Bilijarna funkcija u radnika profesionalno izloženih aluminijskoj prašini i dimu

This study investigated billiary secretory function in workers occupationally exposed to aluminium dust and fumes. It included a group of 34 male workers aged (44.1±7.8) years and exposed up to 4.6 mg m-3 of aluminium dust and fumes in workplace air for (21.6±2.5) years, and a group of 30 unexposed control male workers. Serum and urine aluminium levels were measured in both groups before and after chelating treatment with 1 g deferoxamine by intramuscular injection. Billiary function was assessed by measuring gamma-glutamyl transpeptidase, alkaline phosphatase, 5-nucleotidase, cholesterol and its fractions, total and indirect bilirubin, and bile acids. We then analysed the relationship between Al exposure and billiary function. In the exposed group mean serum aluminium was significantly higher [(4.91±3.86) µg L-1] than in controls. The same was true for urine Al before [(1.57±1.93) µg L-1] and after deferoxamine [(11.51±14.97) µg L-1]. Total and indirect bilirubin and alkaline phosphatase were significantly higher in the exposed than in control workers, and they correlated with urine Al after the chelating treatment. Our findings suggest that chronic occupational exposure to aluminium dust and fumes leads to a significant body retention of aluminium. The impaired biliary secretion in the exposed workers manifested itself in subclinical signs of cholestasis.Eksperimentalna istraživanja na životinjama pokazuju da kronična izloženost aluminiju može izazvati smanjen prijenos organskih aniona preko žučnih kanalića, što ima za posljedicu poremećaje sekrecije žuči i kolestazu. Učinci kronične izloženosti aluminiju na bilijarnu funkciju u ljudi do sada nisu istraživani. Procjenjivali smo učinke na bilijarnu funkciju radnika koji su profesionalno izloženi prašini i dimu aluminija. U izloženoj skupini bila su 34 muškarca, životne dobi (44,1±7,8) godina koji su tijekom (21,6±2,5) godina bili izloženi razini do 4,6 mg m-3 prašine i dima aluminija. Kontrolna skupina sastojala se od 30 neizloženih radnika. Vrijednosti aluminija određene su u serumu i mokraći u obje skupine prije i nakon davanja kelatirajućeg spoja (deferoksamin u dozi od 1 g im.). Za procjenu bilijarne funkcije rabljeni su ovi pokazatelji: γ-glutamil transpeptidaza, alkalna fosfataza, 5-nukleozidaza, kolesterol, ukupni i indirektni bilirubin te žučne kiseline. Analizirana je korelacija između izloženosti aluminiju i bilijarne funkcije. Srednja vrijednost Al u serumu izloženih radnika [(4,91±3,86) µg L-1], kao i koncentracije Al u mokraći prije [(1,57±1,93) µg L-1] i nakon primjene kelatirajućeg spoja [(11,5±15,0) µg L-1] bile su statistički značajno više u odnosu na vrijednosti u kontrolnih ispitanika. Vrijednosti ukupnog i indirektnoog bilirubina te alkalne fosfataze bile su statistički značajno više u izloženih radnika i pozitivno su korelirale s ukupnim Al izlučenim mokraćom nakon primjene kelatora. Može se zaključiti da kronična profesionalna izloženost prašini i dimu aluminija dovodi do tjelesnog opterećenja aluminijem i poremećaja bilijarne funkcije, što se odražava supkliničkim znakovima kolestaze

AIBP Regulates TRPV1 Activation in Chemotherapy-Induced Peripheral Neuropathy by Controlling Lipid Raft Dynamics and Proximity to TLR4 in Dorsal Root Ganglion Neurons

Nociceptive afferent signaling evoked by inflammation and nerve injury is mediated by the opening of ligand-gated and voltage-gated receptors or channels localized to cholesterol-rich lipid raft membrane domains. Dorsal root ganglion (DRG) nociceptors express high levels of toll-like receptor 4 (TLR4), which also localize to lipid rafts. Genetic deletion or pharmacologic blocking of TLR4 diminishes pain associated with chemotherapy-induced peripheral neuropathy (CIPN). In DRGs of mice with paclitaxel-induced CIPN, we analyzed DRG neuronal lipid rafts, expression of TLR4, activation of transient receptor potential cation channel subfamily V member 1 (TRPV1), and TLR4-TRPV1 interaction. Using proximity ligation assay, flow cytometry, and whole-mount DRG microscopy, we found that CIPN increased DRG neuronal lipid rafts and TLR4 expression. These effects were reversed by intrathecal injection of apolipoprotein A-I binding protein (AIBP), a protein that binds to TLR4 and specifically targets cholesterol depletion from TLR4-expressing cells. Chemotherapy-induced peripheral neuropathy increased TRPV1 phosphorylation, localization to neuronal lipid rafts, and proximity to TLR4. These effects were also reversed by AIBP treatment. Regulation of TRPV1-TLR4 interactions and their associated lipid rafts by AIBP covaried with the enduring reversal of mechanical allodynia otherwise observed in CIPN. In addition, AIBP reduced intracellular calcium in response to the TRPV1 agonist capsaicin, which was increased in DRG neurons from paclitaxel-treated mice and in the naïve mouse DRG neurons incubated in vitro with paclitaxel. Together, these results suggest that the assembly of nociceptive and inflammatory receptors in the environment of lipid rafts regulates nociceptive signaling in DRG neurons and that AIBP can control lipid raft-associated nociceptive processing

Hydrazines as versatile chemical biology probes and drug-discovery tools for cofactor-dependent enzymes [preprint]

Known chemoproteomic probes generally use warheads that tag a single type of amino acid or modified form thereof to identify cases in which its hyper-reactivity underpins function. Much important biochemistry derives from electron-poor enzyme cofactors, transient intermediates and chemically-labile regulatory modifications, but probes for such species are underdeveloped. Here, we have innovated a versatile class of chemoproteomic probes for this less charted hemisphere of the proteome by using hydrazine as the common chemical warhead. Its electron-rich nature allows it to react by both polar and radicaloid mechanisms and to target multiple, pharmacologically important functional classes of enzymes bearing diverse organic and inorganic cofactors. Probe attachment can be blocked by active-site-directed inhibitors, and elaboration of the warhead supports connection of a target to a lead compound. The capacity of substituted hydrazines to profile, discover and inhibit diverse cofactor-dependent enzymes enables cell and tissue imaging and makes this platform useful for enzyme and drug discovery

Clinical Focus on Lung Cancer: A snapshot of lung cancer for Ontario health care providers and managers

This monograph on lung cancer has been prepared to provide information on patterns of practice to those directly involved in the provision of care to lung cancer patients. As well, it should be helpful to those who are responsible for managing aspects of the cancer system that impact on the care that lung cancer patients receive across the province of Ontario. The practice patterns are shown against the backdrop of the evidence-based guidelines developed by the Lung Disease Site Group of Cancer Care Ontario’s Program in Evidence based Care. In addition to information on patterns of practice, this monograph provides information on the timeliness of access to care, as well as a brief overview of the incidence and mortality of lung cancer, and the trends in the main risk factor for developing lung cancer, namely smoking. In brief, it provides a snapshot of the quality of care for lung cancer patients in the province of Ontario. It is hoped that this monograph will assist those responsible for care delivery to achieve the best possible results for patients with a diagnosis of lung cancer

The role of measuring exhaled breath biomarkers in sarcoidosis: A systematic review

Introduction: Sarcoidosis is a chronic granulomatous disease of unknown aetiology with a variable clinical course and prognosis. There is a growing need to identify non-invasive biomarkers to differentiate between clinical phenotypes, identify those at risk of disease progression and monitor response to treatment. Objectives: We undertook a systematic review and meta-analysis, to evaluate the utility of breath-based biomarkers in discriminating sarcoidosis from healthy controls, alongside correlation with existing non-breath based biomarkers used in clinical practice, radiological stage, markers of disease activity and response to treatment. Methods: Electronic searches were undertaken during November 2017 using PubMed, Ebsco, Embase and Web of Science to capture relevant studies evaluating breath-based biomarkers in adult patients with sarcoidosis. Results: 353 papers were screened; 21 met the inclusion criteria and assessed 25 different biomarkers alongside VOCs in exhaled breath gas or condensate. Considerable heterogeneity existed amongst the studies in terms of participant characteristics, sampling and analytical methods. Elevated biomarkers in sarcoidosis included 8-isoprostane, carbon monoxide, neopterin, TGF-β1, TNFα, CysLT and several metallic elements including chromium, silicon and nickel. Three studies exploring VOCs were able to distinguish sarcoidosis from controls. Meta-analysis of four studies assessing alveolar nitric oxide showed no significant difference between sarcoidosis and healthy controls (2.22ppb; 95% CI -0.83, 5.27) however, a high degree of heterogeneity was observed with an I2 of 93.4% (p<0.001). Inconsistent or statistically insignificant results were observed for correlations between several biomarkers and radiological stage, markers of disease activity or treatment. Conclusions: The evidence for using breath biomarkers to diagnose and monitor sarcoidosis remains inconclusive with many studies limited by small sample sizes and lack of standardisation. VOCs have shown promising potential but further research is required to evaluate their prognostic role

A Qualitative Evaluation of IoT-driven eHealth: Knowledge Management, Business Models and Opportunities, Deployment and Evolution

eHealth has a major potential, and its adoption may be considered necessary to achieve increased ambulant and remote medical care, increased quality, reduced personnel needs, and reduced costs potential in healthcare. In this paper the authors try to give a reasonable, qualitative evaluation of IoT-driven eHealth from theoretical and practical viewpoints. They look at associated knowledge management issues and contributions of IoT to eHealth, along with requirements, benefits, limitations and entry barriers. Important attention is given to security and privacy issues. Finally, the conditions for business plans and accompanying value chains are realistically analyzed. The resulting implementation issues and required commitments are also discussed based on a case study analysis. The authors confirm that IoT-driven eHealth can happen and will happen; however, much more needs to be addressed to bring it back in sync with medical and general technological developments in an industrial state-of-the-art perspective and to get recognized and get timely the benefits

Nitroimidazole Action in Entamoeba histolytica: A Central Role for Thioredoxin Reductase

Metronidazole, a 5-nitroimidazole drug, has been the gold standard for several decades in the treatment of infections with microaerophilic protist parasites, including Entamoeba histolytica. For activation, the drug must be chemically reduced, but little is known about the targets of the active metabolites. Applying two-dimensional gel electrophoresis and mass spectrometry, we searched for protein targets in E. histolytica. Of all proteins visualized, only five were found to form adducts with metronidazole metabolites: thioredoxin, thioredoxin reductase, superoxide dismutase, purine nucleoside phosphorylase, and a previously unknown protein. Recombinant thioredoxin reductase carrying the modification displayed reduced enzymatic activity. In treated cells, essential non-protein thiols such as free cysteine were also affected by covalent adduct formation, their levels being drastically reduced. Accordingly, addition of cysteine allowed E. histolytica to survive in the presence of otherwise lethal metronidazole concentrations and reduced protein adduct formation. Finally, we discovered that thioredoxin reductase reduces metronidazole and other nitro compounds, suggesting a new model of metronidazole activation in E. histolytica with a central role for thioredoxin reductase. By reducing metronidazole, the enzyme renders itself and associated thiol-containing proteins vulnerable to adduct formation. Because thioredoxin reductase is a ubiquitous enzyme, similar processes could occur in other eukaryotic or prokaryotic organisms

Lipid Peroxidative Damage on Cisplatin Exposure and Alterations in Antioxidant Defense System in Rat Kidneys: A Possible Protective Effect of Selenium

Cisplatin (Cis-diamminedichloroplatinum II, CP) is an important chemotherapeutic agent, useful in the treatment of several cancers, but with several side effects such as nephrotoxicity. The present study investigated the possible protective effect of selenium (Se) against CP-induced oxidative stress in the rat kidneys. Male Wistar albino rats were injected with a single dose of cisplatin (7 mg CP/kg b.m., i.p.) and selenium (6 mg Se/kg b.m, as Na2SeO3, i.p.), alone or in combination. The obtained results showed that CP increased lipid peroxidation (LPO) and decreased reduced glutathione (GSH) concentrations, suggesting the CP-induced oxidative stress, while Se treatment reversed this change to control values. Acute intoxication of rats with CP was followed by statistically significant decreased activity of antioxidant defense enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and glutathione-S-transferase (GST). Treatment with Se reversed CP-induced alterations of antioxidant defense enzyme activities and significantly prevented the CP-induced kidney damage

A case-control study of GST polymorphisms and arsenic related skin lesions

BACKGROUND: Polymorphisms in GSTT1, GSTM1 and GSTP1 impact detoxification of carcinogens by GSTs and have been reported to increase susceptibility to environmentally related health outcomes. Individual factors in arsenic biotransformation may influence disease susceptibility. GST activity is involved in the metabolism of endogenous and exogenous compounds, including catalyzing the formation of arsenic-GSH conjugates. METHODS: We investigated whether polymorphisms in GSTT1, GSTP1 and GSTM1 were associated with risk of skin lesions and whether these polymorphisms modify the relationship between drinking water arsenic exposure and skin lesions in a case control study of 1200 subjects frequency matched on age and gender in community clinics in Pabna, Bangladesh in 2001–2002. RESULTS AND DISCUSSION: GSTT1 homozygous wildtype status was associated with increased odds of skin lesions compared to the null status (OR1.56 95% CI 1.10–2.19). The GSTP1 GG polymorphism was associated with greater odds of skin lesions compared to GSTP1 AA, (OR 1.86 (95%CI 1.15–3.00). No evidence of effect modification by GSTT1, GSTM1 or GSTP1 polymorphisms on the association between arsenic exposure and skin lesions was detected. CONCLUSION: GSTT1 wildtype and GSTP1 GG are associated with increased risk of skin lesions

NMR-based metabolic characterization of chicken tissues and biofluids: a model for avian research

Introduction Poultry is one of the most consumed meat in the world and its related industry is always looking for ways to improve animal welfare and productivity. It is therefore essential to understand the metabolic response of the chicken to new feed formulas, various supplements, infections and treatments. Objectives As a basis for future research investigating the impact of diet and infections on chicken’s metabolism, we established a high-resolution proton nuclear magnetic resonance (NMR)-based metabolic atlas of the healthy chicken (Gallus gallus). Methods Metabolic extractions were performed prior to 1H-NMR and 2D NMR spectra acquisition on twelve biological matrices: liver, kidney, spleen, plasma, egg yolk and white, colon, caecum, faecal water, ileum, pectoral muscle and brain of 6 chickens. Metabolic profiles were then exhaustively characterized. Results Nearly 80 metabolites were identified. A cross-comparison of these matrices was performed to determine metabolic variations between and within each section and highlighted that only eight core metabolites were systematically found in every matrice. Conclusion This work constitutes a database for future NMR-based metabolomic investigations in relation to avian production and health