Nitrite and nitroso compounds can serve as specific catalase inhibitors

Objective: We present evidence that nitrite and nitrosothiols, nitrosoamines and non-heme dinitrosyl iron complexes can reversibly inhibit catalase with equal effectiveness.

Methods: Catalase activity was evaluated by the permanganatometric and calorimetric assays.

Results: This inhibition is not the result of chemical transformations of these compounds to a single inhibitor, as well as it is not the result of NO release from these substances (as NO traps have no effect on the extent of inhibition). It was found that chloride and bromide in concentration above 80 mM and thiocyanate in concentration above 20 μM enhance catalase inhibition by nitrite and the nitroso compounds more than 100 times. The inhibition degree in this case is comparable with that induced by azide.

Discussion: We propose that the direct catalase inhibitor is a positively charged NO-group. This group acquires a positive charge in the active center of enzyme by interaction of nitrite or nitroso compounds with some enzyme groups. Halides and thiocyanate protect the NO⁺ group from hydration and thus increase its inhibition effect. It is probable that a comparatively low chloride concentration in many cells is the main factor to protect catalase from inhibition by nitrite and nitroso compounds.     

Propeptide big-endothelin,N-terminal-pro brain natriuretic peptide and mortality. The Ludwigshafen risk and cardiovascular health (LURIC) study

Context: The endothelin system (Big-ET-1) is a key regulator in cardiovascular (CV) disease and congestive heart failure (CHF).

Objectives: We have examined the incremental value of Big-ET-1 in predicting total and CV mortality next to the well-established CV risk marker N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP).

Methods: Big-ET-1 and NT-proBNP were determined in 2829 participants referred for coronary angiography (follow-up 9.9 years).

Results: Big-ET-1 is an independent predictor of total, CV mortality and death due to CHF.

Discussion: The conjunct use of Big-ET-1 and NT-proBNP improves the risk stratification of patients with intermediate to high risk of CV death and CHF.

Conclusions: Big-ET-1improves risk stratification in patients referred for coronary angiography.     

Circulating adiponectin as a biomarker in renal cell carcinoma: a systematic review and meta-analysis

Context: Metabolic imbalance in renal cell carcinoma (RCC) can lead to abnormal adiponectin levels.

Objective: To evaluate circulating adiponectin as a detection or predictive marker for RCC.

Methods: A comprehensive literature search and meta-analysis was performed on studies reporting circulating adiponectin levels and RCC. The meta-analysis was performed using RevMan.

Results: Seven studies compared the circulating adiponection levels between RCC cases and controls. Adiponectin level was significantly lower in RCC cases compared to controls at pre-diagnosis and pre-operative time-points. RCC stage, grade and subtype did not affect adiponectin levels.

Conclusion: Low circulating adiponectin could be a predictive or risk factor for RCC.     

Biomarker discovery for drug-induced phospholipidosis: phenylacetylglycine to hippuric acid ratio in urine and plasma as potential markers

Context: Drug-induced phospholipidosis is one of the significant concerns in drug development, especially in safety assessment and noninvasive diagnostic tool is highly desirable.

Objective: The objective of this study is to explored novel biomarkers for phospholipidosis using a metabolomic approach.

Method: NMR spectrometry and LC/MS/MS analyses were applied to urine and plasma of rats administrated cationic amphiphilic drugs.

Results: The phenylacetylglycine to hippuric acid ratio in plasma was increased in time and dose-dependent manners; and it was well correlated with histopathological observation.

Conclusion: The plasma phenylacetylglycine to hippuric acid ratio is a potential marker in monitoring drug-induced phospholipidosis.     

Riboflavin as an independent and accurate biomarker for adherence in a randomized double-blind and placebo-controlled clinical trial

Background: Medication adherence is critical for success of clinical trials.

Objective: To assess oral riboflavin is an adherence marker.

Methods: Riboflavin was incorporated into active treatment and placebo pills for a clinical trial lasting for 2 years.

Results: The accuracy (area under the receiver operating curve) of urinary riboflavin was 0.91 as a binary classifier of adherence, and was similar or better than for two active study ingredients daidzein (0.92) and genistein (0.87) (all p?<?0.0001). Decreased adherence over time was similar in the two study groups.

Conclusion: Riboflavin is an accurate and useful biomarker for study pill ingestion.     

Association of IL-10 (-819T/C, -592A/C and -1082A/G) and IL-6 -174G/C gene polymorphism and the risk of pneumonia-induced sepsis

Context: Association between inherited variants and the risks of sepsis is controversial.

Objective: To evaluate the risk of pneumonia-induced sepsis by examining its linkage with polymorphisms of IL-6 and IL-10.

Materials and methods: Samples were obtained from 188 pneumonia-induced sepsis patients, 162 pneumonia patients and 200 healthy controls.

Results: Subjects with IL-10 -1082 AA genotypes and IL-6 -174?CC genotype had a higher risk of sepsis and increased mRNA levels.

Conclusion: The variants of IL-10 -1082 A allele and IL-6 -174 C allele contributed to an increased risk of pneumonia-induced sepsis.     

Circulating levels of apoptotic markers and oxidative stress parameters in women with polycystic ovary syndrome: a case-controlled descriptive study

Context: Apoptotic dysregulation plays a role in the pathogenesis of polycystic ovary syndrome (PCOS).

Objective: To evaluate circulatory apoptotic markers and oxidative stress in patients with PCOS.

Materials and methods: Forty-four women with PCOS, and 44 healthy women as controls were enrolled in the study. Oxidative stress parameters and caspases levels were measured in serum.

Results: The caspase 9 level was significantly lower and related with oxidant status in patients with PCOS, while the circulating levels of caspases 3 and 7 were statistically similar in both groups.

Discussion: This study is the first report demonstrating the circulating levels of apoptotic markers and their relationship with oxidant status in PCOS.

Conclusion: The circulating caspase 9 and oxidant status might contribute to apoptotic dysregulation in PCOS.     

Differential expression of circulating vascular cell adhesion molecule-1 in subjects with coronary artery disease and cardiac syndrome X without known diabetes mellitus

Context: Inflammation is one of the mechanisms underlying cardiac syndrome X (CSX).

Objectives: Few studies have compared the expression of inflammatory or adhesion molecules between coronary artery disease (CAD) versus CSX.

Materials and methods: Ninety-two CSX and 145 CAD subjects without known diabetes mellitus underwent coronary angiogram for angina.

Results: Vascular cell adhesion molecule (VCAM)-1 (median, 507 versus 431?ng/ml, p?=?0.001) was significantly higher in the CAD group. In the binary regression, VCAM-1 was a significant differential factor for CAD versus CSX.

Discussion and conclusion: Adhesion molecules might be implicated in the differential expression of macro versus microvascular coronary disease.

Trial registration number: NCT01198730 at https://clinicaltrials.gov     

Bacterial pili,with emphasis on Mycobacterium tuberculosis curli pili: potential biomarkers for point-of care tests and therapeutics

Context: Novel biomarkers are essential for developing rapid diagnostics and therapeutic interventions

Objective: This review aimed to highlight biomarker characterisation and assessment of unique bacterial pili.

Methods: A PubMed search for bacterial pili, diagnostics, vaccine and therapeutics was performed, with emphasis on the well characterised pili.

Results: In total, 46 papers were identified and reviewed.

Conclusion: Extensive analyses of pili enabled by advanced nanotechnology and whole genome sequencing provide evidence that they are strong biomarker candidates. Mycobacterium tuberculosis curli pili are emphasised as important epitopes for the development of much needed point-of-care diagnostics and therapeutics.     

Release kinetics of high-sensitivity cardiac troponins I and T and troponin T upstream open reading frame peptide (TnTuORF) in clinically induced acute myocardial infarction

Context: Troponin T upstream open reading frame peptide (TnTuORF) may be useful as a novel biomarker in acute cardiac syndromes.

Objective: The study examined the early release kinetics of TnTuORF.

Materials and methods: We analyzed the time course of the release of cardiac troponins I and T and TnTuORF in patients (n?=?31) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy (TASH).

Results: Fifteen minutes after TASH, the levels of both troponins increased significantly (cTnT median: 18?ng/L versus 27?ng/L; cTnI median: 15?ng/L versus 25?ng/L). TnTuORF showed no variation.

Discussion: We observed a significantly greater increase in cTnI compared with cTnT.

Conclusion: Our results demonstrate that troponin assays allow early detection of myocardial injury, whereas TnTuORF levels remain unchanged in this setting.     

Blood markers of inflammation and endothelial dysfunction in cardioembolic stroke: systematic review and meta-analysis

Context: Various processes including inflammation and endothelial dysfunction have been implicated in the pathogenesis of cardioembolic (CE) strokes.

Objective: To review the evidence and investigate the association between immune-inflammatory biomarkers and CE strokes versus other stroke subtypes.

Methods: We systematically reviewed the literature (sources: MEDLINE, web-based register http://stroke-biomarkers.com, reference lists) with quality assessment and meta-analysis of selected articles.

Results: The most consistent association was found between C-reactive protein (CRP) and CE strokes when compared to other stroke subtypes (standardized mean difference 0.223 (0.116, 0.343); p?<?0.001)

Conclusions: Our findings confirm a possible association between selected inflammatory biomarkers and CE stroke.     

Soluble CD40 ligand in haemodialysis patients: survival impact and cardiovascular prognostic role

Context: Soluble CD40 ligand (sCD40l) can predict cardiovascular events (CVE) and mortality in haemodialysis (HD) patients (short-, medium-term follow-up studies).

Objective: To evaluate the relationship between sCD40l and survival, CVE and mortality in HD patients on long-term follow-up.

Methods: We registered 46?HD patients’ baseline characteristics, mortality and CVE for 108 months.

Results: SCD40l correlated positively with C-reactive protein, was higher in survivors, but had no impact on survival and was not predictive for CVE or CV mortality.

Conclusion: The levels of sCD40l have no influence on survival or CVE and mortality in HD patients in a long-term follow-up.     

Epidermal growth factor,growth differentiation factor-15, and survivin as novel biocompatibility markers in children on chronic dialysis

Context: Chronic dialysis results in aggravation of apoptosis and cell damage, triggered by bioincompatibility of dialysis membranes and peritoneal fluids.

Objective: The aim of study was to assess the usefulness of epidermal growth factor (EGF), growth differentiation factor (GDF)-15, and survivin as novel markers of biocompatibility in dialyzed children.

Materials and methods: Parameters were assessed by ELISA in 19 patients on hemodialysis and 22 children on peritoneal dialysis.

Results: Serum concentrations of analyzed parameters in children on chronic dialysis differed significantly from controls and depended strongly on the dialysis technique.

Conclusions: EGF, GDF-15, and survivin may serve as new biocompatibility markers in children on chronic dialysis.     

Methionine metabolism and multiple sclerosis

Context: Methylation reactions are particularly important in the brain and their inhibition can lead to a number of serious pathologies. Multiple sclerosis is one of the most common neurological disorders caused by interaction of genetic and environmental factors, but little is known about its cause or factors that contribute to the disorder. Although multiple sclerosis is primarily regarded as demyelinating disorder, there are no many articles focusing on methionine determination.

Objective: The aim of this work was to investigate whether serum methionine and its related compounds like homocysteine, cysteine, glutathione and asymmetric dimethylarginine were changed in multiple sclerosis patients.

Materials and methods: Sulphur-containing compounds were determined by using high-performance liquid chromatography with electrochemical detection in a single run for providing more complex view on methionine metabolism and asymmetric dimetylarginine was measured by a commercial enzyme-linked immunosorbent assay kit.

Results: Methionine and glutathione were decreased, but homocysteine, asymmetric dimethylarginine and cysteine were unchanged in patients with multiple sclerosis compared with controls.

Conclusions: Methionine and glutathione seem to be potential biomarkers for prognosis of the disease.     

Association between polymorphisms in IL21 gene and risk for sepsis

Context: Sepsis is now the leading cause of death in the noncardiovascular intensive care unit (ICU).

Objective: To investigate whether polymorphisms in IL21 gene contribute to sepsis susceptibility.

Materials and methods: Three single-nucleotide polymorphisms of IL21 (rs907715, rs2055979, rs12508721) were genotyped by TaqMan assay in patients with sepsis and control subjects.

Results: Polymorphisms rs2055979 and rs12508721 in IL21 were more frequent in sepsis patients compared to general population. But allele frequency of rs907715 was not significantly different between sepsis patients and control subjects.

Conclusion: Polymorphisms in IL21 may be associated with sepsis risk.     

Physiological conditions of parent and offspring Black-browed Albatrosses Thalassarche melanophris

Capsule: In Black-browed Albatrosses Thalassarche melanophris nutritional condition is correlated between parents and their offspring.

Aims: To test resource allocation hypotheses analysing the relationship between parental and offspring nutritional condition.

Methods: We measured blood chemistry parameters related with nutritional condition in 24 parents and their nestlings in a colony of Black-browed Albatrosses.

Results: There were no significant differences in blood parameters between sexes or location of the nest within the colony, neither among adults nor among nestlings. We found a significant positive correlation between parents and the nutritional condition of their offspring, measured as urea, uric acid and beta-hydroxybutyrate concentrations in blood.

Discussion: These relationships demonstrate that condition of the young seems to be merely a reflection of parental condition. An interesting relationship between alkaline phosphatase concentration in adults and nutritional condition of their nestlings was found, suggesting that age of the parents would be a key factor explaining quality of the nestling.     

Impact of CT-apelin and NT-proBNP on identifying non-responders to cardiac resynchronization therapy

Context: Assessment of response to cardiac resynchronization therapy (CRT) is essential.

Objective: To assess the predictive value of CT-apelin together with NT-proBNP in patients undergoing CRT.

Methods: Serum CT-apelin and NT-proBNP were measured by ELISA before, and six months after CRT. Primary endpoint was non-response (<4% increase in LVEF) after six months.

Results: From 81 patients, 15 proved to be non-responders. Six-month CT-apelin was superior compared to NT-proBNP in identifying non-responders by multivariate ROC (CT-apelin: p?=?0.01, NT-proBNP: p?=?0.13) and by logistic regression (CT-apelin: p?=?0.01, NT-proBNP: p?=?0.41) analyses.

Conclusion: Six-month CT-apelin might be a valuable novel biomarker in identifying non-responders to CRT that was superior to NT-proBNP.     

Future breeding and foraging sites of a southern edge population of the locally endangered Black Guillemot Cepphus grylle

Capsule: One of the southernmost populations of the Black Guillemot Cepphus grylle is currently endangered, and the risk may be exacerbated by climate change.

Aims: We evaluated the future vulnerability of the Black Guillemot by predicting the impact of climate change on the geographic distribution of its breeding and foraging range in the Baltic Sea.

Methods: We used MaxEnt, a species distribution modelling technique, to predict the current and future breeding grounds and foraging sites.

Results: We found that although the foraging range is expected to increase in the southern Baltic Sea in future, these areas will no longer be suitable as breeding grounds due to a changing climate, creating a spatial mismatch.

Conclusion: Our predictions indicate where threats to the species may be most severe and can be used to guide conservation planning. We advocate conservation measures which integrate potential future threats and focus on breeding sites across the current and future potential geographic range of the Black Guillemot.     

Beta-2-glycoprotein-1 and alpha-1-antitrypsin as urinary markers of renal cancer in von Hippel–Lindau patients

Context: Von Hippel–Lindau disease (VHLD) is a rare inherited neoplastic syndrome. Among all the VHLD-associated tumors, clear cell renal cell carcinoma (ccRCC) is the major cause of death.

Objective: The aim of this paper is the discovery of new non-invasive biomarker for the monitoring of VHLD patients.

Materials and methods: We compared the urinary proteome of VHLD patients, ccRCC patients and healthy volunteers.

Results: Among all differentially expressed proteins, alpha-1-antitrypsin (A1AT) and APOH (beta-2-glycoprotein-1) are strongly over-abundant only in the urine of VHLD patients with a history of ccRCC.

Discussion and conclusion: A1AT and APOH could be promising non-invasive biomarkers.     

Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy

Bortezomib (BTZ) is the first proteasome inhibitor entered in clinical practice. Peripheral neuropathy is likely to be a class side effect of these drugs, although its severity is largely variable, and it deserves to be further investigated, since the mechanisms of BTZ-induced peripheral neurotoxicity (BiPN) are still unknown.

In our study, we investigated in vivo and in vitro possible pathogenic events relevant to BiPN using a well-established rat model, with particular reference to the extent of proteasome inhibition and the effects on α-tubulin polymerization in sciatic nerves and dorsal root ganglia specimens obtained from animals treated with chronic regimens at a dose of 0.2 mg/kg intravenously. The same assessments were also performed after a single injection. Moreover, these studies were replicated in vitro using embryonic DRG neurons exposed to 100 nM BTZ and adult DRG neurons exposed to 10–50 nM BTZ for 24 h and 48 h.

A significant increase in the polymerized fraction of α-tubulin and prolonged proteasome inhibition were observed after the chronic BTZ treatment in vivo. Recovery to physiological levels was observed after a 4-week follow-up post-treatment period. Proteasome inhibition and increased α-tubulin polymerization were also observed following BTZ treatment of both embryonic and adult DRG neurons in vitro.

Our in vivo results suggest that proteasome inhibition and alteration of tubulin dynamics contribute to BiPN. The in vitro systems here described reliably replicate the in vivo results, and might therefore be used for further mechanistic studies on the effects of proteasome inhibitors on neurons.