Regulation of GDF-15, a distant TGF-β superfamily member, in a mouse model of cerebral ischemia

GDF-15 is a novel distant member of the TGF-β superfamily and is widely distributed in the brain and peripheral nervous system. We have previously reported that GDF-15 is a potent neurotrophic factor for lesioned dopaminergic neurons in the substantia nigra, and that GDF-15-deficient mice show progressive postnatal losses of motor and sensory neurons. We have now investigated the regulation of GDF-15 mRNA and immunoreactivity in the murine hippocampal formation and selected cortical areas following an ischemic lesion by occlusion of the middle cerebral artery (MCAO). MCAO prominently upregulates GDF-15 mRNA in the hippocampus and parietal cortex at 3 h and 24 h after lesion. GDF-15 immunoreactivity, which is hardly detectable in the unlesioned brain, is drastically upregulated in neurons identified by double-staining with NeuN. NeuN staining reveals that most, if not all, neurons in the granular layer of the dentate gyrus and pyramidal layers of the cornu ammonis become GDF-15-immunoreactive. Moderate induction of GDF-15 immunoreactivity has been observed in a small number of microglial cells identified by labeling with tomato lectin, whereas astroglial cells remain GDF-15-negative after MCAO. Comparative analysis of the size of the infarcted area after MCAO in GDF-15 wild-type and knockout mice has failed to reveal significant differences. Together, our data substantiate the notion that GDF-15 is prominently upregulated in the lesioned brain and might be involved in orchestrating post-lesional responses other than the trophic support of neurons

High doses of medroxyprogesterone as the cause of disappearance of adherence of the zona pellucida to an oocyte

The zona pellucida (ZP) is an external glycoprotein membrane of oocytes of mammals and embryos in the early stage of their development. ZP first appears in growing ovarian follicles as an extracellular substance between the oocyte and granular cells. The zona pellucid markedly affects the development and maturation of the oocyte. The morphology of the ZP-oocyte complex allows a more precise determination of the oocyte maturity. According to numerous experimental studies, ZP is essential for preimplantation embryonic development of humans and other mammals. It prevents dispersion of blastomeres and enhances their mutual interactions. ZP is a dynamic structure responsible for the provision of nutrients to early forms of oocytes in mammals. The aim of the present study was untrastructural evaluation of the ZP-oocyte contact during inhibited ovulation. Female white rats (Wistar strain) received a suspension of medroxyprogesterone acetate (MPA) in incremental intramuscular bolus doses of 3.7 mg (therapeutic dose), 7.4 mg and 11.1 mg. The animals were decapitated 5 days after the administration of MPA. Ovarian sections were evaluated under a transmission electron microscope (TEM) Zeiss EM 900. Morphometric analysis of ZP was conducted using the cell imaging system by Olympus. In females exposed to therapeutic doses of MPA, ZP showed the structure of granular-fibrous reticulum of a medium electron density with single cytoplasmic processes originating from the surrounding structures. The oocyte cell membrane generated single, delicate processes directed toward ZP. Microvilli of the oocyte were short and thin. In the group receiving 7.4 mg of MPA, ZP had the structure of a delicate, loose granular-fibrous reticulum, and the oocyte cell membrane generated single microvilli directed toward ZP. In both those groups, the close ZP-oocyte contact was observed. Otherwise, in the group exposed to the highest MPA doses (11.1 mg), thicker and more numerous oocyte microvilli were found, which did not penetrate ZP matrix. They were dense, irregularly separated contour, forming a barrier between ZP and oocyte. The present findings are likely to suggest that MPA has inhibiting effects on the synthesis of binding proteins and causes the loss of the oocyte contact with ZP

Plasma MIC-1 correlates with systemic inflammation but is not an independent determinant of nutritional status or survival in oesophago-gastric cancer

BACKGROUND: Macrophage inhibitory cytokine-1(MIC-1) is a potential modulator of systemic inflammation and nutritional depletion, both of which are adverse prognostic factors in oesophago-gastric cancer (OGC). METHODS: Plasma MIC-1, systemic inflammation (defined as plasma C-reactive protein (CRP) of ⩾10 mg l(–1) or modified Glasgow prognostic score (mGPS) of ⩾1), and nutritional status were assessed in newly diagnosed OGC patients (n=293). Healthy volunteers (n=35) served as controls. RESULTS: MIC-1 was elevated in patients (median=1371 pg ml(–1); range 141–39 053) when compared with controls (median=377 pg ml(–1); range 141–3786; P<0.001). Patients with gastric tumours (median=1592 pg ml(–1); range 141–12 643) showed higher MIC-1 concentrations than patients with junctional (median=1337 pg ml(–1); range 383–39 053) and oesophageal tumours (median=1180 pg ml(–1); range 258–31 184; P=0.015). Patients showed a median weight loss of 6.4% (range 0.0–33.4%), and 42% of patients had an mGPS of ⩾1 or plasma CRP of ⩾10 mg l(–1) (median=9 mg l(–1); range 1–200). MIC-1 correlated positively with disease stage (r(2)=0.217; P<0.001), age (r(2)=0.332; P<0.001), CRP (r(2)=0.314; P<0.001), and mGPS (r(2)=0.336; P<0.001), and negatively with Karnofsky Performance Score (r(2)=−0.269; P<0.001). However, although MIC-1 correlated weakly with dietary intake (r(2)=0.157; P=0.031), it did not correlate with weight loss, BMI, or anthropometry. Patients with MIC-1 levels in the upper quartile showed reduced survival (median=204 days; 95% CI 157–251) when compared with patients with MIC-1 levels in the lower three quartiles (median=316 days; 95% CI 259–373; P=0.036), but MIC-1 was not an independent prognostic indicator. CONCLUSIONS: There is no independent link between plasma MIC-1 levels and depleted nutritional status or survival in OGC

Serum macrophage inhibitory cytokine 1 in rheumatoid arthritis: a potential marker of erosive joint destruction

OBJECTIVE: The transforming growth factor beta superfamily member macrophage inhibitory cytokine 1 (MIC-1) is expressed upon macrophage activation, regulated by the p53 pathway, and linked to clinical events in atherosclerosis and cancer. Since rheumatoid arthritis (RA) shares similar etiopathologic mechanisms with the above diseases, we sought to determine the clinical utility of determining MIC-1 serum levels and MIC-1 genotype in the management of RA. METHODS: Ninety-one RA patients were recruited. Serum was collected from 83 of these patients and synovial biopsy samples were collected from the remaining 8 patients. Of the 83 patients from whom serum was collected, 61 were treated on an outpatient basis (defined as having nonsevere disease), and 22 patients went on to undergo hemopoietic stem cell transplantation (HSCT) (defined as having severe disease). RESULTS: Serum levels of MIC-1 were higher in RA patients and reflected disease severity independently of classic disease markers. MIC-1 was detected in rheumatoid synovial specimens, and allelic variation of MIC-1 was associated with earlier erosive disease and severe treatment-resistant chronic RA. Additionally, algorithms including serum and/or allelic variation in MIC-1 predicted response to HSCT, the presence of severe disease, and joint erosions. CONCLUSION: Determination of serum levels of MIC-1 and MIC-1 genotype may be clinically useful in the management of RA as well as in selection of patients for HSCT, since they predict disease course and response to therapy. The data indicate a potential role for MIC-1 in RA pathogenesis. These results warrant larger prospective studies to fully delineate and confirm a role for MIC-1 genotyping and serum estimation in patient selection for HSCT and in the management of R