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Biomedical subjects

R W Kelly

Publications and source records attributed to R W Kelly.

At least 55 records · Page 3Linked to original sources
PubMed1997

Prostaglandins in primate semen: biasing the immune system to benefit spermatozoa and virus?

The levels of prostaglandins in human semen are many orders of magnitude higher than those found elsewhere in the body and semen contains 19-hydroxy PGE which has not been found in other tissues. The reason for the presence of these prostaglandins is now becoming apparent with the demonstration of powerful effects of PGE and 19-hydroxy PGE on the balance of cytokines (stimulating IL-10 and inhibiting IL-12) released by antigen presenting cells. The effects of the seminal prostaglandins will be two-fold. First, there will be cAMP mediated direct effect on T cells, inhibiting clonal proliferation, inhibiting natural killer cell function and biasing the CD4 cells to a T-helper-2 pattern of cytokine production away from one that would favour a cell-mediated response. Second, and perhaps the major effect, is at the level of the antigen presenting cell that will reinforce the direct effects and induce a tolerance of antigens that are presented together with the IL-10, or PGE. Such tolerance might be necessary for the survival of the spermatozoa under adverse conditions, for instance, in the presence of infection Viruses and other invading organisms would also benefit from this switch in cytokines and the inhibition of the cell-mediated defences. Particular concerns are human immunodeficiency virus (HIV) and human papilloma virus (HPV) which can be transmitted in semen. Not only will the initial immune response be affected, but also repeated exposure to semen will reduce immunesurveillance and the removal of virally infected cells.

Animals↗
PubMed1997

A cytokine switch induced by human seminal plasma: an immune modulation with implications for sexually transmitted disease.

The immunosuppressive activity of human seminal plasma may be one factor in the aetiology of sexually transmitted disease and could be particularly important for the spread of human immunodeficiency virus (HIV). The advent of virus that can preferentially infect Langerhans cells of the genital mucosa underscores the relevance of seminal plasma effects. Virally infected cells are eradicated by the killing activity of T cells and natural killer (NK) cells and this cytotoxicity is stimulated by IL-12 (previously known as natural killer cell stimulatory factor) and partly inhibited by IL-10 (previously known as cytokine synthesis inhibitory factor). We have examined the effects of human seminal plasma on the production of these key cytokines. Cytokine production was measured in rapidly diluted, fresh, lipopolysaccharide (LPS)-stimulated, whole blood since this provided leukocytes with minimal exposure to prostaglandin. Prostaglandin concentrations and cytokine release were measured by ELISA. Addition of human seminal plasma diluted up to 100,000 times (0.001%) to blood cell cultures led to a marked increase in the IL-10/IL-12 ratio (P <0.02). A dose-dependent increase in the ratio was observed in five separate experiments, from a control value of 1 (no seminal plasma) to a mean value of 80 (1% seminal plasma). This cytokine switch was also seen when seminal plasma was substituted by pure prostaglandin E (PGE) and 19-OH PGE (the main prostaglandin constituent of human seminal plasma). Lipid-extracted seminal plasma was considerably less active at high dilutions than whole seminal plasma at the same dilution. However, its activity could be restored by the addition of synthetic PGE and 19-hydroxy PGE. A stimulation of IL-10 and a decrease in IL-12 in host-defence cells of the lower female reproductive tract will seriously affect the ability of cytotoxic T cells and NK cells to recognise and destroy virally infected cells. In addition, the stimulation of IL-10 will inhibit the release of the anti-HIV activity from CD8+ve cells. The cytokine switch reported here, activated by semen deposition, would exercise a key inhibitory control over vital immune defences in the lower genital tract, with ablation of cell-mediated responses and immunosurveillance.

Female↗
PubMed1997

Chemokine and cyclooxygenase-2 expression in human endometrium coincides with leukocyte accumulation.

The endometrium contains a resident population of leukocytes, the number and subtype of which vary throughout the menstrual cycle and in early pregnancy. Factors controlling these fluctuations are unknown, but a combination of proliferation in situ and migration from the vasculature has been proposed. Locally acting inflammatory mediators, including specific chemokines and prostaglandins, have been implicated in these processes. Interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) are potent chemoattractants and activators for neutrophils and monocytes respectively. Locally acting prostaglandins modulate vascular permeability, and a synergistic action of prostaglandin E (PGE) with IL-8 has been described. In the present study IL-8, MCP-1 and cyclooxygenase-2 (COX-2), the inducible isoform of prostaglandin synthase, were all localized in the endometrium by immunohistochemistry throughout the menstrual cycle and in early pregnancy. All three inflammatory mediators were localized to the perivascular cells of blood vessels in endometrium and decidua, and additional immunoreactivity for COX-2 was identified in the glandular epithelium. The intensity of immunostaining was reduced in the periovulatory, early and mid-secretory phases and significantly increased premenstrually. These results further support the hypothesis that there is a premenstrual migration of leukocytes into the endometrium mediated by chemokines.

Chemokine CCL2↗
PubMed1997

Immunomodulation by human seminal plasma: a benefit for spermatozoon and pathogen?

The immunosuppressive effect of human seminal plasma and its implications for sperm survival are reviewed. Human semen contains high concentrations of prostaglandins that can effect a cytokine-mediated switch away from a cell-mediated immune response. This effect on antigen presenting cells would induce a state of non-responsiveness to sperm antigens in the female reproductive tract. It is postulated that the induction of anergy to sperm antigen may be fundamental to the continuing fecundity of the individual. However, although this immune system modulation will benefit the spermatozoa, the response to infective agents present in semen will also be affected, which may play a critical role in the aetiology and progress of sexually transmitted disease.

Animals↗
PubMed1996

The ontogeny of key endoplasmic reticulum proteins in human embryonic and fetal red blood cells.

Recently, using immunohistochemical methods, we surprisingly found that endoplasmic reticulum glucose-6-phosphatase is present in human embryonic and fetal red blood cells (RBCs) but not in adult RBCs. The fact that an endoplasmic reticulum enzyme, whose major site of expression in adults is the liver, is present in human embryonic and fetal RBCs, particularly nucleated cells, indicated that it would be sensible to determine whether these cells also contain other endoplasmic reticulum enzyme systems normally found in adult liver. Therefore, we have studied the expression of other endoplasmic reticulum proteins and found that human embryonic and fetal RBC precursors contain other protein components of the glucose-6-phosphatase system, ie, the phosphate and glucose transport proteins as well as other enzymes (eg, uridine diphosphate-glucuronosyltransferases, cytochrome P450 isozymes, nicotinamide adenine dinucleotide phosphate cytochrome P450 oxidoreductase, and prostaglandin H synthase). In addition, we also found the predominantly cytosolic markers 15-hydroxyprostaglandin dehydrogenase, prostaglandins PGE2 and 13,14-dihydro-15-keto-PGE2. The expression of key enzymes that control glucose production, detoxification of endobiotics and xenobiotics, and the regulation of prostaglandin levels in embryonic and early fetal RBCs means that these cells may have an important role in protecting the developing conceptus before it establishes an efficient circulation and before all tissues fully express their normal complement of these enzymes.

Adult↗
PubMed1996

The effects of post-ovulatory administration of onapristone on the developmnent of a secretory endometrium.

The purpose of this study was to assess the ability of the anti-progestin onapristone administered in the immediate post-ovulatory period to disrupt endometrial differentiation as a potential method of fertility control. In all, 10 healthy female volunteers were given 400 mg onapristone 2 days after the mid-cycle luteinizing hormone (LH) surge in urine (LH+2). An endometrial biopsy was taken 4 or 6 days after the LH surge (i.e. LH+4 or LH+6) in a control cycle and on the corresponding day of the treatment cycle. Biopsies were assessed for histological dating and immunolocalization of oestrogen receptors, progesterone receptors and 15-hydroxyprostaglandin dehydrogenase (PGDH). On day LH+12, blood was taken for the measurement of insulin-like growth factor binding protein-1 (IGFBP-1) and placental protein 14 (PP14). Hormonal measurements in blood and urine were used to monitor the effects on the menstrual cycle. In addition, the concentration of cortisol in plasma was measured to determine if this dose of onapristone exerted significant anti-glucocorticoid activity. Treatment with onapristone retarded the development of secretory changes within the endometrium without affecting the length of the luteal phase. Intense nuclear immunostaining of oestrogen and progesterone receptors was evident in glands and stroma after treatment, suggesting that the progesterone-dependent down-regulation of steroid receptors was inhibited by the anti-progestin. Onapristone also affected the production of luteal phase endometrial proteins, as judged by the pronounced reduction in immunostaining of PGDH within the glands and the significant reduction in plasma concentrations of PP14. However, plasma concentrations of IGFBP-1 did not differ between cycles. Onapristone did not appear to exert significant anti-glucocorticoid activity because concentrations of cortisol were unaffected. These findings suggest that onapristone could potentially be used as a method of postovulatory fertility control.

Adult↗
PubMed1996

Sex steroid regulation of leukocyte traffic in human decidua.

Endometrial leukocyte subpopulations vary over the reproductive cycle, but no data exist on the mechanism regulating their recruitment into uterine tissue. This study has evaluated the role of progesterone in the recruitment of selected leukocyte populations in early pregnancy decidua. Decidua was collected from women in early pregnancy at the time of vacuum aspiration of the uterus 6, 12, 24 and 36 h after taking 200 mg mifepristone (RU486). Standard immunohistochemical techniques were employed to demonstrate the selected leukocyte populations in decidual tissue and these were analysed using imaged analysis. Fresh decidua was incubated in medium for 24 h and supernatants assayed for interleukin (IL-8) (neutrophil chemotactic factor) and MCP-1 (monocyte chemoattractant protein-1) content. Analysis of variance demonstrated a significant increase in tissue monocyte number in decidua 12-36 h after mifepristone administration. No significant changes in other leukocyte subpopulations were observed. Decidua IL-8 concentrations were significantly increased (P = 0.019) 6 h after mifepristone and decidual MCP-1 concentration rose (non-significant) and fell significantly (P = 0.029) between 6 and 12 h after mifepristone. Progesterone withdrawal may initiate a local cascade of events involving inflammatory mediators which in turn are responsible for the influx of monocytes. This influx may be essential in the process of shedding of endometrium or decidua since monocytes and neutrophils are important sources of proteases and collagenases. Furthermore, these cells are potential local sources of immunomodulatory cytokines.

Decidua↗
PubMed1996

Inflammatory mediators and parturition.

A role for inflammatory mechanisms in ovulation and parturition has been proposed on many occasions. In addition, many agents directly implicated in parturition, such as cytokines and prostaglandins, can be pro-inflammatory. The cervix can be softened and labour induced in women by mechanical trauma (sweeping the membranes), prostaglandins, antiprogestins or chemokines such as interleukin 8 (IL-8). This review presents evidence that invading cells, such as neutrophils, may be involved in the softening of the cervix and the onset of birth, and describes pathways in which this action can be controlled by cytokines and vasodilatory agents such as prostaglandins. Such mechanisms may, in turn, be controlled by steroids. The role of progesterone is enigmatic since progesterone concentrations do not fall in the peripheral circulation of women at the time of birth and yet antiprogestins soften the cervix in a manner indistinguishable from that seen during parturition. Prostaglandin E (PGE) can be both pro-inflammatory and anti-inflammatory, the former action probably occurs at the level of the blood vessel, whereas the latter is associated with the change in cytokine profile induced by PGE. This latter effect may contribute to pregnancy maintenance by maintaining a favourable cytokine profile in decidua. In contrast, the pro-inflammatory action of PGE may be involved in a synergistic action with chemokines such as IL-8 and play a role in parturition. In early pregnancy decidua, this pro-inflammatory action is likely to be controlled by progesterone-dependent prostaglandin dehydrogenase associated with the small blood vessels in decidua.

Animals↗
PubMed1996

Altered urinary interleukin-8/creatinine ratio in peptic ulcer disease: pathological and diagnostic implications.

OBJECTIVES AND METHODS: To assess its clinicopathological and diagnostic significance, interleukin-8 (IL-8) was measured by radioimmunoassay in fasting urine specimens and in gastric mucosal incubates taken from 54 patients with dyspepsia. The presence of Helicobacter pylori, the activity of gastritis, and urine creatinine levels were also assessed. RESULTS: The median urinary IL-8/creatinine ratio was 0.1 x 10(-6) in patients with current peptic ulcers (n = 13) and 0.2 x 10(-6) in patients with a history of ulcers (n = 8), compared with 0.4 x 10(-6) (p < 0.0001) in patients without ulcers who were infected with H. pylori (n = 20) or not infected (n = 13). The activity of gastritis had a positive correlation with gastric IL-8 (r = 0.5870, p < 0.01) and a negative correlation with urinary IL-8/creatinine ratio (r = -0.6447, p < 0.005). The improvement in the activity of gastritis in 20 patients given anti-H. pylori triple therapy was associated with a significant fall in gastric mucosal IL-8 and a rise in urinary IL-8/creatinine ratio. CONCLUSIONS: An inverse relationship seems to exist between urinary IL-8 and the activity of gastritis and gastric IL-8. This may represent another concept in the pathogenesis of peptic ulcers and can assist in the noninvasive diagnosis of peptic ulcer disease.

Adult↗
PubMed1995

Gender influences on earnings of obstetrician-gynecologists.

OBJECTIVE: To test the hypothesis that the observed difference in earnings between male and female obstetrician-gynecologists could be explained by variations in productivity and human capital. METHODS: Data from a 1991 national survey of ACOG Fellows were used to provide a descriptive analysis of male and female obstetrician-gynecologists' demographic characteristics, net income, experience, practice characteristics, workload, and practice activities. Variables found to have a significant impact on net income or to vary significantly by sex were included in a multiple regression analysis. RESULTS: Twenty-one percent of the 1286 survey respondents were female obstetrician-gynecologists. Women were almost twice as likely as men to be in salaried positions (P < .001) and more than twice as likely to have less than 10 years of experience (P < .001). Women reported fewer annual patient-contact hours (P < .05) and performed fewer than half as many hysterectomies (P < .001). Average annual earnings for women were 71% of men's annual net income (P < .001). The multivariate regression analysis found that male-female differences in the factors included in the analysis (ie, workload, experience, practice type) resulted in an 18.7% male-female income gap. The analysis also revealed an income gap of 14.2% that was not accounted for by differences in the objective factors included in the model. CONCLUSION: More than half of the overall male-female income gap was explained by differences in personal and practice characteristics. However, female obstetrician-gynecologists earned 14.2% less than men, after controlling for variations in productivity and human capital.

Adult↗
PubMed1995

Immunomodulatory effects of extracellular secretory vesicles isolated from bovine semen.

We demonstrate that extracellular secretory vesicles isolated from bovine seminal plasma have immunomodulatory properties. They inhibit mitogen induced proliferation of bovine and human peripheral blood lymphocytes in a dose dependent fashion. They also inhibit phagocytosis of latex particles by bovine neutrophils. Phagocytosis of opsonised Staphylococcus aureus however was not affected. Furthermore phorbol ester and chemotactic peptide induced superoxide production was decreased especially when a suboptimal dose of stimulants was used. We suggest that extracellular secretory vesicles may preserve sperm survival in the female reproductive tract.

Animals↗
PubMed1995

Prostaglandin and cytokine release by trophoblastic villi.

Trophoblastic villi may have several protective mechanisms against the maternal immune system. They do not display major human leukocyte antigen antigens, and therefore a T cell-mediated response is unlikely. The syncytiotrophoblast provides a seamless coating, and the microvilli on its surface represent a very large surface area which has a high capacity for absorbing antibody. The syncytiotrophoblast also contains inhibitors of complement. Although these mechanisms are essential, they may not be sufficient protection. An additional mechanism by which the trophoblast could control its immediate environment in the decidua or maternal blood may be through the release of prostaglandins (PG) and cytokines. This possibility has been investigated here by measuring PG and several cytokines released from first trimester trophoblastic villi cultured for 24 h. PGE is the main primary prostaglandin with a release of 240 +/- 95 pg/mg/24 h. There was an extensive accompanying production of metabolites (13,14-dihydro-15-keto PGF, 2.4 +/- 0.4 ng/mg/24 h, and 13,14-dihydro-15-keto PGE, 0.61 +/- 0.11 ng/mg/24 h). Cytokines were measured in culture fluid by specific enzyme-linked immunosorbent assays. Interleukin (IL)-2 and IL-10 release were not detectable, but IL-1 beta (5.2 +/- 1.1 pg/mg/24 h) and tumour necrosis factor (TNF) alpha (2.3 +/- 0.5 pg/mg/24 h) were found to be accompanied by much higher concentrations of inhibitors, IL-1 receptor antagonist (200 +/- 44 pg/mg/24 h) and soluble receptors for TNF types I (19.5 +/- 1.6 pg/mg/24 h) and II (19.3 +/- 2.8 pg/mg/24 h). Because PGE can influence the function of many leukocytes by raising intracellular cAMP concentrations, the release of humoral factors from the villous trophoblast might be important in pregnancy maintenance.

Chorionic Villi↗
PubMed1995

Immunosuppressive mechanisms in semen: implications for contraception.

The immunosuppressive effects of human seminal plasma are mediated by several factors. The prostaglandins (PG) of the E series (PGE and 19-hydroxy PGE) predominate and raise intracellular cAMP in leukocytes. By this mechanism they suppress lymphocyte proliferation, natural killer (NK) cell activity and are likely to modify cytokine release from antigen presenting cells (APC). In this way, acquired and innate responses (including immune surveillance) in the reproductive tract will be curtailed, at least temporarily, after intercourse. Semen contains several inhibitors of complement and a unique reservoirs of CD59, a major complement inhibitor, is found on the prostasomes which are sub-micron organelles with lipid membranes. The prostasomes also inhibit lymphocyte proliferation and the activity of phagocytic cells. Other suppressive agents are also present in semen and may exert specific effects, for example, transforming growth factor-beta which may inhibit primed responses to antigen, and receptors for Fc fraction of gamma-globulin which might bind inflammatory agents. A thesis is proposed that the balance between maximum chances of survival for spermatozoa and minimum chances for micro-organisms has been disturbed by an increased use of non-barrier contraception, an increase in population mobility and sexual contact and the arrival of new diseases such as AIDS. A further major concern is that following infection of cells of the cervix with virus, repeated exposure to human seminal plasma may accelerate the progression of disease.

Complement System Proteins↗
PubMed1995

Changes in urinary cytokines and soluble intercellular adhesion molecule-1 (ICAM-1) in bladder cancer patients after bacillus Calmette-Guérin (BCG) immunotherapy.

Intravesical immunotherapy for carcinoma in situ of the bladder is arguably the most effective form of tumour immunotherapy described to date. Following repeated instillations of BCG organisms into the bladder, large quantities of cytokines are detected in patients' urine. This study concerns the production of IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and soluble ICAM-1 (sICAM-1) throughout the six weekly instillations which comprise a therapeutic course. Sequential instillations of BCG induced secretion of IL-1 beta, IL-2, IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma and sICAM-1 into urine. The responses were heterogeneous between patients and cytokines, but some general trends were evident. Although cytokine levels were initially low, their concentration increased with repeated instillation of BCG. Certain cytokines (e.g. IL-6, IL-8 and IL-10) could be detected after the first instillation, whilst others (e.g. IL-2 and IFN-gamma) were not detected until after the third or fourth instillation. Interestingly, IL-4 was not detected, perhaps suggesting a differential effect on Th2-like responses. Some patients produced particularly elevated or non-detectable levels of cytokines, and a positive correlation was found between the production of various cytokines. The production of a particular cytokine did not correspond with lack of production of another species. Whether monitoring the production of cytokines following therapy may be of prognostic value will be determined in a larger series of patients. However, as these potent immunomodulators are thought to be important for the 75% complete clinical response observed with BCG therapy, there remains the possibility that detection of the products of an activated immune system may correlate with eventual clinical outcome. This study is a necessary forerunner to full prognostic evaluation of such immunological data.

BCG Vaccine↗
PubMed1995

Changes in prostaglandin synthesis and metabolism associated with labour, and the influence of dexamethasone, RU 486 and progesterone.

The objective was to compare the changes in prostaglandin synthesis and metabolism occurring within the fetal membranes that are associated with the onset of parturition and to study the effect of steroid hormones on prostaglandin metabolism. A tissue explant study was made of discs of amnion and chorion obtained from 24 pregnant women at 37-42 weeks' gestation following spontaneous labour and delivery (12 women) and elective caesarean section (12 women). Significantly more prostaglandin E2 (PGE2) and PGF2 alpha were synthesized by amnion obtained following spontaneous labour than elective caesarean section. Arachidonic acid stimulated both PGE2 and PGF2 alpha synthesis by amnion in both groups. Phorbol myristoyl acetate stimulated PGE2 synthesis in both groups. There was no difference between the groups in the capacity of the chorion to metabolize prostaglandins. Mifepristone (RU 486) reduced the metabolism of added PGE2 following spontaneous labour, while dexamethasone and progesterone had no effect on prostaglandin metabolism. In conclusion, the increase in concentration of PGE2 and PGF2 alpha associated with the onset of spontaneous labour is the result of an increase in synthesis rather than a reduction in metabolism. There was no decrease in metabolism to account for the increase in prostaglandin concentrations and, with the exception of mifepristone, metabolism was not altered by the addition of steroid hormones.

Amnion↗
PubMed1994

Lipid peroxidation and prostaglandins in colorectal cancer.

Dietary fat, arachidonic acid metabolism and lipid peroxidation have all been implicated in colorectal carcinogenesis. Fatty acids, prostaglandins (PGE2, PGF2 alpha) and malondialdehyde (MDA), the stable end-product of lipid peroxidation of polyunsaturated fatty acids (PUFAs), were studied in paired tumour and normal mucosa of 20 patients with colorectal cancer. Levels of arachidonic acid and total PUFAs were increased in the phospholipid fraction of tumours (P < 0.05). Levels of PGE2 and MDA were also higher in tumours (P < 0.001) and there was a significant correlation between MDA and PGE2 concentrations (rs = 0.69, P < 0.01). In contrast to previously reported in vitro studies, this work suggests that lipid peroxidation may be enhanced in human colorectal tumours. As PGE2 and MDA have been shown to be involved in carcinogenesis, these may be considered potential therapeutic targets for preventing or treating colorectal carcinoma.

Aged↗
PubMed1994

Catecholamine response to ultrasonographically guided percutaneous blood sampling in fetal sheep.

OBJECTIVE: The purpose of this study was to investigate the fetal catecholamine and arterial blood gas responses to ultrasonographically guided percutaneous needle aspiration of blood from a fetal cardiac ventricle. STUDY DESIGN: A crossover trial design was used. Nine pregnant sheep of 120 to 130 days' gestation were stratified to either percutaneous fetal blood sampling or a sham experiment performed on the first day, and the alternative study on the following day. Arterial blood samples were withdrawn from chronically implanted catheters. RESULTS: Percutaneous fetal blood sampling caused small but statistically significant increases in mean plasma epinephrine and norepinephrine levels 5 seconds after the procedure. Levels thereafter were similar to baseline values. Arterial pH and PCO2 values were unaltered except in one fetus, where blood sampling was followed by bradycardia with acidosis and elevated catecholamine levels. CONCLUSIONS: Ultrasonographically guided percutaneous fetal blood sampling from a cardiac ventricle in sheep produces a rise in catecholamine levels that return to baseline values within 5 minutes. This technique provides an alternative to chronic catheterization for some experiments in which blood sampling or drug injection is required. The results also indicate that needle insertion produces only a modest and transient stress response in the fetus.

Animals↗