Subarachnoid hemorrhage following spontaneous intracranial carotid artery dissection

Summary Subarachnoid hemorrhage due to spontaneous dissection of intracranial vessels is uncommon. Most such cases are confined to the posterior circulation. Dissection of an intracranial carotid artery producing subarachnoid hemorrhage without a focal ischemic event is rarely documented. We report a case and review the subject.     

Non-expression of a common mutation in the 21-hydroxylase gene: implications for prenatal diagnosis and carrier testing.

Mutation analysis in the family of a child with 21-hydroxylase deficiency showed that the father and affected child were homozygous for a mutation, A/C655G, believed to activate a cryptic splice site in intron 2 of the 21-hydroxylase gene. The father, who was clinically asymptomatic, showed no biochemical evidence of disease. These results create problems for the management of future pregnancies in such families and for the interpretation of the risk associated with carrier status for this mutation.     

The fate and toxicity of Raman-active silica-gold nanoparticles in mice

Raman spectroscopy is an optical imaging method that is based on the Raman effect, the inelastic scattering of a photon when energy is absorbed from light by a surface. Although Raman spectroscopy is widely used for chemical and molecular analysis, its clinical application has been hindered by the inherently weak nature of the Raman effect. Raman-silica-gold-nanoparticles (R-Si-Au-NPs) overcome this limitation by producing larger Raman signals through surface-enhanced Raman scattering. Because we are developing these particles for use as targeted molecular imaging agents, we examined the acute toxicity and biodistribution of core polyethylene glycol (PEG)-ylated R-Si-Au-NPs after different routes of administration in mice. After intravenous administration, PEG-R-Si-Au-NPs were removed from the circulation by macrophages in the liver and spleen (that is, the reticuloendothelial system). At 24 hours, PEG-R-Si-Au-NPs elicited a mild inflammatory response and an increase in oxidative stress in the liver, which subsided by 2 weeks after administration. No evidence of significant toxicity was observed by measuring clinical, histological, biochemical, or cardiovascular parameters for 2 weeks. Because we are designing targeted PEG-R-Si-Au-NPs (for example, PEG-R-Si-Au-NPs labeled with an affibody that binds specifically to the epidermal growth factor receptor) to detect colorectal cancer after administration into the bowel lumen, we tested the toxicity of the core nanoparticle after administration per rectum. We observed no significant bowel or systemic toxicity, and no PEG-R-Si-Au-NPs were detected systemically. Although additional studies are required to investigate the long-term effects of PEG-R-Si-Au-NPs and their toxicity when carrying the targeting moiety, the results presented here support the idea that PEG-R-Si-Au-NPs can be safely used in living subjects, especially when administered rectally.     

gp49B1 suppresses stem cell factor-induced mast cell activation-secretion and attendant inflammation in vivo

We report that gp49B1, a mast cell membrane receptor with two immunoreceptor tyrosine-based inhibitory motifs (ITIM), constitutively inhibits mast cell activation-secretion induced by stem cell factor (SCF), a tissue-derived cytokine that also regulates mast cell development. The intradermal injection of SCF into the ears of gp49B1 null (gp49B(-/-)) mice elicited approximately 4- and 2.5-fold more degranulating mast cells and tissue swelling caused by edema, respectively, than in gp49B(+/+) mice. SCF did not induce tissue swelling in mast cell-deficient mice, and the responsiveness of gp49B(-/-) mice to mast cell-associated amine and lipid mediators was unaltered. When gp49B(+/+) and gp49B(-/-) mice were pretreated with antagonists of the amines, SCF-induced tissue swelling was reduced by >90% and 60%, respectively, and it was reduced by >90% in both genotypes when a cysteinyl leukotriene receptor antagonist was also provided. Hence, the dominant contribution of secretory granule amines to SCF-induced tissue swelling is the result of gp49B1-mediated inhibition of the production of cysteinyl leukotrienes by mast cells. Our findings also provide the first example of an ITIM-bearing receptor that constitutively suppresses inflammation generated in vivo independently of the adaptive immune response by a receptor that signals through intrinsic tyrosine kinase activity rather than immunoreceptor tyrosine-based activation motifs.     

MMP14 gene polymorphisms in chronic obstructive pulmonary disease

Proteinase/antiproteinase imbalance is a widely accepted theory for the pathogenesis of COPD. Among various proteinases, matrix metalloproteinases (MMPs) digest extracellular matrix of the lung and play significant roles in the development of COPD. Polymorphisms of an MMP that upregulate its activity may result in the degradation of the lung matrix. A case-control study was performed to investigate the association of polymorphisms of the MMP14 gene with COPD. Japanese subjects (96 COPD patients and 61 controls) and Egyptian subjects (106 COPD patients and 72 controls) were recruited. Each subject was genotyped for seven single nucleotide polymorphisms (SNPs) of the MMP14 gene; -165 G/T and -72 G/A in the promoter region, +221 C/T in exon 1, +6727 C/G and +6767 G/A in exon 5, +7096 T/C in exon 6, and +8153 G/A in exon 8. The distributions of the genotype frequencies of these SNPs were not significantly different between the COPD patients and the controls in either ethnic group after correction of multiple comparisons. In the haplotype analysis, however, the haplotype -165 T : +221 T : +6727 C : +7096 C had a significantly higher frequency in the Egyptian COPD group than the control group (pcorr = 0.0063). The haplotype of the MMP14 gene, -165 T : +221 T : +6727 C : +7096 C, might be involved in the pathogenesis of COPD.     

The Effect of miR-200c Inhibition on Chemosensitivity (5- FluoroUracil) in Colorectal Cancer

5-Fluorouracil (5-FU) as a chemotherapeutic drug is used to treat colorectal cancer (CRC). However, 5-FU is associated with acquired CRC resistance, which decreases the therapeutic potential of 5-FU. Several studies indicated that miR-200c is also involved in chemotherapeutic drug resistance, but the exact mechanism of miR-200c mediated chemoresistance has not yet been fully understood. In this study, we examined the effect of inhibition of miR-200c on the sensitivity of HCT-116 cells to 5-FU. HCT-116 cells were transfected with LNA-anti- miR-200c for 48 h. mRNA expression of miR-200c was investigated by qRT-PCR. The protein expression of phosphatase and tensin homolog (PTEN) and E-cadherin were evaluated by western blotting. Annexin V/ PI staining and caspase 3 activity were used to detect apoptosis. LNA-anti-miR-200c inhibited the miR-200c expression in the transfected cells compared with that in the control group. LNA-anti-miR-200c suppressed the expression of PTEN and E-cadherin independent of the presence of the chemotherapeutic drug 5-FU. LNA-anti-miR-200c reduced the 5-FU-induced apoptosis and caspase 3 activity. miR-200c, as a novel prognostic marker in CRC, can be a potential therapeutic approach to overcome chemoresistance during 5-FU chemotherapy.