Unregulated activity of myofibroblasts, highly contractile cells that deposit abundant extracellular matrix (ECM), leads to fibrosis. To study the modulation of myofibroblast activity, we used human ...adipose-derived mesenchymal stem cells (ADSCs), which have much potential in regenerative medicine. We found that ADSCs treated with TGF-β developed a myofibroblastic phenotype with increases in α-smooth muscle actin (α-SMA), a myofibroblast marker, and ECM proteins type I collagen and fibronectin. In contrast, treatment with bFGF had the opposite effect. bFGF-differentiated ADSCs showed marked down-regulation of α-SMA expression, collagen I, and fibronectin, and loss of focal adhesions and stress fibers. Functionally, bFGF-differentiated ADSCs were significantly more migratory, which correlated with up-regulation of tenascin-C, an anti-adhesive ECM protein, and vimentin, a pro-migratory cytoskeletal protein. On the other hand, TGF-β-differentiated ADSCs were significantly more contractile than bFGF-differentiated cells. Interestingly, cells completely reversed their morphologies, marker expression, signaling pathways, and contractility versus migratory profiles when switched from culture with one growth factor to the other, demonstrating that the myofibroblast differentiation process is not terminal. Cell differentiation was associated with activation of Smad2 downstream of TGF-β and of ERK/MAP kinase downstream of bFGF. Reversibility of the TGF-β-induced myofibroblastic phenotype depends, in part, on bFGF-induced ERK/MAP kinase signaling. These findings show that ADSC differentiation into myofibroblasts and re-differentiation into fibroblast-like cells can be manipulated with growth factors, which may have implications in the development of novel therapeutic strategies to reduce the risk of fibrosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hyaluronan is an oligosaccharide found in the pericellular matrix of numerous cell types and hyaluronan-induced signaling is known to facilitate fibrosis and cancer progression in some tissues. ...Hyaluronan is also commonly instilled into the eye during cataract surgery to protect the corneal endothelium from damage. Despite this, little is known about the distribution of hyaluronan or its receptors in the normal ocular lens. In this study, hyaluronan was found throughout the mouse lens, with apparently higher concentrations in the lens epithelium. CD44, a major cellular receptor for hyaluronan, is expressed predominately in mouse secondary lens fiber cells born from late embryogenesis into adulthood. Surgical removal of lens fiber cells from adult mice resulted in a robust upregulation of CD44 protein, which preceded the upregulation of α-smooth muscle actin expression typically used as a marker of epithelial–mesenchyma transition in this model of lens epithelial cell fibrosis. Mice lacking the CD44 gene had morphologically normal lenses with a response to lens fiber cell removal similar to wildtype, although they exhibited an increase in cell-associated hyaluronan. Overall, these data suggest that lens cells have a hyaluronan-containing pericellular matrix whose structure is partially regulated by CD44. Further, these data indicate that CD44 upregulation in the lens epithelium may be an earlier marker of lens injury responses in the mouse lens than the upregulation of α-smooth muscle actin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
BackgroundIntroduction: Childhood stroke, although rare, occurs and can cause significant long-term morbidity. Compared to adult’s stroke, paediatric stroke is a heterogenous entity, both of ...aetiology and presentation. This makes accurate and timely diagnosis challenging. In 2017, new paediatric stroke guideline, endorsed by RCPCH/Stroke Association, was published to address these challenges.ObjectivesWe presented 2 similar cases of childhood stroke that happened before and after the publication of the guideline. The second case demonstrated how we adapted current guidelines into the management of the patient.MethodsCase 1 (2011): 3-year-old girl presented with inability to stand and left hand weakness while playing in the garden. Examination revealed weakness to both arm and leg, with facial droop. No history of trauma. CT head was reported to be normal. She was given aspirin and arranged for transfer to tertiary centre the day after for MR/MRA imaging which confirmed stroke.Case 2 (2020): 3-year-old girl presented with left sided facial droop, weakness of left side of her body and slurred speech during family visit to the safari park. The new 2017 guideline was used to aid assessment and management. She scored 6 of PedNIHSS and both CT and CTA was normal. Her assessment and imaging was done within thrombolysis window (4.5 hours). She was transferred to tertiary centre afterwards. MRA confirmed right MCA territory acute infarct.ConclusionsConclusionDespite the new stroke guideline, we encountered several challenges in managing the child in the DGH settings. The assessment and imaging were significantly delayed due difficulty in assessing children, unfamiliarity with the new guidelines, difficulty in reporting paediatric neuroradiology imaging and absence of clear guidance with regards to thrombolysis administration in children. This experience has highlighted the need for regional paediatric stroke assessment centre and decision-making for thrombolysis.
We performed a systematic review with network meta‐analysis (NMA) to compare the efficacy of different approaches in primary prevention of esophageal variceal bleeding and overall survival in ...patients with cirrhosis with large varices. Thirty‐two randomized clinical trials (RCTs) with 3,362 adults with cirrhosis with large esophageal varices and no prior history of bleeding, with a minimum of 12 months of follow‐up, were included. Nonselective beta‐blockers (NSBB), isosorbide‐mononitrate (ISMN), carvedilol, and variceal band ligation (VBL), alone or in combination, were compared with each other or placebo. Primary outcomes were reduction of all‐cause mortality and prevention of esophageal variceal bleeding. Random‐effects NMA was performed and summary estimates were expressed as odds ratio and 95% confidence intervals (OR; CI). Quality of evidence was critically appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach. Moderate quality evidence supports NSBB monotherapy (0.70; 0.49‐1.00) or in combination with VBL (0.49; 0.23‐1.02) or ISMN (0.44; 0.21‐0.93) for decreasing mortality in patients with cirrhosis with large esophageal varices and no prior history of bleeding. Moderate‐quality evidence supports carvedilol (0.21; 0.08‐0.56) and VBL monotherapy (0.33; 0.19‐0.55) or in combination with NSBB (0.34; 0.14‐0.86), and low‐quality evidence supports NSBB monotherapy (0.64; 0.38‐1.07) for primary prevention of variceal bleeding. VBL carries a higher risk of serious adverse events compared with NSBB. Conclusion: NSBB monotherapy may decrease all‐cause mortality and the risk of first variceal bleeding in patients with cirrhosis with large esophageal varices. Additionally, NSBB carries a lower risk of serious complications compared with VBL. Therefore, NSBB may be the preferred initial approach for primary prophylaxis of esophageal variceal bleeding.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Patients admitted to the hospital for alcoholic hepatitis (AH) are at increased risk of readmission and death. We aimed to identify factors associated with readmission, alcohol relapse, and ...mortality.
We performed a retrospective analysis of consecutive patients admitted with AH to a tertiary care hospital from 1999 through 2016 (test cohort, n = 135). We validated our findings in a prospective analysis of patients in a multi-center AH research consortium from 2013 through 2017 (validation cohort, n = 159). Alcohol relapse was defined as any amount of alcohol consumption within 30 days after hospital discharge. Early alcohol rehabilitation was defined as residential or outpatient addiction treatment or mutual support group participation within 30 days after hospital discharge.
Thirty-day readmission rates were 30% in both cohorts. Alcohol relapse rates were 37% in the test and 34% in the validation cohort. Following hospital discharge, 27 patients (20%) in the test cohort and 19 patients (16%) in the validation cohort attended early alcohol rehabilitation. There were 53 deaths (39%) in a median follow-up time of 2.8 years and 42 deaths (26%) in a median follow-up time of 1.3 years, respectively. In the test cohort, early alcohol rehabilitation reduced odds for 30-day readmission (adjusted odds ratios AOR 0.16; 95% CI, 0.04-0.65; P = .01), 30-day alcohol relapse (AOR, 0.11; 95% CI, 0.02-0.53; P < .001), and death (adjusted hazard ratio AHR, 0.20; 95% CI, 0.05-0.56; P = .001). In the validation cohort early alcohol rehabilitation reduced odds for 30-day readmission (AOR, 0.30; 95% CI, 0.09-0.98; P = .04), 30-day alcohol relapse (AOR 0.09; 95% CI, 0.01-0.73; P = .02), and death (AHR, 0.20; 95% CI, 0.01-0.94; P = .04). A model combining alcohol rehabilitation and bilirubin identified patients with readmission to the hospital within 30 days with an area under the receiver operating characteristic curve of 0.73.
In an analysis from two cohorts of patients admitted with AH, early alcohol rehabilitation can reduce risk of hospital readmission, alcohol relapse, and death and should be considered as a quality indicator in AH hospitalization treatment.
Identifying patients at high risk for acute kidney injury (AKI) during hospitalization among patients admitted with severe alcoholic hepatitis (AH) is an unmet clinical need. We performed a ...multicentric prospective cohort study using data from 4 different cohorts on well‐characterized patients hospitalized with severe AH. Data collected on 773 AH patients from 4 cohorts across the globe were randomly split into test (n = 390) and validation (n = 383) cohorts. We found that 32% of the patients developed inpatient AKI in the test cohort. Approximately 60% of patients met criteria for systemic inflammatory response syndrome (SIRS) at admission. Hepatic encephalopathy, SIRS, and Model for End‐Stage Liver Disease score at admission predicted inpatient AKI with odds ratios of 3.86, 2.24, and 1.14, respectively. The AKI risk score developed using these predictors stratified risk of inpatient AKI to low (score <3), moderate (3‐4), and high (>4). These findings were replicated in the validation cohort. In the whole study cohort, patients with AKI had a lower 90‐day survival (53% versus 77%; P < 0.001). Those with AKI risk score of >4 had significantly lower 90‐day survival as compared with those with risk scores between 3 and 4 and <3 (47% versus 68% versus 88%; P < 0.001). In conclusion, AKI occurs frequently in AH patients and negatively impacts short‐term mortality. The AKI risk score is useful in identifying patients at high risk for inpatient AKI and may be useful for developing new therapeutic strategies to prevent AKI in patients with AH.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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