Cerebral infarct volume is typically smaller in premenopausal females than in age-matched males after ischemic stroke, but the underlying mechanisms are poorly understood. In this study we provide evidence in mice that this gender difference only occurs when the ischemic brain is reperfused. The limited tissue salvage achieved by reperfusion in male mice is associated with increased expression of proinflammatory proteins, including cyclooxygenase-2 (Cox-2), Nox2, and vascular cell adhesion molecule-1 (VCAM-1), and infiltration of Nox2-containing T lymphocytes into the infarcted brain, whereas such changes are minimal in female mice after ischemia–reperfusion (I-R). Infarct volume after I-R was no greater at 72 h than at 24 h in either gender. Infarct development was Nox2 dependent in male but not in female mice, and Nox2 within the infarct was predominantly localized in T lymphocytes. Stroke resulted in an ∼15-fold increase in Nox2-dependent superoxide production by circulating, but not spleen-derived, T lymphocytes in male mice, and this was ∼sevenfold greater than in female mice. These circulating immune cells may thus represent a major and previously unrecognized source of superoxide in the acutely ischemic and reperfused brain of males (and potentially in postmenopausal females). Our findings provide novel insights into mechanisms that could be therapeutically targeted in acute ischemic stroke patients who receive thrombolysis therapy to induce cerebral reperfusion.

The trefoil factors (TFF) 1, TFF2, and TFF3 form a family of secreted proteins characterized by a triple loop structure, the trefoil domain.¹ x 1 Wright, N.A., Hoffmann, W., Otto, W.R. et al. Rolling in the clover: trefoil factor family (TFF)-domain peptides, cell migration and cancer. FEBS Lett. 1997; 408: 121–123 Abstract | Full Text | Full Text PDF | PubMed | Scopus (149) | Google Scholar See all References Gastric TFF1 expression is restricted to surface mucus and pit epithelium of the fundus and antrum, whereas TFF2 is expressed in fundic mucus neck cells (MNCs), antrum, and duodenal Brunner's glands.² x 2 Lefebvre, O., Wolf, C., Kedinger, M. et al. The mouse one P-domain (pS2) and two P-domain (mSP) genes exhibit distinct patterns of expression. J Cell Biol. 1993; 122: 191–198 Crossref | PubMed | Scopus (75) | Google Scholar See all References ^{, 3} x 3 Taupin, D.R., Pang, K.C., Green, S.P. et al. The trefoil peptides spasmolytic polypeptide and intestinal trefoil factor are major secretory products of the rat gut. Peptides. 1995; 16: 1001–1005 Crossref | PubMed | Scopus (41) | Google Scholar See all References TFF3 expression is restricted to intestinal goblet cells.⁴ x 4 Suemori, S., Lynch-Devaney, K., and Podolsky, D.K. Identification and characterization of rat intestinal trefoil factor: tissue- and cell-specific member of the trefoil protein family. Proc Natl Acad Sci U S A. 1991; 88: 11017–11021 Crossref | PubMed | Scopus (260) | Google Scholar See all References TFF functions include mucus stabilization and barrier protection,⁵ x 5 Kindon, H., Pothoulakis, C., Thim, L. et al. Trefoil peptide protection of intestinal epithelial barrier function: cooperative interaction with mucin glycoprotein. Gastroenterology. 1995; 109: 516–523 Abstract | Full Text PDF | PubMed | Scopus (286) | Google Scholar See all References regulation of cell migration during wound healing,⁶ x 6 Dignass, A., Lynch-Devaney, K., Kindon, H. et al. Trefoil peptides promote epithelial migration through a transforming growth factor β-independent pathway. J Clin Invest. 1994; 94: 376–383 Crossref | PubMed | Scopus (374) | Google Scholar See all References ^{, 7} x 7 Playford, R.J., Marchbank, T., Chinery, R. et al. Human spasmolytic polypeptide is a cytoprotective agent that stimulates cell migration. Gastroenterology. 1995; 108: 108–116 Abstract | Full Text PDF | PubMed | Scopus (244) | Google Scholar See all References gastric cell differentiation,⁸ x 8 Familari, M., Cook, G.A., Taupin, D.R. et al. Trefoil peptides are early markers of gastrointestinal maturation in the rat. Int J Dev Biol. 1998; 42: 783–789 PubMed | Google Scholar See all References proliferation, and apoptosis.⁹ x 9 Bossenmeyer-Pourie, C., Kannan, R., Ribieras, S. et al. The trefoil factor 1 participates in gastrointestinal cell differentiation by delaying G1-S phase transition and reducing apoptosis. J Cell Biol. 2002; 157: 761–770 Crossref | PubMed | Scopus (144) | Google Scholar See all References ^{, 10} x 10 Lefebvre, O., Chenard, M.P., Masson, R. et al. Gastric mucosa abnormalities and tumorigenesis in mice lacking the pS2 trefoil protein. Science. 1996; 274: 259–262 Crossref | PubMed | Scopus (411) | Google Scholar See all References

Background: Helicobacter pylori remains a global health hazard, and vaccination would be ideal for its control. Natural infection appears not to induce protective immunity. Thus, the feasibility of a vaccine for humans is doubtful. Methods: In two prospective, randomised, double-blind, controlled studies (Paul Ehrlich Institute application nos 0802/02 and 1097/01), live vaccines against H pylori were tested in human volunteers seronegative for, and without evidence of, active H pylori infection. Volunteers (n = 58) were immunised orally with Salmonella enterica serovar Typhi Ty21a expressing H pylori urease or HP0231, or solely with Ty21a, and then challenged with 2×10 ⁵ cagPAI ⁻ H pylori. Adverse events, infection, humoral, cellular and mucosal immune response were monitored. Gastric biopsies were taken before and after vaccination, and postchallenge. Infection was terminated with antibiotics. Results: Vaccines were well tolerated. Challenge infection induced transient, mild to moderate dyspeptic symptoms, and histological and transcriptional changes in the mucosa known from chronic infection. Vaccines did not show satisfactory protection. However, 13 of 58 volunteers, 8 vaccinees and 5 controls, became breath test negative and either cleared H pylori (5/13) completely or reduced the H pylori burden (8/13). H pylori -specific T helper cells were detected in 9 of these 13 (69%), but only in 6 of 45 (13%) breath test-positive volunteers (p = 0.0002; Fisher exact test). T cells were either vaccine induced or pre-existing, depending on the volunteer. Conclusion: Challenge infection offers a controlled model for vaccine testing. Importantly, it revealed evidence for T cell-mediated immunity against H pylori infection in humans.

Elevated reactive oxygen species (ROS) formation in the vascular wall is a key feature of cardiovascular diseases and a likely contributor to oxidative stress, endothelial dysfunction and vascular inflammation. The NADPH oxidases are a family of ROS generating enzymes, of which four members (Nox1, Nox2, Nox4 and Nox5) are expressed in blood vessels. Numerous studies have demonstrated that expression and activity of at least two isoforms of NADPH oxidase – Nox1 and Nox2 – are up-regulated in animal models of hypertension, diabetes and atherosclerosis. However, these observations are merely suggestive of a role for NADPH oxidases in vessel pathology and by no means establish cause and effect. Furthermore, questions surrounding the specificity of current pharmacological inhibitors of NADPH oxidase mean that findings obtained with these compounds must be viewed with caution. Here, we review the literature on studies utilising genetically-modified mouse strains to investigate the roles of NADPH oxidases in experimental models of vascular disease. While several studies on transgenic over-expressing or knockout mice support roles for Nox1- and/or Nox2-containing oxidases as sources of excessive vascular ROS production and causes of endothelial dysfunction in hypertension, atherosclerosis and diabetes, there are still no published reports on the effects of genetic modification of Nox4 or Nox5 in vascular or indeed any other contexts. Further understanding of the roles of specific isoforms of NADPH oxidase in vascular (patho)physiology should provide direction for future programs aimed at developing selective inhibitors of these enzymes as novel therapeutics in cardiovascular disease.

Helicobacter pylori is the etiological agent of human chronic gastritis, a condition seen as a precursor to the development of gastrointestinal ulcers or gastric cancer. This study utilized the murine model of chronic H. pylori infection to characterize the role of macrophages in the induction of specific immune responses and gastritis and in the control of the bacterial burden following H. pylori infection and vaccination. Drug-loaded liposomes were injected intravenously to deplete macrophages from C57BL/6 mice, and effective removal of CD11b ⁺ cells from the spleens and stomachs of mice was confirmed by immunofluorescence microscopy. Transient elimination of macrophages from C57BL/6 mice during the early period of infection reduced the gastric pathology induced by H. pylori SS1 but did not affect the bacterial load in the stomach. These data suggest that macrophages are important to the severity of gastric inflammation during H. pylori infection.