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.

Input: Consider Input: Context: Critical size defects (CSDs) of bone are defined as defects that do not heal spontaneously to new bone during the lifetime of an adult individual. In contrast, immature animals are capable to heal defects of identical size. It was our hypothesis that age-related paracrine effects are relevant for this difference in regeneration.', 'The pooled supernatant of primary rat calvarial osteoblast-like cell cultures (POBC) derived from prenatal or postnatal donors was concentrated and applied into CSDs of adult recipient organisms (n = 10). In addition, the supernatant of POBC derived from prenatal donors was pooled and purified by reverse-phase chromatography. Each pre-purified fraction was tested in a proliferation indicating bioassay. Peptide fractions containing proliferative activities were re-chromatographed and re-tested in a bioassay. Finally, a proliferative activity was purified, identified by sequence analysis and applied into CSDs of adult recipients.', 'The application of POBC derived from prenatal donors resulted in osseous regeneration of a CSD in adult recipients, while the supernatant of postnatal donors had much smaller effects. The morphologic features resembled the spontaneous osseous healing of calvarial defects of the same size in immature organisms. The polypeptide "tissue inhibitor of metalloproteinases type II"(TIMP-2) was isolated from the supernatant of cultures of POBC derived from prenatal donors by measuring the induction of their proliferation. Additionally, the application of human TIMP-2 injected into calvarial CSDs of adult organisms resulted in osseous healing.
Answer: We conclude that one component responsible for the healing effect of CSDs of POBC supernatants derived from prenatal donors is TIMP-2.

Output: Is tissue inhibitor of metalloproteinases II ( TIMP-2 ) an osteoanabolic factor in vitro and in vivo?


Input: Consider Input: Context: Molecular staging of sentinel lymph nodes (SLNs) may identify patients who are node-negative by standard microscopic staging but are at increased risk for regional nodal recurrence; such patients may benefit from completion lymph node dissection (CLND).', 'In a multicenter, randomized clinical trial, patients with tumor-negative SLNs by standard pathology (hematoxylin and eosin [H and E] serial sections and immunohistochemistry [IHC]) underwent reverse transcriptase polymerase chain reaction (PCR) analysis of SLNs for melanoma-specific mRNA. Microscopically negative/PCR+ patients were randomized to observation, CLND, or CLND with high-dose interferon (HDI). For this post-hoc analysis, clinicopathologic features and survival outcomes, including overall survival (OS) and disease-free survival (DFS), were compared between PCR+ patients who underwent CLND vs observation. Microscopic and molecular node-negative (PCR-) patients were included for comparison.', 'A total of 556 patients were PCR+: 180 underwent observation, and 376 underwent CLND. An additional 908 PCR- patients were observed. Median follow-up was 72 months. Disease-free survival (DFS) was significantly better for PCR+ patients who underwent CLND compared with observation (p\xa0= 0.0218). No statistically significant differences in OS or distant disease-free survival (DDFS) were seen. Regional lymph node recurrence-free survival (LNRFS) was improved in PCR+ patients with CLND compared to observation (p\xa0=\xa00.0065). The PCR+ patients in the observation group had the worst DFS; those with CLND had similar DFS to that in the PCR- group (p\xa0= 0.9044).
Answer: Patients with microscopically negative/PCR+ SLN have an increased risk of nodal recurrence that was mitigated by CLND. Although CLND did not affect OS, these data suggest that molecular detection of melanoma-specific mRNA in the SLN predicts a greater risk of nodal recurrence and deserves further study.

Output: Does molecular Staging of Sentinel Lymph Nodes identify Melanoma Patients at Increased Risk of Nodal Recurrence?


Input: Consider Input: Context: The aims of this study were to test the hypothesis that short-term high salt intake reduces macrovascular and microvascular endothelial function in the absence of changes in blood pressure and to determine whether acute exercise restores endothelial function after high salt in women.', 'Twelve women were administered high salt (11\u200ag of sodium chloride for 7 days) and then underwent a weightlifting session. Brachial artery flow-mediated dilation and nitroglycerin dilation were measured with ultrasound at baseline, after high salt, and after weightlifting. Subcutaneous fat tissue biopsies were obtained at baseline, after high salt, and after weightlifting. Resistance arteries from biopsies were cannulated for vascular reactivity measurements in response to flow [flow-induced dilation (FID)] and acetylcholine.', 'Blood pressure was similar before and after high salt diet. Brachial flow-mediated dilation was reduced after high salt diet but was not affected by acute weightlifting. Brachial nitroglycerin dilations were similar before and after high salt. FID and acetylcholine-induced dilation of resistance arteries were similar to that of before and after high salt diet. FID and acetylcholine-induced dilation was not altered by weightlifting after high salt diet. However, N-nitro-L-arginine methyl ester significantly reduced FID at baseline and after exercise but had no effect dilator reactivity after high salt diet alone.
Answer: These data suggest that high salt intake reduces brachial artery endothelial function and switches the mediator of vasodilation in the microcirculation to a non-nitric oxide-dependent mechanism in healthy adults and acute exercise may switch the dilator mechanism back to nitric oxide during high salt diet.


Output: Does short-term high salt intake reduce brachial artery and microvascular function in the absence of changes in blood pressure?