Absence Of Fibrosis Research Articles

The prevalent I686T human variant and loss-of-function mutations in the cardiomyocyte-specific kinase gene TNNI3K cause adverse contractility and concentric remodeling in mice.

TNNI3K expression worsens disease progression in several mouse heart pathology models. TNNI3K expression also reduces the number of diploid cardiomyocytes, which may be detrimental to adult heart regeneration. However, the gene is evolutionarily conserved, suggesting a beneficial function that has remained obscure. Here, we show that C57BL/6J-inbred Tnni3k mutant mice develop concentric remodeling, characterized by ventricular wall thickening and substantial reduction of cardiomyocyte aspect ratio. This pathology occurs in mice carrying a Tnni3k null allele, a K489R point mutation rendering the protein kinase-dead, or an allele corresponding to human I686T, the most common human non-synonymous TNNI3K variant, which is hypomorphic for kinase activity. Mutant mice develop these conditions in the absence of fibrosis or hypertension, implying a primary cardiomyocyte etiology. In culture, mutant cardiomyocytes were impaired in contractility and calcium dynamics and in protein kinase A signaling in response to isoproterenol, indicating diminished contractile reserve. These results demonstrate a beneficial function of TNNI3K in the adult heart that might explain its evolutionary conservation and imply that human TNNI3K variants, in particular the widespread I686T allele, may convey elevated risk for altered heart geometry and hypertrophy.

Value of liver iron concentration in healthy volunteers assessed by MRI

Iron overload is a relatively common clinical condition resulting from disorders such as hereditary hemochromatosis, thalassemia, sickle cell disease, and myelodysplasia that can lead to progressive fibrosis and eventually cirrhosis of the liver. Therefore, it is essential to recognize the disease process at the earliest stage. Liver biopsy is the reference test for the assessment of liver fibrosis. It also allows for quantifying liver iron concentration (LIC) in patients. However, this is an invasive method with significant limitations and possible risks. Magnetic resonance imaging (MRI) and evaluation of the R2* relaxation rate can be an alternative to biopsy for assessing LIC. However, it causes a need for accurate R2* data corresponding to standard value for further comparison with examined patients. This study aimed to assess the normative values of liver R2* in healthy individuals. A total of 100 volunteers that met established criteria were enrolled in the study: 36 (36%) men and 64 (64%) women. The mean age was 22.9 years (range 20 to 32 years). R2* was estimated by an MRI exam with a 1.5 T clinical magnetic resonance scanner. Images for measuring the LIC and liver fat concentration were obtained using the IDEAL-IQ technique for liver imaging. The Mean (SD) liver R2* was 28.34 (2.25) s−1 (95% CI, 27.78–28.90, range 23.67–33.00 s−1) in females, 29.57 (3.20) s−1 (95% CI, 28.49–30.66, range 23.93–37.77 s−1) in males, and 28.72 (2.69) s−1 (range 23.67–37.77 s−1) in the whole group. R2* value in this particular population with a high proportion of young women did not exceed 38 s−1. In the absence of fibrosis or steatosis, liver stiffness and fat fraction did not show any relationship with R2*.

Steatosis as main determinant of portal hypertension through a restriction of hepatic sinusoidal area in a dietary rat nash model.

Portal hypertension (PH) can be present in pre-cirrhotic stages, even in absence of fibrosis in non-alcoholic steatohepatitis (NASH) patients. Liver endothelial dysfunction (ED) has been shown as responsible for this effect in short-term dietary animal models. We evaluated the persistence of PH and underlying mechanisms in a long-term rat model of NASH. Sprague-Dawley rats were fed 8 or 36weeks with control diet or high-fat high-glucose/fructose diet. Metabolic parameters, histology, ED and haemodynamics were characterized. Structural characteristics of liver sections were analysed using image analysis. Both interventions reproduced NASH histological hallmarks (with steatosis being particularly increased at 36weeks), but neither induced fibrosis. The 36-week intervention induced a significant increase in portal pressure (PP) compared to controls (12.1 vs 8.7mmHg, P<.001) and the 8-week model (10.7mmHg, P=.006), but all features of ED were normalized at 36weeks. Image analysis revealed that the increased steatosis at 36-week was associated to an increase in hepatocyte area and a significant decrease in the sinusoidal area, which was inversely correlated with PP. The analysis provided a critical sinusoidal area above which animals were protected from developing PH and below which sinusoidal flux was compromised and PP started to increase. Liver steatosis per se (in absence of fibrosis) can induce PH through a decrease in the sinusoidal area secondary to the increase in hepatocyte area in a long-term diet-induced rat model of NASH. Image analysis of the sinusoidal area might predict the presence of PH.

Nasal polyps in eosinophilic granulomatosis with polyangiitis: Structured histopathology and CD105 expression.

Distinguishing the prodromal nasal polyposis of eosinophilic granulomatosis with polyangiitis (EGPA) from chronic rhinosinusitis with nasal polyps (CRSwNP) is a challenge for rhinologists and rheumatologists. It has recently been reported that angiogenesis and CD105 expressed on vascular endothelial cells could have a role in the pathogenesis and development of nasal polyps. This exploratory study examined the structured histopathology of nasal polyps in patients with EGPA and CRSwNP, comparing CD105 expression in their nasal tissue with that of a control group with no chronic sinonasal inflammation. A structured histopathological study was performed on surgical specimens of nasal tissue from 32 adults (13 with EGPA, 14 with CRSwNP, 5 controls), considering CD105 as a marker to determine microvessel density (MVD). The mean eosinophil count was higher in EGPA patients with tissue inflammation (p=.002), and in CRSwNP patients with sub-epithelial edema (p=.009). Neutrophil infiltration was significantly associated with severe tissue inflammation in EGPA patients (p=.04), but with the absence of fibrosis in CRSwNP patients (p=.04). In the EGPA group, CD105-MVD correlated with tissue eosinophil count (p=.05). Mean CD105-MVD was significantly higher in EGPA patients with mucosal ulceration (p=.004). In the CRSwNP group, a CD105-MVD correlated positively and significantly with tissue eosinophil count (p=.01). Alongside the known abundance of eosinophils, other cells might contribute to inflammatory processes. Neutrophils may amplify inflammation, eosinophil recruitment and tissue damage. CD105 expression in CRSwNP and EGPA nasal polyps supports the hypothesized involvement of angiogenesis in the pathogenesis and development of nasal polyps.

Approach to the patient with acute severe autoimmune hepatitis.

SummaryAutoimmune hepatitis is associated with varied clinical presentations and natural history, as well as somewhat unpredictable treatment responses. Understanding how to stratify patients who require further escalation of therapy will help clinicians manage these patients. The presentation of acute severe autoimmune hepatitis (AS-AIH) is relatively uncommon, although its prevalence is potentially greater than currently perceived. Previous studies consist of small retrospective single-centre series and are not directly comparable due to the diversity of presentations, disease definitions and non-standardised treatment regimens. We define AS-AIH as those who present acutely with AIH and are icteric with an international normalised ratio ≥1.5 and no evidence of hepatic encephalopathy. Those with hepatic encephalopathy should be defined as having AS-AIH with acute liver failure. In this review, we provide a structured practical approach for diagnosing and managing this unique group of patients.

45 Severe secondary mitral regurgitation due to left ventricular non- compactation cardiomyopathy- a rare cause of heart failure

Abstract Introduction Left ventricular non-compaction is a rare form of cardiomyopathy charactherized by the presence of a two layered ventricular wall- a thinner epicardial layer and an inner, non-compacted layer with prominent trabeculations associated with deep, intratrabecular recesses that communicate with left ventricle cavity. Clinical manifestations vary in severity, including symptoms of heart failure, thromboembolic events or arrhythmias. Left ventricular (LV) dysfunction leads to tethering of the mitral apparatus and is a cause for secondary significant mitral regurgitation. Case presentation We report the case of a 57 year-old female patient, diagnosed with severe mitral regurgitation one year before presentation, with severe heart failure (HF) symptoms, referred to our clinic for the surgical replacement of the mitral valve. Clinical examination revealed no signs of pulmonary or systemic congestion and systolic apical murmur. Blood tests were normal, except for the elevated BNP (552 pg/ml). Electrocardiogram showed sinus rhythm and left ventricular hypertrophy. Coronary angiogram did not identify any coronary artery lesions. Echocardiography revealed mildly dilated left ventricle, but wih proeminent trabeculations and two distinct myocardial layers with a non-compacted/compacted ratio of 2:1 in the anterior and lateral walls, diagnostic for left ventricular non-compaction cardiomyopathy. LV ejection fraction was 40% , with severe secondary mitral regurgitation due to significant antero-posterior dilation of the mitral ring, with intact mitral leaflets; mild pulmonary hypertension was present. Magnetic resonance imaging (MRI) identified a two layer antero-lateral myocardium and confirmed the echo diagnosis; there was no evidence of scarring as there was absent late gadolinium enhacement. In the absence of fibrosis on MRI or any arrhythmic events on repeated Holter ECG monitoring, the implantation of a cardiac defibrillator was deferred. Given the secondary cause for mitral regurgitation (LV dysfunction), specific HF medication with beta blocker and renin-angiotensin-aldosterone blockade was initiated and titrated to optimal doses. With medical treatment the evolution was favourable. Currently, 3 years after the initial diagnosis, 6 minutes walk test revealed good functional capacity (510 m), a BNP value of 104 pg/l, without any worsening of LV systolic function nor progression of pulmonary hypertension. Conclusion Left ventricular non-compaction cardiomyopathy is a rare cause of heart failure, but due to advances in imaging modalities and increasing awareness, its prevalence is growing. Its pathogenesis and prognosis largely remain unknown, but early and adequate initiation of neurohormonal medication may be just as essential in order to prevent complications and improve long term prognosis, as for other forms of cardiomiopathy, even in the presence of severe secondary mitral regurgitation.

1181 A novel insight into pathophysiology of hypertrophic cardiomyopathy using simultaneous three-dimensional volume-strain loops

Abstract Funding Acknowledgements Supported with a scholarship by the Greek State Scholarship Foundation (IKY). Background Strain assessment offers a robust evaluation of myocardial mechanics and systolic function, however reporting only peak strain values in hypertrophic cardiomyopathy (HCM) may impose limitations in the conception of its complex remodeling. Therefore, combined plotting of deformation parameters against other indices [e.g. arterial pressure, left ventricular (LV) volume] might offer additional insights into the pathophysiology of the disease. Purpose Aim of this study was i) to apply strain-volume loops in HCM based on simultaneous frame-by-frame strain and volume changes’ recordings acquired by means of three-dimensional (3D) speckle tracking imaging and ii) to take advantage of the previous methodology to gain further insights into HCM pathophysiology. Methods We included 40 HCM patients (54.1 ± 14.3 years, 82.5% male, maximum wall thickness 19.3 ± 4.8mm) who have consecutively undergone 3D-speckle tracking echocardiography and cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE). Values of 3D strain were plotted vs. volume for each frame to build a strain–volume loop. Peak of radial, longitudinal, and circumferential systolic strain (Rsp, Lsp, and Csp, respectively), systolic slopes of the loops (RsSl, LsSl, CsSl), and strain to end-diastolic volume (EDV) ratio (Rs/V, Ls/V, Cs/V) were computed for the analysis (panel A). Additionally, burden of fibrosis (percentage of LV mass) was defined by LGE extent (&amp;gt;5 standard deviations compared to nulled myocardium) in CMR slices. Results All HCM patients had preserved EF (60.5 ± 5,7%), while 16 (40%) had LV outflow tract obstruction (LVOTO &amp;gt; 30 mm Hg at rest). Mean LV mass index was 78.9 ± 14.5 g (evaluated by 3D echocardiography). LGE was observed in 23 patients (57.5%) occupying 5.2 ± 4.5% of LV mass. Concerning strain-volume loops the following values were recorded for radial (Rsp 30.8 ± 9.8%, RsSl 0.4 ± 0.13 and Rs/V 0.25 ± 0.09), longitudinal (Lsp -9.4 ± 3.7%, LsSl 0.12 ± 0.06 and Ls/V 0.08 ± 0.04) and circumferential deformation (Csp -14.2 ± 3.5%, CsSl 0.18 ± 0.05 and Cs/V 0.11 ± 0.03). Among typical HCM characteristics tested (LV mass, LVOTO and LGE), only LV mass presented significant correlations with LsSl (r=-0.41, p &amp;lt; 0.01). Interestingly, HCM patients with smaller LVMI and without LGE presented steeper and narrower (difference between systolic and diastolic strain for the same volume) longitudinal strain-volume loops compared to patients with larger LVMIs and fibrosis (panel B). Conclusions Strain-volume loop is an innovative application of 3D deformation imaging in HCM. According to this new non-invasive method, increase of LVMI in HCM is accompanied by less longitudinal contribution to stroke volume, whereas absence of fibrosis and severe hypertrophy is accompanied by better systolic-diastolic coupling. Abstract 1181 Figure.

MISOPROSTOL ATTENUATES CARDIOMYOCYTE PROLIFERATION IN THE NEONATAL HEART THROUGH A BNIP3-DELTA-EXON3/MEF2-DEPENDENT SIGNALLING PATHWAY

Systemic hypoxia resulting from preterm birth, placental abnormalities, and cyanotic congenital heart disease is known to impede the regulatory and developmental pathways in the neonatal heart. While the molecular mechanisms are still unknown, stressors that result from systemic hypoxia drive aberrant cardiomyocyte proliferation, which may be initially adaptive, but ultimately can program the heart to fail in early life. Recent evidence has suggested that the prostaglandin E1 analogue, Misoprostol, is cytoprotective in the hypoxia-exposed neonatal heart through promoting the expression of the BCL-2/adenovirus E1B 19 kd-interacting protein 3 (Bnip3) isoform lacking the third exon (Bnip3-Delta-Exon3). Using a rodent model of neonatal hypoxia, in combination with rat primary ventricular neonatal cardiomyocytes (PVNC’s) and H9c2 cells, we sought to determine if Misoprostol can prevent cardiomyocyte proliferation and what the key molecular players may be in this pathway. At post-natal day (PND) 5, hypoxia-exposed rat pups demonstrated elevated heart weights, while histological analysis confirmed, significant increases in left-ventricular wall thickness in the absence of fibrosis (P < 0.05) and increased nuclei number (P < 0.05), which was completely attenuated with the addition of 10 μg/kg/day Misoprostol. Concurrently, molecular markers of proliferation, including Cyclin-D1 were significantly elevated in hypoxia-exposed hearts and cells, which was also prevented in the presence of Misoprostol (P < 0.05). We further describe a critical role for Bnip3-Delta-Exon3 in the regulation of cardiomyocyte proliferation at the transcriptional level, where this isoform reduced the expression of myocardin, while favoring expression of the cardiac maturation factors, BMP-2 and MEF2A over their proliferative counterparts, BMP-10 and MEF2C. These observations were further supported with knockdown studies in H9c2 cells, where we are able to restore hypoxia-induced cardiomyocyte proliferation in Misoprostol-treated cells with the addition of an siRNA targeting Bnip3-Delta-Exon3. Taken together this data demonstrates a clear mechanism for hypoxia-induced neonatal cardiomyocyte proliferation which can ultimately be reversed pharmacologically with the addition of exogenous PGE1 signaling, through Misoprostol.

Global Longitudinal Strain Analysis Using Cardiac MRI in Aortic Stenosis: Comparison with Left Ventricular Remodeling, Myocardial Fibrosis, and 2-year Clinical Outcomes.

To use global longitudinal strain (GLS) as a marker of left ventricular decompensation in aortic stenosis and to investigate the relationship of GLS measured with cardiac MRI with markers of myocardial fibrosis, symptom development, remodeling, and clinical outcomes. Patients with aortic stenosis and healthy control subjects were assessed. GLS was assessed by using cardiac MRI feature tracking, diffuse fibrosis by T1 mapping, and replacement fibrosis using late gadolinium enhancement. Follow-up was prospective for the primary endpoint of all-cause mortality. GLS was reduced in aortic stenosis (n = 159) compared with control subjects (n = 41) (-17.6% ± 3.1 [standard deviation] vs -18.9% ± 2.6, P = .02). GLS demonstrated weak associations with aortic stenosis severity (Vmax; r = 0.24, P = .0005) but showed moderate correlation with T1 mapping measures of myocardial fibrosis (eg, indexed extracellular volume [iECV]; r = 0.43, P < .0001). Moreover, GLS was reduced in patients with midwall fibrosis compared with control subjects (P < .001), although values were similar to those of patients with myocardial infarction (P = .25). In adjusted analyses, GLS was associated with total myocardial fibrosis burden (iECV) and ejection fraction (both P < .001). GLS offered poor discrimination between disease states, inability to distinguish between control subjects and patients (area under the curve [AUC], 0.60), presence or absence of fibrosis (AUC, 0.63), or symptomatic severity (left ventricular decompensation AUC, 0.64). At follow-up (median, 1466 days), 21 patients died. GLS did not independently predict clinical outcomes. GLS correlates with established markers of myocardial fibrosis. However, widespread utility of single GLS measurements may be limited by overlap between disease states and its inability to predict clinical outcomes beyond current established markers.© RSNA, 2019Supplemental material is available for this article.

Abstract 153: Dexamethasone Inhibits Regeneration and Causes Ventricular Aneurysm in the Neonatal Porcine Heart After Myocardial Infarction

Background: The adult mammalian heart has limited ability to repair itself following injury. Zebrafish, newts and neonatal mice can regenerate cardiac tissue, largely by cardiac myocyte (CM) proliferation. More recently, we demonstrated that the hearts of neonatal pigs (2-day old) have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after birth. The current study aims to determine whether acute inflammation is required for CM regeneration after myocardial infarction (MI). Methods: We examined the role of acute inflammation on regenerative capacity of the neonatal pig heart (ages: 2 days postnatal) by intramuscular injection of dexamethasone (Dex) during the first week post-MI surgery. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance (CMR) imaging. Bromodeoxyuridine pulse-chase labeling, histology, and immunohistochemistry were performed to study CM cytokinesis and to quantify myocardial fibrosis. Results: After MI, there was early and sustained recovery of cardiac function and wall thickness in the absence of fibrosis in 2-day old pigs. In contrast, piglets received Dex injection developed ventricular aneurysm and did not recover function. Dex limited CM cytokinesis via inhibiting aurora-B protein expression and caused mature scar and thinned walls at infarct site. Conclusions: Dex suppresses acute inflammation, inhibits CM regeneration, and causes ventricular aneurysm in neonatal pig hearts after MI.

Characteristics of hypersensitivity pneumonitis diagnosed by interstitial and occupational lung disease multi-disciplinary team consensus.

The causes of hypersensitivity pneumonitis (HP) in the UK are changing as working practices evolve, and metalworking fluid (MWF) is now a frequently reported causative exposure. We aimed to review and describe all cases of HP from our UK regional service, with respect to the causative exposure and diagnostic characteristics. In a retrospective, cross-sectional study, we collected patient data for all 206 cases of HP diagnosed within our UK-based regional NHS interstitial and occupational lung disease service, 2002-17. This included demographics, environmental and occupational exposures, clinical features, and diagnostic tests (CT imaging, bronchiolo-alveolar cell count, lung function, histology). We grouped the data by cause (occupational, non-occupational and unknown) and by presence or absence of fibrosis on CT, in order to undertake hypothesis testing. Cases were occupational (n = 50), non-occupational (n = 56) or cryptogenic (n = 100) in aetiology. The commonest causes were birds = 37 (18%) and MWF = 36 (17%). Other occupational causes included humidifiers and household or commercial waste, but only one case of farmers' lung. Cryptogenic cases were associated with significantly older age, female gender, lower lung function parameters, fewer alveolar lymphocyte counts >20%, and fibrosis on CT; exposure information was missing in 22-33% of cryptogenic cases. MWF is the commonest occupational cause of HP, where workers usually present with more acute/subacute features and less fibrosis on CT; refuse work is an emerging cause. Cryptogenic HP has a fibrotic phenotype, and a full occupational history should be taken, as historical workplace exposures may be relevant.

In Vivo Implications of Potential Probiotic Lactobacillus reuteri LR6 on the Gut and Immunological Parameters as an Adjuvant Against Protein Energy Malnutrition.

The present study investigated the impact of probiotic Lactobacillus reuteri LR6 on the gut and systemic immunity using protein energy malnourished (PEM) murine model. Thirty male Swiss albino mice were divided into five groups: control (C), malnourished (M), probiotic fermented milk (PFM), skim milk (SM), and bacterial suspension (BS) with six mice per group. Group C was fed with conventional diet throughout the study while the other groups were fed with protein calorie restricted diet until the development of malnutrition. After development of malnutrition, group M was continued with the restricted diet while other groups were fed with re-nourished diet supplemented with PFM, SM, and BS for 1week, respectively. Thereafter, mice were sacrificed and different histological, microbiological, and immunological parameters were studied. Probiotics feeding in PEM model as fermented product or bacterial suspension improved the intestinal health in terms of intact morphology of colonic crypts, normal goblet cells, and intact lamina propria with no inflammation in large intestine, absence of fibrosis, and no inflammation in spleen. The number of secretory IgA+ cells was significantly higher in group PFM and BS. Also, increase in the phagocytic percentage of the macrophages and bone marrow derived dendritic cells (DCs) were observed in the PFM and BS group in comparison to the group M. In comparison to the group M and SM, lactobacilli, bifidobacteria, and Firmicutes counts were significantly higher in the group PFM and BS. This study concludes that probiotic supplementation to re-nutrition diet could emerge as wonder therapeutics against PEM.

Liver MR relaxometry at 3T \u2013 segmental normal T1 and T2* values in patients without focal or diffuse liver disease and in patients with increased liver fat and elevated liver stiffness

Magnetic resonance (MR) T1 and T2* mapping allows quantification of liver relaxation times for non-invasive characterization of diffuse liver disease. We hypothesized that liver relaxation times are not only influenced by liver fibrosis, inflammation and fat, but also by air in liver segments adjacent to the lung – especially in MR imaging at 3T. A total of 161 study participants were recruited, while 6 patients had to be excluded due to claustrophobia or technically uninterpretable MR elastography. Resulting study population consisted of 12 healthy volunteers and 143 patients who prospectively underwent multiparametric MR imaging at 3T. Of those 143 patients, 79 had normal liver stiffness in MR elastography (shear modulus <2.8 kPa, indicating absence of fibrosis) and normal proton density fat fraction (PDFF < 10%, indicating absence of steatosis), defined as reference population. T1 relaxation times in these patients were significantly shorter in liver segments adjacent to the lung than in those not adjacent to the lung (p < 0.001, mean of differences 33 ms). In liver segments not adjacent to the lung, T1 allowed to differentiate significantly between the reference population and patients with steatosis and/or fibrosis (p ≤ 0.011), while there was no significant difference of T1 between the reference population and healthy volunteers. In conclusion, we propose to measure T1 relaxation times in liver segments not adjacent to the lung. Otherwise, we recommend taking into account slightly shorter T1 values in liver segments adjacent to the lung.

Effects of a\xe7ai on oxidative stress, ER stress, and inflammation-related parameters in mice with high fat diet-fed induced NAFLD

Non-alcoholic fatty liver disease (NAFLD), the most predominant liver disease worldwide, is a progressive condition that encompasses a spectrum of disorders ranging from steatosis to steatohepatitis, and, ultimately, cirrhosis and hepatocellular carcinoma. Although the underlying mechanism is complex and multifactorial, several intracellular events leading to its progression have been identified, including oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, and altered endoplasmic reticulum (ER) homeostasis. Phenolic compounds, such as those present in açai (Euterpe oleracea Mart.), are considered promising therapeutic agents due to their possible beneficial effects on the prevention and treatment of NAFLD. We tested in vitro effects of aqueous açai extract (AAE) in HepG2 cells and its influence on oxidative stress, endoplasmic reticulum stress, and inflammation in a murine model of high fat diet-induced NAFLD. In vitro AAE exhibited high antioxidant capacity, high potential to inhibit reactive oxygen species production, and no cytotoxicity. In vivo, AAE administration (3 g/kg) for six weeks attenuated liver damage (alanine aminotransferase levels), inflammatory process (number of inflammatory cells and serum TNFα), and oxidative stress, through the reduction of lipid peroxidation and carbonylation of proteins determined by OxyBlot and modulation of the antioxidant enzymes: glutathione reductase, SOD and catalase. No change was observed in collagen content indicating an absence of fibrosis, stress-related genes in RE, and protein expression of caspase-3, a marker of apoptosis. With these results, we provide evidence that açai exhibits hepatoprotective effects and may prevent the progression of liver damage related to NAFLD by targeting pathways involved in its progression.

PLATELETS, ASPARTATE AMINOTRANSFERASE, TUMOR NECROSIS FACTOR-α: LABORATORY PANEL FOR DIAGNOSIS OF LIVER FIBROSIS STAGE

Aim. To study significance of platelet count and values of aspartate aminotransferase and tumor necrosis factor-α in the evaluation of the severity of liver fibrosis in chronic hepatitis C and for the development of fibrosis index calculation formula.Material and Methods. The study included 70 patients with chronic hepatitis C end 30 healthy persons. Liver density was estimated by ultrasound elastography.Results. The correlation analysis revealed strong relationships between the ultrasound elastography findings of fibrosis stage and the platelet count (r=0.83), aspartate aminotransferase (r=0.83), and tumor necrosis factor-α (r=0.81). The optimal separation points of laboratory tests for fibrosis exclusion were identified as follows: platelet count&gt;270×109 /L (test sensitivity=96.2%), aspartate aminotransferase level&lt;44 E/L (sensitivity=96.2%), and tumor necrosis factor-α concentration below 1.9 pg/mL (sensitivity=92.3%). The obtained values of laboratory parameters were used for calculation of the liver fibrosis index. The value of the fibrosis index ranging between 0 and 0.5 indicated the absence of fibrosis (stage F0), the value of the fibrosis index ranging between 0.6 and 2.5 corresponded to the moderate stage of fibrosis (F1-2), and the value of the fibrosis index&gt;2.5 corresponded to the severe fibrosis/cirrhosis of the liver (F3-4) with diagnostic sensitivity of 83% and specificity of 78%.Conclusion. Platelet count, the values of aspartate aminotransferase and tumor necrosis factor-α levels, fibrosis index, and laboratory test data can be used for ruling out fibrosis in chronic hepatitis C patients as well as for stratification of liver fibrosis stages.

PLATELETS, ASPARTATE AMINOTRANSFERASE, TUMOR NECROSIS FACTOR-α: LABORATORY PANEL FOR DIAGNOSIS OF LIVER FIBROSIS STAGE

Aim. To study significance of platelet count and values of aspartate aminotransferase and tumor necrosis factor-α in the evaluation of the severity of liver fibrosis in chronic hepatitis C and for the development of fibrosis index calculation formula.Material and Methods. The study included 70 patients with chronic hepatitis C end 30 healthy persons. Liver density was estimated by ultrasound elastography.Results. The correlation analysis revealed strong relationships between the ultrasound elastography findings of fibrosis stage and the platelet count (r=0.83), aspartate aminotransferase (r=0.83), and tumor necrosis factor-α (r=0.81). The optimal separation points of laboratory tests for fibrosis exclusion were identified as follows: platelet count&gt;270×109 /L (test sensitivity=96.2%), aspartate aminotransferase level&lt;44 E/L (sensitivity=96.2%), and tumor necrosis factor-α concentration below 1.9 pg/mL (sensitivity=92.3%). The obtained values of laboratory parameters were used for calculation of the liver fibrosis index. The value of the fibrosis index ranging between 0 and 0.5 indicated the absence of fibrosis (stage F0), the value of the fibrosis index ranging between 0.6 and 2.5 corresponded to the moderate stage of fibrosis (F1-2), and the value of the fibrosis index&gt;2.5 corresponded to the severe fibrosis/cirrhosis of the liver (F3-4) with diagnostic sensitivity of 83% and specificity of 78%.Conclusion. Platelet count, the values of aspartate aminotransferase and tumor necrosis factor-α levels, fibrosis index, and laboratory test data can be used for ruling out fibrosis in chronic hepatitis C patients as well as for stratification of liver fibrosis stages.

SAT-333-Non-alcoholic steatohepatitis significantly decreases microsomal liver function in the absence of fibrosis, which allows the use of the 13C-aminopyrine breath test for its non-invasive detection

SAT-333-Non-alcoholic steatohepatitis significantly decreases microsomal liver function in the absence of fibrosis, which allows the use of the 13C-aminopyrine breath test for its non-invasive detection

Invasive fungal infection by Cryptococcus neoformans var. grubii with bone marrow and meningeal involvement in a HIV-infected patient: a case report

BackgroundCryptococcosis is a common opportunistic infection in patients infected by Human Immunodeficiency Virus (HIV) and is the second leading cause of mortality in Acquired Immunodeficiency Syndrome (AIDS) patients worldwide. The most frequent presentation of cryptococcal infection is subacute meningitis, especially in patients with a CD4+ T Lymphocytes count below 100 cells/μL. However, in severely immunosuppressed individuals Cryptococcus neoformans can infect virtually any human organ, including the bone marrow, which is a rare presentation of cryptococcosis.Case presentationA 45-year-old HIV-infected male patient with a CD4+ T lymphocyte count of 26 cells/μL who presented to the emergency department with fever and pancytopenia. Throughout the diagnostic evaluation, the bone marrow aspirate culture yielded encapsulated yeasts in budding, identified as Cryptococcus sp. The bone marrow biopsy revealed a hypocellularity for age and absence of fibrosis. It was observed presence of loosely formed granuloma composed of multinucleated giant cells encompassing rounded yeast like organisms stained with mucicarmine, compatible with Cryptococcus sp. Then, the patient underwent a lumbar puncture to investigate meningitis, although he had no neurological symptoms and neurological examination was normal. The cerebrospinal fluid culture yielded Cryptococcus sp. The species and genotype identification step showed the infection was caused by Cryptococcus neoformans var. grubii (genotype VNI). The patient was initially treated with amphotericin B deoxycholate plus fluconazole for disseminated cryptococcosis, according to guideline recommendations. However, the patient developed acute kidney injury and the treatment was switched for fluconazole monotherapy. The symptoms disappeared completely with recovery of white blood cells and platelets counts. Cerebrospinal fluid cultures for fungi at one and two-weeks of treatment were negative.ConclusionsBone marrow infection caused by Cryptococcus neoformans is a rare presentation of cryptococcosis. The cryptococcal infection should be included for differential diagnosis in HIV-infected patients with fever and cytopenias, especially when CD4+ T lymphocytes count is below 100 cells/μL.

Preoperative evaluation with computed tomography (CT) of the resectability of mesenteric lymph node metastases in small intestine neuroendocrine neoplasms (si-NENs): New criteria for clinicians and surgeons.

212 Background: The 2016 European Neuroendocrine Tumor Society consensus guidelines update recommends resection of the primary tumor and all mesenteric lymph-nodes for all patients with si-NENs, both with curative and palliative purposes. Current resectability criteria are based on the degree of involvement of the superior mesenteric artery (SMA) by the metastatic lymph nodes. The aim of this work was to test these criteria for the evaluation of our patients; we included as additional criteria the degree of involvement of the superior mesenteric vein (SMV) and peritoneum, two features not covered by current literature. Methods: We retrospectively reviewed the pre-operative CT-scans of all patients with si-NENs operated at IEO (European Institute of Oncology) between 2008 and April 2018. A first analysis classified tumors as “resectable” or “unresectable” according to SMA involvement. A second analysis classified tumors as resectable or unresectable according to SMA involvement, SMV involvement (infiltration of the peripheral or proximal portion) and peritoneal involvement (presence or absence of fibrosis and retraction of the mesentery). We finally reviewed all surgery reports assessing radicality and completeness of the operation. Results: Abdominal CT-scan were available for analysis in 42 out of 47 operated patients. According to the first analysis, all three tumors classified as unresectable underwent incomplete resection, whereas out of the 39 tumors classified as resectable, six received an incomplete resection and 33 were completely resected. According to the second analysis, the nine tumors classified as unresectable underwent an incomplete resection, whereas 33 tumors classified as resectable were completely resected. Conclusions: Our retrospective analysis confirmed that SMA involvement may be useful to evaluate the resectability of the primary tumor and mesenteric lymph nodes. Furthermore, it suggested that the additional evaluation of the SMV and peritoneum involvement can allow to identify further cases of tumors for which complete resection is not possible.

Early Regenerative Capacity in the Porcine Heart.

The adult mammalian heart has limited ability to repair itself after injury. Zebrafish, newts, and neonatal mice can regenerate cardiac tissue, largely by cardiac myocyte (CM) proliferation. It is unknown whether hearts of young large mammals can regenerate. We examined the regenerative capacity of the pig heart in neonatal animals (ages 2, 3, or 14 days postnatal) after myocardial infarction or sham procedure. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance imaging and echocardiography. Bromodeoxyuridine pulse-chase labeling, histology, immunohistochemistry, and Western blotting were performed to study cell proliferation, sarcomere dynamics, and cytokinesis and to quantify myocardial fibrosis. RNA-sequencing was also performed. After myocardial infarction, there was early and sustained recovery of cardiac function and wall thickness in the absence of fibrosis in 2-day-old pigs. In contrast, older animals developed full-thickness myocardial scarring, thinned walls, and did not recover function. Genome-wide analyses of the infarct zone revealed a strong transcriptional signature of fibrosis in 14-day-old animals that was absent in 2-day-old pigs, which instead had enrichment for cytokinesis genes. In regenerating hearts of the younger animals, up to 10% of CMs in the border zone of the myocardial infarction showed evidence of DNA replication that was associated with markers of myocyte division and sarcomere disassembly. Hearts of large mammals have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after birth.