TASK DEFINITION: Given a passage, construct a question on the basis of the information present in the passage. Construct the question in such a way that (i) it is unambiguous, (ii) it is answerable from the passage, (iii) its answer is unique (iv) it answer uses text phrases from the passage. Avoid creating questions that (i) can't be answered correctly without actually understanding the passage and (ii) uses the same words or phrases given in the passage.
PROBLEM: To date, cardiac catheterization and endomyocardial biopsy have been considered the "gold standard" for rejection surveillance after heart transplantation. Factors such as patient size (i.e., infant transplantation), loss of vascular access after repeated catheterizations, and anesthesia requirements all present unique problems and risks related to pediatric rejection surveillance. Therefore, additional methods to monitor for rejection in a non-invasive, reliable and frequent manner have been sought. We studied the utility of echocardiographic measurement of the left ventricular myocardial performance index (LVMPI), a reproducible measure of combined systolic and diastolic performance, in pediatric heart transplant recipients as a method of identifying acute rejection.', 'Two-dimensional/Doppler echocardiographic studies (n = 36) were performed on 21 cardiac transplant patients (ages 6.2 to 21.9 years) at the time of endomyocardial biopsy. The LVMPI, the sum of the isovolumic contraction time and isovolumic relaxation time divided by aortic ejection time, was determined at each study, as well as other echocardiographic measures of systolic and diastolic function. Patients were grouped by concurrent histologic rejection grade and the results compared between groups.', 'Significant differences in LVMPI (p < 0.001) were noted between patients with no rejection (Grade 0; n = 23) and those with moderate to severe rejection (Grade 3; n = 5), as well as between those with no rejection and those with focal moderate (Grade 2; n = 8) rejection (p < 0.05). The LVMPI was 0.42 +/- 0.03 (mean +/- SEM) for the group without rejection, 0.57 +/- 0.06 for those with Grade 2 rejection and 0.73 +/- 0.05 for those with Grade 3 rejection. Although 9 of the 23 studies in the non-rejection group had LVMPI values exceeding 0.44 (upper threshold value), 12 of 13 patients in the rejection groups exceeded this threshold. LVMPI >or= 0.64 was associated with significant rejection in all cases in this study (n = 7). No significant differences were noted between groups for left ventricular ejection fraction or shortening fraction, percent septal or posterior wall thickening, left ventricular mass index or mitral valve deceleration time. In addition, for those individual patients with multiple studies, the LVMPI consistently increased with higher rejection grades and decreased after therapy.

SOLUTION: Does increased myocardial performance index correlate with biopsy-proven rejection in pediatric heart transplant recipients?

PROBLEM: Obstructive sleep apnea (OSA) is a common disorder characterized by chronic intermittent hypoxia (CIH). OSA is prevalent in obese subjects and is associated with endothelial dysfunction and cardiovascular disorders. We tested the hypothesis that the deleterious effects of IH could be further modulated by diet-induced obesity.', 'Thirty adult (8-10 weeks) male C57BL/6J mice were divided into four groups. Mice were subjected to CIH or intermittent air (IA) for 12h a day and fed either a high fat (HF) or a low fat control diet (CD) for 6weeks. We analyzed endothelial function using a wire myograph, and measured markers of oxidative stress (plasma malondialdehyde (MDA) and total antioxidant capacity (TAC)) using colorimetrical assays. We also measured C-reactive protein (CRP) using ELISA and endothelial nitric oxide (eNOS) gene expression using real time PCR.', 'Stimulated endothelial dependent dilation was significantly impaired only in the group fed high fat diet and subjected to CIH (Emax: HFIH 78±2%, p<0.0001) when compared to the other groups (Emax: HFIA 95±0.7%, CDIH 94±2%, CDIA 97±1%). Also basal endothelial dependant dilation was attenuated in the HFIH group compared to the HFIA group (Emax: HFIH: 179±10% vs. HFIA: 149±11% in the presence of L-NAME). Levels of MDA were elevated in the CDIH group when compared to CDIA (0.68±0.04 vs. 0.41±0.03 μM, p<0.05) but were greatest in the HFIH group (0.83±0.08 μM, p<0.05). However, there was no significant increase in MDA levels in the HFIA group (0.45±0.03 μM, p=NS) when compared to all other groups. Similar effects were observed with CRP levels; CRP levels were significantly higher in the CDIH group compared with intermittent air (10.39±0.38 vs. 8.70±0.21 μg/ml, p<0.05) but the HFIH had the greatest levels of CRP (11.87±0.31 μg/ml, p<0.05). In the HFIA group, CRP levels were not elevated (9.96±0.37 μg/ml, p=NS). Nevertheless, total antioxidant capacity and eNOS gene expression were not significantly different in the groups.

SOLUTION: Does chronic intermittent hypoxia cause endothelial dysfunction in a mouse model of diet-induced obesity?

PROBLEM: Chronic ethanol (EtOH) has been shown to augment tumor necrosis factor (TNF)-alpha production, and this has been associated with EtOH-induced liver injury. We have recently described a chronic in vitro cell culture model where chronic ethanol exposure results in significantly augmented TNF production in Mono Mac 6 cells, a human monocytic cell line. This enhanced TNF production was redox regulated and associated with increased levels of TNF messenger RNA (mRNA) as well as increased processing of TNF by TNF converting enzyme (TACE), the enzymatic activity of which is regulated by the cellular redox state. We hypothesized that chronic ethanol through oxidative stress activates TACE-mediated ectodomain shedding of the preformed substrates p75 and p55 TNF receptors in Mono Mac 6 cells and L-selectin in Jurkat T cells.', 'Mono Mac 6 or Jurkat T cells were treated with EtOH (0, 50, or 100 mM) for 4 to 6 days. Shedding of p75 and p55 TNF receptors (Mono Mac 6 cells) or L-selectin (Jurkat T cells) was induced by stimulation with lipopolysaccharide and phorbol myristate acetate for Mono Mac 6 cells and PMA alone for Jurkat T cells. Shedding was assessed by enzyme-linked immunosorbent assay for shed molecules in the cell supernatant as well as the cell-associated proteins recovered from cell pellets. Steady-state mRNA levels for p75 TNF receptor and L-selectin were determined by ribonuclease protection assay. Cell surface L-selectin and TACE were measured by flow cytometry, and cell associated p55 and p75 TNF receptors were measured by enzyme-linked immunosorbent assay.', 'Chronic EtOH exposure for 6 days resulted in a significant dose-dependent increase in shedding of p75 and p55 TNF receptors from Mono Mac 6 cells and L-selectin from Jurkat T-cells. The enhanced shedding was correlated with an alcohol-induced increase in mRNA levels and cell surface protein levels for these TACE substrates. Although chronic EtOH exposure increased the total amount of p75 and p55 TNF receptor and L-selectin shed into the media, the efficiency of shedding was suppressed by EtOH. In the case of Mono Mac 6 cells, the EtOH exposure increased superoxide production. Inhibition of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase and hydrogen peroxide partially prevented the increased production of p75 TNF receptor in these cells.

SOLUTION:
Does chronic ethanol enhance ectodomain shedding in T cells and monocytes?