MMP mediated degradation of type VI collagen is highly associated with liver fibrosis--identification and validation of a novel biochemical marker assay

Background and Aims

During fibrogenesis, in which excessive remodeling of the extracellular matrix occurs, both the quantity of type VI collagen and levels of matrix metalloproteinases, including MMP-2 and MMP-9, increase significantly. Proteolytic degradation of type VI collagen into small fragments, so-called neo-epitopes, may be specific biochemical marker of liver fibrosis. The aim of this study was to develop an ELISA detecting a fragment of type VI collagen generated by MMP-2 and MMP-9, and evaluate this assay in two preclinical models of liver fibrosis.

Methods

Mass spectrometric analysis of cleaved type VI collagen revealed a large number of protease-generated neo-epitopes. A fragment unique to type VI collagen generated by MMP-2 and MMP-9 was selected for ELISA development. The CO6-MMP assay was evaluated in two rat models of liver fibrosis: bile duct ligation (BDL) and carbon tetrachloride (CCl4)-treated rats.

Results

Intra- and inter-assay variation was 4.1% and 10.1% respectively. CO6-MMP levels were significantly elevated in CCl₄-treated rats compared to vehicle-treated rats at weeks 12 (mean 30.9 ng/mL vs. 12.8 ng/mL, p = 0.002); week 16 (mean 34.0 ng/mL vs. 13.7 ng/mL, p = 0.0018); and week 20 (mean 35.3 ng/mL vs. 13.3 ng/mL, p = 0.0033) with a tight correlation between hepatic collagen content and serum levels of CO6-MMP (R² = 0.58, p<0.0001) in CCl₄- treated rats. In BDL rats, serum levels of CO6-MMP were significantly elevated compared to the levels in sham-operated animals both at 2 weeks (mean 29.5 ng/mL vs. 14.2 ng/mL, p = 0.0001) and 4 weeks (mean 33.0 ng/mLvs. 11.8 ng/mL, p = 0.0003).

Conclusions

This novel ELISA is the first assay enabling assessment of MMP degraded type VI collagen, allowing quantification of type VI collagen degradation, which would be relevant for different pathologies. The marker was highly associated with liver fibrosis in two liver fibrosis animal models, suggesting type VI turnover to be a central player in fibrogenesis.     

Sleep pattern is associated with adipokine levels and nutritional markers in resident physicians

Shift work and long hours of work are common in medical training and have been associated with a higher propensity for developing nutritional problems and obesity. Changes in leptin and ghrelin concentrations – two hormones that contribute importantly to the central regulation of food intake – are poorly described in this population. The aim of this study was to identify possible negative associations between sleep patterns, nutritional status and serum levels of adipokines. The study included 72 resident physicians (52 women and 20 men) who underwent the following assessments: nutritional assessment (3-day dietary recall evaluated by the Adapted Healthy Eating Index), anthropometric variables, fasting metabolism, physical activity level, sleep quality and sleepiness. Resident physicians with poor sleep quality reported greater weight gain after the beginning of residency (5.1 and 3.0?kg, respectively; p?=?0.01) and higher frequency of abnormal waist circumference (44.2 and 17.6%, respectively; p?=?0.04) than those with better sleep quality. Mean ghrelin concentration was greater in volunteers with poor sleep quality (64.6?±?67.8 and 26.2?±?25.0?pg/mL, respectively; p?=?0.04). Women identified as having excessive daytime sleepiness had lower levels of leptin (9.57?±?10.4?ng/mL versus 16.49?±?11.4?ng/mL, respectively; p?=?0.03) than those without excessive sleepiness. Furthermore, correlations were found between hours of additional work per week and: intake of cereals, bread and pasta (r?=?0.22, p?=?0.01); intake of servings of fruits (r?=??0.20; p?=?0.02) and beans (r?=??0.21; p?=?0.01); and global score for Adapted Healthy Eating Index (r?=??0.23; p?=?0.008; Table 3). The sleep quality total score correlated with servings of beans (r?=??0.22; p?=?0.01) and servings of oils (r?=?0.23; p?=?0.008). Significant correlations were found between mean of time of sleep and servings of cereals, bread and pasta (r?=?0.20; p?=?0.02), servings of meat (r?=??0.29; p?=?0.02) and cholesterol levels (r?=?0.27; p?=?0.03). These observations indicate that sleep patterns and long working hours of resident physicians are negatively associated with biological markers related to central food control, the lipid profile, cholesterol levels and eating healthy foods. These factors may predispose these shift workers to become overweight and develop metabolic disorders.     

Association of metabolites reflecting type III and VI collagen formation with modified Rodnan skin score in systemic sclerosis – a cross-sectional study

Objective: The objective was to investigate blood-based biomarkers of type I (PRO-C1), III (PRO-C3) and VI (PRO-C6) collagen formation in systemic sclerosis (SSc) patients and examine their correlation to modified Rodnan skin score (mRSS).

Methods: Limited (lSSc, n?=?76) and diffuse SSc (dSSc, n?=?41) fulfilling the ACR/EULAR 1980 and 2013 classification criteria for SSc and asymptomatic controls (n?=?9) were included. PRO-C1, PRO-C3 and PRO-C6 were measured in serum.

Results: LSSc compared to dSSc were significantly older, had longer disease duration and lower mRSS. PRO-C3 was higher in early dSSc compared to early lSSc (mean [95 percentile], 27.4 [13.1–39.1] ng/mL vs 14.9 [8.2–28.8] ng/mL, p?=?0.006). PRO-C6 levels were higher in early dSSc compared to early lSSc and late dSSc (early dSSc: 28.2 [10.4–92.3] ng/ml vs early lSSc: 11.0 [6.9–28.5] ng/ml; p?=?0.006 and late dSSc: 12.6 [6.5–25.3] ng/mL, p?=?0.04). No difference was observed with PRO-C1. PRO-C3 and PRO-C6 were moderately correlated with mRSS with R-partials of 0.36 (p?<?0.001) and 0.29 (p?=?0.002), respectively

Conclusion: Measures of type III and VI collagen formation are potential objective biomarkers of fibrosis in systemic sclerosis. These biomarkers could be useful in monitoring the disease and efficacy of treatment.     

Serum paraoxonase level and paraoxonase polymorphism in patients with acromegaly

Background: Acromegalic patients have increased cardiometabolic risk factors due to an elevation of growth hormone (GH) levels. Human serum paraoxonase (PON), a high-density lipoprotein (HDL)-related enzyme, is one of the major bioscavengers and decreases the oxidation of low-density lipoprotein (LDL), a key regulator in the pathogenesis of atherosclerosis. In this study, we investigated a potential relationship between serum PON levels or PON polymorphisms and acromegaly.

Methods: A total of 48 acromegalic patients and 44 healthy controls were included in this study. Serum GH levels, insulin-like growth factor-1 levels and lipid profiles were measured. Serum PON levels, as well as PON 1 L55M and Q192R gene polymorphisms, were examined.

Results: No significant differences were found in terms of age, gender, presence of diabetes, serum LDL cholesterol (LDL-C), HDL-C, or triglyceride levels between the case and control groups (P?>?0.05). A statistically significant difference was found in serum PON levels between the cases and controls (P?=?0.007). The median serum PON level was 101?±?63.36?U/l in the case group and 63?±?60.50?U/l in the control group. There was a significant correlation between serum PON levels and IGF-1 levels (P?=?0.004, r?=?0.319); however, no significant differences were found in PON1 L55M and PON Q192R polymorphisms between the patients and controls (P?=?0.607 and P?=?0.308, respectively). In addition, no significant differences were found in serum PON levels in acromegalic patients who were and were not in remission (P?=?0.385), nor between those with PON1 L55M and Q192R polymorphisms (P?=?0.161 and P?=?0.336, respectively).

Conclusions: Elevated serum PON levels were detected in acromegalic patients, independently of their remission status. This suggests protective effects for cardiometabolic risk parameters.     

Thiol/disulphide homeostasis in pregnant women with Familial Mediterranean fever

Objective: To investigate the presence of oxidative stress (OS) in pregnant women with Familial Mediterranean fever (FMF) in the first trimester by evaluating thiol/disulphide homeostasis.

Study design: A total of 31 pregnant women with a diagnosis of FMF, between 11⁰ and 13⁶ weeks of gestation, were compared with 51 healthy pregnant controls at the same gestational weeks. A recently defined method was used to measure plasma native thiol, total thiol and disulphide levels.

Results: There were no differences between groups in terms of maternal age, body mass index and numbers of gravida and parity. Antenatal complications (45.2% vs. 9.8%, P?=?0.001) and primary caesarean section (22.6% vs. 5.9%, P?=?0.037) were higher in the FMF group. Pregnant women with FMF had significantly lower first trimester serum levels of native thiol (297.5?μmol/l (153.2–441.8) vs. 366.1?μmol/l (288.7–432.4), P?=?0.000), total thiol (327.2?μmol/l (171.0–471.0) vs. 389.9?μmol/l (317.1–449.8), P?=?0.000) and higher levels of disulphide (14.2?±?4.5?μmol/l vs. 12.4?±?3.4?μmol/l, P?=?0.045). No differences were found in these parameters among FMF patients with and without antenatal complications.

Conclusions: The main outcome demonstrates a relation between OS and pregnant women with FMF in the first trimester of gestation. OS in the first trimester may be a major aetiological factor of unfavourable pregancy outcomes in this group of patients.     

The effect of tumor necrosis factor alpha (-308G/a) and interferon gamma (+874T/a) polymorphisms on susceptibility to coronary heart disease

Abstract

Background: Coronary heart disease (CHD) is a chronic inflammatory disease, which is still regarded as a major cause of morbidity and mortality worldwide. Several studies have suggested that polymorphisms in cytokine genes are associated with the pathogenesis of CHD. The genotype distribution of Tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) genes polymorphisms have been shown to be different in various ethnic populations. This study was aimed to investigate the association of TNF-α-308?G/A and IFN-γ?+?874T/A polymorphisms with risk of CHD in an Iranian population.

Methods: A total of 187 unrelated subjects comprised 96 CHD patients and 91 healthy controls were enrolled in this cross-sectional study. The TNF-α-308?G/A and IFN-γ?+?874T/A polymorphisms were genotyped using amplification refractory mutation system-PCR (ARMS-PCR). The chi-square and logistic regression tests were used to calculate the odds ratios (ORs) as a measure of differences in genotype frequencies.

Results: A significant differences in the allelic and genotypic distribution of TNF-α-308?G/A and IFN-γ?+?874T/A polymorphisms was found between CHD patients and healthy controls (P?=?0.017, P?=?0.011, P?=?0.006 and P?=?0.002, respectively). Logistic regression analyses were also revealed statistically significant risk for CHD with respect to TNF-α-308?A and IFN-γ?+?874?T carriers either in crude or after adjustment for potential confounders (P?=?0.003 and P?=?0.006, respectively).

Conclusion: This study provides strong evidence supporting the association of TNF-α-308G/A and IFN-γ?+?874T/A polymorphisms with the increased risk of CHD. Therefore, these two cytokine polymorphisms may play a role in predisposition to coronary heart disease.     

Plasma levels of pentraxin 3 in patients with spondyloarthritis

Context: Determining the disease’s inflammatory activity in spondyloarthritis (SpA) is difficult although very important as it is this that drives treatment.

Objective: To investigate if plasma pentraxin-3 (PTX3) could act as an inflammatory marker in SpA.

Methods: Eighty one SpA patients (11 with psoriatic arthritis (PsoA) and 70 with ankylosing spondylitis (AS)) and 90 gender and age paired controls were studied for plasma PTX3 levels by ELISA. Patients had determinations of disease activity through C reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP. Epidemiological, clinical and treatment data were collected through chart review.

Results: SpA patients had lower concentrations of plasma PTX3 than controls (median of 0.95?ng/mL vs 1.64?ng/mL; p?p?=?0.42). Uveitis, presence of HLA B27, tobacco exposure, age and disease duration did not influence PTX3 levels.

Conclusions: PTX3 plasma levels do not reflect disease activity in SpA. However, it probably participates in the ethiopathogenetic process, as it is consumed in these patients.     

Alteration of thiol-disulphide homeostasis in acute tonsillopharyngitis

Objective: Thiol-disulphide homeostasis (TDH) has a critical role in various clinical disorders. We aimed to assess the association of TDH with acute tonsillopharyngitis (AT) in children.

Methods: This study included 94 (73 viral and 21 bacterial) tonsillopharyngitis patients and 88 control children. Their native thiol, total thiol, and disulphide levels were measured.

Results: Viral and bacterial tonsillopharyngitis patients had lower native thiol levels compared with healthy children (P?P?=?0.008, respectively). Both groups had lower total thiol levels compared with control children (P?=?0.002 for viral, P?=?0.011 for bacterial). The disulphide levels were lower in bacterial than in viral tonsillopharyngitis patients (P?=?0.04), and there was a significant difference between viral tonsillopharyngitis patients and the control group (P?P?P?=?0.017 for bacterial). The disulphide/native thiol and disulphide/total thiol ratios were significantly higher in viral (P?P?=?0.017 for both) than in healthy children. In all patients, a correlation was found between the levels of C-reactive protein (CRP) and native thiol (r?=??0.211, P?=?0.04), CRP and total thiol (r?=??0.217, P?=?0.036), white blood cell (WBC) and native thiol (r?=??0.228, P?=?0.002), WBC and total thiol (r?=??0.191, P?=?0.01), and WBC and disulphide (r?=?0.160, P?=?0.03).

Discussion: TDH is altered in AT in children. The alteration is more prominent in viral than in bacterial tonsillopharyngitis.     

Plasma PCSK9 levels and lipoprotein distribution are preserved in carriers of genetic HDL disorders

Proprotein convertase subtilisin/kexin 9 (PCSK9), a protein regulating the number of cell-surface LDL receptors (LDLR), circulates partially associated to plasma lipoproteins. How this interaction alters PCSK9 plasma levels is still unclear. In the present study, we took advantage of the availability of a large cohort of carriers of genetic HDL disorders to evaluate how HDL defects affect plasma PCSK9 levels and its distribution among lipoproteins. Plasma PCSK9 concentrations were determined by ELISA in carriers of mutations in LCAT, ABCA1, or APOAI genes, and lipoprotein distribution was analyzed by FPLC. Carriers of one or two mutations in the LCAT gene show plasma PCSK9 levels comparable to that of unaffected family controls (homozygotes, 159.4?ng/mL (124.9;243.3); heterozygotes, 180.3?ng/mL (127.6;251.5) and controls, 190.4?ng/mL (146.7;264.4); P for trend?=?0.33). Measurement of PCSK9 in plasma of subjects carrying mutations in ABCA1 or APOAI genes confirmed normal values. When fractionated by FPLC, PCSK9 peaked in a region between LDL and HDL in control subjects. In carriers of all HDL defects, lipoprotein profile shows a strong reduction of HDL, but the distribution of PCSK9 was superimposable to that of controls. In conclusion, the present study demonstrates that in genetically determined low HDL states plasma PCSK9 concentrations and lipoprotein distribution are preserved, thus suggesting that HDL may not be involved in PCSK9 transport in plasma.     

The Influences of Chromium Supplementation on Glycemic Control,Markers of Cardio-Metabolic Risk,and Oxidative Stress in Infertile Polycystic ovary Syndrome Women Candidate for In vitro Fertilization: a Randomized,Double-Blind,Placebo-Controlled Trial

This study was carried out to investigate the effects of chromium intake on glycemic control, markers of cardio-metabolic risk, and oxidative stress in infertile polycystic ovary syndrome (PCOS) women candidate for in vitro fertilization (IVF). This randomized double-blind, placebo-controlled trial was done among 40 subjects with infertile PCOS candidate for IVF, aged 18–40 years old. Individuals were randomly allocated into two groups to take either 200 μg/day of chromium (n?=?20) or placebo (n?=?20) for 8 weeks. Biochemical parameters were assessed at baseline and at end-of-trial. Compared with the placebo, taking chromium supplements led to significant reductions in fasting plasma glucose (??2.3?±?5.7 vs. +?0.9?±?3.1 mg/dL, P?=?0.03), insulin levels (??1.4?±?2.1 vs. +?0.4?±?1.7 μIU/mL, P?=?0.004), homeostatic model of assessment for insulin resistance (??0.3?±?0.5 vs. +?0.1?±?0.4, P?=?0.005), and a significant increase in quantitative insulin sensitivity check index (+?0.004?±?0.008 vs. ??0.001?±?0.008, P?=?0.03). In addition, chromium supplementation significantly decreased serum triglycerides (??19.2?±?33.8 vs. +?8.3?±?21.7 mg/dL, P?=?0.004), VLDL- (??3.8?±?6.8 vs. +?1.7?±?4.3 mg/dL, P?=?0.004) and total cholesterol concentrations (??15.3?±?26.2 vs. ??0.6?±?15.9 mg/dL, P?=?0.03) compared with the placebo. Additionally, taking chromium supplements was associated with a significant increase in plasma total antioxidant capacity (+?153.9?±?46.1 vs. ??7.8?±?43.9 mmol/L, P?<?0.001) and a significant reduction in malondialdehyde values (?0.3?±?0.3 vs. +?0.1?±?0.2 μmol/L, P?=?0.001) compared with the placebo. Overall, our study supported that chromium administration for 8 weeks to infertile PCOS women candidate for IVF had beneficial impacts on glycemic control, few variables of cardio-metabolic risk, and oxidative stress.     

Soluble ST2 is associated with disease severity in arrhythmogenic right ventricular cardiomyopathy

Purpose: Diagnostic and prognostic evaluation remains challenging in arrhythmogenic right ventricular cardiomyopathy (ARVC). We measured plasma concentration of soluble ST2 (sST2) and assessed its association with right ventricular (RV) function and ventricular arrhythmias in patients with ARVC.

Methods: We included patients with ARVC and genotype positive relatives. Soluble ST2 was determined by ELISA. We assessed myocardial function by echocardiography including strain by speckle tracking technique.

Results: We included 44 subjects (age 41?±?15 years, 21 (48%) female). Soluble ST2 was associated with RV global strain (r?=?0.44; p?=?0.008), as well as with left ventricular (LV) function. Plasma levels of sST2 were higher in patients with ventricular arrhythmias than in patients without ventricular arrhythmias (35?±?13?ng/mL vs. 26?±?7?ng/mL, p?=?0.009). The association between sST2 and ventricular arrhythmias remained significant even after adjusting for RV function (Wald?=?5.2; p?=?0.02).

Conclusions: Soluble ST2 is associated with RV and LV function in patients with ARVC. Soluble ST2 may aid in the determination of disease severity in ARVC.     

Fine mapping the KLK3 locus on chromosome 19q13.33 associated with prostate cancer susceptibility and PSA levels

Measurements of serum prostate-specific antigen (PSA) protein levels form the basis for a widely used test to screen men for prostate cancer. Germline variants in the gene that encodes the PSA protein (KLK3) have been shown to be associated with both serum PSA levels and prostate cancer. Based on a resequencing analysis of a 56?kb region on chromosome 19q13.33, centered on the KLK3 gene, we fine mapped this locus by genotyping tag SNPs in 3,522 prostate cancer cases and 3,338 controls from five case?Ccontrol studies. We did not observe a strong association with the KLK3 variant, reported in previous studies to confer risk for prostate cancer (rs2735839; P?=?0.20) but did observe three highly correlated SNPs (rs17632542, rs62113212 and rs62113214) associated with prostate cancer [P?=?3.41?×?10^?4, per-allele trend odds ratio (OR)?=?0.77, 95% CI?=?0.67?C0.89]. The signal was apparent only for nonaggressive prostate cancer cases with Gleason score <7 and disease stage <III (P?=?4.72?×?10^?5, per-allele trend OR?=?0.68, 95% CI?=?0.57?C0.82) and not for advanced cases with Gleason score >8 or stage ??III (P?=?0.31, per-allele trend OR?=?1.12, 95% CI?=?0.90?C1.40). One of the three highly correlated SNPs, rs17632542, introduces a non-synonymous amino acid change in the KLK3 protein with a predicted benign or neutral functional impact. Baseline PSA levels were 43.7% higher in control subjects with no minor alleles (1.61?ng/ml, 95% CI?=?1.49?C1.72) than in those with one or more minor alleles at any one of the three SNPs (1.12?ng/ml, 95% CI?=?0.96?C1.28) (P?=?9.70?×?10^?5). Together our results suggest that germline KLK3 variants could influence the diagnosis of nonaggressive prostate cancer by influencing the likelihood of biopsy.     

Anaemia, Folate, Zinc and Copper Deficiencies Among Adolescent Schoolgirls in Eastern Sudan

Anaemia is a widespread problem especially in the tropics. Among adolescent girls, it has negative consequences on growth, school performance, morbidity and reproductive performance. A cross-sectional study was conducted to investigate the prevalence of anaemia, iron, folate, zinc and copper deficiencies amongst adolescent schoolgirls in New Halfa, eastern Sudan, and to examine the relationship of these micronutrients with haemoglobin (Hb) levels. Out of 187 adolescent schoolgirls, 181 (96.8%) had anaemia (Hb?<?12 g/dl); 21% had mild anaemia (Hb 11.0–11.9 g/dl); 66.8.1% had moderate anaemia (Hb 8.0–10.9 g/dl), and 12.1% had severe anaemia (Hb?<?8 g/dl), respectively. Iron deficiency (S-ferritin?<?12 μg/l), iron deficiency anaemia (<12 m/dl and S- ferritin?<?12 μg/l) and folate deficiency (S-folate?<?3 ng/ml) were prevalent in 17.6%, 16.5% and 69% of these girls, respectively. Nine percent and 5.9% of these girls had zinc (<75 μg/ml) and copper deficiency (<75 μg/ml), respectively. Twenty-six (14%) girls had ≥2 micronutrient deficiencies. S-ferritin and zinc were significantly lower in patients with severe anaemia. Haemoglobin levels were significantly positively correlated with zinc levels (r?=?0.161, P?=?0.03) and with copper levels (r?=?0.151, P?=?0.03). Thus, interventions are required to prevent and control anaemia in this setting. Further research is needed.     

Simvastatin prevents vascular complications in the chronic reactive oxygen species murine model of systemic sclerosis

Aims Systemic sclerosis (SSc) is characterized by vasculopathy and organ fibrosis. Although microvascular alterations are very well characterized, structural and functional abnormalities of large vessels are not well defined. Therefore, we evaluated the effect of simvastatin administration on aortic and small renal arteries thickening, and on myofibroblasts differentiation in a murine model of SSc. Methods and results SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl, 100?μl) for 6 weeks. Mice (n?=?23) were randomized to receive: HOCl (n?=?10); HOCl plus simvastatin (40?mg/kg; n?=?8); or vehicle (n?=?5). Simvastatin administration started 30?min after HOCl injection, and up to week 6. Aortic and small renal arteries intima–media thickness was evaluated by histological analysis. Immunostaining for α-smooth muscle actin (SMA), vascular endothelial growth factor receptor 2 (VEGFR2), and CD31 in aortic tissues was performed to evaluate myofibroblast differentiation and endothelial markers.In HOCl-treated mice, intima–media thickening with reduced lumen diameter was observed in the aorta and in small renal arteries and simvastatin administration prevented this increase. Aortic and renal myofibroblasts count, as expressed by α-SMA?+?density, was lower in the group of mice treated with simvastatin compared to HOCl-treated mice. Simvastatin prevented the reduction in VEGFR2 and CD31 expression induced by HOCl. Conclusions The administration of simvastatin regulates collagen deposition in the aortic tissues and in the small renal arteries by modulating myofibroblasts differentiation and vascular markers. Further studies are needed to better address the effect of statins in the macrovascular component of SSc.     

SPARCL1 as a biomarker of maladaptive right ventricular remodelling in pulmonary hypertension

Abstract

Aim: This study assessed the utility of SPARC-like protein 1 (SPARCL1) as a biomarker of maladaptive right ventricular (RV) function in patients with pulmonary hypertension (PH).

Methods: In this prospective study, we examined SPARCL1 levels in 105 patients with adaptive (n?=?34) and maladaptive RV (n?=?32) pressure overload caused by PH, dilated cardiomyopathy (DCM, n?=?18) with LVEF < 35% and preserved RV function and controls without LV or RV abnormalities (n?=?21).

Results: The median SPARCL1 concentration in patients with maladaptive RV function was higher than in those with adaptive RV function (p?<?0.01), DCM (p?<?0.001) or controls (p?<?0.001). Patients with adaptive RV function had higher SPARCL1 concentrations than controls (p?<?0.05), whereas there was no difference between adaptive RV and DCM. SPARCL1 showed good predictive power for maladaptive RV (AUC 0.77, p?<?0.001) with an optimal cut-off value of 9.66?ng/ml. The TAPSE/PASP ratio was the only independent predictor of SPARCL1?≥?9.66?ng/ml in multivariable logistic regression analysis.

Conclusion: SPARCL1 shows potential as novel biomarker of RV pathological remodelling and is associated with RV maladaptation and ventriculoarterial uncoupling in PH.     

Hyperglycaemia,oxidative stress and inflammatory markers

Introduction: The increasing prevalence of hyperglycaemia implicates a state of oxidative stress and inflammation. Traditional and emerging biomarkers associated with increasing hyperglycaemia were assessed to clarify their role they play in hyperglycaemia.

Results: 309 participants attending a rural diabetic screening program were categorised into control and quintile groups based upon glucose levels: 1st quintile - <4.5?mmol/L and 4th, 5th quintile - >6.1?mmol/L. Significant results were obtained for anthropometric data and biochemical markers - glucose, HbA1c and total cholesterol (P?P?P?P?Conclusion: This study provided further evidence that inflammatory and oxidative stress biomarkers may contribute to diagnostic information associated with preclinical increases in BGL. Further we have provided a unique study in the analysis of ratios of inflammatory biomarkers and correlations with increasing BGL.     

Ultrasound-guided continuous femoral nerve block: a randomized trial on the influence of femoral nerve catheter orifice configuration (six-hole versus end-hole) on post-operative analgesia after total knee arthroplasty

Background

Multiorifice catheters have been shown to provide superior analgesia and significantly reduce local anesthetic consumption compared with end-hole catheters in epidural studies. This prospective, blinded, randomized study tested the hypothesis that, in continuous femoral nerve block (CFNB) under ultrasound guidance, multiorifice catheter would reduce local anesthetic consumption at 24?h compared with end-hole catheter.

Methods

Eighty adult patients (aged ≥18?years) scheduled to undergo primary total knee arthroplasty under a combination of CFNB, sciatic nerve block and general anesthesia were randomized to CFNB using either a 3-pair micro-hole (Contiplex, BRAUN®, 20G - 400?mm) or an end-hole (Silverstim VYGON®, 20G - 500?mm) catheter. Once the femoral catheter was sited, a bolus of 20?mL lidocaine 1% was injected. An electronic pump then delivered an automated 5?mL bolus of ropivacaine 0.2% hourly, with 10?mL self-administered patient controlled analgesia boluses.

Results

There was no inter-group difference in either median number of ropivacaine boluses on demand during the first 24?h (4(2–7) vs. 4(2–8) in six-hole and end-hole groups, respectively; P?=?0.832) or median ropivacaine consumption at 48?h (365(295–418) vs. 387(323–466); P?=?0.452).No significant differences were recorded between the groups at 24?h regarding median average verbal rate pain scale (2(0–3) vs. 2(0–4); P?=?0.486) or morphine consumption (0(0–20) vs. 0(0–20); P?=?0.749). Quadriceps muscle strength declined to 7% (0–20) and 10% (0–28) in the six-hole and end-hole groups, respectively, at 24?h after surgery (P?=?0.733).

Conclusions

In this superiority trial, catheter orifice configuration did not influence the effectiveness of CFNB in this setting: quality of analgesia was similar, with no reduction in either local anesthetic or morphine consumption, and equivalent postoperative quadriceps weakness.

Trial registration

Retrospectively registered at (NCT03376178). Date: 21 November 2017.

     

Thioredoxin interacting protein expression in the urinary sediment associates with renal function decline in type 1 diabetes

Aims: Thioredoxin interacting protein (TXNIP), an inhibitor of antioxidant thioredoxin (Trx), is upregulated by hyperglycemia and implicated in pathogenesis of diabetes complications. We evaluated mRNA expressions of genes encoding TXNIP and Trx (TXN) in urinary sediment and peripheral blood mononuclear cells (PBMC) of type 1 diabetes (T1D) patients with different degrees of chronic complications. Methods: qPCR was employed to quantify target genes in urinary sediment (n?=?55) and PBMC (n?=?161) from patients sorted by presence or absence of diabetic nephropathy (DN), retinopathy, peripheral and cardiovascular neuropathy; 26 healthy controls and 13 patients presenting non-diabetic nephropathy (focal and segmental glomerulosclerosis, FSGS) were also included. Results: Regarding the urinary sediment, TXNIP (but not TXN) expression was higher in T1D (p?=?0.0023) and FSGS (p?=?0.0027) patients versus controls. Expressions of TXNIP and TXN were higher, respectively, in T1D patients with versus without DN (p?=?0.032) and in those with estimated glomerular filtration rate (eGFR)?<?60 versus?≥60 mL/min/1.73 m² (p?=?0.008). eGFR negatively correlated with TXNIP (p?=?0.04, r?=??0.28) and TXN (p?=?0.04, r?=??0.30) expressions. T1D patients who lost?≥5 mL/min/1.73 m² yearly of eGFR presented higher basal TXNIP expression than those who lost?<5 mL/min/1.73 m² yearly after median follow-up of 24 months. TXNIP (p?<?0.0001) and TXN (p?=?0.002) expressions in PBMC of T1D patients were significantly higher than in controls but no differences were observed between patients with or without chronic complications. Conclusions: TXNIP and TXN are upregulated in urinary sediment of T1D patients with diabetic kidney disease (DKD), but only TXNIP expression is associated with magnitude of eGFR decline.     

Plasma soluble urokinase plasminogen activator receptor (suPAR) levels in systemic lupus erythematosus

Objective: Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of systemic inflammation. We aimed to characterize plasma suPAR levels in SLE patients.

Methods: We measured plasma suPAR, C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in 89 SLE patients and 29 healthy controls.

Results: suPAR and ESR values were higher in SLE than in controls, while CRP levels were comparable. ROC analysis of suPAR levels indicated a cut-off value of 5.70?ng/mL to distinguish patients with high disease activity (SLEDAI >8).

Conclusion: suPAR might be an objective marker for identifying SLE patients with active disease.     

Comparison of β2-microglobulin serum level between Alzheimer’s patients,cognitive healthy and mild cognitive impaired individuals

Background: Several studies performed in the last years on the brain, showed that beta2-microglobulin (β2m) and MHC can act independently of their canonical immune function to regulate normal brain development, synaptic plasticity and behaviour. Increased systemic levels of soluble β2m have been implicated in cognitive impairments like that associated with chronic haemodialysis, or aortic valve replacement. Increased soluble β2m has also been detected in the cerebral spinal fluid (CSF) of patients with HIV-associated dementia and Alzheimer’s disease (AD).

Objective: To compare plasma β2m levels in healthy subjects and subjects with dementia or cognitive impairment.

Methods: We measured the concentration of β2m in a cohort of 245 individuals and compared sex matched, cognitive healthy individuals.

Results: We found higher levels of β2m in AD patients compared to non-AD MCI and healthy controls (2063?ng/mL ±852 versus 1613?±?503 and 1832?±?382?ng/mL, pp?>?0.05).

Conclusions: Our data confirm that β2m could play a role in AD. However, a replication study in an independent cohort would be necessary to confirm our preliminary results.