Sex-specific differences in polygenic (essential) hypertension are commonly attributed to the role of sex steroid hormone-receptor systems attenuating sex-common disease mechanisms in premenopausal women. However, emerging observations indicate sex-specific genetic susceptibility in various traits, thus requiring systematic study. Here we report a comparative analysis of independent total genome scans for salt-sensitive hypertension susceptibility quantitative trait loci (QTLs) in male and female F2 [Dahl R/jrHS x S/jrHS] intercross rats exposed to high-salt (8% NaCl) rat diets. Hypertension was phenotyped with three quantitative traits: blood pressure (BP) elevation associated with increased hypertensive renal disease [glomerular injury score (GIS)] and increased cardiac mass [relative heart weight (RHW)] obtained 8-12 wk after high-salt challenge; 24-h nonstress, telemetric BP measurements were used. Although sex-common QTLs were detected for BP [chromosome (chr) 1-144.3 Mbp; chr 1-208.8 Mbp], GIS (chr 1-208.8 Mbp), and cardiac mass (chr 5-150.3 Mbp), most QTLs across the three phenotypes studied are gender specific as follows: female QTLs for BP (chr 2-106.7 Mbp, chr 2-181.7 Mbp, chr 5-113.9 Mbp, chr 5-146.7 Mbp, chr 12-12.8 Mbp), GIS (chr 15-59.6 Mbp), and RHW (chr 2-31.5 Mbp, chr 5-154.7 Mbp, chr 5-110.9 Mbp); male QTLs for BP (chr 2-196.7 Mbp, chr 11-48.0 Mbp, chr 20-35.7 Mbp), GIS (chr 6-3.3 Mbp, chr 20-40.7 Mbp), and RHW (chr 6-3.3 Mbp, chr 20-40.7 Mbp). Furthermore, interacting loci with significant linkage were detected only in female F2 intercross rats for BP and hypertensive renal disease. Comparative analyses revealed concordance of BP QTL peaks with previously reported rat model and human hypertension susceptibility genes and with BP QTLs in previous Dahl S-derived F2 intercross studies and also suggest strain-specific genetic modifiers of sex-specific determinants. Altogether, the data provide key experimental bases for sex-specific investigation of mechanisms and intervention and prevention strategies for polygenic hypertension in humans.
A priori, a common receptor induced in tumor microvessels, cancer cells and cancer stem-like cells (CSCs) that is involved in tumor angiogenesis, invasiveness, and CSC anoikis resistance and survival, could underlie contemporaneous coordination of these events rather than assume stochasticity. Here we show that functional analysis of the dual endothelin1/VEGFsignal peptide receptor, DEspR, (formerly named Dear, Chr.4q31.2) supports the putative common receptor paradigm in pancreatic ductal adenocarcinoma (PDAC) and glioblastoma (GBM) selected for their invasiveness, CD133+CSCs, and polar angiogenic features. Unlike normal tissue, DEspR is detected in PDAC and GBM microvessels, tumor cells, and CSCs isolated from PDAC-Panc1 and GBM-U87 cells. DEspR-inhibition decreased angiogenesis, invasiveness, CSC-survival and anoikis resistance in vitro, and decreased Panc1-CSC and U87-CSC xenograft tumor growth, vasculo-angiogenesis and invasiveness in nudenu/nu rats, suggesting that DEspR activation would coordinate these tumor progression events. As an accessible, cell-surface ‘common receptor coordinator’, DEspR-inhibition defines a novel targeted-therapy paradigm for pancreatic cancer and glioblastoma.
Oral administration of live Labre significantly increased IFN-alpha production in a dose-dependent manner. Labre intake tended to be most beneficial in subjects with initially low levels of IFN-alpha production. Heat-treated Labre did not elicit a response similar to that of the live bacteria.
Abstractwhich may contribute to the pulmonary involvement in patients with sarcoidosis. Background -Sarcoidosis is a systemic (Thorax 1997;52:431-437) granulomatous disorder of unknown origin characterised by accumulation of T Keywords: adhesion molecules, chemokines, pullymphocytes and macrophages in multiple monary sarcoidosis.organs. Several cytokines and adhesion molecules may contribute to the accumulation of T lymphocytes in pulmonary sarcoidosis. The distribution of T Sarcoidosis is a chronic systemic disorder charlymphocyte subsets, T cell bearing CD11a acterised by the presence of non-caseating and chemokines such as regulated on granulomas and accumulation of T lymphoactivation normal T expressed and se-cytes and macrophages in multiple organs. 1 T lymphocytes, alveolar macrophages, and sevcreted (RANTES), macrophage inflameral cytokines are thought to play an important matory peptide 1 (MIP-1 ), and role in sarcoidosis, 2-4 although the aetiology of macrophage chemoattractant protein 1 the disease is still unknown. Recent studies (MCP-1) in bronchoalveolar lavage (BAL) using monoclonal antibodies to cell surface fluid and peripheral blood were compared antigens have demonstrated the presence of in untreated patients with sarcoidosis and subsets of T cells and expression of cell adnormal subjects.hesion molecules on peripheral blood lymMethods -Flow cytometric analysis with phocytes such as CD11a/CD18 (lymphocyte monoclonal antibodies to cell surface anfunction associated antigen 1, LFA-1) in sartigens was used to identify T lymphocyte coidosis. 5 Furthermore, analysis of bronchosubsets in the BAL fluid of untreated alveolar lavage (BAL) fluid in patients with patients with sarcoidosis (n=40) -either pulmonary sarcoidosis has also shown the preswithout (group A, n=12) or with (group B, ence of activated CD4+ and CD8+ T lymn=28) radiological evidence of pulmonary phocytes expressing HLA-DR antigen, 6 7 involvement -and in 22 normal subjects.increased alveolar macrophages, and preThe level of different chemokines was dominance of CD29+ memory T cells. 5 8 9 estimated by enzyme linked immunoLeucocyte adhesion molecules such as LFAsorbent assay (ELISA).1 of the 2 family are involved in leucocyteResults -A high percentage of CD3+ cells, endothelial adherence in the lung, 10 and the CD4+ cells expressing HLA-DR antigen, mechanism of T cell migration into the lung is and a high CD4/CD8 ratio were detected also initially dependent on the presence of in the BAL fluid of patients compared with adhesion molecules of both endothelial cells normal subjects. In particular, CD4+ and leucocytes. The 2 family shares a common CD29+ memory T cells were significantly chain (CD18) which is combined with three increased in patients with sarcoidosis. different chains (LFA-1, CD11a; Mac-1, Furthermore, these cells were higher in CD11b; p150/95, CD11c), and intercellular those in group B than group A. The level sible interaction between activated mem-phages. RANTES is a selective chemotactic
SUMMARYWe investigated the contribution of T cells in diffuse panbronchiolitis (DPB) by identifying T cell subsets in BALF of 36 patients with DPB, before and after long-term treatment with macrolide antibiotics, and 16 healthy control subjects. The percentages of lymphocytes and CD3þ gd þ cells in BALF of DPB patients and control subjects were similar, but the absolute number of these cells was higher in DPB patients. Treatment resulted in a significant reduction in the absolute number of these cells. A further two-colour analysis of T cell subsets in BALF showed a significantly higher ratio and number of CD8 þ HLA-DR þ cells in DPB patients. Treatment resulted in a significant reduction of activated T cells. Most BALF CD8 þ cells were CD8The number of these cells in BALF of DPB patients (26 . 69 Ϯ 5 . 86 × 10 3 /ml) was higher than the control (2 . 02 Ϯ 0 . 38 × 10 3 /ml; P < 0 . 001), and a significant reduction was observed after treatment (7 . 69 Ϯ 2 . 59 × 10 3 /ml; P < 0 . 01). The number of CD4 þ cells was also higher in DPB patients than in controls, and most were CD4 þ CD29þ memory T cells. However, treatment did not influence the number of these cells. The number of lymphocytes, CD3 and CD4þ CD29 þ cells was higher in patients with bacterial infection than in those without bacterial infection, and interestingly, macrolide therapy reduced the number of lymphocytes,þ CD11b ¹ and CD8 þ HLA-DR þ cells, irrespective of bacterial infection. In peripheral blood, the percentage of CD8 þ HLA-DR þ cells was also higher in DPB patients than in healthy subjects, and significantly decreased after treatment. The percentage of CD8 þ CD11b ¹ cells in peripheral blood was similar in DPB patients and normal subjects, and treatment significantly reduced the percentage of these cells. Finally, the expression of the adhesion molecules CD11a/CD18 (a/b-chains of LFA-1) on lung CD3 þ cells and CD49d (a-chain of VLA) on lung CD4 þ cells was enhanced compared with that on peripheral blood in DPB patients. Our results suggest that elevation of memory T cells and activation of CD8 þ cells, mainly cytotoxic T cells, in the airway lumen of DPB patients may contribute to chronic bronchial inflammation, possibly through up-regulation of adhesion molecules. Our findings also indicate that macrolide antibiotics may have a direct or indirect suppressive effect on cytotoxic T cells, and as such, reduce inflammation and improve clinical condition.
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