The impact of obstructive sleep apnea on exercise capacity in a cardiac rehabilitation program

PurposeCardiac rehabilitation (CR) improves clinical outcomes in patients with cardiovascular disease (CDV). Patients with CVD often have multiple comorbidities, including obstructive sleep apnea (OSA), potentially affecting their ability to participate and achieve functional improvement during CR. We aimed to test the hypothesis that OSA reduces peak exercise capacity (EC) in patients undergoing CR and to explore if OSA treatment modifies this relationship.MethodsData from a retrospective cohort of CR patients was analyzed. OSA was defined as a respiratory event index > 5/h or physician diagnosis. Patients with OSA were considered "treated" if using continuous positive airway pressure regularly during the CR period. Change in METs was the primary study outcome.ResultsAmong 312 CR patients, median age of 67 years, 103 (33%) had known OSA (30 treated, 73 untreated). Patients with OSA vs. those with no OSA were more likely to be obese and male; otherwise, groups were similar. Compared with the no OSA group, patients with OSA had lower pre-CR METs (3.3 [2.9-4.5] vs. 3.9 [3.1-5], P = .01) and lower post-CR METs (5.3 [4-7] vs. 6 [4.6-7.6], P = .04), but achieved a similar increase in METs post-CR (1.8 [0.6-2.6] vs. 2.0 [0.9-3], P = .22). Furthermore, compared to no OSA, pre-CR and post-CR METs tended to be similar in patients with treated OSA, but lower in untreated patients, with similar increases in METs across all groups, even when adjusting for covariates via multivariable regression.ConclusionOSA is prevalent in patients with CVD undergoing CR. CR substantially improves exercise capacity independent of OSA status, but screening for-and treatment of-OSA may improve the absolute exercise capacity achieved through CR

The antimetastatic activity of orlistat is accompanied by an antitumoral immune response in mouse melanoma

Purpose Fatty acid synthase (FASN), the multifunctional enzyme responsible for endogenous fatty acid synthesis, is highly expressed and associated with poor prognosis in several human cancers, including melanoma. Our group has previously shown that pharmacological inhibition of FASN with orlistat decreases proliferation, promotes apoptosis, and reduces the metastatic spread of B16-F10 cells in experimental models of melanoma. While most of the orlistat antitumor properties seem to be closely related to direct effects on malignant cells, its impact on the host immune system is still unknown. Methods The effects of orlistat on the phenotype and activation status of infiltrating leukocytes in primary tumors and metastatic lymph nodes were assessed using a model of spontaneous melanoma metastasis (B16-F10 cells/C57BL/6 mice). Cells from the primary tumors and lymph nodes were mechanically dissociated and immune cells phenotyped by flow cytometry. The expression of IL-12p35, IL-12p40, and inducible nitric oxide synthase (iNOS) was analyzed by qRT-PCR and production of nitrite (NO2-) evaluated in serum samples with the Griess method. Results Orlistat-treated mice exhibited a 25% reduction in the number of mediastinal lymph node metastases (mean 3.96 +/- 0.78, 95% CI 3.63-4.28) compared to the controls (mean 5.7 +/- 1.72; 95% CI 5.01-6.43). The drug elicited an antitumor immune response against experimental melanomas by increasing maturation of intratumoral dendritic cells (DC), stimulating the expression of cytotoxicity markers in CD8 T lymphocytes and natural killer (NK) cells, as well as reducing regulatory T cells (Tregs). Moreover, the orlistat-treatment increased serum levels of nitric oxide (NO) concentrations. Conclusion Taken together, these findings suggest that orlistat supports an antitumor response against experimental melanomas by increasing CD80/CD81-positive and IL-12-positive DC populations, granzyme b/NKG2D-positive NK populations, and perforin/granzyme b-positive CD8 T lymphocytes as well as reducing Tregs counts within experimental melanomas85321330CAPES - Coordenação de Aperfeiçoamento de Pessoal e Nível SuperiorFAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulonão tem2008/57471-7; 2012/25160-8; 2010/52670-

Toll Like Receptor 3 Plays a Critical Role in the Progression and Severity of Acetaminophen-Induced Hepatotoxicity

<div><p>Toll-like receptor (TLR) activation has been implicated in acetaminophen (APAP)-induced hepatotoxicity. Herein, we hypothesize that TLR3 activation significantly contributed to APAP-induced liver injury. In fasted wildtype (WT) mice, APAP caused significant cellular necrosis, edema, and inflammation in the liver, and the <i>de novo</i> expression and activation of TLR3 was found to be necessary for APAP-induced liver failure. Specifically, liver tissues from similarly fasted TLR3-deficient (<i>tlr3^−/−</i>) mice exhibited significantly less histological and biochemical evidence of injury after APAP challenge. Similar protective effects were observed in WT mice in which TLR3 was targeted through immunoneutralization at 3 h post-APAP challenge. Among three important death ligands (i.e. TNFα, TRAIL, and FASL) known to promote hepatocyte death after APAP challenge, TNFα was the only ligand that was significantly reduced in APAP-challenged <i>tlr3^−/−</i> mice compared with APAP-challenged WT controls. <i>In vivo</i> studies demonstrated that TLR3 activation contributed to TNFα production in the liver presumably via F4/80⁺ and CD11c⁺ immune cells. <i>In vitro</i> studies indicated that there was cooperation between TNFα and TLR3 in the activation of JNK signaling in isolated and cultured liver epithelial cells (i.e. nMuLi). Moreover, TLR3 activation enhanced the expression of phosphorylated JNK in APAP injured livers. Thus, the current study demonstrates that TLR3 activation contributes to APAP-induced hepatotoxicity.</p></div

<i>Tlr3</i>^−/− mice exhibit markedly less hepatotoxicity following APAP.

<p>(<b>A–B</b>) Representative histological liver samples from WT and <i>tlr3</i>^−/− mice after APAP. (<b>C</b>) Lung sections from WT mice at 24 h post APAP. Original magnifications: (<b>A</b>) 100× or (<b>B–C</b>) 200×. (<b>A–C</b>). Data from 4 and 16 h after APAP are representative of 2 independent experiments (<i>n</i> = 5 mice/group). Data from 24 h after APAP are representative of 5 independent experiments (<i>n</i> = 5 mice/group), and data from 48 h post APAP is representative of 3 independent experiments (n = 4–9 mice/group). (<b>D</b>) Serum ALT and AST levels were measured at various time points after APAP. Values represent mean±SEM obtained from 2–3 independent experiments (n = 4–5 per group) (*p<0.05; **p<0.01). (<b>E</b>) Survival of WT and <i>tlr3</i>^−/− mice after 500 mg/kg of APAP. The data are from 2 independent experiments. Each experiment was performed with 10 WT mice and 9–10 <i>tlr3</i>^−/− mice. **p = 0.0037 (Mantel-Cox test). (<b>F</b>) Hepatic GSH levels after APAP injection (<i>n</i> = 3–4 mice/group). Values represent means±SEM of 2 independent experiments. **p<0.01 when <i>tlr3</i>^−/− was compared with WT mice. (<b>G</b>) Liver lysates of WT and <i>tlr3</i>^−/− mice were prepared and pooled for Western blotting analysis using anti-Cyp2e1 and β-actin antibodies. (<b>H</b>) Concentration of APAP was determined in serum from WT and <i>tlr3</i>^−/− at the indicated time points. Values indicate mean ± SEM of 5–6 individual mice. ns = not significant.</p

TLR3 activation increased chemokine levels following APAP-induced hepatotoxicity.

<p>Chemokine transcript levels (<b>A–D</b>) and protein levels (<b>E–H</b>) in WT and <i>tlr3</i>^−/− livers homogenates after APAP. The data represent mean±SEM obtained from 2–3 independent experiments (<i>n</i> = 5/group). *p<0.05; **p<0.01 and ***p<0.001 when WT were compared with <i>tlr3</i>^−/− mice.</p

TLR3 modulates the expression TNFα after APAP.

<p>Total liver transcript levels of (<b>A</b>) <i>fasl</i>, (<b>B</b>) <i>trail</i>, (<b>C</b>) <i>tnf</i> and (<b>D–E</b>) AP-1 genes in WT and <i>tlr3</i>^−/− mice. (<b>F</b>) Total liver TNFα protein levels in WT and <i>tlr3</i>^−/− mice after APAP. Statistically significant differences are indicated (*p<0.05; **p<0.01 and ***p<0.001). Data are presented as the mean ± SEM of 2–3 independent experiments. (<b>G–H</b>) Percentage of TNFα+ cells in different liver cell populations isolated from WT and <i>tlr3^−/−</i> mice at 24 h post APAP. Gating is indicated on the left, population statistics are indicated in the bar graph on the right. Rat IgG1, kappa light chain antibody was used as an isotype control for TNFα staining (<b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065899#pone.0065899.s007" target="_blank">Figure S7</a></b>). Representative population of LSECs (CD45⁻CD31⁺) is shown. Data is representative of two independent experiments. Data represent mean ± SEM (<i>n</i> = 3/group in each experiment).</p