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Biomedical subjects

I T Cameron

Publications and source records attributed to I T Cameron.

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

Randomised comparative trial of the levonorgestrel intrauterine system and norethisterone for treatment of idiopathic menorrhagia.

OBJECTIVE: To compare the efficacy and acceptability of the levonorgestrel intrauterine system and norethisterone for the treatment of idiopathic menorrhagia. DESIGN: A randomised comparative parallel group study. SETTING: Gynaecology outpatient clinic in a teaching hospital. PARTICIPANTS: Forty-four women with heavy regular periods and a measured menstrual blood loss exceeding 80 ml. METHODS: Twenty-two women had a levonorgestrel intrauterine system inserted within the first seven days of menses, and 22 women received norethisterone (5 mg three times daily) from day 5 to day 26 of the cycle for three cycles. MAIN OUTCOME MEASURES: The main outcome measure was the change in objectively assessed menstrual blood loss after three months of treatment. RESULTS: When menstrual blood loss at three months was expressed as a percentage of the control, the levonorgestrel intrauterine system reduced menstrual blood loss by 94% (median reduction 103 ml; range 70 to 733 ml), and oral norethisterone by 87% (median reduction 95 ml; range 56 to 212 ml). After three cycles of treatment 76% of the women in the levonorgestrel intrauterine system group wished to continue with the treatment, compared with only 22% of the norethisterone group. CONCLUSIONS: Both the levonorgestrel intrauterine system and oral norethisterone in this regimen provided an effective treatment for menorrhagia in terms of reducing menstrual blood loss to within normal limits. The levonorgestrel intrauterine system was associated with higher rates of satisfaction and continuation with treatment, and thus offers an effective alternative to currently available medical and surgical treatments for menorrhagia.

Adult↗
PubMed1998

Corticotropin-releasing hormone and proopiomelanocortin-derived peptides are present in human myometrium.

CRH and POMC-derived peptides are produced at a number of intrauterine sites in both the nonpregnant and pregnant states. It is hypothesized that CRH and POMC-derived peptides may be produced locally by the uterus to modulate myometrial contractility. This study has examined the distribution of these peptides in human uterine tissue during the ovulatory cycle and pregnancy. The immunoperoxidase staining method was used to localize CRH and POMC-derived peptides: ACTH, beta-endorphin, and alphaMSH. Immunoreactive (IR-) CRH and IR-POMC-derived peptides, beta-endorphin and alphaMSH, were observed in the myometrial smooth muscle, vascular smooth muscle, endometrial glandular epithelium, and luminal epithelium of the nonpregnant uterus (n = 17). Staining for IR-CRH did not change during the cycle from the proliferative (n = 8) to the secretory phases (n = 9). Conversely, staining for IR-beta-endorphin and IR-alphaMSH was only observed during the secretory phase of the cycle (n = 9). In uterine tissue obtained from pregnant women (n = 20) IR-CRH was present in the myometrial smooth muscle, vascular smooth muscle, decidua, and glandular epithelium. IR-POMC-derived peptides were not detectable at any uterine site during pregnancy (n = 20). IR-CRH was measurable in myometrial extracts collected from pregnant women undergoing cesarean section (20.9+/-3.8 ng/g wet wt; n = 7) and from nonpregnant premenopausal women undergoing hysterectomy (7.7+/-2.1 ng/g wet wt; n = 6). IR-CRH concentrations significantly increased with pregnancy. Levels of messenger ribonucleic acid encoding for CRH were examined in nonpregnant (n = 4) and pregnant (n = 10) myometrial smooth muscle and were also significantly increased with pregnancy. This study has demonstrated that levels of CRH and POMC peptide in human uterine tissue change with pregnancy and that CRH is produced locally by myometrial smooth muscle cells. These studies are consistent with the possibility that the CRH peptide has an autocrine/paracrine activity during pregnancy and labor that may be related to the modulation of myometrial contractility.

Corticotropin-Releasing Hormone↗
PubMed1997

Expression of superoxide dismutase and xanthine oxidase in myometrium, fetal membranes and placenta during normal human pregnancy and parturition.

Superoxide, an agent which attenuates the half-life of nitric oxide, is metabolized and synthesized by superoxide dismutase (SOD) and xanthine oxidase, respectively. Over the last few years much work has focused on the role of nitric oxide in human parturition. The aim of this study was to determine whether the onset of human parturition is associated with a change in the expression of copper/zinc superoxide dismutase (Cu/Zn SOD), manganese superoxide dismutase (Mn SOD) or xanthine oxidase within the uterus. Samples of myometrium, placenta, decidua and fetal membranes were obtained from women before and after the onset of labour at term. Immunocytochemistry was used to localize Cu/Zn SOD, Mn SOD and xanthine oxidase and measure SOD enzyme activity. Cu/Zn and Mn SOD-like immunoreactivity was detected in syncytiotrophoblast cells, villous stromal cells and endothelial cells of blood vessels in the placenta. In the myometrium Cu/Zn and Mn SOD were localized to myocytes and endothelial cells and to some vascular smooth muscle cells. In the fetal membranes we observed staining for Cu/Zn SOD and Mn SOD in the amnion, chorion, extravillous trophoblast and decidua. There was no difference in SOD enzyme activity or staining intensity for SOD between different cell types before and during labour. Xanthine oxidase immunoreactivity was identified in each of the tissues examined and again there was no difference in immunostaining in tissues obtained from women delivered before or after the onset of labour. These results show that the pregnant uterus is capable of both synthesizing and degrading superoxide and suggest that superoxide dismutase and xanthine oxidase may play a role in the maintenance of uterine quiescence during pregnancy, but not in the initiation of parturition.

Antibodies, Monoclonal↗
PubMed1997

Nitric oxide synthase activity and localization do not change in uterus and placenta during human parturition.

Animal studies have suggested that nitric oxide, a smooth muscle relaxant, is a fundamental mediator in the initiation of parturition. The purpose of this study was to test the hypothesis that the onset of human labour is associated with a reduction in the activity of the enzyme nitric oxide synthase (NOS), within the uterus. Samples of myometrium, placenta, decidua and fetal membranes were collected during Caesarean section from 11 women before and 11 women after the onset of labour at term. Immunocytochemistry was used to localize each of the three isoforms of NOS (endothelial NOS, brain NOS, and inducible NOS) in each of these tissues and the intensity of staining was qualitatively assessed. NOS enzyme activity was determined in homogenates of frozen myometrium, placenta and fetal membranes (with attached decidua), by measuring conversion of radio-labelled L-arginine to L-citrulline. Each of the three isoforms of NOS was localized in each of the tissues. We found no difference in either the expression or enzyme activity of NOS in myometrium, placenta or fetal membranes before and during labour at term. These results suggest that, in contrast to animal studies, a decrease in NOS enzyme activity may not be involved in the onset of parturition at term in the human.

Enzyme Activation↗
PubMed1997

Expression of endothelial and inducible nitric oxide synthase in non-pregnant and decidualized human endometrium.

Immunocytochemistry was used to localize endothelial (eNOS) and inducible (iNOS) nitric oxide synthase in human uterine tissues collected at various stages of the menstrual cycle, after exposure to exogenous progestagens, and in early pregnancy. Endothelial NOS-like immunoreactivity was detected in all specimens in endothelial cells lining blood vessels in the myometrium and endometrium, and in endometrial glandular epithelial cells. Inducible NOS-like immunoreactivity was also demonstrated in glandular epithelial cells. For both eNOS and iNOS there was considerable variation in the intensity of epithelial cell staining between samples, which was not related to the stage of the menstrual cycle at which the tissue was collected. Messenger RNA for eNOS and iNOS was detected by reverse transcription-polymerase chain reaction (RT-PCR) using total RNA purified from isolated endometrial gland fragments. Immunoreactivity for eNOS and iNOS was not present in endometrial stroma throughout the menstrual cycle, but iNOS-like immunoreactivity was seen in decidualized stromal cells both following treatment with exogenous progestagen (intrauterine L-norgestrel) and in tissues obtained in the first trimester of pregnancy. The detection of protein and mRNA for eNOS and iNOS in normal human endometrium suggests that NO may play a role in the local control of endometrial function.

Decidua↗
PubMed1997

Nitric oxide donors induce ripening of the human uterine cervix: a randomised controlled trial.

OBJECTIVE: To determine whether nitric oxide donors can induce cervical ripening before surgical termination of pregnancy in the first trimester. DESIGN: Prospective, randomised controlled trial. SETTING: Department of Obstetrics and Gynaecology, Royal Infirmary, Glasgow. PARTICIPANTS: Forty-eight primigravid women undergoing surgical termination of pregnancy before 12 weeks of gestation. METHODS: The women were randomised to receive per vaginam before surgery either the nitric oxide donor isosorbide mononitrate, the nitric oxide donor glyceryl trinitrate, the prostaglandin analogue gemeprost, or no treatment. MAIN OUTCOME MEASURES: The cumulative force required to dilate the cervix to 8 mm was measured objectively and the cervical diameter before surgical dilatation was recorded. RESULTS: Following isosorbide mononitrate or gemeprost, a lower cumulative force was required to dilate the cervix to 8 mm and a higher cervical diameter before dilatation was recorded. Pretreatment with glyceryl trinitrate reduced the cumulative force required to dilate the cervix but had no effect on cervical diameter. CONCLUSIONS: Like the prostaglandin analogue gemeprost, the nitric oxide donors isosorbide mononitrate and glyceryl trinitrate can effect cervical ripening. Nitric oxide donors may provide an alternative to prostaglandins for cervical ripening before surgical procedures in the first trimester.

Abortifacient Agents, Nonsteroidal↗
PubMed1997

Effects of cGMP and the nitric oxide donors glyceryl trinitrate and sodium nitroprusside on contractions in vitro of isolated myometrial tissue from pregnant women.

The purpose of this study was to determine the relaxant effects in vitro of two nitric oxide donors, glyceryl trinitrate and sodium nitroprusside, which are currently available for use in vivo, on contractions of non-labouring myometrium from pregnant women. Since nitric oxide also mediates relaxation by increasing the concentration of cGMP, sensitivity to 8-bromo-cGMP (a cGMP analogue) was also determined. The effects of the K(+)-channel opener lemakalim and of the Ca(2+)-channel blocker nifedipine were studied for comparison. After the addition of glyceryl trinitrate (0.1-100 mumol l-1), sodium nitroprusside (0.1-100 mumol l-1) or 8-bromo-cGMP (0.001-3 mmol l-1), the spontaneous rhythmic contractility of myometrial strips was inhibited in a concentration-dependent manner: the maximum inhibition produced by the highest tested concentration of each drug was 40 +/- 7%, 53 +/- 8% and 39 +/- 8% of the original degree of contraction, respectively. Myometrial contractions were completely abolished by lemakalim and by nifedipine and verapamil at concentrations of > or = 10(-5) mol l-1. The nitric oxide donors, glyceryl trinitrate and sodium nitroprusside, attenuate myometrial contractions and are therefore useful as tocolytic agents. However, at equimolar concentrations in vitro, the ability of glyceryl trinitrate and sodium nitroprusside to attenuate myometrial contractions is less than that of lemakalin, nifedipine and verapamil. Controlled trials are required to determine the side-effects and clinical efficacy of each of these agents in vivo.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Localization of endothelin receptors in human uterus throughout the menstrual cycle.

Quantitative autoradiography employing the ETA selective ligand [125I]PD 151242 and the ETB selective ligand [125I]BQ3020 was used to assess the localization of ETA and ETB receptors in human uterus throughout the menstrual cycle. ETA and ETB receptors were present in endometrium and myometrium across the menstrual cycle. In myometrium, neither ETA nor ETB receptor density showed any detectable change across the menstrual cycle. ETA receptors were expressed in stroma throughout the endometrium and showed an increase in density in proliferative endometrium compared with secretory and menstrual endometrium. Endometrial ETB receptors were expressed at low density in the proliferative phase. In the early secretory phase there was an increase in ETB receptor density in the glandular epithelium of the basal region of the endometrium but not in functional endometrium. In the late secretory phase ETB receptor expression was increased in glandular epithelium throughout the endometrium. The highest density of ETB receptors was seen in menstrual endometrium, where they were present in stromal as well as epithelial cells. These results suggest that ovarian steroid hormones may play a role in the control of expression of ETA and ETB receptors in endometrial stromal and epithelial cells respectively.

Autoradiography↗
PubMed1996

Nitric oxide in the human uterus.

Nitric oxide (NO) plays a crucial role in many biological systems. Recent evidence indicates that NO is found in the human uterus. During pregnancy, it is produced in the placenta, the decidua and the myometrium. In the nonpregnant state, nitric oxide synthase, the enzyme that catalyses the production of NO, has been identified in both the myometrium and the endometrium. Potential roles for NO in the human uterus are speculative, but include vasodilatation (both before implantation, and in the uteroplacental and systemic circulation during pregnancy), inhibition of platelet activation during menstruation, and suppression of myometrial contractility during pregnancy. Nitric oxide may also be involved in uterine pathology. Excessive NO production by the uterus during menstruation could lead to menorrhagia. During pregnancy, a change in NO production may be implicated in pre-eclampsia, and animal studies have shown that inhibition of NO production leads to intrauterine growth retardation. If a role for NO is confirmed in these various uterine conditions, pharmacological modification of NO activity may lead to novel therapeutic applications. However, these notions are still conjectural, and extensive work is required before such treatments can be introduced into clinical practice.

Animals↗
PubMed1995

Endothelin expression in the uterus.

The endothelins (ETs) comprise a family of 21 amino acid peptides, ET-1, ET-2 and ET-3, first demonstrated as products of vascular endothelium. Subsequent work showed that they are also found in non-endothelial cells from a variety of tissues such as breast, parathyroid and adrenal gland. At first, the ETs were recognized for their pressor effects. However, ET administration in vivo initially caused hypotension at low concentrations by triggering the paracrine release of endothelial-derived vasodilators. The ETs exert powerful contractile actions on myometrium and other types of smooth muscle and are mitogenic, or co-mitogenic for fibroblasts, vascular smooth muscle and other cells. Demonstration of extravascular ET in endometrium has revealed a powerful vasoconstrictor which might act on the spiral arterioles to effect a powerful and sustained contraction of vascular smooth muscle. ETs might also contribute to the process of endometrial repair. In addition, the ETs appear to play a fundamental role in the control of uterine function in pregnancy. Effects on myometrial contractility have been implicated in the mechanisms governing the onset of normal and pre-term labour, and the peptides are likely to be key determinants of placental blood flow by binding to vascular smooth muscle receptors in the placenta.

Amino Acid Sequence↗
PubMed1995

Identification of nitric oxide synthase in human uterus.

The aim of this study was to investigate the presence of nitric oxide synthase (NOS) in human uterus. Tissues were obtained at operation from 10 women undergoing hysterectomy for benign disease. In-situ hybridization was used to determine the distribution of mRNA for NOS with a 483 bp digoxigenin-labelled antisense riboprobe. Localization of NOS was detected by (i) immunocytochemistry using a monoclonal antibody raised against bovine constitutive endothelial NOS, and (ii) NADPH diaphorase, which has been suggested to co-localize with brain NOS. Messenger RNA for NOS was detected in endometrium and myometrium from nine of 10 women, predominantly in endometrial glandular epithelium and stroma and myometrial blood vessels. NOS-like immunoreactivity was seen in endometrial stroma and myometrial blood vessels, whereas NADPH diaphorase activity was localized mainly to endometrial glandular epithelium and myometrial blood vessels. These studies suggest that different forms of constitutive NOS are present in human endometrium and myometrium, and that nitric oxide may play a role in the paracrine control of the uterine vascular bed.

Adult↗
PubMed1995

Comparative study of tranexamic acid and norethisterone in the treatment of ovulatory menorrhagia.

OBJECTIVE: To compare the efficacy and safety of tranexamic acid and norethisterone in the treatment of ovulatory menorrhagia. DESIGN: A randomised, double-blind, placebo controlled study. SETTING: University Department of Obstetrics and Gynaecology, Addenbrooke's Hospital, Cambridge. SUBJECTS: One hundred and three women complaining of heavy periods with a regular cycle recruited directly from general practitioners within the hospital catchment area and from consultants' gynaecology clinics. INTERVENTIONS: There were forty-six women on placebo with confirmed ovulatory menorrhagia, defined as menstrual blood loss greater than 80 ml/cycle and mid-luteal serum progesterone concentration greater than 9 nmol/l). Twenty-one received norethisterone (5 mg twice a day on days 19 and 26) and 25 received tranexamic acid (1 g four times daily on days 1 to 4) for two cycles. MAIN OUTCOME MEASURES: Menstrual blood loss was measured using the alkaline haematin method. Haematological assessments were made both at the beginning and at the end of the study, questionnaires were given to assess subjective endpoints, and patients were asked to report any adverse events during all cycles. RESULTS: Tranexamic acid reduced mean menstrual blood loss by 45%, from 175 ml to 97 ml (95% CI for the difference in menstrual blood loss 52 to 108, P < 0.0001), norethisterone increased mean blood loss by 20% from 173 ml to 208 ml (95% CI for the difference in menstrual blood loss -64 to 2, P = 0.26). Fourteen (56%) women who received tranexamic acid achieved a mean menstrual loss of less than 80 ml per cycle during treatment, but only two (9.5%) who received norethisterone achieved this mean menstrual loss. There were no serious adverse events reported for either drug. CONCLUSIONS: Tranexamic acid is a safe and effective form of medical therapy in women with menorrhagia and is highly likely to normalise blood loss in women losing 80 to 200 ml prior to treatment. Norethisterone at this dose is not effective therapy for ovulatory menorrhagia.

Adolescent↗
PubMed1995

ETA and ETB endothelin receptors in human myometrium characterized by the subtype selective ligands BQ123, BQ3020, FR139317 and PD151242.

ETA selective (BQ123, FR139317, PD151242) and ETB selective (BQ3020) ligands were used to define the binding characteristics and contractile function of endothelin receptor subtypes in human myometrium. In saturation binding assays with 10 microns-thick tissue sections [125I]endothelin-1 (ET-1) bound with a single affinity to receptors in the myometrium (Kd, 1.19 +/- 0.17 nM) and adjacent endometrium (Kd, 1.39 +/- 0.51 nM). Competition binding assays in myometrium revealed a heterogeneous population of receptors with BQ123 (Kd ETA, 1.43 +/- 0.33 nM; Kd ETB, 39.91 +/- 9.06 microM), FR139317 (Kd ETA, 2.54 +/- 0.87 nM; Kd ETB, 89.79 +/- 24.34 microM) and BQ3020 (Kd ETA, 4.57 +/- 0.58 microM; Kd ETB, 90.07 +/- 19.53 nM). The presence of these receptors in myometrium was confirmed by saturation assays with the new ETA selective ligand [125I]PD151242 (Kd, 0.93 +/- 0.08 nM; Bmax 138.7 +/- 1.0 fmol/mg protein) and the ETB selective [125I]BQ3020 (Kd, 0.62 +/- 0.07; Bmax 44.5 +/- 1.1 fmol/mg protein). Reverse-transcriptase PCR assays detected mRNA encoding both receptor subtypes in myometrium. Autoradiography with radiolabelled PD151242 and BQ3020 demonstrated that ETA receptors were the predominant subtype in the myometrium and identified a population of ETB receptors in the endometrium. In tissue bath experiments, an ET-1-induced increase in contractility of myometrial strips was antagonized by 10 microM FR139317 but not by BQ123 at the same concentration. The ETB agonist BQ3020, which is a potent agonist in animal tissue, did not increase contractility when tested at concentrations up to 2 microM.

Azepines↗
PubMed1993

Alternatively spliced mRNAs for human endothelin-2 and their tissue distribution.

The cDNA for Endothelin-2 (ET-2) has been previously cloned and characterised; however, ET-2 remains the least studied of the endothelin isopeptides and little is known of its function and location. In the present study reverse transcriptase-polymerase chain reaction revealed the presence of seven alternatively spliced mRNA variants encoding ET-2, with a specific pattern of distribution in various human tissues. Computer alignment and analysis of the DNA sequences demonstrated alternative splicing of five exons of 52, 169, 123, 99 and 174 base pairs, in the carboxy terminal region of the mRNA encoding preproET-2. This region contains sites for the post-transcriptional processing of preproET-2 into mature ET-2, therefore we postulate that post-transcriptional processing may be disrupted or altered in these variants.

Alternative Splicing↗
PubMed1993

Endothelin-2 mRNA splice variants detected by RT-PCR in cultured human vascular smooth muscle and endothelial cells.

Our aim was to examine the hypothesis that vascular smooth-muscle cells (VSMCs) express only ETA mRNA and endothelial cells express only ETB mRNA and to determine which ET mRNA isoforms are expressed in these cell cultures. Using the reverse transcriptase polymerase chain reaction, we were able to detect ETB, ET-1 and splice variant ET-2 mRNA in cultured human umbilical vein endothelial cells (HUVECs) and ETA and splice variant ET-2 mRNA in cultured aortic smooth-muscle cells. The presence of ET-2 mRNA in cultured VSMCs has not been previously reported. These results agree with the hypothesis that ET-1 may be released from vascular endothelial cells to act predominantly on ETA receptors on VSMCs to stimulate contraction of the underlying smooth-muscle cells, and that endothelium-derived relaxing factor release may be mediated predominantly via the ETB receptors on HUVECs. The role of ET-2 expression from HUVECs and VSMCs is less clear.

Base Sequence↗
PubMed1993

Identification of endothelin-1, endothelin-2 and endothelin-3 in human endometrium.

This study determined the presence of specific endothelin isoforms in human endometrium using high performance liquid chromatography (HPLC) combined with radioimmunoassay, and immunocytochemistry to detect the endothelin precursors (proendothelin-1, proendothelin-2 and proendothelin-3). Endothelin-like immunoreactivity was measured in HPLC eluates using antisera raised in rabbits against the carboxy-terminal heptapeptide of endothelin-1, which is common to the three endothelin isoforms. Of eight endometrial samples analysed by HPLC, three were in the proliferative phase of the cycle, and five in the secretory phase. Endothelin-1 was detected in seven samples, whereas endothelin-2 and endothelin-3 were seen in four and five specimens, respectively. No relationship was seen between endothelin isoforms and the stage of the cycle. Immunocytochemistry was performed on five proliferative and three secretory phase tissues. When present, staining for the precursor proendothelins was localized to endometrial glandular and luminal epithelium (proendothelin-1, 5 of 8; proendothelin-2, 5 of 8; proendothelin-3, 6 of 8). In two sections, staining was also seen in vascular endothelium using antibody raised against proendothelin-1 (n = 1) and proendothelin-3 (n = 1). These data provide evidence that the three endothelin isoforms are present in human endometrium, and suggest that these potent vasoactive agents may play a role in the paracrine control of the uterine vascular bed.

Chromatography, High Pressure Liquid↗
PubMed1992

Presence of messenger ribonucleic acid for endothelin-1, endothelin-2, and endothelin-3 in human endometrium and a change in the ratio of ETA and ETB receptor subtype across the menstrual cycle.

The aim of the present study was to determine whether mRNA for the three endothelin peptides (endothelin-1, endothelin-2, and endothelin-3) and the two known receptor subtypes (ETA and ETB) was present in human endometrium at different stages of the menstrual cycle (menstrual, early and mid-proliferative, and early, mid-, and late secretory). Endometrium was obtained from women undergoing surgery for benign disease, and total RNA was extracted using a guanidinium isothiocyanate method. mRNA for endothelin peptide and receptor was detected using the reverse transcriptase-polymerase chain reaction with nested oligonucleotide primers. mRNA for endothelin-1, endothelin-2, and endothelin-3 was demonstrated throughout the menstrual cycle, and three splice variants of mRNA encoding endothelin-3 were found in all samples. The ratio of ETA to ETB receptor mRNA was found to change throughout the menstrual cycle. In the proliferative phase, amplified cDNA product was almost exclusively confined to the ETA receptor, whereas an increase in the amplified product of the ETB receptor cDNA was seen in the secretory and menstrual phases. These studies show that mRNA for endothelin-1, endothelin-2, and endothelin-3 is present in human endometrium at all stages of the menstrual cycle and suggest that different physiological actions of the endothelin peptides may be mediated through changes in the ratio of the ETA and ETB receptor subtypes.

Base Sequence↗