Testosterone suppresses protective responses of the liver to blood-stage malaria

Testosterone induces a lethal outcome in otherwise self-healing blood-stage malaria caused by Plasmodium chabaudi. Here, we examine possible testosterone effects on the antimalaria effectors spleen and liver in female C57BL/6 mice. Self-healing malaria activates gating mechanisms in the spleen and liver that lead to a dramatic reduction in trapping activity, as measured by quantifying the uptake of 3-mum-diameter fluorescent polystyrol particles. However, testosterone delays malaria-induced closing of the liver, but not the spleen. Coincidently, testosterone causes an approximately 3- to 28-fold depression of the mRNA levels of nine malaria-responsive genes, out of 299 genes tested, only in the liver and not in the spleen, as shown by cDNA arrays and Northern blotting. Among these are the genes encoding plasminogen activator inhibitor (PAI1) and hydroxysteroid sulfotransferase (STA2). STA2, which detoxifies bile acids, is suppressed 10-fold by malaria and an additional 28-fold by testosterone, suggesting a severe perturbation of bile acid metabolism. PAI1 is protective against malaria, since disruption of the PAI1 gene results in partial loss of the ability to control the course of P. chabaudi infections. Collectively, our data indicate that the liver rather than the spleen is a major target organ for testosterone-mediated suppression of resistance against blood-stage malaria.     

Genetic variants of homocysteine metabolizing enzymes and the risk of coronary artery disease

It is unresolved whether elevated homocysteine in coronary artery disease (CAD) is the cause of arteriosclerosis or its consequence. In contrast, genetic variants of enzymes that metabolize homocysteine cannot be altered by arteriosclerosis. Consequently, their association with CAD would permit to imply causality. We modeled by regression analysis the effect of 11 variants in the methionine cycle upon CAD manifestation in 591 controls and 278 CAD patients. Among the examined variants only the carriership for the c.844ins68 in the cystathionine beta-synthase (CBS) gene was associated with a significantly lowered risk of CAD (OR=0.56; 95% CI=0.35-0.90 in the univariable, and OR=0.41, 95% CI=0.19-0.89 for obese people in the multivariable analysis, respectively). Healthy carriers of the c.844ins68 variant exhibited, compared to the wild type controls, significantly higher postload ratios of blood S-adenosylmethionine to S-adenosylhomocysteine (61.4 vs. 54.9, p=0.001) and of plasma total cysteine to homocysteine (8.6 vs. 7.3, p=0.004). The changes in these metabolites are compatible with an improved methylation status and with enhanced activity of homocysteine transsulfuration. In conclusion, the coincidence of clinical and biochemical effects of a common c.844ins68 CBS variant supports the hypothesis that compounds relating to homocysteine metabolism may play role in the development and/or progression of CAD.     

Telomeric fusion as a mechanism for the loss of 1p in meningioma

Characteristic cytogenetic aberrations are found in the various histopathological designations of meningioma. These aberrations range from the loss of 22q in histologically benign tumors to complex hypodiploid karyotypes in atypical and malignant tumors. This progression is characterized by increasing chromosome loss and instability, with a critical step being the loss of 1p. We report a detailed cytogenetic investigation of chromosome aberrations in a series of 88 meningiomas using Giemsa banding and multicolor spectral karyotyping (SKY). Clonal chromosome aberrations were identified in 46 (52%) tumors by G banding. Thirty-five tumors showing complex chromosome aberrations not fully characterized by G banding were subsequently reanalyzed by SKY. The SKY technique refined the G-band findings in 18 (51%) of the tumors on which it was applied. The most common features of cytogenetic progression in the complex karyotypes were chromosome arm-specific losses relating to the formation of deletions and dicentric chromosomes involving 1p. Part or all of 1p was lost in 19 tumors. Five tumors showed evidence for the loss of 1p in a progressive step-wise series of telomeric fusions involving the formation of unstable intermediates. Five recurring dicentric chromosomes were identified, including dic (1;11)(p11;p11), dic(1;12)(p12 approximately p13;p11), dic(1;22)(p11;q12 approximately q13), dic(7;19)(p11;p11), and dic(19;22)(p11 approximately p13;q11 approximately q13). These findings provide evidence that telomeric fusions play a role in the formation of clonal deletions, dicentrics, and unbalanced translocations of 1p. The loss of 1p has possible diagnostic and prognostic implications in the management of meningioma.     

Comparison of Track XI fluorometric immunoassay with Bio-EnzaBead enzyme-linked immunosorbent assay for detection of serum antibody to mouse hepatitis virus.

The Track XI system (Microbiological Associates, Bethesda, Md.) was compared with the Bio-EnzaBead assay (Organon Teknika, Durham, N.C.) for the detection of antibody to mouse hepatitis virus (MHV). Strain A/J mice were inoculated intranasally with MHV type 3. Sera were collected at 1, 2, 4, and 9 weeks postinoculation and tested. Individual serum samples were retested twice by each method. The results suggested that the Track XI system was more sensitive and reliable than the Bio-EnzaBead assay in detecting antibody to MHV type 3 in individual serum samples from A/J mice.     

Mercury (II) alters mitochondrial activity of monocytes at sublethal doses via oxidative stress mechanisms

The perennial controversy about the safety of mercury in dental amalgams has adversely affected the availability and the quality of dental care. Chronic Hg(II) blood concentrations above 300 nM are known to alter function of the nervous system and the kidney. However, the effects of blood concentrations of 10 to 75 nM, far more common in the general population, are not clear and mechanisms of any effects are not known. The monocyte is an important potential target of Hg(II) because of its critical role in directing inflammatory and immune responses. In the current study we tested the hypothesis that concentrations of Hg(II) of 10 to 300 nM alter monocyte activity via a redox-dependent mechanism. Mitochondrial activity was used to establish inhibitory concentrations of Hg(II) following 6 to 72 h of exposures to THP1 human monocytic cells. Then subinhibitory concentrations were applied, and total glutathione levels and reactive oxygen species (ROS) were measured. Antioxidants [N-acetyl cysteine, (NAC); Na2SeO3, (Se)] and a pro-oxidant (tert-butylhydroquinone, tBHQ) were used to support the hypothesis that Hg(II) effects were redox-mediated. After 72 h of exposure, 20 microM of Hg(II) inhibited monocytic mitochondrial activity by 50%. NAC mitigated Hg(II)-induced mitochondrial suppression only at concentrations of greater than 10 microM, but Se had few effects on Hg-induced mitochondrial responses. tBHQ significantly enhanced mitochondrial suppression at higher Hg(II) concentrations. Hg(II) concentrations of 75 and 300 nM (0.075 and 0.30 microM, respectively) significantly increased total glutathione levels, and NAC mitigated these increases. Se plus Hg(II) significantly elevated Hg-induced total cellular glutathione levels. Increased ROS levels were not detected in monocytes exposed to mercury. Hg(II) acts in monocytic cells, at least in part, through redox-mediated mechanisms at concentrations below those commonly associated with chronic mercury toxicity, but commonly occurring in the blood of some dental patients.     

Long-term protective immune response elicited by vaccination with an expression genomic library of Toxoplasma gondii

Immunization of BALB/c mice with an expression genomic library of Toxoplasma gondii induces a Th1-type immune response, with recognition of several T. gondii proteins (21 to 117 kDa) and long-term protective immunity against a lethal challenge. These results support further investigations to achieve a multicomponent anti-T. gondii DNA vaccine.     

Stoffwechseluntersuchungen bei tiefer Hypothermie unter 20° und langdauerndem artefiziellem Kreislaufstillstand

Ohne Zusammenfassung     

Oral DNA vaccination with a plasmid encoding soluble ICAM-1 modulates cytokine expression profiles in nonobese diabetic mice

Adhesion molecules are important for leukocyte extravasation and for the delivery of costimulatory signals in T cell activation. We therefore interfered in the immune process leading to islet inflammation in diabetes prone NOD mice by oral vaccination with plasmid DNA encoding soluble ICAM-1. Female NOD mice were treated orally with ICAM-1, TGF-beta, or control plasmid DNA and received a single injection of cyclophosphamide for synchronization and acceleration of the disease process in the pancreas. Quantitative RT-PCR analysis of pancreatic mRNA showed that cyclophosphamide induced the expression of Th1 cytokines (IFN-gamma and IL-12p40) in vehicle- or control plasmid-treated mice. Treatment with ICAM-1 and TGF-beta DNA resulted in increased levels of IL-10 mRNA in the pancreas, indicating an anti-inflammatory regulatory immune response. Histological analysis of pancreatic islets showed that the DNA treatment did not alter islet infiltration in response to cyclophosphamide. Hence vaccination with the ICAM-1 plasmid had not suppressed leukocyte migration but rather modulated lymphocyte activity, similarly as seen for the TGF-beta-encoding plasmid. Neither of the three plasmids caused recognizable changes in cytokine expression in the small intestine, Peyer's patches, or mesenteric lymph nodes. We conclude that oral vaccination with DNA encoding immunoregulatory molecules such as ICAM-1 and TGF-beta represents an approach for modulating the ongoing inflammatory process in the pancreas of diabetes prone NOD mice.     

Regulation of glutathione by oxidative stress in bovine pulmonary artery endothelial cells

Glutathione plays important roles as an intracellular antioxidant and in the maintenance of cellular thiol-disulfide balance. In addition, glutathione may regulate cell growth signaling induced by oxidative stress. We previously reported that cellular glutathione is up-regulated by bleomycin in bovine pulmonary artery endothelial cells. The present study examined effects of hydrogen peroxide (H(2)O(2)) on cell growth and glutathione levels. Exogenous addition of H(2)O(2) induced biphasic effects on cell growth; 1 micro M was stimulatory and >10 micro M was inhibitory. However, both growth-promoting and inhibitory levels of H(2)O(2) increased cellular glutathione levels. Whereas 1 micro M H(2)O(2) moderately but significantly increased glutathione, 30 micro M caused a more substantial increase. Like bleomycin, both concentrations of H(2)O(2) activated DNA binding of antioxidant response element (ARE), a regulatory element in the promoter of the gamma-glutamylcysteine synthetase heavy chain subunit, a key regulator of glutathione synthesis. However, only high concentrations of H(2)O(2) activated p44/42 mitogen-activated protein (MAP) kinase. Thus, cellular glutathione is up-regulated by H(2)O(2), perhaps via activating ARE-binding factors in a mechanism independent of MAP kinase. H(2)O(2)-mediated increase in glutathione and activation of ARE binding may play important roles in growth and death of pulmonary artery endothelial cells.