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Biomedical subjects

D Ireland

Publications and source records attributed to D Ireland.

At least 19 recordsLinked to original sources
PubMed2006

Osteoclast formation and bone resorption are inhibited by megakaryocytes.

It has been previously reported that addition of megakaryocytes (MKs) to osteoblasts in vitro results in increased osteoblastic collagen and osteoprotegerin (OPG) production, suggesting a role for MKs in bone formation. To further investigate this role, we have studied the effects of MKs on osteoclast formation and activity. Human osteoclasts were generated from CD14 monocytes isolated from peripheral blood and cultured in the presence of M-CSF and sRANKL on dentine and calcium phosphate substrates. MKs were generated from CD34+ cells isolated from either human peripheral blood or cord blood and cultured in liquid medium for 6 days, after which time maturing MKs (CD61-positive cells) were isolated and added to monocyte cultures. After 6 and 9 days of culture, the number of osteoclasts identified morphologically and by TRAP staining was counted. Cells were removed and the area of resorption was identified by von Kossa staining and quantitatively assessed by image analysis. The addition of MKs to osteoclast cultures at day 0 inhibited the number of osteoclasts formed 1.9-fold (p>0.003), whereas addition at 3 days had no effect on osteoclast number. The presence of MKs inhibited resorption 8.7-fold when co-cultured with osteoclasts from day 0 (p>0.004), but only by 3.1-fold when co-cultured from day 3 (p>0.01). In dose-response experiments, it was found that 1-10% of MKs added to monocyte cultures elicited the greatest inhibition of resorption. Similar osteoclast cultures were treated with CD61-negative cells (non-MKs) to confirm that the inhibition of osteoclast formation and activity was specifically due to MKs. Experiments with a cell-impermeable membrane indicated that both cell to cell contact and release of soluble factor(s) were involved in mediating these effects. These results show that MKs inhibit osteoclast formation and activity. The most pronounced effects were seen when MKs and osteoclasts were co-cultured from day 0, suggesting that MKs act primarily on osteoclast precursors.

Antigens, CD34↗
PubMed2006

Should women with postcoital bleeding be referred for colposcopy?

This study was to determine the risk of finding significant cervical pathological abnormality in women referred to the colposcopy clinic primarily because of postcoital bleeding. We evaluated the cervical smear history of such women and correlated this with any colposcopic or pathological abnormality. There were 142 women seen over a period of 12 months. The age range of the study population was 16 - 61 years (mean age of 34.1 years). There was no case of lower genital tract invasive neoplasia. Out of the 142 cases, 56 women (39.4%) had normal findings at colposcopy and 44 (31%) were secondary to cervical ectopy. A total of 27 (19%) had cervical intraepithelial neoplasia (CIN) out of which there were 15 (10.6%) cases of high-grade disease (CIN II and CIN III); and, 20 (74%) out of the 27 women with CIN had a recently negative cervical smear (within the previous 36 months). Seven women (4.9%) had benign cervical polyps that were removed during colposcopy. The frequency of finding invasive lower genital tract neoplasia in women with postcoital bleeding is low. However, a good proportion of them would have a diagnosis of cervical intraepithelial neoplasia even with a recently negative cervical smear. Therefore, postcoital bleeding should remain an indication for referral to the colposcopy clinic for a detailed evaluation of the lower genital tract.

Adolescent↗
PubMed2004

Joint erosion in rheumatoid arthritis: interactions between tumour necrosis factor alpha, interleukin 1, and receptor activator of nuclear factor kappaB ligand (RANKL) regulate osteoclasts.

BACKGROUND: Osteoclasts, specialised bone resorbing cells regulated by RANKL and M-CSF, are implicated in rheumatoid joint erosion. Lymphocyte-monocyte interactions activate bone resorption, this being attributed to tumour necrosis factor alpha (TNFalpha) and interleukin 1 beta (IL1beta) enhanced osteoblast expression of RANKL. In animal studies, TNF potently increases osteoclast formation in the presence of RANKL. RANKL-independent osteoclastogenesis also occurs, though IL1 is required for resorptive function in most studies. These inflammatory cytokines have a pivotal role in rheumatoid arthritis, OBJECTIVE: To study the interactions of TNFalpha and IL1beta with RANKL, particularly the time course of the interactions and the role of lymphocytes. METHOD: Cultures of lymphocytes and monocytes (osteoclast precursors) or of purified CD14(+) cells alone (osteoclast precursors) were exposed to various combinations of TNFalpha, RANKL, and IL1beta or the inhibitors osteoprotegerin, IL1 receptor antagonist, or neutralising antibodies to RANKL or to IL1. Osteoclastogenesis and resorptive activity were assessed on microscopy of dentine slices. RESULTS: TNFalpha potently increased osteoclast proliferation/differentiation in the presence of RANKL. This effect was greatest when RANKL was present before but not after exposure of osteoclast precursor cells to TNFalpha. The resorptive activity of osteoclasts generated by TNFalpha in the absence of RANKL was critically dependent upon IL1, which was expressed by lymphocyte-monocyte interaction. CONCLUSION: TNFalpha potently enhances RANKL mediated osteoclast activity. Interactions between TNFalpha and IL1 also result in osteoclastic activity independently of RANKL. These findings will inform therapeutic approaches to the prevention of joint erosion in rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed2003

Longer-term primary prevention for alcohol misuse in young people: a systematic review.

OBJECTIVE: To identify and summarize rigorous evaluations of psychosocial and educational interventions aimed at the primary prevention of alcohol misuse by young people aged up to 25 years, especially over the longer term (>3 years). METHODS: Cochrane Collaboration Systematic Review. DATA SOURCES: A comprehensive search of 22 databases and recursive checking of bibliographies for randomized and non-randomized controlled trials and interrupted time-series studies. MAIN OUTCOME MEASURES: Objective or self-report measures of alcohol use and misuse. RESULTS: Fifty-six studies were selected for inclusion in the systematic review. Twenty of the 56 studies showed evidence of ineffectiveness. No firm conclusions about the effectiveness of prevention interventions in the short- and medium term were possible. Over the longer term (>3 years), the Strengthening Families Programme (SFP) showed promise as an effective prevention intervention. The Number Needed to Treat (NNT) for the SFP over 4 years for three alcohol initiation behaviours (alcohol use, alcohol use without permission and first drunkenness) was 9 (for all three behaviours). One study also highlighted the potential value of culturally focused skills training over the longer-term (NNT = 17 over 3.5 years for 4+ drinks in the last week) CONCLUSIONS: (1) Research into important outcome variables needs to be undertaken; (2) the methodology of evaluations needs to be improved; (3) the SFP needs to be evaluated on a larger scale and in different settings; (4) culturally focused interventions require further development and rigorous evaluation; and (5) an international register of alcohol and drug misuse prevention interventions should be established and criteria agreed for rating prevention interventions in terms of safety, efficacy and effectiveness.

Adolescent↗
PubMed2002

Primary prevention for alcohol misuse in young people.

BACKGROUND: Alcohol misuse is a cause of concern for health services, policy makers, prevention workers, the criminal justice system, youth workers, teachers and parents. OBJECTIVES: 1. To identify and summarize rigorous evaluations of psychosocial and educational interventions aimed at the primary prevention of alcohol misuse by young people. 2. To assess the effectiveness of primary prevention interventions over the longer-term (> 3 years). SEARCH STRATEGY: Databases searched (no time limits): Project CORK, BIDS, PSYCLIT, ERIC, ASSIA, MEDLINE, FAMILY-RESOURCES-DATABASE, HEALTH-PERIODICALS-DATABASE, EMBASE, BIDS, Dissertation-Abstracts, SIGLE, DRUG-INFO, SOMED, Social-Work-Abstracts, National-Clearinghouse-on-Alcohol-and-Drug-Information, Mental-Health-Abstracts, DRUG-database, ETOH (all searched Feb-June 2002). SELECTION CRITERIA: 1. randomised controlled and non-randomised controlled and interrupted time series designs. 2. educational and psychosocial primary prevention interventions for young people up to 25 years old. 3. alcohol-specific or generic (drugs; lifestyle) interventions providing alcohol outcomes reported. 4. alcohol outcomes: alcohol use, age of alcohol initiation, drinking 5+ drinks on any one occasion, drunkeness, alcohol related violence, alcohol related crime, alcohol related risky behaviour. DATA COLLECTION AND ANALYSIS: Stage 1: All papers screened by one reviewer against inclusion criteria. Stage 2: For those papers that passed Stage 1, key information was extracted from each paper by 2-3 reviewers. MAIN RESULTS: 20 of the 56 studies included showed evidence of ineffectiveness. No firm conclusions about the effectiveness of prevention interventions in the short- and medium-term were possible. Over the longer-term, the Strengthening Families Program (SFP) showed promise as an effective prevention intervention. The Number Needed to Treat (NNT) for the SFP over 4 years for three alcohol initiation behaviours (alcohol use, alcohol use without permission and first drunkeness) was 9 (for all three behaviours). One study also highlighted the potential value of culturally focused skills training over the longer-term (NNT=17 over three-and-a-half years for 4+ drinks in the last week). REVIEWER'S CONCLUSIONS: 1. Research into important outcome variables needs to be undertaken. 2. Methodology of evaluations needs to be improved. 3. The Strengthening Families Programme needs to be evaluated on a larger scale and in different settings. 4. Culturally-focused interventions require further development and rigorous evaluation. 5. An international register of alcohol and drug misuse prevention interventions should be established and criteria agreed for rating prevention intervention in terms of safety, efficacy and effectiveness.

Adolescent↗
PubMed2001

Multiple changes in gene expression in chronic human Achilles tendinopathy.

Atlas cDNA cell interaction arrays (CLONTECH) were used to examine degenerate tissue from four patients with Achilles tendon disorders, in order to identify changes in expression of genes important in cell-cell and cell-matrix interactions. The greatest difference between normal (post-mortem) and degenerate tissue samples was in the level of MMP-3 (stromelysin) mRNA, which was down-regulated in all the degenerate samples. Quantitative RT-PCR assay of RNA extracted from paired 'normal' and degenerate Achilles tendon tissue samples taken from tendons during surgery mirrored the results of the arrays. Levels of MMP-3 mRNA were lower, whereas levels of type-I and type-III collagen mRNAs were significantly higher, in the degenerate compared to the 'normal' samples. Immunoblotting of proteins extracted from the same tendon samples showed that three of four normal tissue samples taken from individuals without apparent tendon disorder had much higher levels of MMP-3 protein than 'normal' or degenerate samples from patients with tendinosis. We suggest that MMP-3 may play an important role in the regulation of tendon extracellular matrix degradation and tissue remodelling.

Achilles Tendon↗
PubMed2001

Mechanisms by which high-dose estrogen therapy produces anabolic skeletal effects in postmenopausal women: role of locally produced growth factors.

Conventional hormone replacement therapy acts primarily by preserving bone, but cannot restore lost bone in women with established osteoporosis. Studies in rodents have shown that high doses of estrogens have anabolic skeletal effects, and recent observations in a group of women treated long term with high doses of estrogen indicated that similar effects occur in humans. This study examines the hypothesis that locally produced growth factors, including transforming growth factor-beta (TGF-beta) and platelet-derived growth factors (PDGFs), are involved in mediating the anabolic effects of high-dose estrogen. Transiliac-crest bone biopsies were taken from ten women, aged 52-67 years (mean 58 years), who had been treated with high-dose estrogen for 15 years. Control samples were obtained from four age-matched postmenopausal women not receiving estrogen therapy. TGF-betas and PDGFs were analyzed for mRNA and protein expression by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. Results showed both TGF-beta1 and -beta2 mRNA, expressed as a ratio to GAPDH, were increased in the estrogen-treated group with an eightfold increase for TGF-beta1 (0.258 +/- 0.246 [mean +/- SD] vs. 0.032 +/- 0.053 in the control group, p = 0.02) and a twofold increase for TGF-beta2 (p = n.s.). TGF-beta3 analysis showed only negligible amounts in both groups. Protein expression levels for TGF-beta1, -beta2, -betaRI and -RII were higher in the estrogen-treated group than in controls, the most marked effects being seen for TGF-beta1. PDGF-A protein expression was also significantly higher in osteoblasts and osteocytes in women treated with estrogen, whereas PDGF-B showed only modest differences. The percentage of bone surface occupied by osteoclasts, as determined by tartrate-resistant acid phosphatase (TRAP) staining, was significantly reduced in the estrogen-treated group (p = 0.001). These results demonstrate that high-dose estrogen therapy is associated with increased TGF-beta, TGF-betaR, and PDGF synthesis and decreased osteoclast activity, consistent with the hypothesis that these growth factors may mediate the actions of estrogen in bone.

Acid Phosphatase↗
PubMed2001

Colocalization of glucocorticoid and mineralocorticoid receptors in human bone.

Osteoporosis is a poorly understood but common complication of glucocorticoid therapy. The actions of glucocorticoids are mediated via glucocorticoid receptors (GRs), but in vitro, glucocorticoids also can bind to mineralocorticoid receptors (MRs). It is not known if MR protein is present in human bone and little is known of GR isoform expression (GRalpha and GRbeta). GR and MR protein expression and possible sites of action were investigated in neonatal rib and adult iliac crest biopsy specimens using antibodies specific for MR, GRalpha, and GRalphabeta. Colocalization [MR GRalpha] [MR GRalphabeta] was performed using fluorescent-conjugated secondary antibodies. GRalpha, GRbeta, and MR show distinct but overlapping patterns of expression, suggesting important functions for each receptor type. Osteoclasts showed no staining for GRalpha but strong staining for GRalphabeta, indicating expression of GRbeta and a specific role in addition to antagonizing the transcriptional activity of GRalpha. MR also was observed in osteoclasts and colocalized with GRalphabeta. Coexpression of MR, GRalpha, and GRalphabeta was seen in osteoblasts. Reverse-transcription-polymerase chain reaction (RT-PCR) of cultured osteoblast RNA confirmed expression of both GRalpha and GRbeta. Osteocytes stained with MR, GRalpha, and GRalphabeta antibodies but to a lesser degree than osteoblasts. In the neonatal rib cartilage, staining for GRalpha, GRalphabeta, and MR was present in approximately one-half of the resting and hypertrophic chondrocytes and in most of proliferating chondrocytes and chondrocytes within the mineralizing matrix. Identification of MR raises the possibility that the physiological and pharmacologic effects of glucocorticoids on bone may be mediated via MR as well as GR and that GRalpha, GRbeta, and MR synergize to influence corticosteroid metabolism in human bone.

Bone and Bones↗
PubMed2001

A pharmacokinetic and pharmacodynamic comparison of desmopressin administered as whole, chewed and crushed tablets, and as an oral solution.

PURPOSE: We performed a crossover study to determine the relative pharmacokinetic bioavailability and antidiuretic activity of desmopressin in 16 orally hydrated, healthy human subjects. MATERIALS AND METHODS: The investigation included 5 study periods with 1 period used to establish baseline diuresis in the absence of desmopressin and the remaining 4 randomized to a single 0.6 mg. oral dose of desmopressin administered as whole, crushed or chewed tablets, or as an oral solution. Serial plasma samples were collected for 12 hours for desmopressin pharmacokinetic analysis. Pharmacodynamics were assessed by measuring changes in urine volume and osmolality from baseline. Standard bioequivalence metrics were used to compare the pharmacokinetics and pharmacodynamics of crushed and chewed tablets, and oral solution to that of swallowing whole tablets. RESULTS: The 90% confidence interval analysis of log transformed plasma desmopressin area under the plasma concentration-time curve from time 0 to infinity and maximum plasma drug concentration showed that crushed and chewed tablet treatments were bioequivalent to swallowing whole tablets. The 90% confidence interval analysis for the decrease in urine volume and increase in urine osmolality demonstrated that crushed and chewed tablets, and oral solution treatments were equivalent to whole tablet treatment in the area under curve from time 0 to the last sampling time point and maximum drug effect. CONCLUSIONS: The results of this study imply that desmopressin administered orally as crushed or chewed tablets, or as an oral solution has the same net effect on decreasing urine volume and increasing urine osmolality as swallowing tablets whole.

Administration, Oral↗
PubMed2000

Cervical disease in women referred to colposcopy following inadequate smears.

The aim of this audit was to determine if inadequate cervical smears are associated with significant cervical pathology. Case records for 52 women with three consecutive inadequate smears referred for colposcopy to the Leicester Royal Infirmary (LRI) were retrieved. Sixteen women underwent large loop excision of the transformation zone (LLETZ) and cervical intraepithelial neoplasia (CIN) was identified in six cases. There were no cases of inadequate smears initiating the diagnosis in 100 consecutive women with invasive cervical cancer. Inadequate smears are associated with high rates of treatment for a low yield of CIN. To reduce morbidity associated with colposcopy it may be acceptable to repeat an inadequate smear after 6 months rather than arranging immediate recall.

Adult↗
PubMed2000

Platelet-derived endothelial cell growth factor expression and angiogenesis in cervical intraepithelial neoplasia and squamous cell carcinoma of the cervix.

Growth and metastatic spread of invasive carcinoma depends on angiogenesis, the formation of new blood vessels. Platelet-derived endothelial cell growth factor (PD-ECGF) is an angiogenic growth factor for a number of solid tumors, including lung, bladder, colorectal, and renal cell cancer. Cervical intraepithelial neoplasia (CIN) is the precursor to squamous cell cervical carcinoma (SCC). Mean vessel density (MVD) increases from normal cervical tissue, through low- and high-grade CIN to SCC. We evaluated PD-ECGF immunoreactivity and correlated its expression with MVD in normal, premalignant, and malignant cervical tissue. PD-ECGF expression was assessed visually within the epithelial tissues and scored on the extent and intensity of staining. MVD was calculated by counting the number of vessels positive for von Willebrand factor per unit area subtending normal or CIN epithelium or within tumor hotspots for SCC. Cytoplasmic and/or nuclear PD-ECGF immunoreactivity was seen in normal epithelium. PD-ECGF expression significantly increased with histologic grade from normal, through low- and high-grade CIN, to SCC (P < .02). A progressive significant increase in the microvessel density was also seen, ranging from a mean of 28 vessels for normal tissue to 57 for SCC (P < .0005). No correlation was found between PD-ECGF expression and MVD (P = .45). We conclude that PD-ECGF expression and MVD increase as the cervix transforms from a normal to a malignant phenotype. PD-ECGF is thymidine phosphorylase, a key enzyme in the activation of fluoropyrimidines, including 5-fluorouracil. Evaluation of PD-ECGF thymidine phosphorylase expression may be important in designing future chemotherapeutic trials in cervical cancer.

Carcinoma, Squamous Cell↗
PubMed2000

Pediatric legalities.

Health care practitioners must be cognizant of medical malpractice and the criteria that encompass professional liability. The 4 separate but related criteria of professional liability are discussed and explanations given on their importance. Emphasis is placed on pediatric legalities, although there are many aspects of medical malpractice applicable to both the adult and pediatric patient. Specific allegations familiar to nurses are explored and related to the care of the pediatric patient. Individual considerations such as consents, child abuse, and the withdrawal and withholding of treatmentfor the pediatric patient will be discussed. Attempts have been made to provide current, accurate information concerning legal issues in nursing practice. However, because law changes rapidly, new decisions may have been reached by a particular court or through state legislation. It is important for the nurse practicing in the perianesthesia field to keep abreast of changes in the law that have an impact on nursing practice both for the pediatric patient and the adult patient.

Child↗
PubMed2000

Surgical management of advanced ovarian cancer.

Surgery is an essential part of the management of patients presenting with ovarian cancer. Diagnosis, staging, and therapy can be carried out at the time of laparotomy. Unfortunately, the disease often presents at an advanced stage and the outlook for patients is poor with an overall 5-year survival rate of 23%. This review focuses on the surgical management of advanced ovarian cancer and focuses on both primary, secondary, and intervention debulking surgery.

Female↗
PubMed2000

Does histological incomplete excision of cervical intraepithelial neoplasia following large loop excision of transformation zone increase recurrence rates? A six year cytological follow up.

OBJECTIVE: To determine the risk of recurrent cervical intraepithelial neoplasia (CIN) in women with complete or incomplete excision of cervical intraepithelial neoplasia treated by large loop excision of transformation zone (LLETZ). DESIGN: A retrospective study SETTING: One consultant-led colposcopy clinic at Leicester Royal Infirmary POPULATION: Three hundred and ninety-four women referred consecutively to the colposcopy clinic between 1991 and 1992. MAIN OUTCOME MEASURES: The histological recurrence rate of CIN, length of cytological follow up following treatment related to degree of completeness of excision at initial treatment. RESULTS: Three hundred and twenty-two women had complete cytological or histological follow up. The mean length of follow up was 73 months with a mean number of six smears. Women with incomplete excision of CIN had a significantly higher risk of recurrent CIN (relative risk 8.23) occurring in a significantly shorter time compared with women with complete excision. CONCLUSIONS: This study demonstrates that large loop excision of transformation zone is successful in over 95% of cases. Cytological surveillance is satisfactory for follow up of women who have complete excision of CIN. Women with incomplete excision of CIN at initial LLETZ remain at significant risk of developing further CIN and long term colposcopic and cytological follow up is necessary.

Adolescent↗
PubMed1999

A factor analytic study of the dizziness handicap inventory: does it assess phobic avoidance in vestibular referrals?

Panic disorder and agoraphobia have been associated with increased functional disability in individuals who have vestibular problems. The Dizziness Handicap Inventory (DHI), a 25-item self-report questionnaire with three rationally derived subscales, was designed to measure functional, emotional, and physical disability associated with vestibular disturbance. Despite the apparent usefulness of the DHI, there have been few studies of its psychometric properties. The primary purpose of the present study was to assess the factor structure of the DHI. A principal components analysis with oblique rotation was conducted on data collected from 95 patients referred to a tertiary-care vestibular disorders clinic for assessment of vestibular disturbance. Both 2-factor and 3-factor solutions are reported. The 2-factor solution was indicative of General Functional Limitations and Postural Difficulties. In the 3-factor solution, General Functional Limitations was split into factors indicative of Disability in Activities of Daily Living and Phobic Avoidance, while the Postural Difficulties factor remained stable. We also characterized the 3-factor solution by assessing the correlation of factor scores with measures of vestibular symptoms, mood, and anxiety. The general pattern of results does not support the validity of the original subscale structure of the DHI. Implications for revising the DHI to provide a more comprehensive and factorially valid assessment of disability associated with vestibular disturbance are discussed.

Adult↗