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Biomedical subjects

P M O'Brien

Publications and source records attributed to P M O'Brien.

At least 19 recordsLinked to original sources
PubMed2006

A distinct molecular profile associated with mucinous epithelial ovarian cancer.

Mucinous epithelial ovarian cancers (MOC) are clinically and morphologically distinct from the other histological subtypes of ovarian cancer. To determine the genetic basis of MOC and to identify potential tumour markers, gene expression profiling of 49 primary ovarian cancers of different histological subtypes was performed using a customised oligonucleotide microarray containing >59 000 probesets. The results show that MOC express a genetic profile that both differs and overlaps with other subtypes of epithelial ovarian cancer. Concordant with its histological phenotype, MOC express genes characteristic of mucinous carcinomas of varying epithelial origin, including intestinal carcinomas. Differences in gene expression between MOC and other histological subtypes of ovarian cancer were confirmed by RT-PCR and/or immunohistochemistry. In particular, galectin 4 (LGALS4) was highly and specifically expressed in MOC, but expressed at lower levels in benign mucinous cysts and borderline (atypical proliferative) tumours, supporting a malignant progression model of MOC. Hence LGALS4 may have application as an early and differential diagnostic marker of MOC.

Adenocarcinoma, Mucinous↗
PubMed2003

Sequence variants of bovine papillomavirus E5 detected in equine sarcoids.

The equine sarcoid, one of the most common dermatological lesions in equids, is a benign, locally invasive dermal fibroblastic lesion. Previous studies have suggested an association with two bovine papilloma virus (BPV) types, BPV-1 and BPV-2. In the present study, we examined sarcoids from horses from two geographical areas, Switzerland and the UK, for the major transforming gene of BPV, E5. We detected BPV DNA for the E5 open reading frame and viral E5 RNA transcripts in most sarcoids. Sequence analysis of the E5 open reading frame of sarcoid-associated BPV detected several unique DNA sequence variants, three of which resulted in sarcoid specific amino acid sequence variations. It is unclear if these sequence variants contribute to the unique clinical presentation of the sarcoid. However, our work provides further evidence of the association between BPV and sarcoid development and the direct involvement of the virus in the pathogenesis of sarcoids.

Animals↗
PubMed2003

Association of bovine papillomavirus with the equine sarcoid.

The equine sarcoid, a locally aggressive, fibroblastic skin tumour, is the most common dermatological neoplasm reported in horses; there is no consistently effective therapy. It is widely accepted that bovine papillomavirus (BPV) types 1 and 2 are associated with the pathogenesis of sarcoid disease. Most sarcoids appear to contain detectable viral DNA and RNA and are also known to express the BPV types 1 and 2 major transforming protein, E5, but appear not to produce infectious virions. While the mode of transmission of infection has not been elucidated, viral gene expression, in particular of E5, may contribute to virus persistence and disease pathogenesis by downregulating MHC class I expression. Here, the pathology and epidemiology of the sarcoid and its association with BPV is reviewed; the transforming functions of the BPV oncoproteins and their possible role in sarcoid pathogenesis are discussed; and the practical implications of BPV infection for diagnostic and therapeutic purposes are considered.

Animals↗
PubMed2002

Selective serotonin reuptake inhibitors for premenstrual syndrome.

BACKGROUND: Severe premenstrual syndrome affects between 3-5% of women of reproductive age. Such severe PMS is classified under the Diagnostic and Statistical Manual of Mental Disorders as premenstrual dysphoric disorder, PMDD. Selective serotonin reuptake inhibitors (SSRIs) are increasingly being used as a front-line therapy for premenstrual syndrome (PMS). A systematic review was undertaken on the efficacy of SSRIs in the management of severe PMS/PMDD, to assess the evidence for this treatment option. OBJECTIVES: The objective of this review was to evaluate the effectiveness of SSRIs in reducing premenstrual syndrome symptoms in women diagnosed with severe premenstrual syndrome. SEARCH STRATEGY: Electronic searches for relevant randomised controlled trials of the Cochrane Menstrual Disorders and Subfertility Group specialised register of controlled trials, Cochrane Controlled Trials Register, MEDLINE, EMBASE and PsychLit were undertaken. References were searched interactively to identify missed trials. Where insufficient data were presented original authors were contacted for further details. SELECTION CRITERIA: All trials were considered in which women with a prospective diagnosis of PMS/ PMDD were randomised to receive SSRIs or placebo in a double blind trial for the treatment of premenstrual syndrome. DATA COLLECTION AND ANALYSIS: 31 randomised controlled trials were identified which reported the use of SSRIs in the management of PMS. 16 trials were excluded, 15 trials were included in the systematic review, and ten trials were included in the main analyses. The reviewers extracted the data independently and standardised mean differences for continuous outcomes were estimated from the data. MAIN RESULTS: The primary analysis of reduction in overall symptomatology included data on 844 women with premenstrual syndrome. SSRIs were found to be highly effective in treating premenstrual symptoms. Secondary analysis showed that they were as effective in treating physical as well as behavioural symptoms. There was no significant difference between trials funded by pharmaceutical companies and those independently funded. Withdrawals due to side effects were 2.5 times more likely to occur in the treatment group, particularly at higher doses. REVIEWER'S CONCLUSIONS: There is now very good evidence to support the use of selective serotonin reuptake inhibitors in the management of severe premenstrual syndrome.

Female↗
PubMed2001

Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure.

BACKGROUND: Matrix metalloproteinase (MMP) activation contributes to tissue remodeling in several disease states, and increased MMP activity has been observed in left ventricular (LV) failure. The present study tested the hypothesis that MMP inhibition would influence LV remodeling and function in developing LV failure. METHODS AND RESULTS: LV size and function were measured in 5 groups of rats: (1) obese male spontaneously hypertensive heart failure rats (SHHF) at 9 months (n=10), (2) SHHF at 13 months (n=12), (3) SHHF rats treated with an MMP inhibitor during months 9 to 13 (PD166793 5 mg. kg(-1). d(-1) PO; n=14), (4) normotensive Wistar-Furth rats (WF) at 9 months (n=12), and (5) WF at 13 months (n=12). Plasma concentrations of the MMP inhibitor (116+/-11 micromol/L) reduced in vitro LV myocardial MMP-2 activity by approximately 100%. LV function and geometry were similar in WF rats at 9 and 13 months. LV peak +dP/dt was unchanged at 9 months in SHHF but by 13 months was reduced in the SHHF group compared with WF (3578+/-477 versus 5983+/-109 mm Hg/s, P</=0.05). LV volume measured at an equivalent ex vivo pressure (10 mm Hg) was increased in SHHF at 9 months compared with WF (443+/-12 versus 563+/-33 mL, P</=0.05) and increased further by 13 months (899+/-64 mL, P</=0.05). LV myocardial MMP-2 activity was increased by approximately 2-fold in SHHF at 9 and 13 months. With MMP inhibition, LV peak +dP/dt was similar to WF values and LV volume was reduced compared with untreated SHHF values (678+/-28 mL, P</=0.05). CONCLUSIONS: MMP activity contributes to LV dilation and progression to LV dysfunction in a rodent HF model, and direct MMP inhibition can attenuate this process.

Animals↗
PubMed2001

Immunoglobulin genes expressed by B-lymphocytes infiltrating cervical carcinomas show evidence of antigen-driven selection.

Lymphocyte infiltration is often present in cervical cancer lesions, possibly reflecting an ongoing (but ineffective) immune response to the tumour. B-lymphocytes are the predominant lymphocyte infiltrate in pre-malignant cervical lesions, where they are thought to comprise the host immune response to active human papillomavirus (HPV) infection. Although B cells are less frequently detected in cervical tumours, a high proportion of terminally differentiated plasma cells expressing tumour-specific immunoglobulin (Ig) remain. The antigen specificity and functional significance of the antibody response to cervical tumours is unknown. As part of a study to characterise the antibodies expressed by the tumour-infiltrating B cells (TIL-B) in cervical tumours using antibody phage display, we examined expressed Ig gene sequences to determine if there was molecular evidence of a selective response to antigenic changes in the transformed epithelial cells. We found that biased variable region gene usage by the B cells and the rate of somatic hypermutation in the rearranged Ig heavy chain variable regions (VH) both indicated antigenic selection of the B cells. We also found evidence of affinity maturation, as indicated by the detection of antibodies of the IgG1, IgG2 and IgA isotypes, and possible clonal selection of the Ig receptors. These data support the notion that B-lymphocytes and plasma cells infiltrating cervical carcinomas are the result of an antigen-induced response to HPV infection or transformation.

Antigen Presentation↗
PubMed2001

Determination of total menstrual blood loss.

OBJECTIVE: To develop and validate a simple method of measuring total menstrual blood loss using a pictorial representation of blood loss, the menstrual pictogram. DESIGN: A prospective evaluation of total menstrual blood loss measurement by the menstrual pictogram compared to the alkaline hematin technique. SETTING: Academic menorrhagia research clinic. PATIENT(S): One hundred twenty-one women; 62 women complaining of heavy menstrual blood loss, 59 women who considered their menstrual blood loss to be normal. INTERVENTION(S): Participants were asked to complete the menstrual pictogram through the period and collect their feminine hygiene products for an alkaline hematin assessment. MAIN OUTCOME MEASURE(S): Percentage agreement between blood loss measured by the gold standard alkaline hematin method and the menstrual pictogram. Extraneous blood loss was measured using a semiquantitative pictorial method. RESULT(S): The menstrual pictogram had a high level of agreement for blood collected on feminine hygiene products compared with the alkaline hematin method. Some women also lose a significantly large amount of extraneous blood, which is not proportional to the alkaline hematin blood loss assessment. CONCLUSION(S): The menstrual pictogram provides a simple means of measuring menstrual blood loss. It is no longer appropriate to ignore extraneous blood loss, particularly as there is no correlation between extraneous blood loss and that measured on feminine hygiene products.

Adult↗
PubMed2001

Platelet angiotensin II binding may be a useful prognostic indicator for the development of pre-eclampsia in women with pregnancy-induced hypertension: preliminary communication.

This was a preliminary investigation to assess the value of platelet angiotensin II binding as a prognostic indicator for subsequent pre-eclampsia in women admitted with non-proteinuric pregnancy-induced hypertension. Platelet angiotensin II binding was measured in 26 women at the onset of their symptoms. All were primparous, had singleton pregnancies, were normotensive at booking and had an unremarkable medical history. The blood pressure of seven women resolved and returned to normal; 11 women remained stable throughout the remainder of their pregnancy, their blood pressure remained elevated but they did not develop significant proteinuria. Eight women developed pre-eclampsia. Platelet angiotensin II binding in the pre-eclamptic group was significantly higher compared to those who remained stable (P = 0.042) or those whose condition improved (P = 0.021). We conclude that angiotensin II binding measured at the time of admission to hospital for non-proteinuric pregnancy-induced hypertension may have a role in predicting the onset of pre-eclampsia or eclampsia.

Journal Article↗
PubMed2000

Efficacy of selective serotonin-reuptake inhibitors in premenstrual syndrome: a systematic review.

BACKGROUND: Selective serotonin-reuptake inhibitors (SSRIs) are increasingly being used as first-line therapy for severe premenstrual syndrome (PMS). We undertook a meta-analysis on the efficacy of SSRIs in this disorder. METHODS: We searched medical and scientific databases, approached pharmaceutical companies, and reviewed citations of relevant articles to identify 29 studies of the use of SSRIs in PMS. 14 were excluded (no placebo group, preliminary report of included trial, or low quality). 15 randomised placebo-controlled trials were included. Information on study design, participants, drugs used and dosing regimens, outcome measures, side-effects, and sources of funding was extracted. Standardised mean differences between treatment and placebo groups were calculated to obtain an overall estimate of efficacy. The primary outcome measure was a reduction in overall PMS symptoms. FINDINGS: The primary analysis included data on 904 women (570 assigned active treatment and 435 assigned placebo, including 101 in crossover trials). The overall standardised mean difference was -1.066 (95% CI -1.381 to -0.750), which corresponds to an odds ratio of 6.91 (3.90 to 12.2) in favour of SSRIs. SSRIs were effective in treating physical and behavioural symptoms. There was no significant difference in symptom reduction between continuous and intermittent dosing or between trials funded by pharmaceutical companies and those independently funded. Withdrawal due to side-effects was 2.5 times more likely in the active-treatment group than in the placebo group. INTERPRETATION: SSRIs are an effective first-line therapy for severe PMS. The safety of these drugs has been demonstrated in trials of affective disorder, and the side-effects at low doses are generally acceptable.

Female↗
PubMed2000

Structure-activity relationships and pharmacokinetic analysis for a series of potent, systemically available biphenylsulfonamide matrix metalloproteinase inhibitors.

A series of biphenylsulfonamide derivatives of (S)-2-(biphenyl-4-sulfonylamino)-3-methylbutyric acid (5) were prepared and evaluated for their ability to inhibit matrix metalloproteinases (MMPs). For this series of compounds, our objective was to systematically replace substituents appended to the biphenyl and alpha-position of 5 with structurally diverse functionalities to assess the effects these changes have on biological and pharmacokinetic activity. The ensuing structure-activity relationship (SAR) studies showed that biphenylsulfonamides substituted with bromine in the 4'-position (11c) significantly improved in vitro activity and exhibited superior pharmacokinetics (C(max), t(1/2), AUCs), relative to compound 5. Varying the lipophilicity of the alpha-position by replacing the isopropyl group of 11c with a variety of substituents, in general, maintained potency versus MMP-2, -3, and -13 but decreased the oral systemic availability. Subsequent evaluation of its enantiomer, 11c', showed that both compounds were equally effective MMP inhibitors. In contrast, the corresponding hydroxamic acid enantiomeric pair, 16a (S-isomer) and 16a' (R-isomer), stereoselectivity inhibited MMPs. For the first time in this series, 16a' provided nanomolar potency against MMP-1, -7, and -9 (IC(50)'s = 110, 140, and 18 nM, respectively), whereas 16a was less potent against these MMPs (IC(50)'s = 24, 78, and 84 microM, respectively). However, unlike 11c, compound 16a' afforded very low plasma concentrations following a single 5 mg/kg oral dose in rat. Subsequent X-ray crystal structures of the catalytic domain of stromelysin (MMP-3CD) complexed with inhibitors from closely related series established the differences in the binding mode of carboxylic acid-based inhibitors (11c,c') relative to the corresponding hydroxamic acids (16a,a').

Animals↗
PubMed2000

Effect of bright light on cycling performance.

PURPOSE: The purpose of this study was to examine the effect of exposure to three levels of light intensity during cycling on average power output during an all-out 20-min bout of cycle ergometry. METHODS: Twelve male competitive cyclists, with a mean age of 24.3 +/- 3.2 yr, were tested on four separate occasions. During each test session, participants were instructed to produce the highest possible average power output during a 20-min bout of cycle ergometry. Session 1 served as a adaptation trial and was conducted in normal room lighting (approximately 250 lux). In subsequent sessions each participant exercised while sitting in front of a light box. Light intensity was experimentally manipulated through the use of sunglasses that provided high, medium, and low light filtration. Light condition order was counterbalanced. Measurements of heart rate, muscle pain, local perceived exertion, metabolism, and alertness were made during exercise. Mood was assessed before and following exercise with the POMS-BI. RESULTS: There were no statistically significant differences in the average total power output in the 1,411 lux (274.9 +/- 21.8 W), 2,788 lux (274.4 +/- 20.5 W), and 6,434 lux (270.3 +/- 19.8 W) light conditions. The difference between the average power output in the brightest and least bright condition (4.6 W) was approximately one-fourth of a pooled SD (d = 0.22). There were no significant differences among the conditions in alertness, leg muscle pain, perceived exertion, heart rate, VO2, or mood responses to the exercise. CONCLUSION: It is concluded that exposure to bright light resulting in estimated retinal exposures ranging from 1,411 to 6,434 lux did not have a large or systematic influence on the performance of 20 min of maximal cycle ergometry.

Adult↗
PubMed1999

Generation of native bovine mAbs by phage display.

Modeling of disease pathogenesis and immunity often is carried out in large animals that are natural targets for pathogens of human or economic relevance. Although murine mAbs are a valuable tool in identifying certain host/pathogen interactions, progress in comparative immunology would be enhanced by the use of mAbs isolated from the host species. Such antibodies would reflect an authentic host immune response to infection or vaccination, and as they are host derived, would allow the application of in vivo experiments that previously have been unrealizable in large animals because of induction of an antispecies immune response. The advent of antibody phage display technology provides a way of producing host-derived mAbs in animals where the molecular genetics of Ig formation are known. Exploiting recent advances in the molecular immunology of cattle, we report here the design of an optimized phage display vector, pComBov, for the construction of combinatorial libraries of bovine Ig antigen-binding fragments (Fab) of native sequence. By using this system, we initially have generated and characterized a panel of bovine mAbs against a model antigen glutathione S-transferase. The isolated mAbs showed features typical of bovine Igs and recognized glutathione S-transferase with high specificity in ELISA and by Western blotting. The pComBov expression system can be readily adapted for the preparation of libraries from related ruminant species and advances the use of monoclonal reagents derived in this way for comparative studies in animals of economic importance.

Amino Acid Sequence↗
PubMed1999

Randomized controlled trial of the management of premenstrual syndrome and premenstrual mastalgia using luteal phase-only danazol.

OBJECTIVE: Our goal was to evaluate the efficacy and side effects of danazol 200 mg daily given only in the luteal phase of the menstrual cycle to treat premenstrual syndrome and premenstrual mastalgia. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled study of 3 menstrual cycles in a postgraduate medical school and National Health Service hospital. The subjects of the study were 100 women who had been referred to the premenstrual syndrome clinic at the North Staffordshire Hospital for the management of premenstrual syndrome and premenstrual breast pain. Outcome measures for the study included assessment of improvement in symptoms measured by specific daily visual analogue scales for 4 principal symptoms of premenstrual syndrome and for premenstrual mastalgia and assessment of side effects and adverse events. RESULTS: Significant improvement in symptoms was seen in visual analog scores for mastalgia in months 1 (P =.03), 2 (P =.004), and 3 (P =.01) of the study during active therapy compared with placebo. No improvement was seen for any other symptom or for the global premenstrual syndrome score. Side effects on danazol and on placebo were equal and minimal. CONCLUSIONS: Luteal phase-only danazol is not effective for the treatment of the general symptoms of premenstrual syndrome but appears highly effective for the relief of premenstrual mastalgia. This approach to therapy is associated with few side effects. Studies of cyclic mastalgia using strict diagnostic criteria are required to see whether the freedom from symptomatic side effects is found in longer-term studies and to determine whether such a regimen avoids potentially detrimental effects on the lipid status.

Adult↗
PubMed1999

Failure of platelet angiotensin II binding to predict pregnancy-induced hypertension.

OBJECTIVE: To determine whether measurement of platelet angiotensin II binding at 20 weeks' gestation identifies women destined to develop pregnancy-induced hypertension. METHODS: Over a 2-year period, we recruited 325 unselected, normotensive primigravidas from the hospital antenatal department after their routine 20-week scan appointments. Each woman had a singleton pregnancy, was normotensive at the time of entry into the study, and had an unremarkable medical history. Ninety-three nonpregnant women were recruited from the hospital staff for comparison. Platelet angiotensin II binding was measured in all participants. After delivery, the case notes were screened to determine pregnancy outcome. RESULTS: Two hundred sixty-seven women remained normotensive to delivery, 30 developed nonproteinuric pregnancy-induced hypertension, 23 developed proteinuric pregnancy-induced hypertension, four had transient hypertension, and one was diagnosed subsequently as having essential hypertension. The median platelet angiotensin II binding for the nonpregnant subjects was 15.7 fmol/10(9) platelets, which differed significantly from the value for normotensive pregnant subjects (4.8 fmol/10(9) platelets, P < .001) and from the value for those who developed either nonproteinuric pregnancy-induced hypertension (4.95 fmol/10(9) platelets) or proteinuric pregnancy-induced hypertension (7.2 fmol/10(9) platelets, P < .001). There was no significant difference between pregnant women who remained normotensive and those who developed nonproteinuric or proteinuric pregnancy-induced hypertension. CONCLUSION: Measurement of angiotensin II binding in the second trimester has no value as a screening test for nonproteinuric or proteinuric pregnancy-induced hypertension.

Adolescent↗
PubMed1999

The effect of prostanoid precursors and inhibitors on platelet angiotensin II binding.

Pregnancy-induced hypertension is characterised by an imbalance of arachidonic acid metabolites: Prostacyclin (PGI2) is vasodilatory and a potent inhibitor of platelet reactivity. Thromboxane (TXA2) induces vasoconstriction and platelet aggregation. Previous intervention studies have been aimed at increasing vasodilatation and decreasing platelet aggregation using low dose aspirin or dietary manipulation of prostaglandins. The aim of this study was to investigate the value of combining low dose aspirin with dietary fatty acid supplementation and its effects on platelet angiotensin II binding in non-pregnant women. Sixty non-pregnant, healthy female volunteers were recruited and randomly allocated to one of six treatment regimens which included aspirin taken alone and in combination with fish oil or evening primrose oil. A control group took no treatment. Platelet AII binding was determined before and after treatment for 1 month. There was no change in platelet angiotensin II binding after 1 month in the control group or in those who received evening primrose oil or fish oil alone. A significant decrease in binding was found in those who took aspirin in combination with fish oil (P = 0.03). An increase in binding was seen in those who took aspirin only, although this was not statistically significant (P = 0.14). A decrease was found in those who took aspirin in combination with evening primrose oil but again this was not statistically significant (P = 0.07). This study found that the combined effect of low-dose aspirin and fish oil causes a significant decrease in platelet angiotensin II binding not caused by either compound taken alone. Given that angiotensin II exerts its effect in part by direct interaction with vascular AII receptors, (platelets being used as 'models' of vascular myocytes), and that pre-eclampsia is associated with major pathophysiological changes in prostanoid metabolism, these pilot data provide a basis for further investigation.

Clinical Trial↗
PubMed1998

alpha-Substituted malonester amides: tools to define the relationship between ACAT inhibition and adrenal toxicity.

We prepared a series of alpha-substituted malonester amides that were evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyl transferase activity in vitro and to lower plasma total cholesterol levels in a variety of cholesterol-fed animal models. Compounds of this series were also useful in examining the relationship between adrenal toxicity and ACAT inhibition. One compound from this series, 9f, was a potent inhibitor of ACAT in both the microsomal and cellular assays. It was also bioavailable as determined by both a bioassay and a HPLC-UV assay. This compound was evaluated in both guinea pig and dog models of adrenal toxicity and compared to tetrazole amide 15. In the most sensitive species, the dog, both of these compounds achieved good plasma levels; however, compound 9f caused adrenal necrosis, whereas compound 15 had no effect on the adrenal gland. This adds to the growing body of evidence that the adrenal toxicity observed with ACAT inhibitors may not be mechanism related.

Adrenal Glands↗