Human metapneumovirus infection activates the TSLP pathway that drives excessive pulmonary inflammation and viral replication in mice.

Human metapneumovirus (hMPV) is a leading cause of acute respiratory tract infections in children and the elderly. The mechanism by which this virus triggers an inflammatory response still remains unknown. Here, we evaluated whether the thymic stromal lymphopoietin (TSLP) pathway contributes to lung inflammation upon hMPV infection. We found that hMPV infection promotes TSLP expression both in human airway epithelial cells and in the mouse lung. hMPV infection induced lung infiltration of OX40L(+) CD11b(+) DCs. Mice lacking the TSLP receptor deficient mice (tslpr(-/-) ) showed reduced lung inflammation and hMPV replication. These mice displayed a decreased number of neutrophils as well a reduction in levels of thymus and activation-regulated chemokine/CCL17, IL-5, IL-13, and TNF-α in the airways upon hMPV infection. Furthermore, a higher frequency of CD4(+) and CD8(+) T cells was found in tslpr(-/-) mice compared to WT mice, which could contribute to controlling viral spread. Depletion of neutrophils in WT and tslpr(-/-) mice decreased inflammation and hMPV replication. Remarkably, blockage of TSLP or OX40L with specific Abs reduced lung inflammation and viral replication following hMPV challenge in mice. Altogether, these results suggest that activation of the TSLP pathway is pivotal in the development of pulmonary pathology and pulmonary hMPV replication.

Hysteroscopic dynamic assessment of the endometrium in patients treated with long-term tamoxifen.

STUDY OBJECTIVE: To describe the evolutive endometrial hysteroscopic patterns in patients undergoing long-term tamoxifen treatment. DESIGN: Prospective analysis. Analysis of variance test with post hoc Bonferroni test and homogeneity test of percentages were used for hypothesis contrast between the groups. DESIGN CLASSIFICATION: Canadian task force II-2. SETTING: Four Spanish tertiary care hospitals. PATIENTS: A total of 278 patients with breast cancer diagnosed between 2002 and 2004, which completed 5-years adjuvant therapy with tamoxifen. INTERVENTIONS: Ultrasonography and hysteroscopic explorations were performed before starting the treatment and then at yearly intervals during the 5 years of adjuvant treatment. MEASUREMENTS AND MAIN RESULTS: Hysteroscopic endometrial changes were significant throughout the years of treatment. Tamoxifen-exposed endometria present five different patterns: atrophic, cystic, hypervascularized, endometrial polyp, and suspicious of malignancy. Endometrial carcinoma appeared in four patients (1.5%) that bled during the follow-up. CONCLUSION: Tamoxifen produces five different endometrial patterns that evolve dynamically throughout the 5 years of treatment.

Periovulatory follicular volume and vascularization determined by 3D and power Doppler sonography as pregnancy predictors in intrauterine insemination cycles.

PURPOSE: To evaluate the relationship between volume and vascularization of the periovulatory follicle and subfollicular area measured by three-dimensional power Doppler ultrasound (US), and ovulation and pregnancy in patients undergoing intrauterine insemination (IUI). METHODS: We studied 79 consecutive cycles of IUI on hCG administration day. We measured the periovulatory follicle and subfollicular area by means of three-dimensional power Doppler US. The stored volumes were processed with the VOCAL image processing software to calculate the volume of the follicle and the following vascular indices: vascularization index (VI), flow index (FI), and vascularization flow index (VFI). RESULTS: The follicular volume was higher in anovulatory cycles (7.7 ± 3.7 cubic centimeters (CC) versus 4.1 ± 2.0 CC; p < 0.001). There was no difference between the follicular volumes in cycles with or without subsequent pregnancy. The vascular indices of the follicle did not differ significantly between ovulatory and anovulatory cycles, and between cycles that did and did not achieve pregnancy. Periovulatory subfollicular VI and VFI were lower in women who became pregnant (VI: 2.9 ± 2.3% versus 5.6 ± 4.6%; p < 0.05, and VFI: 1.1 ± 0.8 versus 2.2 ± 2.2; p < 0.01). CONCLUSIONS: High values of follicular volume were associated with anovulatory cycles. Subfollicular VI and VFI might be used as markers of follicular quality and pregnancy predictors.

Cardiac, renal and uterine hemodynamics changes throughout pregnancy in rats with a prolonged high fat diet from an early age.

OBJECTIVE: To examine whether the cardiac, renal and uterine physiological hemodynamic changes during gestation are altered in rats with an early and prolonged exposure to a high fat diet (HFD). METHODS: Arterial pressure and cardiac, renal, uterine and radial arteries hemodynamic changes during gestation were examined in adult SD rats exposed to normal (13%) (n = 8) or high (60%) (n = 8) fat diets from weaning. Plethysmography, high-resolution high-frequency ultrasonography and clearance of an inulin analog were used to evaluate the arterial pressure and hemodynamic changes before and at days 7, 14 and 19 of gestation. RESULTS: Arterial pressure was higher (P<0.05) in rats with high than in those with normal (NFD) fat diet before pregnancy (123 ±3 and 110 ±3 mmHg, respectively) and only decreased at day 14 of gestation in rats with NFD (98±4 mmHg, P<0.05). A significant increment in stroke volume (42 ±10%) and cardiac output (51 ±12%) was found at day 19 of pregnancy in rats with NFD. The changes in stroke volume and cardiac output were similar in rats with NFD and HFD. When compared to the values obtained before pregnancy, a transitory elevation in renal blood flow was found at day 14 of pregnancy in both groups. However, glomerular filtration rate only increased (P<0.05) in rats with NFD at days 14 (20 ±7%) and 19 (27 ±8%) of gestation. The significant elevations of mean velocity, and velocity time integral throughout gestation in radial (127 ±26% and 111 ±23%, respectively) and uterine (91 ±16% and 111 ±25%, respectively) arteries of rats with NFD were not found in rats with an early and prolonged HFD. SUMMARY: This study reports novel findings showing that the early and prolonged exposure to a HFD leads to a significant impairment in the renal, uterine and radial arteries hemodynamic changes associated to gestation.

Interleukin-10 Production by T and B Cells Is a Key Factor to Promote Systemic Salmonella enterica Serovar Typhimurium Infection in Mice.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a Gram-negative bacterium that produces disease in numerous hosts. In mice, oral inoculation is followed by intestinal colonization and subsequent systemic dissemination, which leads to severe pathogenesis without the activation of an efficient anti-Salmonella immune response. This feature suggests that the infection caused by S. Typhimurium may promote the production of anti-inflammatory molecules by the host that prevent efficient T cell activation and bacterial clearance. In this study, we describe the contribution of immune cells producing the anti-inflammatory cytokine interleukin-10 (IL-10) to the systemic infection caused by S. Typhimurium in mice. We observed that the production of IL-10 was required by S. Typhimurium to cause a systemic disease, since mice lacking IL-10 (IL-10-/-) were significantly more resistant to die after an infection as compared to wild-type (WT) mice. IL-10-/- mice had reduced bacterial loads in internal organs and increased levels of pro-inflammatory cytokines in serum at 5 days of infection. Importantly, WT mice showed high bacterial loads in tissues and no increase of cytokines in serum after 5 days of S. Typhimurium infection, except for IL-10. In WT mice, we observed a peak of il-10 messenger RNA production in ileum, spleen, and liver after 5 days of infection. Importantly, the adoptive transfer of T or B cells from WT mice restored the susceptibility of IL-10-/- mice to systemic S. Typhimurium infection, suggesting that the generation of regulatory cells in vivo is required to sustain a systemic infection by S. Typhimurium. These findings support the notion that IL-10 production from lymphoid cells is a key process in the infective cycle of S. Typhimurium in mice due to generation of a tolerogenic immune response that prevents bacterial clearance and supports systemic dissemination.

Assessment of the nitric oxide system in the heart, aorta and kidney of aged Wistar-Kyoto and spontaneously hypertensive rats.

OBJECTIVE: To assess the nitric oxide (NO) system in the cardiovascular and renal systems of old Wistar-Kyoto (WKY) rats and old spontaneously hypertensive rats (SHR) compared with young rats of the same strains. DESIGN AND METHODS: The NO pathway was assessed: (i) in analytical studies measuring the concentration of nitrate in plasma and the activity of NO synthases in the left ventricle, renal cortex and renal medulla; and (ii) in functional studies, in which we measured the blood pressure effects of NO blockade with intravenous N-nitro-L-arginine methyl ester (L-NAME, 0.1 mg/kg) in anaesthetized rats. In addition, we studied NO production in the aorta comparing the force attained by isolated segments exposed to cumulative concentrations of L-NAME (10(-7)-10(-3) mol/l). RESULTS: Plasma nitrate was significantly higher in old rats of both strains. Calcium-dependent NO synthase activity was markedly upregulated in the left ventricle, renal cortex and renal medulla of the old rats, both in hypertensive and normotensive animals. Intravenous L-NAME elicited deeper pressor effects in the old rats of either blood pressure condition. Aortic segments from old WKY rats, but not those from SHR, achieved remarkably stronger tension in response to L-NAME compared with the young counterparts. CONCLUSIONS: These findings suggest that the NO system is upregulated in the cardiovascular system and the kidney in senescence, even in hypertension.