agent of the sexually transmitted disease gonorrhea, can be studied using experimental infection of human male volunteers. The desire to avoid introducing new antibiotic resistance markers into strains to be used in human experimental infection has complicated the construction of genetically defined mutants in which expression of potential virulence factors is inactivated. To facilitate construction of such mutants, we have used a two-step mutagenesis strategy that allows for gene replacements without introducing new selectable markers into the final strain. The method uses a two-gene cassette containing both a selectable marker (ermC') and a counterselectable marker (rpsL). The cassette is cloned into the gene of interest and used to replace the wild-type gene on the chromosome by allelic exchange. A second transformation replaces the cassette-containing version of the gene with an engineered version with an unmarked deletion or other mutation. The rpsL gene of Escherichia coli functioned for the counterselection in the gonococcus, albeit with low efficiency. To improve the efficiency of the counterselection, we cloned the gonococcal rpsL gene and incorporated it into the cassette. This technique has been successful in creating defined mutants for human challenge, and also circumvents the limitation in the number of different selectable markers that are useful in Neisseria species.

Anti-Infective Agents↗
PubMed1999

Association of IGF-I and IGF-II with myofiber regeneration in vivo.

This study examined expression of insulinlike growth factor (IGF) in the myofibers and nonmyofibrillar structures of murine soleus muscle following contraction-induced damage. Identifying the cellular sources of this myogenic growth factor could improve muscle rehabilitation strategies. Immunohistochemical analysis of muscle sections indicated that the number of myofibers expressing both IGF-I and IGF-II increased significantly at 4, 7, and 10 days following injury, compared with control. Muscle spindles and vascular tissue expressed only IGF-II, and staining intensity did not change following injury. The number of fibers expressing developmental myosin heavy chain increased significantly at 7 and 10 days postinjury, and these usually coexpressed IGF. No IGF-specific staining of interstitial/inflammatory cells was observed. Therefore, expression of IGF after mechanically induced fiber damage occurs exclusively within regenerating fibers without supplemental delivery of IGF to the tissue by inflammatory cells or changes in constitutive expression of IGF-II in vascular tissue.

Animals↗
PubMed1999

Sex differences in leukocyte invasion in injured murine skeletal muscle.

The three aims of this study were to describe the time course of leukocyte invasion in injured soleus muscles of male and female mice, to determine if differential subsets of leukocytes accumulate in intramyofiber and interstitial sites, and to determine if significant sex differences exist in invading leukocyte concentrations. Fifty sexually mature C57BL/6J mice (aged 11-12 weeks) underwent unilateral hindlimb muscle injury induced by lengthening contractions. This procedure models the muscle injury that can occur through strenuous exercise or overuse in humans. After 1, 3, 5, or 7 days of recovery, the injured and contralateral, uninjured solei were dissected and prepared for morphologic analysis. We found that leukocytes had invaded injured myofibers at 1-day postinjury for both sexes. Different subsets of leukocytes accumulated within damaged myofibers and the interstitium. Significantly fewer myofibers were invaded by acid phosphatase-positive leukocytes in females. Interstitial ER-BMDM1 leukocyte concentrations peaked in females at 7 days postinjury in comparison to 5 days postinjury in males. These findings expand nursing's knowledge base regarding the potential effect of gender on recovery from acute muscle injury.

Animals↗
PubMed1999

Aspirin-induced increases in soluble IL-1 receptor type II concentrations in vitro and in vivo.

This study examined the influence of low-dose aspirin on interleukin (IL)-1alpha , IL-1 receptor antagonist (IL-1ra), and soluble receptor type II (sIL-1RII) secretion in vivo and in vitro. Blood mononuclear cells were isolated from healthy young men who ingested 81 mg of aspirin on alternate days for 2 weeks and from unmedicated controls. Aspirin had minor effects on ex vivo secretion of IL-1beta and no influence on IL-1ra. In contrast, unstimulated ex vivo secretion of sIL-1RII was over twice as high by cells from aspirin-treated subjects (1115+/-123 vs. 460+/-77 pg/mL, P = 0.02). Lipopolysaccharide-stimulated sIL-1RII secretion was influenced similarly. Plasma sIL-1RII concentrations were 23% higher in aspirin-treated subjects (10.2+/-0.6 vs. 8.4+/-0.3 ng/mL, P = 0.03). In addition, cells from unmedicated subjects cultured in vitro with aspirin (10 microg/mL) secreted significantly greater amounts of sIL-1RII. Thus, low-dose aspirin therapy may prevent inflammation by increasing soluble receptor secretion, thereby preventing IL-1 from binding target cells.

Adult↗
PubMed1999

Acute phase responses and cytokine secretion in chronic fatigue syndrome.

This study addresses the hypothesis that clinical manifestations of chronic fatigue syndrome (CFS) are due in part to abnormal production of or sensitivity to cytokines such as interleukin-1beta (IL-1beta) and IL-6 under basal conditions or in response to a particular physical stress: 15 min of exercise consisting of stepping up and down on a platform adjusted to the height of the patella. The study involved 10 CFS patients and 11 age-, sex-, and activity-matched controls: of these, 6 patients and 4 controls were tested in both the follicular and the luteal phases of the menstrual cycle, and the remainder were tested in only one phase, for a total of 31 experimental sessions. Prior to exercise, plasma concentrations of the acute phase reactant alpha2-macroglobulin were 29% higher in CFS patients (P < 0.008) compared to controls. Secretion of IL-6 was generally higher for CFS patients (approximately 38%), however, this difference was statistically significant only if all values over a 3-day period were analyzed by repeated-measures ANOVA (P = 0.035). IL-6 secretion correlated with plasma alpha2-macroglobulin in control subjects at rest (R = 0.767, P = 0.001). Immediately after exercise, the CFS patients reported greater ratings of perceived exertion (P=0.027) compared to the healthy control subjects. Ratings of perceived exertion correlated with IL-1beta secretion by cells from healthy control subjects (R = 0.603, P = 0.022), but not from CFS patients, and IL-1beta secretion was not different between groups. Exercise induced a slight (< 12%) but significant (P = 0.006) increase in IL-6 secretion, but the responses of the CFS patients were not different than controls. Furthermore, no significant exercise-induced changes in body temperature or plasma alpha2-macroglobulin were observed. These data indicate that under basal conditions, CFS is associated with increased IL-6 secretion which is manifested by chronically elevated plasma alpha2-macroglobulin concentrations. These modest differences suggest that cytokine dysregulation is not a singular or dominant factor in the pathogenesis of CFS.

Acute-Phase Reaction↗
PubMed1999

Human experimentation with Neisseria gonorrhoeae: progress and goals.

Infection with Neisseria gonorrhoeae has adverse consequences for reproductive health and facilitates the transmission of the human immunodeficiency virus. A major limitation in the development of gonococcal vaccines has been the lack of an animal model. Urethral infection can be initiated in male volunteer subjects through urethral inoculation. Several hundred patients have participated in studies using this experimental infection model. These studies have helped define the natural history of experimental infection and provided a better understanding of phenotypic and genotypic variation of gonococci in vivo. Isogenic molecular mutants can be used to define a role for gonococcal surface structures, including pilin and transferrin-binding proteins; recent results demonstrate that gonococci unable to express transferrin- and lactoferrin-binding proteins cannot cause urethral infection. The experimental model has proven to be an efficient means of studying gonococcal infection and focusing vaccine development. In addition, this model should allow vaccines to be tested quickly and efficiently.

Animals↗
PubMed1999

A Neisseria gonorrhoeae immunoglobulin A1 protease mutant is infectious in the human challenge model of urethral infection.

Many mucosal pathogens, including Neisseria gonorrhoeae, produce proteases that cleave immunoglobulin A (IgA), the predominant immunoglobulin class produced at mucosal surfaces. While considerable circumstantial evidence suggests that IgA1 protease contributes to gonococcal virulence, there is no direct evidence that N. gonorrhoeae requires IgA1 protease activity to infect a human host. We constructed a N. gonorrhoeae iga mutant without introducing new antibiotic resistance markers into the final mutant strain and used human experimental infection to test the ability of the mutant to colonize the male urethra and to cause gonococcal urethritis. Four of the five male volunteers inoculated with the Iga- mutant became infected. In every respect-clinical signs and symptoms, incubation period between inoculation and infection, and the proportion of volunteers infected-the outcome of human experimental infection with FA1090iga was indistinguishable from that previously reported for a variant of parent strain FA1090 matching the mutant in expression of Opa proteins, lipooligosaccharide, and pilin. These results indicate that N. gonorrhoeae does not require IgA1 protease production to cause experimental urethritis in males.

Genotype↗
PubMed1998

Intrinsic and extrinsic factors in muscle aging.

The regenerative potential of skeletal muscle, and overall muscle mass, decline with age. This regenerative potential may be influenced by autocrine growth factors intrinsic to the muscle itself. Extrinsic host factors that may influence muscle regeneration include hormones, growth factors secreted in a paracrine manner by accessory cells, innervation, and antioxidant mechanisms. Unaccustomed exercise, which involves mechanical overload of myofibers, provides a convenient method for studying muscle regeneration in both humans and animal models. An inflammatory response ensues in which distinctive populations of macrophages infiltrate the affected tissue: some of these macrophages are involved in phagocytosis of damaged fibers; other macrophages arriving at later times may deliver growth factors or cytokines that promote regeneration. These include fibroblast growth factor and insulin-like growth factor, which are important regulators of muscle precursor cell growth and differentiation, as well as nerve growth factor, which is essential for maintenance or reestablishment of neuronal contact. Other cytokines, including interleukin-1, tumor necrosis factor, interleukin-15, and ciliary neurotrophic factor, have a strong influence on the balance between muscle protein synthesis and breakdown. The functional activity of invading macrophages can be influenced by age, by factors in myofibers and extracellular matrix, and can be influenced systemically by the antioxidant status of the host.

Aging↗
PubMed1998

Menstrual- and gender-dependent variations in circulating IL-1 agonists, antagonists, and binding proteins.

This study tested the hypotheses that sex-related differences in circulating binding proteins for interleukin- 1beta (IL- 1beta ) exist and that these binding proteins affect immunoassays for IL-1beta and IL-1Ra. 125I-labeled IL-1beta was added to human plasma samples, then chromatographed. The percentages of total radioactivity eluting in a high-molecular-weight peak were 21.0 + 0.8 for men (n = 6), 19.1+/-0.9 for follicular phase women (n = 6), and 18.0+/-0.8 in luteal phase women (n = 6; men vs. women, P = 0.032; follicular vs. luteal, P = 0.035), and correlated with plasma sIL-1RII concentrations (r = 0.647, P = 0.007). Plasma IL-1beta immunoreactivity did not correspond to concurrent cellular secretion rates due, in part, to interference in the IL-1beta assay by sIL-1RII. Correspondence between plasma IL-1Ra levels and cellular secretion rates was observed only after serial dilutions of the samples. These results indicate that plasma IL-1beta binding capacity differs between men and women and that sIL-1RII is a major contributing factor. Furthermore, relating plasma IL-1 isoform immunoreactivity to functional measures (tracer binding) or concurrent release by isolated cells can lead to insights about assay interferences that may exist in plasma.

Blood Proteins↗
PubMed1998

Cytokines in exertion-induced skeletal muscle injury.

Cytokines are a diverse family of intercellular signaling proteins that influence the movement, proliferation, differentiation, metabolism and membrane processes of target cells. Synthesis and release of cytokines from leukocytes in response to microbial stimuli are well known. This review, however, will present evidence that non-infectious stimuli can induce cytokine secretion from leukocytes and other cells (including muscle cells) following myocellular injury. The biological actions and potential adaptive values of these cytokines through the course of muscle necrosis and regeneration will be described.

Cell Differentiation↗
PubMed1998

Hormonal influences on stress-induced neutrophil mobilization in health and chronic fatigue syndrome.

This investigation tested the hypotheses that women diagnosed with chronic fatigue syndrome (CFS) would exhibit significantly greater systemic indices of exercise-induced leukocyte mobilization and inflammation (neutrophilia, lactoferrin release, complement activation) than controls matched for age, weight, and habitual activity and that responses in the luteal phase of the menstrual cycle would be greater than in the follicular phase. Subjects stepped up and down on a platform adjusted to the height of the patella for 15 min, paced by metronome. Blood samples were collected under basal conditions (the day before exercise) and following exercise for determination of circulating neutrophils and plasma concentrations of lactoferrin, C3a des arg, and creatine kinase. Complete, 24-hr urine collections were made for determination of cortisol excretion. For all subjects, circulating neutrophil counts increased 33% (P < 0.0001) and lactoferrin increased 27% (P = 0.0006) after exercise, whereas plasma C3a des arg and creatine kinase did not increase. No indication of an exaggerated or excessive response was observed in the CFS patients compared to the controls. In healthy women, circulating neutrophil numbers exhibited previously described relationships with physiological variables: basal neutrophil counts correlated with plasma progesterone concentrations (R = 0.726, P = 0.003) and the exercise-induced neutrophilia correlated with both urinary cortisol (R = 0.660, P = 0.007) and plasma creatine kinase (R = 0.523, P = 0.038) concentrations. These relationships were not observed in the CFS patients (R = 0.240, P = 0.370; R = 0.042, P = 0.892; and R = 0.293, P = 0.270; respectively). These results suggest that normal endocrine influences on the circulating neutrophil pool may be disrupted in patients with CFS.

Cell Count↗
PubMed1998

The transferrin receptor expressed by gonococcal strain FA1090 is required for the experimental infection of human male volunteers.

Iron, an essential nutrient for most microorganisms, is sequestered by the host to decrease the concentration of iron available to bacterial pathogens. Neisseria gonorrhoeae, the causative agent of gonorrhoea, can acquire iron by direct interaction with human iron-binding proteins, including the serum glycoprotein, transferrin. Iron internalization from host transferrin requires the expression of a bacterial receptor, which specifically recognizes the human form of transferrin. Two gonococcal transferrin-binding proteins have been implicated in transferrin receptor function, TbpA and TbpB. We constructed a gonococcal transferrin receptor mutant without the introduction of additional antibiotic resistance markers and tested its ability to cause experimental urethritis in human male volunteers. The transferrin receptor mutant was incapable of initiating urethritis, although the same inoculum size of the wild-type parent strain, FA1090, causes urethritis in >90% of inoculated volunteers. To our knowledge, this is the first experimental demonstration that a bacterial iron acquisition system is an essential virulence factor for human infection.

Genes, Bacterial↗
PubMed1997

Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome.

Chronic fatigue syndrome is a condition that affects women in disproportionate numbers, and that is often exacerbated in the premenstrual period and following physical exertion. The signs and symptoms, which include fatigue, myalgia, and low-grade fever, are similar to those experienced by patients infused with cytokines such as interleukin-1. The present study was carried out to test the hypotheses that (1) cellular secretion of interleukin-1 beta (IL-1 beta), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-1 receptor type II (IL-1sRII) is abnormal in female CFS patients compared to age- and activity-matched controls; (2) that these abnormalities may be evident only at certain times in the menstrual cycle; and (3) that physical exertion (stepping up and down on a platform for 15 min) may accentuate differences between these groups. Isolated peripheral blood mononuclear cells from healthy women, but not CFS patients, exhibited significant menstrual cycle-related differences in IL-1 beta secretion that were related to estradiol and progesterone levels (R2 = 0.65, P < 0.01). IL-1Ra secretion for CFS patients was twofold higher than controls during the follicular phase (P = 0.023), but luteal-phase levels were similar between groups. In both phases of the menstrual cycle, IL-1sRII release was significantly higher for CFS patients compared to controls (P = 0.002). The only changes that might be attributable to exertion occurred in the control subjects during the follicular phase, who exhibited an increase in IL-1 beta secretion 48 hr after the stress (P = 0.020). These results suggest that an abnormality exists in IL-1 beta secretion in CFS patients that may be related to altered sensitivity to estradiol and progesterone. Furthermore, the increased release of IL-1Ra and sIL-1RII by cells from CFS patients is consistent with the hypothesis that CFS is associated with chronic, low-level activation of the immune system.

Adult↗