Mortality following a brain tumour diagnosis in patients with multiple sclerosis

Objectives: As brain tumours and their treatment may theoretically have a poorer prognosis in inflammatory central nervous system diseases such as multiple sclerosis (MS), all-cause mortality following a brain tumour diagnosis was compared between patients with and without MS. The potential role of age at tumour diagnosis was also examined. Setting: Hospital inpatients in Sweden with assessment of mortality in hospital or following discharge. Participants: Swedish national registers identified 20 543 patients with an MS diagnosis (1969-2005) and they were matched individually to produce a comparison cohort of 204 163 members of the general population without MS. Everyone with a primary brain tumour diagnosis was selected for this study: 111 with MS and 907 without MS. Primary and secondary outcome measures: 5-year mortality risk following brain tumour diagnosis and age at brain tumour diagnosis. Results: A non-statistically significant lower mortality risk among patients with MS (lower for those with tumours of high-grade and uncertain-grade malignancy and no notable difference for low-grade tumours) produced an unadjusted HR (and 95% CI) of 0.75 (0.56 to 1.02). After adjustment for age at diagnosis, grade of malignancy, sex, region of residence and socioeconomic index, the HR is 0.91 (0.67-1.24). The change in estimate was largely due to adjustment for age at brain tumour diagnosis, as patients with MS were on average 4.7 years younger at brain tumour diagnosis than those in the comparison cohort (p<0.001). Conclusions: Younger age at tumour diagnosis may contribute to mortality reduction in those with highgrade and uncertain-grade brain tumours. Survival following a brain tumour is not worse in patients with MS; even after age at brain tumour diagnosis and grade of malignancy are taken into account

Hospital-diagnosed infections before age 20 and risk of a subsequent multiple sclerosis diagnosis

The involvement of specific viral and bacterial infections as risk factors for multiple sclerosis has been studied extensively. However, whether this extends to infections in a broader sense is less clear and little is known about whether risk of a multiple sclerosis diagnosis is associated with other types and sites of infections, such as of the CNS. This study aims to assess if hospital-diagnosed infections by type and site before age 20 years are associated with risk of a subsequent multiple sclerosis diagnosis and whether this association is explained entirely by infectious mononucleosis, pneumonia, and CNS infections. Individuals born in Sweden between 1970-1994 were identified using the Swedish Total Population Register (n = 2,422,969). Multiple sclerosis diagnoses from age 20 years and hospital-diagnosed infections before age 20 years were identified using the Swedish National Patient Register. Risk of a multiple sclerosis diagnosis associated with various infections in adolescence (11-19 years) and earlier childhood (birth-10 years) was estimated using Cox regression, with adjustment for sex, parental socioeconomic position, and infection type. None of the infections by age 10 years were associated with risk of a multiple sclerosis diagnosis. Any infection in adolescence increased the risk of a multiple sclerosis diagnosis (hazard ratio 1.33, 95% confidence interval 1.21-1.46) and remained statistically significant after exclusion of infectious mononucleosis, pneumonia, and CNS infection (hazard ratio 1.17, 95% confidence interval 1.06-1.30). CNS infection in adolescence (excluding encephalomyelitis to avoid including acute disseminated encephalitis) increased the risk of a multiple sclerosis diagnosis (hazard ratio 1.85, 95% confidence interval 1.11-3.07). The increased risk of a multiple sclerosis diagnosis associated with viral infection in adolescence was largely explained by infectious mononucleosis. Bacterial infections in adolescence increased risk of a multiple sclerosis diagnosis, but the magnitude of risk reduced after excluding infectious mononucleosis, pneumonia and CNS infection (hazard ratio 1.31, 95% confidence interval 1.13-1.51). Respiratory infection in adolescence also increased risk of a multiple sclerosis diagnosis (hazard ratio 1.51, 95% confidence interval 1.30-1.75), but was not statistically significant after excluding infectious mononucleosis and pneumonia. These findings suggest that a variety of serious infections in adolescence, including novel evidence for CNS infections, are risk factors for a subsequent multiple sclerosis diagnosis, further demonstrating adolescence is a critical period of susceptibility to environmental exposures that raise the risk of a multiple sclerosis diagnosis. Importantly, this increased risk cannot be entirely explained by infectious mononucleosis, pneumonia, or CNS infections

Field-induced magnetic structures in the chiral polar antiferromagnet Ni2_2InSbO6_6

We have performed $^{115}$In-NMR spectroscopy for Ni$_{2}$InSbO$_6$ with corundum-related crystal structure to reveal magnetic structures that develop in high magnetic fields. At low fields Ni$_{2}$InSbO$_6$ shows a helical magnetic order with a long wavelength because of its chiral and polar crystal structure. The field-induced magnetic state was not investigated by microscopic experiment because an extremely high magnetic field is required to modify the antiferromagnetically coupled helical structure. From the analysis of our $^{115}$In-NMR spectra obtained at high magnetic fields, we confirm that the canted antiferromagnetic structure appears in fields applied in the $[110]$ direction and the propagation vector of magnetic helix is rotated toward the field direction for fields in the $[001]$ direction. We discuss the effect of magnetic field that modifies the magnetic structure of an antiferromagnetic chiral magnet.Comment: 9 pages, 8 figures, accepted for publication from Phys. Rev.

The Identification of a Small Molecule Compound That Reduces HIV-1 Nef-Mediated Viral Infectivity Enhancement

Nef is a multifunctional HIV-1 protein that accelerates progression to AIDS, and enhances the infectivity of progeny viruses through a mechanism that is not yet understood. Here, we show that the small molecule compound 2c reduces Nef-mediated viral infectivity enhancement. When added to viral producer cells, 2c did not affect the efficiency of viral production itself. However, the infectivity of the viruses produced in the presence of 2c was significantly lower than that of control viruses. Importantly, an inhibitory effect was observed with Nef+ wild-type viruses, but not with viruses produced in the absence of Nef or in the presence of proline-rich PxxP motif-disrupted Nef, both of which displayed significantly reduced intrinsic infectivity. Meanwhile, the overexpression of the SH3 domain of the tyrosine kinase Hck, which binds to a PxxP motif in Nef, also reduced viral infectivity. Importantly, 2c inhibited Hck SH3-Nef binding, which was more marked when Nef was pre-incubated with 2c prior to its incubation with Hck, indicating that both Hck SH3 and 2c directly bind to Nef and that their binding sites overlap. These results imply that both 2c and the Hck SH3 domain inhibit the interaction of Nef with an unidentified host protein and thereby reduce Nef-mediated infectivity enhancement. The first inhibitory compound 2c is therefore a valuable chemical probe for revealing the underlying molecular mechanism by which Nef enhances the infectivity of HIV-1

Latent heat in the chiral phase transition

The chiral phase transition at finite temperature and density is discussed in the framework of the QCD-like gauge field theory. The thermodynamical potential is investigated using a variational approach. Latent heat generated in the first-order phase transition is calculated. It is found that the latent heat is enhanced near the tricritical point and is more than several hundred MeV per quark.Comment: 6 pages, 3 figure

Bile Acid-Induced Virulence Gene Expression of Vibrio parahaemolyticus Reveals a Novel Therapeutic Potential for Bile Acid Sequestrants

Vibrio parahaemolyticus, a bacterial pathogen, causes human gastroenteritis. A type III secretion system (T3SS2) encoded in pathogenicity island (Vp-PAI) is the main contributor to enterotoxicity and expression of Vp-PAI encoded genes is regulated by two transcriptional regulators, VtrA and VtrB. However, a host-derived inducer for the Vp-PAI genes has not been identified. Here, we demonstrate that bile induces production of T3SS2-related proteins under osmotic conditions equivalent to those in the intestinal lumen. We also show that bile induces vtrA-mediated vtrB transcription. Transcriptome analysis of bile-responsive genes revealed that bile strongly induces expression of Vp-PAI genes in a vtrA-dependent manner. The inducing activity of bile was diminished by treatment with bile acid sequestrant cholestyramine. Finally, we demonstrate an in vivo protective effect of cholestyramine on enterotoxicity and show that similar protection is observed in infection with a different type of V. parahaemolyticus or with non-O1/non-O139 V. cholerae strains of vibrios carrying the same kind of T3SS. In summary, these results provide an insight into how bacteria, through the ingenious action of Vp-PAI genes, can take advantage of an otherwise hostile host environment. The results also reveal a new therapeutic potential for widely used bile acid sequestrants in enteric bacterial infections

Renin, endothelial no synthase and endothelin gene expression in the 2Kidney-1clip goldblatt model of long-term renovascular hypertension

<p>Abstract</p> <p>Objective</p> <p>Numerous reports have shown the influence of renin, nitric oxide (NO) and the endothelin (ET) systems for regulation of blood pressure and renal function. Furthermore, interactions between these peptides have been reported. Aim of our study was to investigate the relative contribution of these compounds in long-term renovascular hypertension/renal ischemia.</p> <p>Methods</p> <p>Hypertension/left-sided renal ischemia was induced using the 2K1C-Goldblatt rat model. Renal renin, ET-1, ET-3 and endothelial NO synthase (eNOS) gene expression was measured by means of RNAse protection assay at different timepoints up to 10 weeks after induction of renal artery stenosis.</p> <p>Results</p> <p>Plasma renin activity and renal renin gene expression in the left kidney were increased in the clipped animals while eNOS expression was unchanged. Furthermore, an increase in ET-1 expression and a decrease of ET-3 expression was detected in early stenosis.</p> <p>Conclusions</p> <p>While renin is obviously involved in regulation of blood pressure and renal function in unilateral renal artery stenosis, ET-1, ET-3 and endothelium derived NO do not appear to play an important role in renal adaptation processes in long-term renal artery stenosis, although ET-1 and ET-3 might be involved in short-term adaptation processes.</p

Thermostable Direct Hemolysin Downregulates Human Colon Carcinoma Cell Proliferation with the Involvement of E-Cadherin, and β-Catenin/Tcf-4 Signaling

BACKGROUND: Colon cancers are the frequent causes of cancer mortality worldwide. Recently bacterial toxins have received marked attention as promising approaches in the treatment of colon cancer. Thermostable direct hemolysin (TDH) secreted by Vibrio parahaemolyticus causes influx of extracellular calcium with the subsequent rise in intracellular calcium level in intestinal epithelial cells and it is known that calcium has antiproliferative activity against colon cancer. KEY RESULTS: In the present study it has been shown that TDH, a well-known traditional virulent factor inhibits proliferation of human colon carcinoma cells through the involvement of CaSR in its mechanism. TDH treatment does not induce DNA fragmentation, nor causes the release of lactate dehydrogenase. Therefore, apoptosis and cytotoxicity are not contributing to the TDH-mediated reduction of proliferation rate, and hence the reduction appears to be caused by decrease in cell proliferation. The elevation of E-cadherin, a cell adhesion molecule and suppression of β-catenin, a proto-oncogene have been observed in presence of CaSR agonists whereas reverse effect has been seen in presence of CaSR antagonist as well as si-RNA in TDH treated cells. TDH also triggers a significant reduction of Cyclin-D and cdk2, two important cell cycle regulatory proteins along with an up regulation of cell cycle inhibitory protein p27(Kip1) in presence of CaSR agonists. CONCLUSION: Therefore TDH can downregulate colonic carcinoma cell proliferation and involves CaSR in its mechanism of action. The downregulation occurs mainly through the involvement of E-cadherin-β-catenin mediated pathway and the inhibition of cell cycle regulators as well as upregulation of cell cycle inhibitors