Unbiased analysis of the impact of micropatterned biomaterials on macrophage behaviour provides insights beyond pre-defined polarisation states

Macrophages are master regulators of immune responses towards implanted biomaterials. The activation state adopted by macrophages in response to biomaterials determines their own phenotype and function as well as those of other resident and infiltrating immune and non-immune cells in the area. A wide spectrum of macrophage activation states exists, with M1 (pro-inflammatory) and M2 (anti-inflammatory) representing either ends of the spectrum. In biomaterials research, cellinstructive surfaces that favour or induce M2 macrophages have been considered as beneficial due to the anti-inflammatory and pro-regenerative properties of these cells. In this study, we used a gelatin methacryloyl (GelMA) hydrogel platform to determine whether micropatterned surfaces can modulate the phenotype and function of human macrophages. The effect of microgrooves/ridges and micropillars on macrophage phenotype, function, and gene expression profile were assessed using conventional methods (morphology, cytokine profile, surface marker expression, phagocytosis) and gene microarrays. Our results demonstrated that micropatterns did induce distinct gene expression profiles in human macrophages cultured on microgrooves/ridges and micropillars. Significant changes were observed in genes related to primary metabolic processes such as transcription, translation, protein trafficking, DNA repair and cell survival. However, interestingly conventional phenotyping methods, relying on surface marker expression and cytokine profile, were not able to distinguish between the different conditions, and indicated no clear shift in cell activation towards an M1 or M2 phenotypes. This highlights the limitations of studying the effect of different physicochemical conditions on macrophages by solely relying on conventional markers that are primarily developed to differentiate between cytokine polarised M1 and M2 macrophages. We therefore, propose the adoption of unbiased screening methods in determining macrophage responses to biomaterials. Our data clearly shows that the exclusive use of conventional markers and methods for determining macrophage activation status could lead to missed opportunities for understanding and exploiting macrophage responses to biomaterials

High myopia induced by form deprivation is associated with altered corneal biomechanical properties in chicks

The cornea is a soft, transparent, composite organic tissue, which forms the anterior outer coat of the eyeball. Although high myopia is increasing in prevalence worldwide and is known to alter the structure and biomechanical properties of the sclera, remarkably little is known about its impact on the biomechanics of the cornea. We developed and validated a novel optical-coherence-tomography-indentation probe–to measure corneal biomechanical properties in situ, in chicks having experimentally-induced high myopia, while maintaining intraocular pressure at levels covering the physiological range. We found that the cornea of highly myopic chicks was more steeply curved and softer, at all tested intraocular pressures, than that in contralateral, non-myopic eyes, or in age-matched normal, untreated eyes. These results indicate that the biomechanical properties of the cornea are altered in chicks developing experimentally-induced myopia

Defining the optimal dose of radiation in leukemic patients with extramedullary lesions

<p>Abstract</p> <p>Background</p> <p>Analysis of the clinical response of extramedullary lesions in leukemic patients treated with radiation therapy (RT) and defining the optimal dose of radiation.</p> <p>Methods</p> <p>Forty-two extramedullary lesions found in 24 leukemic patients treated with RT were reviewed. The radiation was delivered usually 2 Gy/day, up to a median of 20 Gy (range: 18.0-40.8). The clinical response and symptom palliation effect were analyzed. The factors affecting the response were also included in the analysis.</p> <p>Results</p> <p>After a median time of 7.9 weeks, the overall response rate was 76.2%. A complete response (CR) was achieved in 35.7%, a partial response in 40.5%. The symptom was relieved in 85.7% sites. The overall response rate was better in patients whose initial tumor size was smaller than 10 cm²(<it>p = 0.010</it>) or who were treated with more than 25 Gy (<it>p = 0.031</it>). The overall CR rate was also higher in those who had smaller tumors (smaller than 6 cm or 30 cm²) (<it>p = 0.015)</it>, or when the tumor was located in soft tissue (<it>p = 0.029</it>).</p> <p>Conclusions</p> <p>Extramedullary lesions in leukemic patients can be successfully treated with RT. The tumor response rate was excellent and symptom relief was achieved in almost all patients. There was a better response to treatment when the tumor was small or it was located in soft tissue. Although, there was no definite correlation between volume reduction and total dose, it seems that higher total dose more of than 25 Gy is needed for better response.</p

Failure of a Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of H. pylori Eradication in H. pylori-Infected Patients with Functional Dyspepsia

BACKGROUND/AIMS: The role of Helicobacter pylori eradication in patients with functional dyspepsia (FD) is still uncertain. We originally planned a randomized clinical study to observe dyspeptic symptoms after H. pylori eradication therapy. However, we failed to complete the study; therefore, we analyzed the factors that affected the failure of the study. METHODS: Interviews and questionnaire surveys were conducted to analyze the factors that induced early termination from the study. RESULTS: Many patients were screened by gastroenterologists at 11 tertiary referral hospitals between July 2009 and August 2010; however, only 4 patients met the enrollment criteria. Most patients who visited our clinics had been experiencing FD symptoms for less than 6 months or were already taking medication. They also demanded to continue taking medications and using other drugs. Only 3 of the 4 patients signed informed consent. CONCLUSIONS: The application of the current Rome III criteria to FD is difficult to evaluate in Korean patients with dyspeptic symptoms because of the early medical evaluation. Most Korean patients who were diagnosed with FD by the Rome III criteria did not overcome their fear of being unable to use rescue medications during the study period.ope

Impact of diabetes mellitus on mortality in patients with acute heart failure: a prospective cohort study

Although more than one-third of the patients with acute heart failure (AHF) have diabetes mellitus (DM), it is unclear if DM has an adverse impact on clinical outcomes. This study compared the outcomes in patients hospitalized for AHF stratified by DM and left ventricular ejection fraction (LVEF). The Korean Acute Heart Failure registry prospectively enrolled and followed 5625 patients from March 2011 to February 2019. The primary endpoints were in-hospital and overall all-cause mortality. We evaluated the impact of DM on these endpoints according to HF subtypes and glycemic control. During a median follow-up of 3.5years, there were 235 (4.4%) in-hospital mortalities and 2500 (46.3%) overall mortalities. DM was significantly associated with increased overall mortality after adjusting for potential confounders (adjusted hazard ratio [HR] 1.11, 95% confidence interval [CI] 1.03–1.22). In the subgroup analysis, DM was associated with higher a risk of overall mortality in heart failure with reduced ejection fraction (HFrEF) only (adjusted HR 1.14, 95% CI 1.02–1.27). Inadequate glycemic control (HbA1c ≥ 7.0% within 1year after discharge) was significantly associated with a higher risk of overall mortality compared with adequate glycemic control (HbA1c < 7.0%) (44.0% vs. 36.8%, log-rank p = 0.016). DM is associated with a higher risk of overall mortality in AHF, especially HFrEF. Well-controlled diabetes (HbA1c < 7.0%) is associated with a lower risk of overall mortality compared to uncontrolled diabetes. Trial registration ClinicalTrial.gov, NCT01389843. Registered July 6, 2011. https://clinicaltrials.gov/ct2/show/NCT01389843This study was supported by Research of Korea Centers for Disease Control and Prevention (2010-E63003-00, 2011-E63002-00, 2012-E63005-00, 2013E63003-00, 2013-E63003-01, 2013-E63003-02, and 2016-ER6303-00)

Delta neutrophil index as an early marker of disease severity in critically ill patients with sepsis

BACKGROUND: The immature granulocyte count has been reported to be a marker of infection and sepsis. The difference in leukocyte subfractions (delta neutrophil index, DNI) in ADVIA 2120 reflects the fraction of circulating immature granulocytes in the blood. This study evaluated the clinical utility of DNI as a severity and prediction marker in critically ill patients with sepsis. METHODS: One hundred and three patients admitted to the medical intensive care unit with sepsis were studied. DNI (the difference in leukocyte subfractions identified by myeloperoxidase and nuclear lobularity channels) was determined using a specific blood cell analyzer. RESULTS: Forty four patients (42.7%) were diagnosed with severe sepsis/septic shock. Overt disseminated intravascular coagulation (DIC) occurred in 40 (38.8%). DNI was significantly higher in patients with severe sepsis/septic shock and overt DIC than in patients without (p 6.5% was a better indicator of severe sepsis/septic shock than C-reactive protein, lactate, white blood cell count, and absolute neutrophil count (sensitivity, 81.3%; specificity, 91.0%; positive predictive value, 88.6%; and negative predictive value, 84.7%). In 36 (82%) of the 44 patients with severe sepsis/septic shock, DNI values were already elevated up to 12 hours before the onset of organ/circulatory failure. CONCLUSIONS: DNI may be used as a marker of disease severity in critically ill patients with sepsis. High levels of DNI may help to identify patients with an impending risk of developing severe sepsis/septic shock.ope

Contributing factors affecting the prognosis surgical outcome for thoracic OLF

The thoracic ossification of ligamentum flavum (OLF) is a disease that produces spastic paraparesis, and there are various factors that may affect the surgical outcome of thoracic OLF patients. The authors of this study treated 19 of these thoracic OLF patients from 1998 to 2002, and retrospectively reviewed the patients′ age, sex, symptom duration, involved disease level, preoperative clinical features, neurological findings, radiological findings, the other combined spinal diseases and the surgical outcomes. There were excellent or good surgical outcomes in 16 patients, but 3 patients did not improve after thoracic OLF surgery: this included 1 patient, whose motor function worsened after decompressive thoracic OLF surgery. The favorable contributing factors of surgical outcome in thoracic OLF are a short preoperative symptom duration, single-level lesion, and unilateral lesion type on CT axial scan. On the contrary, the poor prognostic factors are beak type lesion and intramedullary signal changes on T2-weighted sagittal MRI. The complete preoperative evaluation including radiologic findings will provide valuable aid in presuming the surgical outcome for the thoracic OLF patients.ope

Impact of insulin therapy on the mortality of acute heart failure patients with diabetes mellitus

Background Patients with diabetes mellitus (DM) have a higher prevalence of heart failure (HF) than those without it. Approximately 40 % of HF patients have DM and they tend to have poorer outcomes than those without DM. This study evaluated the impact of insulin therapy on mortality among acute HF patients. Methods A total of 1740 patients from the Korean Acute Heart Failure registry with DM were included in this study. The risk of all-cause mortality according to insulin therapy was assessed using the Cox proportional hazard models with inverse probability of treatment weighting to balance the clinical characteristics (pretreatment covariates) between the groups. Results DM patients had been treated with either oral hypoglycemic agents (OHAs) alone (n = 620), insulin alone (n = 682), or insulin combined with OHAs (n = 438). The insulin alone group was associated with an increased mortality risk compared with the OHA alone group (HR = 1.41, 95 % CI 1.21–1.66]). Insulin therapy combined with OHAs also showed an increased mortality risk (HR = 1.29, 95 % CI 1.14–1.46) compared with the OHA alone group. Insulin therapy was consistently associated with increased mortality risk, regardless of the left ventricular ejection fraction (LVEF) or HF etiology. A significant increase in mortality was observed in patients with good glycemic control (HbA1c < 7.0 %) receiving insulin, whereas there was no significant association in patients with poor glycemic control (HbA1c ≥ 7.0%). Conclusions Insulin therapy was found to be associated with increased mortality compared to OHAs. The insulin therapy was harmful especially in patients with low HbA1c levels which may suggest the necessity of specific management strategies and blood sugar targets when using insulin in patients with HF.This study was supported by the Research of Korea Centers for Disease Control and Prevention (2010-E63003-00, 2011-E63002-00, 2012-E63005-00, 2013E63003-00, 2013-E63003-01, 2013-E63003-02, and 2016-ER6303-00