Oxidative Stress in a Wild Population of the Freshwater Fish Hyphessobrycon Luetkenii Chronically Exposed to a Copper Mining Area: New Insights into Copper Toxicology.

In this study, we examine markers of oxidative stress in the tetra Hyphessobrycon luetkenii collected from two locations in the copper contaminated João Dias creek (southern Brazil). Also, specimens were translocated from a clean reference section of the creek to a polluted stretch and vice-versa. Fish were held at in submerged cages for 96 h and then sacrificed. Nuclear abnormalities in erythrocytes and total antioxidant capacity, lipid peroxidation and protein carbonylation in gills, brain, liver and muscle displayed similar trends in both groups. Lipid peroxidation increased in all tissues of individuals translocated to the polluted site but only in liver and muscle of those translocated to the reference site. Increased protein carbonylation was also observed in gills of individuals translocated to the reference location. These results suggest similar oxidative stress among fish from the reference and polluted locations and that long-term metals exposure may require adaptations toward oxidative stress responses.

Metal Accumulation and Ion Regulation in the Fish Hyphessobrycon luetkenii Living in a Site Chronically Contaminated by Copper: Insights from Translocation Experiments.

Fish living in the João Dias creek (southern Brazil) have to deal with trace-metal contamination in the long-term basis, as this aquatic environment has been historically impacted by copper mining activities. In order to survive in this harsh environment, the local biota had to develop adaptations related to pollution tolerance. The aim of this study was to test if biochemical mechanisms related to osmoregulation were among these adaptations, using translocation experiments. Water ionic and trace-metal compositions were measured in a nonmetal impacted site (NMIS) and in a metal impacted site (MIS) of this creek. Also, whole-body metal accumulation, ion concentration and branchial enzyme activity (Na,K-ATPase and carbonic anhydrase) were evaluated in Hyphessobrycon luetkenii. In both NMIS and MIS, fish were collected and immediately stored, kept caged or translocated from sites. The result shows that waterborne Cu was 3.4-fold higher at the MIS. Accordingly, animals that had contact with this site showed elevated whole-body Cu levels. Moreover, both translocated groups showed elevated Na,K-ATPase activity. Additionally, fish translocated from the NMIS to the MIS showed lower carbonic anhydrase activity. These findings indicate that H. luetkenii chronically or acutely exposed to naturally elevated waterborne Cu showed a rapid Cu bioaccumulation but was unable to readily excrete it. Moreover, classic Cu osmoregulatory toxicity related to Na,K-ATPase inhibition was not observed. Conversely, impacts in ammonia excretion related to carbonic anhydrase inhibition may have occurred.

Medical Assistance in Dying in patients with advanced cancer and their caregivers: a mixed methods longitudinal study protocol.

BACKGROUND: The legal criteria for medical assistance in dying (MAiD) for adults with a grievous and irremediable medical condition were established in Canada in 2016. There has been concern that potentially reversible states of depression or demoralization may contribute to the desire for death (DD) and requests for MAiD. However, little is known about the emergence of the DD in patients, its impact on caregivers, and to what extent supportive care interventions affect the DD and requests for MAiD. The present observational study is designed to determine the prevalence, predictors, and experience of the DD, requests for MAiD and MAiD completion in patients with advanced or metastatic cancer and the impact of these outcomes on their primary caregivers. METHODS: A cohort of patients with advanced or metastatic solid tumour cancers and their primary caregivers will be recruited from a large tertiary cancer centre in Toronto, Ontario, Canada, to a longitudinal, mixed methods study. Participants will be assessed at baseline for diagnostic information, sociodemographic characteristics, medical history, quality of life, physical and psychological distress, attitudes about the DD and MAiD, communication with physicians, advance care planning, and use of psychosocial and palliative care interventions. Measures will subsequently be completed every six months and at the time of MAiD requests. Quantitative assessments will be supplemented by qualitative interviews in a subset of participants, selected using quota sampling methods. DISCUSSION: This study has the potential to add importantly to our understanding of the prevalence and determinants of the DD, MAiD requests and completions in patients with advanced or metastatic cancer and of the experience of both patients and caregivers in this circumstance. The findings from this study may also assist healthcare providers in their conversations about MAiD and the DD with patients and caregivers, inform healthcare providers to ensure appropriate access to MAiD, and guide modifications being considered to broaden MAiD legislation and policy.

Influence of environmentally relevant concentrations of Zn, Cd and Ni and their binary mixtures on metal uptake, bioaccumulation and development in larvae of the purple sea urchin Strongylocentrotus purpuratus.

Metal accumulation, disturbance of Ca2+ homeostasis, and occurrence of abnormalities are well-established consequences of single metal exposure during early development stages of sea urchins. However, the effects caused by low concentrations of metals and metal mixtures need to be better understood in marine invertebrates. Therefore, the present study investigated the effects of environmentally relevant concentrations of Zn (9 µg/L), Cd (30 µg/L) and Ni (5 µg/L) in single and binary exposures (Zn + Cd, Cd + Ni and Ni + Zn) to the early life stages of the purple sea urchin Strongylocentrotus purpuratus. Endpoints checked in all treatments after 48-h exposure were unidirectional metal influx rates, bioaccumulation, and Ca2+ influx rates. Additionally, the presence of abnormal larvae and developmental delay was evaluated at 24 h, 48 h and 72 h of exposure. Unidirectional influx rates of all three metals were significantly higher than control background rates in all single exposures and binary mixtures, and were generally not different between them. Net accumulation (body burden) of both Zn and Cd increased significantly as a result of their respective single exposures, while Ni accumulation decreased considerably. When Zn or Cd were presented in binary exposures with other metals, the net accumulations of Zn or Cd were reduced relative to single exposures to these metals, whereas this did not occur for Ni accumulation. Thus, bioaccumulation proved to be a better metric than influx rate measurements to analyze metal competition at a whole organism level at these low metal concentrations. Short-term Ca2+ influx also did not appear to be a sensitive metric, as the measured rates did not vary among all single and binary exposures, with the exception of a lower rate in Ni + Zn binary exposure. A critical aspect observed was the relationship between bioaccumulation versus influx measurements, which proved positive for Cd, but negative for Zn and Ni, demonstrating possible capacities for both Zn and Ni regulation by sea urchin larvae. Increases in larval abnormalities relative to controls occurred only after binary mixtures, starting at 48 h exposure and maintained until 72 h. However, delay of the sea urchin development by the presence of gastrula stage at 72 h exposure occurred in Zn and Ni single exposures and all metal mixtures, with very high abnormal development when Ni was present.

High prevalence of persistent emotional distress in desmoid tumor.

OBJECTIVE: Clinical experience suggests a high prevalence of emotional distress in patients with desmoid tumor (DT). We examine longitudinal Distress Assessment and Response Tool (DART) scores to estimate prevalence and persistence of distress, and compare cross-sectional data between DT and malignant sarcoma cohorts, to identify predictors of distress. METHODS: Patients with DT completed DART at: T1-diagnosis, T2-during, T3-<6 months, and T4-≥6 months, post-treatment. DART includes patient-reported outcome measures of physical symptoms (ESAS-r), depression (PHQ-9), anxiety (GAD-7), and social difficulties (SDI-21). Descriptive prevalence and persistence of anxiety, depression, and wellbeing are reported, and mixed model regression analyses determine predictors of distress. RESULTS: Between 2012 and 2018, a total of 152 DART screens from 94 patients with DT were completed (T1: n = 44, T2: n = 31, T3: n = 22, T4: n = 55). Patients had a mean age 40 years, 78% were female and DT locations were abdominal wall (48%), extremity (30%), and mesentery (22%). Moderate to severe ESAS-r scores (≥4) persisted at T4 for anxiety (20%), depression (13%), and poor wellbeing (31%). Compared to 402 patients with malignant sarcoma, patients with abdominal wall sited DT reported severe PHQ-9 and GAD-7 scores twice as frequently. Abdominal wall location, female sex, history of mood problems, and psychosocial concerns were significant predictors of anxiety, depression, and poor wellbeing in DT. CONCLUSIONS: Adults with DT experience persistently high emotional distress compared to patients with malignant sarcoma. Women with abdominal wall DT, prior mood, and current psychosocial concerns need early attention within multidisciplinary treatment settings to reduce persistent distress.

Nonesterified Fatty Acids and Depression in Cancer Patients and Caregivers.

BACKGROUND: Nonesterified fatty acids (NEFAs) are known to have inflammatory effects. The inflammatory hypothesis of depression suggests that omega-3 (ω-3) and omega-6 (ω-6) fatty acids might be negatively and positively correlated with depression, respectively. OBJECTIVE: An exploratory study was conducted to determine the association between dietary free fatty acids and depressive symptoms in cancer patients and caregivers. METHODS: Associations between depression and the NEFA pool were investigated in 56 cancer patients and 23 caregivers using a combination of nonparametric tests and regularized regression. Plasma NEFAs were measured using thin layer and gas chromatography with flame ionization detection. Depression was characterized both as a continuous severity score using the GRID-Hamilton Depression Rating Scale (GRID Ham-D), and as a categorical diagnosis of major depression by structured clinical interview. RESULTS: Initial hypotheses regarding the relation between depression and omega-3 or omega-6 fatty acids were not well supported. However, elaidic acid, a trans-unsaturated fatty acid found in hydrogenated vegetable oils, was found to be negatively correlated with continuous depression scores in cancer patients. No significant associations were found in caregivers. CONCLUSIONS: An unexpected negative association between elaidic acid and depression was identified, supporting recent literature on the role of G protein-coupled receptors in depression. Further research is needed to confirm this result and to evaluate the potential role of G protein agonists as therapeutic agents for depression in cancer patients.

Effects of sublethal Cd, Zn, and mixture exposures on antioxidant defense and oxidative stress parameters in early life stages of the purple sea urchin Strongylocentrotus purpuratus.

Oxidative stress parameters were evaluated during the first 72 h of embryonic development of purple sea urchin Strongylocentrotus purpuratus continuously exposed to control conditions, to cadmium alone (Cd, 30 µg/L), to zinc alone (Zn, 9 µg/L) or to a Cd (28 µg/L) plus Zn (9 µg/L) mixture. These sublethal concentrations represent ∼ 10% of the acute EC50. Bioaccumulation, antioxidant capacity against peroxyl radicals (ACAP), total glutathione (GSH) level, glutathione-S-transferase (GST), glucose-6-phosphate dehydrogenase (G6PDH) and superoxide dismutase (SOD) activity, and lipid peroxidation (LPO) were analyzed at 24 h (blastula), 48 h (gastrula), and 72 h (pluteus) stages of development. Zinc (an essential metal) was well-regulated, whereas Cd (non-essential) bioaccumulated and whole-body [Cd] increased from blastula to pluteus stage in sea urchin larvae. In controls, ACAP progressively declined from 24 h to 72 h, while LPO reciprocally increased, but other parameters did not change. Cd alone was more potent than Zn alone as a pro-oxidant, with the major effects being decreases in SOD activity and parallel increases in LPO throughout development; GST activity also increased at 24 h. Zn alone caused only biphasic disturbances of ACAP. In all cases, the simultaneous presence of the other metal prevented the effects, and there was no instance where the oxidative stress response in the presence of the Cd/Zn mixture was greater than in the presence of either Cd or Zn alone. Therefore the sublethal effects of joint exposures were always less than additive or even protective, in agreement with classical toxicity data. Furthermore, our results indicate that SOD and Zn can play important roles in protecting sea urchin embryos against Cd-induced lipid peroxidation.

Testing biomarker feasibility: a case study of Laeonereis culveri (Nereididae, Annelida) exposed to sewage contamination in a subtropical estuary.

The feasibility of biomarkers to accurately detect pollution in estuaries and coastal areas appears to be overestimated in the scientific literature, and is likely stemming from a bias towards publishing only positive results. Herein, we test the applicability of antioxidant capacity and lipid peroxidation to detect potential in situ sewage impacts on a subtropical estuary. We experimentally assessed variation in malondialdehyde (MDA, an indicator of lipid peroxidation) and total antioxidant capacity against peroxyl radicals (ACAP) through transplantations of the worm Laeonereis culveri from control to sewage-polluted areas. Variations in biomarkers were more related to natural environmental variability and small-scale heterogeneity among areas than to experimental exposure to sewage. Use of oxidative stress biomarkers is promising but further experimental work under real-life conditions is necessary to further validate and establish their accuracy and feasibility for practical purposes.

Effects of life-time exposure to waterborne copper on the somatotropic axis of the viviparous fish Poecilia vivipara.

Reduced fish growth following chronic exposure to dissolved copper (Cu) is well reported in the literature. Nevertheless, information on the mechanism(s) involved in this process is scarce. Therefore, we evaluated growth, gene expression and concentrations of proteins related to growth regulation in the viviparous guppy Poecilia vivipara chronically exposed to dissolved Cu. Newborn (<24 h after birth) fish were kept under control conditions or exposed to environmentally relevant concentrations of Cu (5 and 9 µg/L) in salt water (24 ppt) for 345 days. After exposure, fish growth was evaluated based on body weight and length. Also, growth hormone (gh) mRNA expression was evaluated in brain, while growth hormone receptor 1 (ghr1) and 2 (ghr2) mRNA expressions were analyzed in brain, skeletal muscle and liver. In turn, insulin-like growth factor 1 (igf1) and 2 (igf2) mRNA expressions were evaluated in skeletal muscle and liver. Additionally, Gh concentration was assessed in brain, while Ghr concentration was evaluated in skeletal muscle and liver. Exposure to 9 µg/L Cu reduced fish body weigh and length. Metal exposure affected mRNA expression only in skeletal muscle. Reduced ghr2 mRNA expression was observed in guppies exposed to 5 and 9 µg/L Cu. Additionally, reduced igf1 and igf2 mRNA expressions were observed in guppies exposed to 9 µg/L Cu. However, no significant change in Ghr concentration was observed. The reduced ghr2 mRNA expression suggests that chronic Cu exposure induced an insensitivity of the skeletal muscle to Gh, thus resulting in reduced igf1 and igf2 mRNA expression which lead to reduced fish growth. These findings indicate that chronic exposure to dissolved Cu disrupts the somatotropic axis regulation, thus helping to elucidate the mechanism underlying the Cu-dependent inhibition of growth observed in the viviparous fish P. vivipara.