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Biomedical subjects

Geraldine M McCarthy

Publications and source records attributed to Geraldine M McCarthy.

17 recordsLinked to original sources
PubMed2007

Person-centered nursing practice with older people in Ireland.

This column presents an analysis of McCormack's conceptual framework for person-centered practice with older people as a theoretical basis for the delivery of care of older adults in an Irish context. The evaluative process is guided by the framework proposed by Fawcett (2000) for the analysis and evaluation of conceptual models of nursing. The historical evolution, philosophical claims, and an overview of the content of the model are addressed. The following criteria are then applied: logical congruence, the generation of the theory, the credibility of the model, and the contribution of the model to the discipline of nursing.

Aged↗
PubMed2006

Basic calcium phosphate crystals: pathways to joint degeneration.

PURPOSE OF REVIEW: Basic calcium phosphate crystals have long been associated with rheumatic syndromes. Although an understanding of the molecular mechanisms involved in generating these pathological effects has been significantly advanced in recent years, it is still incomplete. RECENT FINDINGS: Basic calcium phosphate crystals have been shown to increase prostaglandin E(2) production in human fibroblasts, mediated by the induction of both cyclooxygenases 1 and 2. Basic calcium phosphate crystals have also been found to upregulate IL-1beta in fibroblasts and chondrocytes. The upregulation of inducible nitric oxide synthase and stimulation of nitric oxide production in chondrocytes by octacalcium phosphate crystals has been demonstrated. The involvement of protein kinase C isoforms in basic calcium phosphate crystal-mediated matrix metalloproteinase 1 and 3 expression in human fibroblasts has been clarified. Two pathways are involved: protein kinase Calpha mediates the calcium-dependent pathway, whereas protein kinase Cmu activates the extracellular-regulated kinase pathway in a calcium-independent cascade. In addition, basic calcium phosphate crystals activate the transcription factor Egr-1, an effect that may contribute to the mitogenic effect of these crystals on fibroblasts. SUMMARY: Recent findings have emphasized the potential for basic calcium phosphate crystals to stimulate the production of a variety of inflammatory mediators such as prostaglandin E(2), nitric oxide, IL-1beta and matrix metalloproteinases, and have helped to elucidate the mechanisms of these effects. Such advances are essential for the ongoing search for effective therapies for basic calcium phosphate crystal-associated diseases.

Calcinosis↗
PubMed2005

Proinflammatory activation of macrophages by basic calcium phosphate crystals via protein kinase C and MAP kinase pathways: a vicious cycle of inflammation and arterial calcification?

Basic calcium phosphate (BCP) crystal deposition underlies the development of arterial calcification. Inflammatory macrophages colocalize with BCP deposits in developing atherosclerotic lesions and in vitro can promote calcification through the release of TNF alpha. Here we have investigated whether BCP crystals can elicit a proinflammatory response from monocyte-macrophages. BCP microcrystals were internalized into vacuoles of human monocyte-derived macrophages in vitro. This was associated with secretion of proinflammatory cytokines (TNFalpha, IL-1beta and IL-8) capable of activating cultured endothelial cells and promoting capture of flowing leukocytes under shear flow. Critical roles for PKC, ERK1/2, JNK, but not p38 intracellular signaling pathways were identified in the secretion of TNF alpha, with activation of ERK1/2 but not JNK being dependent on upstream activation of PKC. Using confocal microscopy and adenoviral transfection approaches, we determined a specific role for the PKC-alpha isozyme. The response of macrophages to BCP crystals suggests that pathological calcification is not merely a passive consequence of chronic inflammatory disease but may lead to a positive feed-back loop of calcification and inflammation driving disease progression.

Arteries↗
PubMed2005

Basic calcium phosphate crystals as a unique therapeutic target in osteoarthritis.

Osteoarthritis (OA) is the most common form of arthritis that occurs in humans. Despite its prevalence, the pathogenesis of OA is not fully understood. Intraarticular basic calcium phosphate (BCP) (an inclusive term for partially carbonate-substituted hydroxyapatite, octacalcium phosphate and tricalcium phosphate) crystals are implicated in OA and are associated with severe degenerative arthritis characterized by marked synovial hyperplasia, aggravated joint degeneration and large joint effusions. Their pathogenicity relates, at least in part, to their ability to stimulate cellular mitogenesis in a number of cell types including macrophages, porcine articular chondrocytes (PAC) and human fibroblasts (HF) and induce prostaglandin, cytokine and matrix metalloproteinase synthesis and secretion in HF and PAC. Identification of BCP crystals in OA joints remains problematic because of the lack of a simple and reliable analytic procedure. There is currently no drug available that prevents the formation or modifies the biological effects of BCP crystals. This review highlights the recent advances in our knowledge of BCP crystal deposition diseases and discusses the potential therapeutic strategies for BCP crystal-associated OA.

Animals↗
PubMed2005

Microcalcifications associated with breast cancer: an epiphenomenon or biologically significant feature of selected tumors?

Radiographic mammary calcifications occur in 30-50% of breast cancers and constitute one of the most important diagnostic markers of both benign and malignant lesions of the breast. The presence of oxalate-type microcalcification appears to be a reliable criterion in favor of the benign nature of the lesion or, at most, of a lobular carcinoma in situ. In contrast, calcium hydroxyapatite (HA) crystals are associated with both benign and malignant breast tumors. Although the diagnostic value of microcalcifications in breast cancer is of great importance, the genesis of these calcifications is unclear. Despite numerous histological ultrastructure studies of HA deposits in breast carcinomas, to date there have been limited investigations of the potential role of these crystals in breast cancer. We review the literature examining the biological effects of HA crystals in breast cancer cell lines, specifically the mechanism of HA-induced mitogenesis and upregulation of gene expression.

Breast↗
PubMed2005

Eicosanoids, osteoarthritis, and crystal deposition diseases.

PURPOSE OF REVIEW: Eicosanoids are produced by chondrocytes, synoviocytes, and subchondral osteoblasts within the osteoarthritic joint and are involved in normal joint physiology as well as in the pathogenesis of joint disorders such as osteoarthritis. Calcium-containing crystals are found in most osteoarthritic joints and have been implicated in osteoarthritis. Recent advances in the understanding of the potential role of eicosanoids in the pathogenesis of osteoarthritis and in potential therapeutic targeting of eicosanoid pathways are reviewed. RECENT FINDINGS: The ability of interleukin-1beta to upregulate microsomal prostaglandin E2 synthase-1 in synovial fibroblasts and chondrocytes of patients with osteoarthritis has been demonstrated. A potential role for prostaglandin E2 in downregulating interleukin-1beta-induced inflammatory responses has also been described. Basic calcium phosphate crystals can upregulate cyclooxygenase-1 and cocylooxygenase-2 expression, both of which contributed to the observed increase in prostaglandin E2 production in human fibroblasts. Novel potential mechanisms of inhibition of eicosanoid synthesis are also discussed. Last, further evidence of amelioration of osteoarthritis in animal models by the dual 5-lipoxygenase/cyclooxygenase inhibitor licofelone has been reported. SUMMARY: The inhibition of prostaglandin synthesis has long been a ornerstone of the pharmacologic treatment of osteoarthritis. Nevertheless, prostaglandins may have potentially beneficial as well as deleterious effects in osteoarthritis. In addition, other eicosanoids such as leukotrienes have also been implicated in the pathogenesis of osteoarthritis. Therefore, more selective inhibition of prostaglandin pathways and/or inhibition of leukotriene activity may prove to be effective therapeutic strategies in osteoarthritis.

Animals↗
PubMed2005

Polymyalgia rheumatica as an unusual cause of pleural and pericardial effusion.

We report a patient with polymyalgia rheumatica (PMR) who initially presented with chest pain pleural and pericardial effusions. A history was then obtained of shoulder girdle aching and stiffness, suggestive of PMR, and laboratory investigations supported the diagnosis. A rapid response to 15 mg prednisolone once daily was noted, with resolution of effusion and symptoms. Although pericardial effusion has previously been reported, this is the first reported case of pleuropericardial effusions in PMR. Rheumatologists should be aware that PMR may occasionally be the explanation for pleuropericardial effusion in the elderly.

Aged↗
PubMed2004

Polymorphisms in the MAOA, MAOB, and COMT genes and aggressive behavior in schizophrenia.

Some studies have reported associations between COMT and MAO genotypes and aggression, though results have been inconsistent. We examined the relationship between Overt aggression scale (OAS) scores, and both MAOA and MAOB polymorphisms in a well-powered sample of 346 subjects with schizophrenia. We also examined COMT in a Stage II replication sample of 150 individuals, and combined these results with our previously reported (Stage I) findings for COMT. We found no evidence of any associations between OAS ratings and any of the polymorphisms investigated under different genetic models. There was no evidence of epistatic interaction between MAOA and COMT on OAS scores. These results fail to support the theory that functional polymorphisms within the MAOA, MAOB, or COMT genes, as determinants of catecholamine enzymatic activity, are risk factors for aggressive behavior.

Aggression↗
PubMed2004

Basic calcium phosphate crystal-induced prostaglandin E2 production in human fibroblasts: role of cyclooxygenase 1, cyclooxygenase 2, and interleukin-1beta.

OBJECTIVE: To elucidate the mechanism of basic calcium phosphate (BCP) crystal-induced prostaglandin E(2) (PGE(2)) production in human foreskin fibroblasts (HFFs), to identify the signaling pathway involved in the induction of cyclooxygenase 2 (COX-2) messenger RNA (mRNA) by BCP crystals, to examine the effect of BCP crystals on interleukin-1beta (IL-1beta) mRNA expression, and to investigate the potential of phosphocitrate to abrogate the BCP crystal-induced effects. METHODS: PGE(2) levels were quantified using a commercial enzyme immunoassay kit. COX-2 and COX-1 transcript levels were quantified using real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Induction of IL-1beta and COX-2 mRNA was examined by end-point RT-PCR. COX-2 protein expression was assessed by Western blotting. RESULTS: PGE(2) production measured 4 and 30 hours after BCP crystal treatment was higher in BCP crystal-treated (mean +/- SEM 1,891 +/- 273 pg/microg and 1,792 +/- 233 pg/microg, respectively) than in untreated (88 +/- 5 pg/microg and 205 +/- 93 pg/microg, respectively) HFFs. The PGE(2) produced after 4 hours was sensitive to inhibition with NS398, a selective COX-2 inhibitor, implying that it was COX-2 mediated, whereas the PGE(2) produced at 30 hours could not be completely inhibited by NS398. Real-time RT-PCR demonstrated a 23-fold increase in COX-2 mRNA that was maximal at 4 hours, whereas analysis of mRNA for COX-1 showed up-regulation of transcript peaking at 24 hours poststimulation (1.75-fold increase). The protein kinase C and phosphatidylinositol 3-kinase signal-transduction inhibitors bisindolylmaleimide I and LY294002, respectively, blocked BCP crystal-induced COX-2 mRNA in HFFs. In addition, BCP crystals were found to up-regulate the proinflammatory cytokine IL-1beta (maximal at 8 hours). The induction of both COX-2 and IL-1beta by BCP crystals was attenuated when the cells were treated with phosphocitrate. CONCLUSION: These findings indicate that BCP crystals may be an important amplifier of PGE(2) production through induction of the COX enzymes and the proinflammatory cytokine IL-1beta.

Calcium Phosphates↗
PubMed2004

How crystals damage tissue.

Basic calcium phosphate, calcium pyrophosphate dihydrate, and monosodium urate crystals are the most common types of crystals associated with human disease. Although there is a well-established association between these crystals and various forms of joint disease, recent evidence points to an association of basic calcium phosphate crystals with breast cancer and atherosclerosis. Crystal-induced tissue damage is affected by degradative proteases, cytokines, chemokines, and prostanoids produced by cells stimulated by crystals. In the case of basic calcium phosphate and calcium pyrophosphate dihydrate crystals, these responses are augmented by the cellular proliferation that results from their induction of mitogenesis. The understanding of the molecular mechanisms involved in generating these pathologic effects has been significantly advanced in recent years. Such advances are essential to the ongoing search for more effective therapies for crystal-associated diseases.

Arteriosclerosis↗
PubMed2004

Basic calcium phosphate deposition in the joint: a potential therapeutic target in osteoarthritis.

PURPOSE OF REVIEW: Basic calcium phosphate crystals are responsible for a number of clinical syndromes. The study of basic calcium phosphate crystal deposition diseases has been hindered by a lack of readily available, accurate, diagnostic tests. Recent data have provided further understanding of the mechanisms by which basic calcium phosphate crystals induce inflammation and degeneration within the joint, as well as their potential role in other conditions such as cancer and atherosclerosis. RECENT FINDINGS: New information on the effects of basic calcium phosphate crystals on matrix metalloproteinases and mitogenesis further supports a role for basic calcium phosphate crystals in the pathogenesis of osteoarthritis. Phosphocitrate remains the most promising of the potential therapeutic agents, which could antagonize the effects of basic calcium phosphate crystals, although other therapies have also been examined. SUMMARY: Further work is needed to clarify the exact role basic calcium phosphate crystals play in the development of osteoarthritis.

Arteriosclerosis↗
PubMed2003

Hydroxyapatite deposition disease of the joint.

Basic calcium phosphate (BCP) crystals include partially carbonate-substituted hydroxyapatite, octacalcium phosphate, and tricalcium phosphate. They may form deposits, which are frequently asymptomatic but may give rise to a number of clinical syndromes including calcific periarthritis, Milwaukee shoulder syndrome, and osteoarthritis, in and around joints. Recent data suggest that magnesium whitlockite, another form of BCP, may play a pathologic role in arthritis. Data from the past year have provided further understanding of the mechanisms by which BCP crystals induce inflammation and degeneration. There remains no specific treatment to modify the effects of BCP crystals. Although potential drugs are being identified as the complex pathophysiology of BCP crystals is unraveled, much work remains to be done in order to translate research advances to date into tangible clinical benefits.

Calcium Metabolism Disorders↗
PubMed2003

Phosphocitrate inhibits calcium hydroxyapatite induced mitogenesis and upregulation of matrix metalloproteinase-1, interleukin-1beta and cyclooxygenase-2 mRNA in human breast cancer cell lines.

Microcalcifications containing calcium hydroxyapatite (HA) are often associated with malignant human breast lesions. Frequently, they are the only mammographic features that indicate the presence of a tumoural lesion. We previously reported the induction of both mitogenesis and prostaglandin E2 (PGE2) production and the increased activities of matrix metalloproteinases (MMPs) MMP-2 and MMP-9 in normal human mammary epithelial cells and breast cancer cell lines, treated with HA. In the present study we attempted to elucidate the mechanism of these biological effects. Firstly, we found that direct cell-crystal contact was required for induction of mitogenesis as the effect was not merely a result of isotopic exchange of calcium into the culture medium. Treatment with bafilomycin A1, a proton pump inhibitor, abrogated HA-induced mitogenesis to control cell levels. These results suggest that phagocytosis and intracellular crystal dissolution is required for HA-induced mitogenesis. We also demonstrated that the increase in prostaglandin E2, previously reported, is due, at least in part, to HA-induced upregulation of cyclooxygenase-2 (COX-2) in Hs578T cells. An accumulation of MMP-1 mRNA was also shown in response to HA stimulation in Hs578T cells. Furthermore, a HA-induced increase in interleukin-1beta (IL-1beta), a potent inducer of MMP-1 gene expression, was demonstrated in Hs578T cells at 2 and 4 h. Treatment with phosphocitrate (PC) (a naturally occurring inhibitor of calcium phosphate crystallisation, which is known to block a number of HA-induced biological effects in other cell types) blocked HA-mediated mitogenesis, as well as, COX-2, MMP-1 and IL-1beta induction, at the transcriptional level. These results show that calcium HA crystals are capable of exerting significant biological effects on surrounding cells which can be abrogated by PC and emphasise the role of calcium HA in amplifying the pathological process involved in breast cancer.

Adenocarcinoma↗
PubMed2002

Signaling mechanisms involved in crystal-induced tissue damage.

The association of crystal deposition with osteoarthritis and joint destruction is well established. Recent advances in understanding the mechanisms whereby calcium crystals contribute to cartilage damage are highlighted in this review. In vitro studies have shown that when calcium-containing crystals come in contact with cells they cause an influx in Ca 2+ concentration and activation of p42/44 mitogen-activated protein kinases. This is followed by induction of proto-oncogenes (c- fos, c- jun ) and induction of the nuclear transcription factors activator protein-1 and nuclear factor-kappaB, which in turn lead to crystal-induced modulation of normal gene expression. Some of the downstream effects known to date include increased mitogenesis, up-regulation of members of the matrix metalloproteinase family, down-regulation of tissue inhibitor of metalloproteinase-1 and -2 in fibroblasts, induction of neutrophil chemotactic chemokines such as interleukin-8, activation and degranulation of neutrophils, and inhibition of neutrophil apoptosis. Because no known drug prevents or treats the consequences of basic calcium phosphate crystal deposition, an improved understanding of the molecular mechanisms leading to crystal-induced joint degeneration is essential to the development of a rational approach to target the consequences of crystal deposition.

Animals↗
PubMed2002

Hereditary hemochromatosis: a common, often unrecognized, genetic disease.

Hereditary hemochromatosis in people of northern European descent is more common than many physicians realize. It causes excessive gastrointestinal absorption of iron, leading to potentially fatal iron deposition in multiple organs. Early diagnosis and phlebotomy to reduce iron stores can prevent complications and provide normal life expectancy. Genetic testing of relatives of patients with hemochromatosis is warranted in some circumstances.

Algorithms↗