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Heather Brown

Publications and source records attributed to Heather Brown.

13 recordsLinked to original sources
PubMed2005

RANKL is a marker and mediator of local and systemic bone loss in two rat models of inflammatory arthritis.

UNLABELLED: RANKL is an essential mediator of bone erosions, but the role of RANKL in systemic bone loss had not been studied in arthritis. RANKL protein was increased in rat joint extracts and serum at the earliest stages of arthritis. Osteoprotegerin (OPG) treatment reversed local and systemic bone loss, suggesting that RANKL is both a marker and mediator of bone loss in arthritis. INTRODUCTION: RANKL is well established as an essential mediator of bone erosions in inflammatory arthritis, but the role of RANKL in systemic bone loss in arthritis had not been studied. We hypothesized that serum RANKL could serve as both a mediator and as a novel biomarker for local and systemic bone loss in arthritis. We challenged this hypothesis in two established rat models of inflammatory arthritis. We sought to determine whether serum RANKL was elevated early in disease progression and whether RANKL suppression could prevent both local and systemic bone loss in these models. MATERIALS AND METHODS: Detailed time-course studies were conducted in animals with collagen-induced (CIA) or adjuvant-induced (AIA) arthritis to evaluate the onset and progression of inflammation (paw swelling), bone erosions, osteoclast numbers, and RANKL protein levels in arthritic joints and in serum. Additional CIA and AIA rats (n=8/group) received placebo (PBS) or recombinant OPG (3 mg/kg three times weekly) for 10 days beginning 4 days after disease onset (first macroscopic evidence of hind paw erythema and edema) to assess the role of RANKL in local and systemic bone loss. RESULTS: RANKL protein was significantly elevated in the joints and serum of CIA and AIA rats within 1-2 days of disease onset. Increased RANKL levels were associated with local (hind paw) and systemic (vertebral) osteopenia in both models. The RANKL inhibitor OPG prevented local and systemic osteopenia in both models of established disease. CONCLUSIONS: RANKL protein is significantly increased both locally and systemically during the earliest stages of inflammatory arthritis in rats, suggesting that serum RANKL might have prognostic value for bone erosions and systemic osteopenia in this condition. RANKL inhibition through OPG prevented local and systemic bone loss in these arthritis models, suggesting that RANKL inhibition is a promising new approach for treating bone loss in arthritis.

Animals↗
PubMed2005

Additive bone-protective effects of anabolic treatment when used in conjunction with RANKL and tumor necrosis factor inhibition in two rat arthritis models.

OBJECTIVE: To investigate whether the bone-preserving effects of a RANKL antagonist or a tumor necrosis factor (TNF) antagonist could be further improved by the addition of a bone anabolic agent in inflammatory arthritis. METHODS: Lewis rats with either adjuvant-induced arthritis (AIA) or collagen-induced arthritis (CIA) were treated for 10 days with PEGylated soluble tumor necrosis factor receptor type I (PEG sTNFRI), interleukin-1 receptor antagonist (IL-1Ra), osteoprotegerin (OPG), parathyroid hormone (PTH), or combinations of these agents starting on day 4 after disease onset. Treatment effects were assessed clinically, radiologically, and histologically, and by morphometry for the extent of paw swelling, bone erosive changes, and synovial inflammation. RESULTS: Paw swelling and synovial inflammation were significantly inhibited by PEG sTNFRI in AIA and CIA, and by IL-1Ra in CIA. OPG and PTH had no significant effect on these parameters. Analysis of bone erosion revealed a significant bone-sparing effect of monotherapy with PEG sTNFRI or OPG in both models, whereas IL-1Ra was only effective in CIA. PTH treatment alone did not show a bone-protective effect in either model. With the combination of PEG sTNFRI and PTH, erosion scores (-74% in AIA and -61% in CIA versus controls) were significantly lower than those elicited by PEG sTNFRI alone (-41% and -29%, respectively, versus controls). Similar results were also obtained with the combination of OPG and PTH (-88% in AIA and -73% in CIA, compared with -70% and -55%, respectively, with OPG monotherapy). Coadministration of IL-1Ra and PTH had no synergistic bone-sparing effect. Morphometric analysis revealed that the addition of PTH to PEG sTNFRI or OPG resulted in higher bone volume and higher osteoblast numbers in both AIA and CIA. CONCLUSION: The bone-protective effects resulting from RANKL or TNF antagonism can be further improved by the addition of a bone anabolic agent.

Animals↗
PubMed2005

Analysis of the kinetics of osteoclastogenesis in arthritic rats.

OBJECTIVE: To analyze the kinetics of osteoclastogenesis in 2 models of chronic immune-mediated arthritis and 1 model of acute arthritis. METHODS: Adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) in Lewis rats were used as models of chronic arthritis. Acute arthritis was induced in Lewis rats by injecting carrageenan into the hind paw. Osteoclasts were identified by cathepsin K immunohistochemistry at various time points after the onset of arthritis. The location, size, and nucleation of osteoclasts were also analyzed. RESULTS: In both AIA and CIA, multinucleated and cathepsin K-positive osteoclasts first were observed on the day of disease onset. Initially, osteoclasts were localized at the periosteum next to the synovial membrane and in subchondral bone channels. The number, size, and nucleation of osteoclasts rapidly increased, leading to severe bone loss within days after disease onset. In addition, numerous mononucleated cathepsin K-positive osteoclast precursor cells emerged in the synovial membrane. All osteoclasts (cathepsin K-positive, multinucleated, attached to bone) and osteoclast precursors (cathepsin K-positive, mononucleated or multinucleated, within synovial tissue) were also positive for a macrophage-specific marker. Upon induction of acute arthritis with carrageenan, osteoclasts formed transiently in subchondral bone, but regressed 7 days after disease onset. CONCLUSION: Functional osteoclasts are generated at the earliest stage of arthritis, and new precursors are continuously formed in the synovial membrane to replenish the osteoclast pool. These data indicate that anti-resorptive therapies may provide the most effective bone protection, when treatment is started soon after the onset of arthritis.

Acute Disease↗
PubMed2005

Gene expression profiling in squamous cell carcinoma of the oral cavity shows abnormalities in several signaling pathways.

OBJECTIVES/HYPOTHESIS: To examine gene expression profiles in squamous cell carcinoma of the oral cavity (oral SCC) compared with histologically matched normal tissue. STUDY DESIGN: Fresh-frozen tissue was prospectively obtained from individuals undergoing surgical resections for oral SCC. METHODS: RNA was extracted from seven sets of oral SCC and matched normal tissue. Gene expression profiles were obtained by interrogation of Affymetrix Gene Chip Arrays with cRNA prepared from the tissue. Expression values were subjected to a paired t test. Genes that were judged to differ between oral SCC and normal tissue were annotated according to their name in the Affymetrix Netaffx database and according to their function as indicated by their Gene Ontology Consortium number. RESULTS: Of the 10,599 probe sets that were analyzed, 523 genes were abnormally expressed in SCC of the head and neck (P < or = .01), and 417 of these genes were abnormally expressed in all seven tumors in the same manner. Hierarchical clustering of the 121 genes that were abnormally expressed in cancerous relative to normal tissue (P < or = .001) showed that the tissue segregated into two groups consisting of normal and transformed tissue, as expected. The abnormal expression of two genes that were up regulated in oral SCC (ADAM 12 and PTHLH) and two genes that were down-regulated in SCCHN (EMP-1 and P11) were confirmed by real-time polymerase chain reaction and immunohistochemistry (ADAM 12) using additional sets of tissue. CONCLUSIONS: The data showed that oral SCC aberrantly express genes in cellular pathways related to proliferation, apoptosis, extracellular matrix degradation, adhesion, transforming growth factor-beta signaling, and transcription. Further work is needed to determine the role of these genes in the development and progression of oral SCC.

ADAM Proteins↗
PubMed2005

The impact of age on the epidemiology of incomplete abortions in South Africa after legislative change.

OBJECTIVE: In 1996 termination of pregnancy was legalised in South Africa. This article examines the impact of age on the epidemiology of incomplete abortion after legislative change. It draws comparison with the findings of a similar study undertaken in 1994. DESIGN: Multicentre, prospective, descriptive study. SETTING: Forty-seven public hospitals in all nine provinces. SAMPLE: A stratified random sample of all hospitals treating gynaecological emergencies was drawn. All women of gestation under 22 weeks who presented with incomplete abortion during three weeks of data collection in 2000 were included. METHODS: A data capture sheet completed by a clinician from the case notes. MAIN OUTCOME MEASURES: Demographic characteristics and clinical findings on admission by age of women. RESULTS: Overall, there was a significant increase in the proportion of cases with no signs of infection on admission (from 79.5% to 90.1%) and a significant decrease in evidence of interference on evacuation (4.5% to 0.6%) between 1994 and 2000. Substantial age differentials were seen. Women over 30 were significantly less likely than those 21-30 years or under 21 to be low severity (65.5% vs 75.2% vs 76.4%, P= 0.0087) and more likely to have offensive products (16.3% vs 6.0% vs 6.4%, P= 0.01) than the younger women. CONCLUSIONS: Legalisation of abortion had an immediate positive impact on morbidity, especially in younger women. This is an important change as teenagers had the highest morbidity in 1994. The trend is supported by evidence from the 1999-2001 Confidential Enquiry into Maternal Deaths, which further suggested that abortion mortality dropped by more than 90% since 1994.

Abortion, Incomplete↗
PubMed2005

Why are women still aborting outside designated facilities in metropolitan South Africa?

OBJECTIVE: To explore why South African women still abort outside designated services where there is substantial legal service provision. DESIGN: Descriptive study. SETTING: Three hospitals in Gauteng Province in South Africa. Sample Forty-six women attending hospital with incomplete abortion who had abortions induced outside of designated facilities. METHODS: An interviewer-administered questionnaire with open and closed questions was completed. Induction status was determined from answers to a set of closed questions. Open-ended questions explored the circumstances of induction. Main focus of interviews Methods of induction used, barriers to legal service use. RESULTS: Nearly two-thirds of women (n= 38) had self-induced or had consulted a traditional healer. A minority of these women (n= 11) indicated that they did this because they experienced barriers to legal service use. For others it was presented as a 'natural' response to a health problem (unwanted pregnancy). Several women (n= 10) were given misoprostol by a doctor, nurse, or pharmacist. Fifty-four percent of the women had not used legal services because they did not know about the law, while 15% knew of their legal rights, but did not know of a legal facility. Others did know where to access legal services but feared rude staff (17%) or breaches of confidentiality (6.5%). Others (6.5%) had been unable to get a legal abortion early enough in pregnancy to comply with the law. CONCLUSIONS: Lack of information on abortion rights under the Act and perceived poor quality of designated facilities were the most important barriers to access and should be addressed by policymakers and health service management. The willingness of women to self-medicate and visit traditional healers in these circumstances may influence the overall ability of the new legislation to reduce abortion morbidity.

Abortifacient Agents↗
PubMed2004

Evidence-based obstetric care in South Africa--influencing practice through the 'Better Births Initiative'.

Ensuring that health professionals practise according to evidence-based standards is important since it affects the quality and cost of care patients receive. The purpose of this research was to use a focused change programme (the Better Births Initiative) to influence obstetric practice of 10 hospitals in Gauteng, South Africa. The findings show some important improvements in practice following the implementation of the BBI; providers at some sites reduced the use of enemas, shaving and episiotomy, and increased use of oral fluids and companionship during labour. Qualitative data suggest that an interactive approach to implementing evidence-based practice can influence health professionals decisions to change practice, and that good working relationships and enthusiastic staff are central to effective change.

Delivery, Obstetric↗
PubMed2003

Regulatory effects of osteoprotegerin on cellular and humoral immune responses.

The interaction between receptor activator of nuclear factor-kappaB ligand (RANKL) and RANK has been reported to regulate immunity in addition to bone metabolism. The aim of this study was to determine if osteoprotegerin (OPG), an inhibitor of the RANKL-RANK interaction and possibly a new drug against osteoporosis, would adversely affect immunity. OPG was used to treat mice developing different models of cellular and humoral immune responses and also in vitro in T and B cell assays. In mice, OPG does not affect cell-mediated reactions such as contact hypersensitivity to the hapten oxazolone and liver damage, granuloma formation, and infectious load induced by mycobacterial infection. However, OPG increases humoral reactions such as the production of IgM, IgG, and IgE against the T cell dependent antigen keyhole limpet hemocyanin and the production of IgM against the T cell independent antigen Pneumovax. In vitro, OPG modestly co-stimulates T cells but does not affect the proliferation of B cells. OPG has modest immunoregulatory effects that seem to be confined to the humoral response to specific antigens.

Animals↗
PubMed2003

Abortion service provision in South Africa three years after liberalization of the law.

In 1996, South Africa introduced legislation that liberalized women's access to termination of pregnancy. This study presents the findings of a survey undertaken to describe the availability and accessibility of abortion services in 1999, three years after the law was passed. All facilities that had been officially designated to perform these services were contacted by telephone to determine whether they were providing the services, their capacity, whether they were performing second-trimester as well as first-trimester terminations, and how long women had to wait for these services. Nationally, 292 facilities had been designated, but in 1999 only 32 percent were functioning. Of the functioning facilities, 27 percent were in the private sector. Mapping of available services indicated that substantial parts of the country were entirely without such services. Half of the country's induced abortions were being performed in Gauteng province, although only 19 percent of women of reproductive age were living there. This finding indicates that service provision in other provinces was inadequate or lacking. Although in the first years following the new legislation efforts were made to establish abortion services, this study reveals gross inequality in service availability. Strategies for improving coverage are suggested.

Abortion, Legal↗