Role of endogenous and exogenous female sex hormones in arthritis and osteoporosis development in B10.Q-ncf1*/* mice with collagen-induced chronic arthritis

<p>Abstract</p> <p>Background</p> <p>Collagen-induced arthritis (CIA) is an often-used murine model for human rheumatoid arthritis (RA). Earlier studies have shown potent anti-arthritic effects with the female sex hormone estradiol and the selective estrogen receptor modulator (SERM) raloxifene in CIA in DBA/1-mice. B10.Q-ncf1^*/*mice are B10.Q mice with a mutated Ncf1 gene. In B10.Q-ncf1^*/*mice, CIA develops as a chronic relapsing disease, which more accurately mimics human RA. We investigated the role of endogenous and exogenous sex steroids and raloxifene in the course of this model of chronic arthritis. We also examined whether treatment would prevent the development of inflammation-triggered generalized osteoporosis.</p> <p>Methods</p> <p>Female B10.Q-ncf1^*/*mice were sham-operated or ovariectomized, and CIA was induced. 22 days later, when 30% of the mice had developed arthritis, treatment with raloxifene, estradiol or vehicle was started, and the clinical disease was evaluated continuously. Treatment was continued until day 56 after immunization. At termination of the experiment (day 73), bone mineral density (BMD) was analyzed, paws were collected for histological examination, and sera were analyzed for markers of cartilage turnover and pro-inflammatory cytokines.</p> <p>Results</p> <p>Raloxifene and estradiol treatment, as well as endogenous estrogen, decreased the frequency of arthritis, prevented joint destruction and countered generalized osteoporosis. These effects were associated with lower serum levels of the pro-inflammatory cytokine IL-6.</p> <p>Conclusions</p> <p>This is the first study to show that raloxifene and estradiol can ameliorate established erosive arthritis and inflammation-triggered osteoporosis in this chronic arthritis model. We propose that treatment with raloxifene could be a beneficial addition to the treatment of postmenopausal RA.</p

Co expression of SCF and KIT in gastrointestinal stromal tumours (GISTs) suggests an autocrine/paracrine mechanism

KIT is a tyrosine kinase receptor expressed by several tumours, which has for specific ligand the stem cell factor (SCF). KIT is the main oncogene in gastrointestinal stromal tumours (GISTs), and gain-of-function KIT mutations are present in 70% of these tumours. The aim of the study was to measure and investigate the mechanisms of KIT activation in 80 KIT-positive GIST patients. KIT activation was quantified by detecting phosphotyrosine residues in Western blotting. SCF production was determined by reverse transcriptase–PCR, ELISA and/or immunohistochemistry. Primary cultures established from three GISTs were also analysed. The results show that KIT activation was detected in all cases, even in absence of KIT mutations. The fraction of activated KIT was not correlated with the mutational status of GISTs. Membrane and soluble isoforms of SCF mRNA were present in all GISTs analysed. Additionally, SCF was also detected in up to 93% of GISTs, and seen to be present within GIST cells. Likewise, the two SCF mRNA isoforms were found to be expressed in GIST-derived primary cultures. Thus, KIT activation in GISTs may in part result from the presence of SCF within the tumours

Mutually Positive Regulatory Feedback Loop between Interferons and Estrogen Receptor-α in Mice: Implications for Sex Bias in Autoimmunity

gene) and stimulates expression of target genes. female mice had relatively higher steady-state levels of mRNAs encoded by the IFN and ERα-responsive genes as compared to the age-matched males.Our observations identify a novel mutually positive regulatory feedback loop between IFNs and ERα in immune cells in mice and support the idea that activation of this regulatory loop contributes to sex bias in SLE

Brain Abnormalities and Glioma-Like Lesions in Mice Overexpressing the Long Isoform of PDGF-A in Astrocytic Cells

BACKGROUND: Deregulation of platelet-derived growth factor (PDGF) signaling is a hallmark of malignant glioma. Two alternatively spliced PDGF-A mRNAs have been described, corresponding to a long (L) and a short (S) isoform of PDGF-A. In contrast to PDGF-A(S), the PDGF-A(L) isoform has a lysine and arginine rich carboxy-terminal extension that acts as an extracellular matrix retention motif. However, the exact role of PDGF-A(L) and how it functionally differs from the shorter isoform is not well understood.\ud \ud METHODOLOGY/PRINCIPAL FINDINGS: We overexpressed PDGF-A(L) as a transgene under control of the glial fibrillary acidic protein (GFAP) promoter in the mouse brain. This directs expression of the transgene to astrocytic cells and GFAP expressing neural stem cells throughout the developing and adult central nervous system. Transgenic mice exhibited a phenotype with enlarged skull at approximately 6-16 weeks of age and they died between 1.5 months and 2 years of age. We detected an increased number of undifferentiated cells in all areas of transgene expression, such as in the subependymal zone around the lateral ventricle and in the cerebellar medulla. The cells stained positive for Pdgfr-α, Olig2 and NG2 but this population did only partially overlap with cells positive for Gfap and the transgene reporter. Interestingly, a few mice presented with overt neoplastic glioma-like lesions composed of both Olig2 and Gfap positive cell populations and with microvascular proliferation, in a wild-type p53 background.\ud \ud CONCLUSIONS: Our findings show that PDGF-A(L) can induce accumulation of immature cells in the mouse brain. The strong expression of NG2, Pdgfr-α and Olig2 in PDGF-A(L) brains suggests that a fraction of these cells are oligodendrocyte progenitors. In addition, accumulation of fluid in the subarachnoid space and skull enlargement indicate that an increased intracranial pressure contributed to the observed lethality.\ud \u

Daidzein Prevents the Increase in CD4+CD28null T Cells and B Lymphopoesis in Ovariectomized Mice: A Key Mechanism for Anti-Osteoclastogenic Effect

Estrogen deficiency leads to an upregulation of TNF-α producing T cells and B-lymphopoesis which augments osteoclastogenesis. Estrogen deficiency also increases the population of premature senescent CD4+CD28null T cells which secrete a higher amount of TNF-α thus leading to enhanced osteoclastogenesis. Isoflavonoids like daidzein and genistein are found mostly in soybeans, legumes, and peas. These share structural similarity with 17β-stradiol (E2) and have osteoprotective role. This study explores the effect of daidzein (Daid) on the proliferation of TNF-α producing T cells, premature senescent T cells and B cell lymphopoesis under estrogen deficient conditions. For this study adult Balb/c mice were treated with Daid at 10 mg/kg body weight dose by oral gavage daily post ovariectomy (Ovx). After six weeks animals were autopsied and bone marrow and spleen cells were collected for FACS analysis. Blood serum was collected for ELISA. It was observed that Ovx mice treated with Daid for six weeks show reduction in Ovx induced expansion of CD4+ T cells in bone marrow and spleen when analysed by flow cytometry. Estrogen deficiency led to increased prevalence of TNF-α secreting CD4+CD28null T cells, however, treatment with Daid increased the percentage of CD4+CD28+ T cells. Co-culture of CD4+CD28null T cells and bone marrow resulted in enhanced osteoclastogenesis as evident by increased tartarate resistant acid phosphatase (TRAP) expression, an osteoclast marker. However, treatment with Daid resulted in reduced osteoclastogenesis in CD4+CD28null T cells and bone marrow cell co-culture. Daid also regulated B lymphopoesis and decreased mRNA levels of RANKL in B220+ cells. Taken together, we propose that one of the mechanisms by which Daid prevents bone loss is by reversing the detrimental immune changes as a result of estrogen deficiency

Antiviral activity of the mineralocorticoid receptor NR3C2 against Herpes simplex virus Type 1 (HSV-1) infection

Abstract Analysis of a genome-scale RNA interference screen of host factors affecting herpes simplex virus type 1 (HSV-1) revealed that the mineralocorticoid receptor (MR) inhibits HSV-1 replication. As a ligand-activated transcription factor the MR regulates sodium transport and blood pressure in the kidney in response to aldosterone, but roles have recently been elucidated for the MR in other cellular processes. Here, we show that the MR and other members of the mineralocorticoid signalling pathway including HSP90 and FKBP4, possess anti-viral activity against HSV-1 independent of their effect on sodium transport, as shown by sodium channel inhibitors. Expression of the MR is upregulated upon infection in an interferon (IFN) and viral transcriptional activator VP16-dependent fashion. Furthermore, the MR and VP16, together with the cellular co-activator Oct-1, transactivate the hormone response element (HRE) present in the MR promoter and those of its transcriptional targets. As the MR induces IFN expression, our data suggests the MR is involved in a positive feedback loop that controls HSV-1 infection

Mothers' accounts of their stillbirth experiences and of their subsequent relationships with their living infant:an interpretative phenomenological analysis

BACKGROUND: Due to contradictory findings regarding the effects of seeing and holding stillborn infants on women's worsening mental health symptoms, there is a lack of clear of guidance in stillbirth bereavement care. Although some current research examines this phenomenon we are still not certain of the meaning of such experiences to women and what effects there may be on her subsequent parenting. Thus the present study focuses on the meaning of the stillbirth experience to women and its influence on the subsequent pregnancy and subsequent parenting from the mothers' own experiences. METHODS: A purposive sample of six women who experienced a stillbirth during their first pregnancy and who then went on to give birth to a living child after a further pregnancy, took part in email interviews, providing rich and detailed experiential narratives about both the stillbirth itself, and their relationship with their living child. An Interpretive Phenomenological Analysis was carried out in order to focus on mothers making sense of such experiences. RESULTS: Analysis of written accounts led to the development of three overarching themes. In 'Broken Canopy', 'How This Happened' and 'Continuing Bonds', their accounts revealed an ongoing process where women accepted a new 'unsafe' view of the world, re-evaluated their view of self and others, and established relationships with both the deceased and the living infant. CONCLUSIONS: This study provided an insight into the stillbirth experience of mothers and its meaning to them with an existential focus. Typically the mother struggled with the contradictory process of accepting the existence of her deceased baby (this baby once lived) while being aware of the nonexistence (this baby). Meeting the dead baby was a crucial point at which the mother started processing her grief. The importance of individual differences in dealing with stressful situations was highlighted in terms of attachment strategies. Subsequent parenting experiences of mothers were very much influenced by their own previous experiences. Although some mothers managed to integrate this trauma into their life some remained very concerned and anxious about future and this anxiety then translated into their parenting experiences

PDGF and PDGF receptors in glioma

The family of platelet-derived growth factors (PDGFs) plays a number of critical roles in normal embryonic development, cellular differentiation, and response to tissue damage. Not surprisingly, as it is a multi-faceted regulatory system, numerous pathological conditions are associated with aberrant activity of the PDGFs and their receptors. As we and others have shown, human gliomas, especially glioblastoma, express all PDGF ligands and both the two cell surface receptors, PDGFR-α and -β. The cellular distribution of these proteins in tumors indicates that glial tumor cells are stimulated via PDGF/PDGFR-α autocrine and paracrine loops, while tumor vessels are stimulated via the PDGFR-β. Here we summarize the initial discoveries on the role of PDGF and PDGF receptors in gliomas and provide a brief overview of what is known in this field

Autocrine PDGF stimulation in malignancies

Platelet-derived growth factor (PDGF) isoforms are important mitogens for different types of mesenchymal cells, which have important functions during the embryonal development and in the adult during wound healing and tissue homeostasis. In tumors, PDGF isoforms are often over-expressed and contribute to the growth of both normal and malignant cells. This review focuses on tumors expressing PDGF isoforms together with their tyrosine kinase receptors, thus resulting in autocrine stimulation of growth and survival. Patients with such tumors could benefit from treatment with inhibitors of either PDGF or PDGF receptors

Assessment of different quantification metrics of [¹⁸F]-NaF PET/CT images of patients with abdominal aortic aneurysm

Background: We aim to assess the spill-in effect and the benefit in quantitative accuracy for [18F]-NaF PET/CT imaging of abdominal aortic aneurysms (AAA) using the background correction (BC) technique. Methods: Seventy-two datasets of patients diagnosed with AAA were reconstructed with ordered subset expectation maximization algorithm incorporating point spread function (PSF). Spill-in effect was investigated for the entire aneurysm (AAA), and part of the aneurysm excluding the region close to the bone (AAAexc). Quantifications of PSF and PSF+BC images using different thresholds (% of max. SUV in target regions-of-interest) to derive target-to-background (TBR) values (TBRmax, TBR90, TBR70 and TBR50) were compared at 3 and 10 iterations. Results: TBR differences were observed between AAA and AAAexc due to spill-in effect from the bone into the aneurysm. TBRmax showed the highest sensitivity to the spill-in effect while TBR50 showed the least. The spill-in effect was reduced at 10 iterations compared to 3 iterations, but at the expense of reduced contrast-to-noise ratio (CNR). TBR50 yielded the best trade-off between increased CNR and reduced spill-in effect. PSF+BC method reduced TBR sensitivity to spill-in effect, especially at 3 iterations, compared to PSF (P-value ≤ 0.05). Conclusion: TBR50 is robust metric for reduced spill-in and increased CNR