Function Of Clinical Severity Research Articles

Expression profile of adrenomedullin and its specific receptors in liver tissues from patients with hepatocellular carcinoma and in tumorigenic cell line-secreted extracellular vesicles.

The transcriptional profile of adrenomedullin (AM), a new metastasis-related factor involved in hepatocellular carcinoma (HCC), and its specific receptors (CLR, RAMP1, RAMP3) were evaluated in liver tissues of HCV-positive HCC subjects undergoing liver transplantation (LR) and in donors (LD). AM and its specific receptor expression were also assessed in extracellular vesicles (EVs) secreted by tumorigenic (HepG2) and non-tumorigenic (WRL68) cells by Real-Time PCR. AM expression resulted significantly elevated in LR concerning LD (p=0.0038) and, for the first time, significantly higher levels in HCC patients as a function of clinical severity (MELD score), were observed. RAMP3 and CLR expression increased in LR as a function of clinical severity while RAMP1 decreased. Positive correlations were found among AM, its receptors, and apoptotic markers. No AM mRNA expression difference was observed between HepG2 and WRL68 EVs. RAMP1 and RAMP3 resulted lower in HepG2 concerning WRL68 while significantly higher levels were observed for CLR. While results at tissue level characterize AM as a regulator of carcinogenesis-tumor progression, those obtained in EVs do not indicate AM as a target candidate, neither as a pathological biomarker nor as a marker involved in cancer therapy.

Self-Representations of Military Veterans Suffering From Chronic Post-traumatic Stress Disorder: The Role of Sport.

Background: Post-traumatic stress disorder (PTSD) is a psychiatric illness that is very prevalent in both civilian and military environments. The clinical course, regardless of management, is chronic for a number of patients, especially veterans. Persistent PTSD symptoms interact with representations of the person and their body, and may negatively impact rehabilitation. Sport is known to help psychiatric patients such as those suffering from PTSD, as it improves the connection with the body, and supports physiological and emotional regulation. However, the impact of sport on self-representations has not yet been studied. The first aim of this study is to explore person and body representations in a population of military veterans suffering from chronic PTSD, as a function of clinical severity. Second, it aims to explore how a 9-day sport program, which includes an element of socio-professional rehabilitation, changes representations of the person and their body.Methods: This exploratory qualitative study examined the self-representation of veterans with chronic PTSD before a sport rehabilitation program. Veterans were given the prompts “body” and “person” and asked to free associate. PTSD severity and the mind–body connection were assessed using the Posttraumatic Stress Disorder Checklist for DSM-5, and the Freiburg Mindfulness Inventory, respectively. Parasympathetic activity was recorded at rest. A subgroup of the population volunteered to participate in a post-program session to record the same semantic, psychological, and physiological variables.Results: Although before the program, veterans gave more negatively than positively valenced words, no relation was observed between the overall number of negative words and PTSD severity. Post-program, changes were observed in terms of valence. Specifically, some negatively-valenced categories of words disappeared, and some positive categories appeared. At the same time, there was a fall in PTSD severity, an increase in the mind–body connection, and a decrease in parasympathetic activation.Conclusions: This study highlighted that veterans with chronic PTSD have a negative representation of the self. A dedicated, 9-day program that included regular sport improved self-representations related to both the person and their body, and reduced PTSD symptoms. The findings underline the importance of ensuring that programs for patients suffering from chronic PTSD should include sporting activity, and highlight the benefits. Sport appears to be a path to the reappropriation of a positive image of the self, by improving the representation of the body. This relationship could be consistent with improved interoception, but our results need further investigation.

The concordance between the evolutionary trend and the clinical manifestation of the two SARS-CoV-2 variants.

Abstract The spread of COVID-19, the disease caused by SARS-CoV-2, has progressed into a global pandemic. To date, thousands of genetic variants have been identified across strains of SARS-CoV-2 isolated from worldwide patients. However, there is still little direct evidence linking viral variants and clinical features. Based on two tightly linked SNPs, we previously divided SARS-CoV-2 into two major lineages: the ancestral ‘S lineage’ (U8,782 and C28,144) and the derived ‘L lineage’ (C8,782 and U28,144). Here, we identified SARS-CoV-2 lineages from 271 COVID-19 patients during the early outbreak of this pandemic in Wuhan, including 73 S- and 198 L-lineage patients. The S-lineage patients exhibited significantly worse clinical severity than the L-lineage patients, even after excluding other risk factors. This study suggests that SARS-CoV-2 lineage may provide useful clinical information for the management of COVID-19 and support the argument that viral clades should be analyzed as a function of clinical severity.

Do pentraxin 3 and neural pentraxin 2 have different facet function in hepatocellular carcinoma?

The long pentraxin (PTX) 3 and the neuronal pentraxin (NPTX) 2 has been found to exert pleiotropic roles in cancers due to their action in inflammation. However, the accurate clinical significance of PTX3 and NPTX2 in hepatocellular carcinoma (HCC), one of the commonest cancers in the world has not been well-defined. The aim of the study was to analyze the expression profile of PTX3 and NPTX2 in liver biopsies of HCV-positive HCC patients (liver recipients, LR, n = 14, age 59.4 ± 1.8years) undergoing liver transplantation and in donors (LD, n = 14, age 62.1 ± 17.3years), trying both to identify them as predictive biomarkers of clinical liver severity in HCC patients and to understand if they were mutually substitutable. The PTX3 and NPTX2 transcripts were significantly up regulated in HCC tissues (p = 0.004 and p = 0.02 LD vs. LR, respectively). Dividing patients following MELD score, PTX3 expression increased as a function of liver disease severity, while this trend was not observed for NPTX2, which mRNA level increased similarly in both MELD group, reaching the significance only in patients with MELD score < 9 (p = 0.01). A positive correlation was found between PTX3 and NPTX2 expression (p = 0.001; r = 0.69). This is the first study that concerns PTX3 and NPTX2 as a function of clinical severity from which emerged that both of them are unequivocally involved in HCC, but only PTX3 could be considered a staging marker in these HCV-related HCC patients, unlike NPTX2, which could only play a role as an inflammatory marker.

Evaluation of Apelin/APJ system expression in hepatocellular carcinoma as a function of clinical severity.

Apelin, a peptide of 77 amino acids, and its endogenous ligand, angiotensin-like-receptor 1 (APJ), play a key role in the development of tumors by enhancing angiogenesis, metastasis, cell proliferation, development of cancer stem cells and drug resistance and inhibiting apoptosis of cancer cells. However, little is known about Apelin/APJ system involvement in hepatocellular carcinoma (HCC). The aim of this study was to evaluate Apelin and APJ expression in liver specimens, obtained from subjects with HCV-positive HCC who underwent liver transplantation, according to liver disease severity (liver recipients, LR, n = 14, age 59.4 ± 1.8) and in donors (liver donors, LD, n = 14, age 62.1 ± 17.3). Apelin/APJ axis, apoptotic and inflammatory markers were evaluated by Real-Time PCR analysis. The Apelin/APJ system expression resulted significantly higher in LR in comparison with LD (p < 0.05), in particular in those with more severe liver disease. The apoptotic (Bcl-2, BAX, NOTCH-1, Casp-3) and inflammatory (IL-6, TNF-α) markers were increased as a function of diseaseseverity (p < 0.05). Multiple significant positive correlations were found between Apelin/APJ axis and the other markers. Although further investigations are needed to better understand the role of Apelin/APJ axis in HCC, our result indicated a potential role of this axis in its development and progression as well as in recognizing novel therapeutic targets opening a new avenue for treatment.

Pentraxin 3, a novel inflammatory marker in heart failure patients: its expression in whole blood as a function of clinical severity

Pentraxin 3, a novel inflammatory marker in heart failure patients: its expression in whole blood as a function of clinical severity

P3401Pentraxin 3, a novel inflammatory marker in heart failure patients: its expression in circulating leukocytes as a function of clinical severity

P3401Pentraxin 3, a novel inflammatory marker in heart failure patients: its expression in circulating leukocytes as a function of clinical severity

Osteopontin in hepatocellular carcinoma: A possible biomarker for diagnosis and follow-up

Recently osteopontin (OPN), a protein of the extracellular matrix, has generated in hepatocellular carcinoma (HCC) a significant interest as a prognostic factor. Aim of this study was to confirm, in liver tissues of subjects with HCV-positive HCC undergoing liver transplantation (RL, n=10) and of donors (DL, n=14), the increase of OPN plasma and tissue concentration, the OPN splicing isoforms expression profiling together with those of thrombin, and to evaluate a possible association between OPN measurements. Their association with Notch-1, IV-Collagen-7s domain, IL-6 and TNF-α were also evaluated. Real-Time PCR experiments and immunometric assay were performed. mRNA expression resulted higher in RL than in DL for all analyzed genes and several correlations were found between them. The more relevant association were between OPN-a and OPN-b (p<0.0001), between thrombin and OPN-a (p=0.007), between 7s-collagen and OPN isoforms (p<0.05) and between Notch-1 with OPN-c (p=0.004). Both OPN plasma and liver tissue extract concentrations were assessed confirming the trend observed at the mRNA level. An important association was found between OPN plasma and protein (p<0.0001, r=0.96) even splitting patients in DL (p<0.0001, r=0.93) and RL (p<0.0001, r=0.96). A reduction of OPN plasma levels was found at 6months after transplantation. Considering MELD score as liver disease severity, the mRNA expression of our markers as well as of OPN plasma and tissue concentrations resulted increased as a function of clinical severity. Our results might be considered a useful starting point to validate OPN as a prognostic and diagnostic marker of HCC.

Adrenomedullin and intermedin gene transcription is increased in leukocytes of patients with chronic heart failure at different stages of the disease

Adrenomedullin (ADM) is a vasodilatory peptide expressed in many tissues. Its levels are elevated in various diseases including chronic heart failure (CHF) and it has been suggested that the up-regulation of ADM in cardiac disease represents a protective mechanism. Similarly, intermedin (IMD), a novel member of the calcitonin/calcitonin gene-related peptide family, is considered a potential endogenous protector of the heart. Previous studies demonstrated that in CHF patients, elevated plasma concentrations of ADM and IMD reflect the patient's disease severity and prognosis, while the behavior of mRNA expression is not known. The aim of this study was to evaluate ADM/IDM transcriptomic profiling in human leukocytes of CHF patients as a function of clinical severity, assessing possible changes with respect to healthy subjects (C). mRNA expression was evaluated by Real-Time PCR and total RNA was extracted from leukocytes of C (n=8) and from CHF patients (NYHA I–II n=10; NYHA III–IV n=14) with PAXgene Blood RNA Kit. Significantly higher levels of ADM and IMD mRNA were found in CHF as a function of clinical severity (ADM: C=0.03±0.013, NYHA I–II=0.11±0.084, NYHA III–IV=11.46±4.72, p=0.037 C vs NYHA III–IV, p=0.028 NYHA I–II vs NYHA III–IV; IMD: C=0.158±0.041, NYHA I–II=0.93±0.40, NYHA III–IV=2.6±0.67, p=0.014 C vs NYHA III–IV, p=0.014 NYHA I–II vs NYHA III–IV). This study highlights, for the first time, the possibility of evaluating ADM and IMD mRNA expression in human whole blood samples by Real-Time PCR study providing further relevant information and providing a more complete interpretation of the pathophysiology of the disease.

C-type natriuretic peptide transcriptomic profiling increases in human leukocytes of patients with chronic heart failure as a function of clinical severity

The aim of this study was to evaluate the transcriptomic profiling of C-type natriuretic peptide (CNP) and of its specific receptor, NPR-B in human leukocytes of heart failure (HF) patients as a function of clinical severity, assessing the possible changes with respect to healthy subjects (C). mRNA expression was evaluated by Real-Time PCR and total RNA was extracted from leukocytes of C (n=8) and of HF patients (NYHA I–II, n=7; NYHA III–IV, n=13) with PAXgene Blood RNA Kit. Significantly higher levels of CNP mRNA expression were found in HF patients as a function of clinical severity (C=0.23±0.058, NYHA I–II=0.47±0.18, NYHA III–IV=2.58±0.71, p=0.005 C vs NYHA III–IV, p=0.017 NYHA I–II vs NYHA III–IV) and NPR-B transcript levels resulted down-regulated in HF patients with higher NYHA class (C=2.2±0.61, NYHA I–II=2.76±0.46, NYHA III–IV=0.29±0.13, p=0.001 C vs NYHA III–IV, p<0.0001 NYHA I–II vs NYHA III–IV). A significant negative correlation between CNP and NPR-B mRNA expression (r=0.5, p=0.03) was also observed. These results suggest a co-regulation of NPR-B and CNP expression supporting the relevance of this receptor in human disease characterized by a marked inflammatory/immune component and suggesting the possibility of manipulating inflammation via pharmacological agents selective for this receptor.

Transcriptomic Profiling of the Four Adenosine Receptors in Human Leukocytes of Heart Failure Patients

In this study the transcriptomic profiling of adenosine receptors (ARs) in human leukocytes of heart failure (HF) patients as a function of clinical severity, assessing the possible changes with respect to healthy subjects (C), was evaluated. Total RNA was extracted from leukocytes of C (n = 8) and of HF patients (NYHA I-II n = 9; NYHA III-IV n = 14) with a PAXgene Blood RNA Kit. An increase as a function of clinical severity was observed in each AR (A1R: C = 0.02 ± 0.009, NYHA I-II = 0.21 ± 0.09, NYHA III-IV = 3.6 ± 1.3, P = 0.03 C versus NYHA III-IV, P = 0.02 NYHA I-II versus NYHA III-IV; A2aR: C = 0.2 ± 0.05, NYHA I-II = 0.19 ± 0.04, NYHA III-IV = 1.32 ± 0.33, P = 0.005 C versus NYHA III-IV, P = 0.003 NYHA I-II versus NYHA III-IV; A2bR: C = 1.78 ± 0.36, NYHA I-II = 1.35 ± 0.29, NYHA III-IV = 4.07 ± 1.21, P = 0.03: NYHA I-II versus NYHA III-IV; A3R: C = 0.76 ± 0.21, NYHA I-II = 0.94 ± 0.19, NYHA III-IV = 3.14 ± 0.77, P = 0.01 C versus NYHA III-IV and NYHA I-II versus NYHA III-IV, resp.). The mRNA expression of the ectonucleoside triphosphate diphosphohydrolase (CD39) and the ecto-5′-nucleotidase (CD73) were also evaluated. They resulted up-regulated. These findings show that components of adenosine metabolism and signalling are altered to promote adenosine production and signalling in HF patients. Thus, HF may benefit from adenosine-based drug therapy after confirmation by clinical trials.

Comparison of NT-proCNP and CNP plasma levels in heart failure, diabetes and cirrhosis patients

C-type natriuretic peptide (CNP) plasma levels are extremely low and a pre-analytical phase is necessary to assay plasma CNP concentrations. Amino-terminal CNP (NT-proCNP) circulates at higher concentrations than CNP, allowing a direct assay and the use of smaller amounts of plasma. Aim of this study was to evaluate the analytical performance of a direct NT-proCNP assay and to measure its plasma levels in heart failure (CHF), diabetes and chirrosis patients. NT-proCNP and CNP were measured in 130 CHF, 19 patients with diabetes, 24 with hepatic cirrhosis and 73 controls. Plasma NT-proCNP was higher in all the clinical conditions studied (controls:45.5 ± 1.84 pg/ml, CHF:67.09 ± 7.36, diabetes:51.5 ± 5.75 cirrhosis:78.4 ± 19.9; p = 0.034, p = 0.04 controls vs. CHF and cirrhosis, respectively) and in CHF NT-proCNP concentration showed a significant increase as a function of clinical severity. By comparison of ROC curves, CNP assay resulted better associated with disease than NT-proCNP assay in all the different clinical conditions probably due to different release and clearance. The determination of NT-proCNP adds a piece of information to better understanding the molecular mechanisms at the basis of CNP action in different diseases. Due to its higher analytical feasibility, this determination could become widespread in clinical biochemistry laboratories and serve as a complementary marker of disease conditions.

C-type natriuretic peptide and its relation to non-invasive indices of left ventricular function in patients with chronic heart failure

C-type natriuretic peptide (CNP) significantly increases in chronic heart failure (CHF) patients as a function of clinical severity. Aim of this study was to evaluate in CHF patients the relationship between circulating CNP concentrations and echo-Doppler conventional indices of left ventricular (LV) function as well as less load independent parameters as d P/d t. LV ejection fraction (EF), left ventricular end-diastolic dimension (LVEDD) and LV d P/d t were evaluated together with plasma CNP levels in 38 patients with CHF and in 63 controls. CNP levels resulted significantly higher in CHF patients than in controls (7.19 ± 0.59 pg/ml vs. 2.52 ± 0.12 pg/ml, p < 0.0001). A significant correlation between d P/d t and CNP levels ( r = −0.61, p < 0.0001) was observed. A good correlation with EF ( r = −0.55, p < 0.001) and a less significant relation with LVEDD ( r = 0.316, p < 0.05) were also reported. When patients were divided according to d P/d t values a very significant difference in CNP levels was observed: Group I (<600, n = 25) vs. Group II (>600, n = 13): 8.46 ± 0.69 and 4.75 ± 0.75 pg/ml, respectively, p < 0.001. This is the first study that reports a correlation between CNP and d P/d t in CHF patients, thus suggesting a possible role on cardiac contractility.

C‐type natriuretic peptide plasma levels increase in patients with chronic heart failure as a function of clinical severity

[corrected] C-type natriuretic peptide (CNP), secreted by the endothelium and the heart, is structurally related to atrial and brain natriuretic peptides, but its clinical significance in chronic heart failure (CHF) is controversial. To investigate the role of CNP in CHF, plasma CNP levels were determined in a prospective series of 133 patients with CHF (age 64 +/- 1 years, left ventricular ejection fraction (EF), 31.5 +/- 0.7%, mean +/-S.E.M.) and in 21 age-matched healthy subjects. CNP was measured by a radioimmunoassay (sensitivity: 0.41+/-0.009 pg/tube) after a preliminary solid-phase extraction. Plasma level of CNP in healthy subjects was 2.7 +/- 0.2 pg/ml and significantly increased in CHF, as a function of clinical severity: 4.9 +/- 0.7 pg/ml in NYHA class I; 7.0 +/- 0.4 pg/ml in class II (p < 0.001 vs. controls); 9.6 +/- 0.7 pg/ml in class III (p < 0.001 vs. controls and class I and II), and 11.8 +/- 2.0 pg/ml in class IV (p < 0.001 vs. controls, class I and II; Fisher's test after ANOVA). A significant relation was also found between CNP plasma levels and EF (R = 0.40, p < 0.001). Plasma CNP elevation is related to clinical and functional disease severity. These findings suggest a pathophysiological role for this peptide that, for its vasorelaxing activity, could influence the endothelial vasomotor response in CHF.

Strength deficits in primary focal hand dystonia

Cortical activation is reduced when patients with focal dystonia perform movements that do not induce dystonic posturing. This finding suggests that the cortical drive to muscles may in some circumstances actually be reduced not increased, as suggested by basal ganglia models of dystonia as a hyperkinetic disorder. The purpose of this study was to examine flexor and extensor strength at the wrist (a clinically affected joint) and elbow (a nonclinically affected joint) in 18 patients with primary focal hand dystonia compared to matched control subjects. We measured peak torque from maximum voluntary contractions, and agonist and antagonist muscle activation by means of surface electromyograms. Patients were significantly weaker than controls at both the elbow and wrist joints and in both flexors and extensors compared to controls. Peak elbow flexion torque was, on average, 14.4% lower in the dystonic compared to the control group, elbow extensor peak torque was 28.6% lower, wrist flexor peak torque was 17.4% lower, and wrist extensor peak torque was 20.7% lower. Strength did not differ as a function of clinical severity. Reductions in peak torque were accompanied by reduced agonist activation, although this finding only reached statistical significance at the elbow. The amount of co-contraction of antagonistic muscles was not significantly different between the two groups. These results are discussed in the context of dystonia as a disorder resulting from dysfunction of basal ganglia output.