Given a passage with a context and an answer, 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.

Q: Context: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of growth factors that have been implicated in skin patho-physiology. Although endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) appear to be involved in mitogenesis and chemotaxis in epidermal keratinocytes, the activation of eNOS and VEGF production induced by HB-EGF and its signaling mechanism remains undefined.', 'We examined possible signal transduction pathways by which HB-EGF leads to eNOS activation and VEGF production in human epidermal keratinocyte cell line (HaCaT cells).', 'The phosphorylation of epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK; p42/p44 MAPK), Akt and eNOS were examined by Western blotting analysis. VEGF production was determined by enzyme-linked immunosorbent assay. Various inhibitors were utilized to investigate the signaling mechanisms of eNOS activation and VEGF production.', 'HB-EGF-induced phosphorylation of EGFR with maximum phosphorylation at 1h. HB-EGF-induced phosphorylation of p42/p44 MAPK in a few minutes. It activated Akt with maximum phosphorylation at 1h and eNOS with maximum phosphorylation at 3h. The HB-EGF-induced eNOS activation was significantly blocked by the p42/p44 MAPK inhibitor U0126 and the phosphatidylinositol 3-kinase (P13K) inhibitor LY294002. HB-EGF increased VEGF production. The HB-EGF-induced VEGF production was blocked by U0126 and LY294002. Finally, the HB-EGF-induced activation of Akt and eNOS was suppressed by VEGF competitive antagonist, CBO-P11.
Answer: These results demonstrate that HB-EGF-induced eNOS activation depends on p42/p44 MAPK, PI3K/Akt pathways and endogenous VEGF in HaCaT cells.

A: Do hB-EGF-induced VEGF production and eNOS activation depend on both PI3 kinase and MAP kinase in HaCaT cells?
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Q: Context: Facial dog bite injuries pose a significant public health problem.', 'Seventy-five consecutive patients (45 males, 30 females) treated solely by plastic surgery service for facial dog bite injuries at a Level I trauma center in the Denver Metro area between 2006 and 2012 were retrospectively reviewed. The following information were recorded: breed, relationship of patient to dog, location and number of wounds, the duration between injury and surgical repair and dog bite incident, type of repair, and antibiotic prophylaxis. Primary end points measured were wound infection, the need for revision surgery, and patient satisfaction.', 'Ninety-eight wounds in the head and neck region were repaired (46 children; mean age, 6.8 years) and (29 adults; mean age, 47.3 years). Twelve different breeds were identified. There was no significant association between the type of dog breed and the number of bite injuries. The duration between injury and repair ranged from 4 hours to 72 hours (mean [SD], 13.7 [10.9] hours). The majority of bite wounds (76 of 98) involved the cheek, lip, nose, and chin region. Direct repair was the most common surgical approach (60 of 98 wounds) (p < 0.05). There was no statistically significant association between wounds needing reconstruction versus direct repair according to dog breed (p = 0.25). Ten wounds required grafting. Twenty-five wounds were managed by one-stage or two-stage flaps. Only three patients (3.06 %) underwent replantation/revascularization of amputated partial lip (n = 2) and of cheek (n = 1). There was one postoperative infection. Data from five-point Likert scale were available for fifty-two patients. Forty patients were satisfied (5) with the outcome, while five patients were somewhat satisfied (4), and seven were neutral.
Answer: Availability of the plastic surgery service at a Level I trauma center is vital for the optimal treatment of facial dog bite injuries. Direct repair and reconstruction of facial dog bite injuries at the earliest opportunity resulted in good outcomes as evidenced by the satisfaction survey data and low complication rate.

A: Do retrospective analysis of facial dog bite injuries at a Level I trauma center in the Denver metro area?
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Q: Context: Although Alzheimer's disease (AD) is associated with early death, its life expectancy differs greatly between patients. A better understanding of this heterogeneity may reveal important disease mechanisms underlying the malignancy of AD. The aim of this study was to examine the relation between AD pathologies and early death in AD caused by dementia.", 'At a memory clinic, 247 referred consecutive patients with AD were monitored during 12.61.6 years. Multivariate Cox regression analyses were performed with baseline measures of amyloid beta (A) pathology (APOE genotype, cerebrospinal fluid (CSF) A42) tau pathology (CSF phosphorylated tau and total tau), cerebrovascular pathology (white-matter lesions and CSF/serum albumin ratio), neuroinflammatory pathology (CSF soluble vascular cell adhesion molecule-1, sVCAM-1), frontal, temporal, and central brain atrophies, global cognition, sex, and age. Comorbidities and medications also were analyzed. All continuous variables were transformed to z scores to compare hazard ratios (HRs) and 95% confidence intervals (CIs).', 'At follow-up, 89% of the patients had died. The mean survival time was 6.43.0 years. The AD pathology that independently predicted an early death caused by dementia was cerebral inflammation (sVCAM-1; HR, 1.32; 95% CI, 1.07-1.64). Other independent predictors were lower global cognition (HR, 0.51; 95% CI, 0.43-0.61), frontal atrophy (HR, 1.38; 95% CI, 1.12-1.70), and medial temporal atrophy (HR, 1.23; 95% CI, 1.02-1.49). When examining death caused by dementia and related causes (vascular diseases and infections), age (HR, 1.23; 95% CI, 1.04-1.46) and cerebrovascular pathology (white-matter lesions: HR, 1.17; 95% CI, 1.01-1.36; and CSF/serum albumin ratio: HR, 1.16; 95% CI, 1.001-1.34) were also significant risk factors in addition to the previous variables. No comorbidity or medication was significant in the specific-cause models.
Answer: This is the first study to link neuroinflammation independently to early death in AD and, hence, a rapidly progressing disease. Frontal and medial temporal atrophies and low cognition were also significant predictors. These are probably downstream biomarkers that reflect neuronal degeneration and late-stage disease. Our results suggest that inflammation, and not amyloid or tau pathology, is an independent underlying mechanism in the malignancy of AD.

A:
Is cerebral inflammation an underlying mechanism of early death in Alzheimer 's disease : a 13-year cause-specific multivariate mortality study?
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