Investigation on the mancozeb toxicity in adult zebrafish (Danio rerio).

Agriculture has gained increasing importance in response to the continuous growth of the world population and constant need for food. To avoid production losses, farmers commonly use pesticides. Mancozeb is a fungicide used in agriculture as this compound is effective in combating fungi that harm crops. However, this fungicide may also produce damage to non-target organisms present in soil and water. Therefore, this study aimed to investigate the influence of exposure to mancozeb on survival rate, locomotor activity, behavior, and oxidative status utilizing adult zebrafish (Danio rerio) as a model following exposure to environmentally relevant concentrations of this pesticide. The experimental groups were negative control, positive control, and mancozeb (0.3; 1.02; 3.47; 11.8 or 40 µg/L). Zebrafish were exposed to the respective treatments for 96 hr. Exposure to mancozeb did not markedly alter survival rate and oxidative status of Danio rerio. At a concentration of 11.8 µg/L, the fungicide initiated changes in locomotor pattern of the animals. The results obtained suggest that the presence of mancozeb in the environment might produce locomotor alterations in adult zebrafish, which subsequently disrupt the animals' innate defense mechanisms. In nature, this effect attributed to mancozeb on non-target organisms might result in adverse population impacts and ecological imbalance.

Resting-State Networks of Awake Adolescent and Adult Squirrel Monkeys Using Ultra-High Field (9.4†T) Functional Magnetic Resonance Imaging.

Resting-state networks (RSNs) are increasingly forwarded as candidate biomarkers for neuropsychiatric disorders. Such biomarkers may provide objective measures for evaluating novel therapeutic interventions in nonhuman primates often used in translational neuroimaging research. This study aimed to characterize the RSNs of awake squirrel monkeys and compare the characteristics of those networks in adolescent and adult subjects. Twenty-seven squirrel monkeys [n = 12 adolescents (6 male/6 female) ∼2.5 years and n = 15 adults (7 male/8 female) ∼9.5 years] were gradually acclimated to awake scanning procedures; whole-brain fMRI images were acquired with a 9.4 T scanner. Group-level independent component analysis (ICA; 30 ICs) with dual regression was used to detect and compare RSNs. Twenty ICs corresponding to physiologically meaningful networks representing a range of neural functions, including motor, sensory, reward, and cognitive processes, were identified in both adolescent and adult monkeys. The reproducibility of these RSNs was evaluated across several ICA model orders. Adults showed a trend for greater connectivity compared with adolescent subjects in two of the networks of interest: (1) in the right occipital region with the OFC network and (2) in the left temporal cortex, bilateral occipital cortex, and cerebellum with the posterior cingulate network. However, when age was entered into the above model, this trend for significance was lost. These results demonstrate that squirrel monkey RSNs are stable and consistent with RSNs previously identified in humans, rodents, and other nonhuman primate species. These data also identify several networks in adolescence that are conserved and others that may change into adulthood.

Brain and cortisol responses to smoking cues are linked in tobacco-smoking individuals.

Cues associated with smoking can induce relapse, which is likely driven by cue-induced neurobiological and physiological mechanisms. For instance, greater relapse vulnerability is associated with increases in cue-induced insula activation and heightened cortisol concentrations. Determining if there is a link between such cue-induced responses is critical given the need for biomarkers that can be easily measured in clinical settings and used to drive targeted treatment. Further, comprehensively characterising biological reactions to cues promises to aid in the development of therapies that address this specific relapse risk factor. To determine whether brain and cortisol responses to smoking cues are linked, this study recruited 27 nicotine-dependent tobacco-smoking individuals and acquired whole-brain functional activation during a cue reactivity task; salivary cortisol was measured before and after scanning. The results showed that increases in blood-oxygen-level-dependent activation in the right anterior insula and right dorsolateral prefrontal cortex (DLPFC) when viewing smoking versus neutral cues were positively correlated with a post-scan rise in salivary cortisol concentrations. These brain regions have been previously implicated in substance use disorders for their role in salience, interoception and executive processes. These findings show that those who have a rise in cortisol following smoking cue exposure also have a related rise in cue-induced brain reactivity, in brain regions previously linked with heightened relapse vulnerability. This is clinically relevant as measuring cue-induced cortisol responses is a more accessible proxy for assessing the engagement of cue-induced neurobiological processes associated with the maintenance of nicotine dependence.

Epidemiological profile, temporal analysis, and future projections of suicide cases in rural cities in the extreme south of Brazil.

The present study aimed to verify the time series (2000-2017) of death rates by suicide and its associated factors in 4 municipalities in the extreme south of Brazil. Data were obtained through the analysis of medical reports and police report bulletins at the Instituto Médico Legal, in the city of Rio Grande. The suicide rate in the Rio Grande region varied from 4 to 11 suicides per 100,000 inhabitants and it is estimated that by 2030 this rate could reach 16.5 suicides per 100,000 inhabitants. The rural cities of Santa Vitória do Palmar and Chuí present even higher suicide averages when compared to Rio Grande, the most populous city of the four. The death rate from suicide increased gradually in the period analyzed, with the prevalence rising among the youngest and the elderly population. A more comprehensive understanding of the influences of environmental issues on suicidal decisions constitutes an important action that needs to be taken, both because of regional vulnerabilities and the target population identified. Evidence indicates that knowledge of factors affecting individuals residing in this Brazilian region where increased suicide rates are recorded needs to be recognized as a priority.

Beneficial effects of mate-herb, Ilex paraguariensis St. Hil. against potassium dichromate-induced oxidative stress and nephrotoxicity.

Chimarrão is a typical beverage made from the infusion of dried and ground leaves and stems of Ilex paraguariensis (popularly known as Yerba mate or mate herb) which is widely consumed in parts of South America. The aim of this study was to examine the effects of the chimarrão against nephrotoxicity and oxidative stress induced by the potassium dichromate (PD) salt in male Wistar rats. The experiment lasted 17 days, and in the first 15 days animals ingested a chimarrão infusion or control drinking water and then submitted to an intraperitoneal injection (15 mg/kg) of PD (or saline solution) and euthanized after 48 hr at which time animals still received infusion or drinking water. Blood plasma and 24 hr-urine samples were collected to measure creatinine levels as an estimate of glomerular filtration rate (GFR). Concomitantly oxidative stress was determined in the kidneys as evidenced by levels of carbonyl groups, malondialdehyde (MDA) and antioxidant capacity against peroxyl radicals. Potassium dichromate induced oxidative stress in the kidneys and reduced GFR. Treatment with chimarrão during the 15 days prior to PD injection reduced PD salt-mediated oxidative stress. Further, treatment with post-injection chimarrão to PD-administered rats improved the GFR. Our findings support that the use of the chimarrão beverage may be considered as an important nephroprotective substance.

Oxidative damage in the Vesper mouse (Calomys laucha) exposed to a simulated oil spill-a multi-organ study.

Small wild mammals have been used to measure the damage caused by exposure to oil-contaminated soil, including deer mice. However, the study of toxic effects of crude oil using oxidative damage biomarkers in the wild rodent Calomys laucha (Vesper mouse) is absent. This investigation aimed to evaluate the effects of acute exposure to contaminated soil with different concentrations of crude oil (0, 1, 2, 4 and 8% w/w), simulating an accidental spill, using oxidative stress biomarkers in the liver, kidneys, lungs, testes, paw muscle, and lymphocytes of C. laucha. Animals exposed to the contaminated soil showed increases in lipid peroxidation and protein carbonylation at the highest exposure concentrations in most organ homogenates analyzed and also in blood cells, but responses to total antioxidant capacity were tissue-dependent. These results showed that acute exposure to oil-contaminated soil caused oxidative damage in C. laucha and indicate these small mammals may be susceptible to suffer the impacts of such contamination in its occurrence region, threatening the species' survival.

Oxycodone self-administration and reinstatement in male and female squirrel monkeys: Effects of alternative reinforcer availability.

The use of non-drug alternative reinforcers has long been utilized as a component of therapeutic interventions for the management of substance use disorder; however, the conditions under which alternative reinforcers are most effective are not well characterized. This study evaluated the impact of varying the magnitude of an alternative reinforcer on oxycodone self-administration and reinstatement in male and female squirrel monkeys. Subjects (n=4/sex) were trained under concurrent second-order schedules of reinforcement for intravenous oxycodone (0.001-0.1mg/kg/inj) on one lever, and sweetened condensed milk (5, 10, 20, 30% in water) on another. Oxycodone-primed reinstatement was evaluated by administering 0.32mg/kg oxycodone prior to sessions in which saline was available on the drug-paired lever. During oxycodone self-administration sessions, milk availability decreased oxycodone self-administration and preference in a concentration-dependent manner; low milk concentrations were more effective at decreasing oxycodone’s reinforcing potency in males. During reinstatement tests, milk significantly attenuated oxycodone-primed responding in both males and females; low milk concentrations were more effective at decreasing the priming effects of oxycodone in females. That alternative reinforcers differentially impacted self-administration and reinstatement in a sex-dependent manner suggests that treatment strategies that utilize alternative reinforcers may be more effective in males or females depending on when they are implemented.

Resting state networks of awake adolescent and adult squirrel monkeys using ultra-high field (9.4T) functional magnetic resonance imaging.

Resting state networks (RSNs) are increasingly forwarded as candidate biomarkers for neuropsychiatric disorders. Such biomarkers may provide objective measures for evaluating novel therapeutic interventions in nonhuman primates often used in translational neuroimaging research. This study aimed to characterize the RSNs of awake squirrel monkeys and compare the characteristics of those networks in adolescent and adult subjects. Twenty-seven squirrel monkeys ( n =12 adolescents [6 male/6 female] ∼2.5 years and n =15 adults [7 male/8 female] ∼9.5 years) were gradually acclimated to awake scanning procedures; whole-brain fMRI images were acquired with a 9.4 Tesla scanner. Group level independent component (IC) analysis (30 ICs) with dual regression was used to detect and compare RSNs. Twenty ICs corresponding to physiologically meaningful networks representing a range of neural functions, including motor, sensory, reward (e.g., basal ganglia), and cognitive processes were identified in both adolescent and adult monkeys. Significant age-related differences between the adult and adolescent subjects (adult > adolescent) were found in two networks of interest: (1) the right upper occipital region with an OFC IC and (2) the left temporal cortex, bilateral visual areas, and cerebellum with the cingulate IC. These results demonstrate that squirrel monkey RSNs are stable and consistent with RSNs previously identified in humans, rodents, and other nonhuman primate species. These data also identify several networks in adolescence that are conserved and others that may change into adulthood. Significance Statement: Functional magnetic resonance imaging procedures have revealed important information about how the brain is modified by experimental manipulations, disease states, and aging throughout the lifespan. Preclinical neuroimaging, especially in nonhuman primates, has become a frequently used means to answer targeted questions related to brain resting-state functional connectivity. The present study characterized resting state networks (RSNs) in adult and adolescent squirrel monkeys; twenty RSNs corresponding to networks representing a range of neural functions were identified. The RSNs identified here can be utilized in future studies examining the effects of experimental manipulations on brain connectivity in squirrel monkeys. These data also may be useful for comparative analysis with other primate species to provide an evolutionary perspective for understanding brain function and organization.

2030 Agenda: discussion on Brazilian priorities facing air pollution and climate change challenges.

The advance of human activities in a disorderly way has accelerated in recent decades, intensifying the environmental impacts directly linked to these practices. The atmosphere, essential for the maintenance of life, is increasingly saturated with pollutants, offering risks to practically all the inhabitants of the planet, a process that, in addition to causing illness and early mortality, is related to serious financial losses (including in the production of goods), dangerous temperature increase and severe natural disasters. Although this perception is not recent, the global initiative to control the different mechanisms that trigger the commitment of biodiversity and irreversible climate changes arising from pollution is still very incipient, given that global initiatives on the subject emerged just over 50 years ago. Brazil is a territory that centralizes many of these discussions, as it still faces both political and economic obstacles in achieving a sustainable growth model as it was agreed through the United Nations 2030 Agenda. Even though there is little time left for the completion of these goals, much remains to be done, and despite the fulfillment of this deadline, the works will certainly need to be extended for much longer until an effective reorientation of consciousness occurs. Scientific researches and discussions are fundamental tools to the understanding of issues still little explored in this field.

Better understanding the behavior of air pollutants at shutdown times - results of a short full lockdown.

Numerous studies have evaluated the effects of lockdowns during the COVID-19 pandemic, but most of them have concerned large cities and regions. This study aimed to evaluate the dynamics of air pollutants during and after the implementation of a short lockdown in the medium-sized city of Pelotas, Brazil, using hourly measurements of pollutants. The evaluation period included in this study was between August 9th and 12th, 2020. A machine learning model was used to investigate the expected behavior against what was observed during the study period. All pollutants presented a gradual reduction until a dynamic plateau established 48 hours after the start of the lockdown: NO2 (↓4%), O3 (↓34%), SO2 (↓24%), CO (↓48%), PM10 (↓82%) and PM2.5 (↓82%). At the end of the restriction measures, the PM10 and PM2.5 levels continued to decline beyond expectations. Our findings show that these measures can positively affect the air quality in medium-sized cities.

"Non-metastatic, Castration-resistant Prostate Cancer: Diagnostic and Treatment Recommendations by an Expert Panel from Brazil".

INTRODUCTION: Non-metastatic, castration-resistant prostate cancer (nmCRPC) is an important clinical stage of prostate cancer, prior to morbidity and mortality from clinical metastases. In particular, the introduction of novel androgen-receptor signaling inhibitors (ARSi) has changed the therapeutic landscape in nmCRPC. Given recent developments in this field, we update our recommendations for the management of nmCRPC. METHODS: A panel of 51 invited medical oncologists and urologists convened in May of 2021 with the aim of discussing and providing recommendations regarding the most relevant issues concerning staging methods, antineoplastic therapy, osteoclast-targeted therapy, and patient follow-up in nmCRPC. Panel members considered the available evidence and their practical experience to address the 73 multiple-choice questions presented. RESULTS: Key recommendations and findings include the reliance on prostate-specific antigen doubling time for treatment decisions, the absence of a clear preference between conventional and novel (i.e., positron-emission tomography-based) imaging techniques, the increasing role of ARSis in various settings, the general view that ARSis have similar efficacy. Panelists highlighted the slight preference for darolutamide, when safety is of greater concern, and a continued need to develop high-level evidence to guide the intensity of follow-up in this subset of prostate cancer. DISCUSSION: Despite the limitations associated with a consensus panel, the topics addressed are relevant in current practice, and the recommendations can help practicing clinicians to provide state-of-the-art treatment to patients with nmCRPC in Brazil and other countries with similar healthcare settings.

Gestational and Neonatal Outcomes in Cities in the Largest Coal Mining Region in Brazil.

Brazil has one of the largest mineral coal reserves in the world. More than 40% of this ore is in the Candiota Mine, in the extreme south of Brazil, which was previously identified as a hotspot of environmental pollution. In addition, an important part of Brazil's population suffers from socioeconomic vulnerability. Since there is no information on unfavorable gestational and neonatal outcomes associated with these problems, we conducted a cross-sectional study with 1950 mother-child binomials, aiming to evaluate the association between these outcomes and air pollution as well as socioeconomic, demographic and health variables in seven cities in the region. Of the total births, 11.6% were preterm and 9.5% of neonates had low birth weight (<2500 g). These conditions were also associated with skin color, previous abortions, birth type and prenatal care, as well as exposure to higher levels of coarse particulate matter (PM10) during the first trimester of pregnancy. Regarding air pollutants, although the daily limits for PM10 were exceeded on less than 5% of days, the annual average overtook the values proposed by WHO. Thus, we concluded that prematurity and low birth weight in this region are related to air pollution, and to socioeconomic variables and health care.

Fentanyl-induced changes in brain activity in awake nonhuman primates at 9.4 Tesla.

Functional magnetic resonance imaging (fMRI) has been used to study the influence of opioids on neural circuitry implicated in opioid use disorder, such as the cortico-striatal-thalamo-cortical (CSTC) circuit. Given the increase in fentanyl-related deaths, this study was conducted to characterize the effects of fentanyl on patterns of brain activation in awake nonhuman primates. Four squirrel monkeys were acclimated to awake scanning procedures conducted at 9.4 Tesla. Subsequently, test sessions were conducted in which a dose of fentanyl that reliably maintains intravenous (IV) self-administration behavior in monkeys, 1 µg/kg, was administered and the effects on patterns of brain activity were assessed using: (1) a pharmacological regressor to elucidate fentanyl-induced patterns of neural activity, and (2) seed-based approaches targeting bilateral anterior cingulate, thalamus, or nucleus accumbens (NAc) to determine alterations in CSTC functional connectivity. Results showed a functional inhibition of BOLD signal in brain regions that mediate behavioral effects of opioid agonists, such as cingulate cortex, striatum and midbrain. Functional connectivity between each of the seed regions and areas involved in motoric, sensory and cognition-related behavior generally decreased. In contrast, NAc functional connectivity with other striatal regions increased. These results indicate that fentanyl produces changes within CSTC circuitry that may reflect key features of opioid use disorder (e.g. persistent drug-taking/seeking) and thereby contribute to long-term disruptions in behavior and addiction. They also indicate that fMRI in alert nonhuman primates can detect drug-induced changes in neural circuits and, in turn, may be useful for investigating the effectiveness of medications to reverse drug-induced dysregulation.

Enhancement of Opioid Antinociception by Nicotinic Ligands.

Nicotine has previously been shown to augment the antinociceptive effects of µ-opioid agonists in squirrel monkeys without producing a concomitant increase in behavioral disruption. The present studies were conducted to extend these findings by determining the ability of the nicotinic acetylcholine receptor (nAChR) agonist epibatidine and partial α4ß2 nAChR agonist varenicline to selectively augment the antinociceptive effects of the µ-opioid receptor (MOR) full agonist fentanyl, the MOR partial agonist nalbuphine, and the κ-opioid receptor (KOR) agonist U69,593 in male squirrel monkeys. Results indicate that both nAChR ligands selectively increased the antinociceptive effects of nalbuphine and that epibatidine increased the antinociceptive effects of U69,593 without altering effects on operant behavior. However, neither epibatidine nor varenicline enhanced the antinociceptive effects of fentanyl, perhaps due to its high efficacy. The enhancement of nalbuphine's antinociceptive effects by epibatidine, but not varenicline, could be antagonized by either mecamylamine or dihydro-ß-erythroidine, consistent with α4ß2 mediation of epibatidine's effects but suggesting the involvement of non-nAChR mechanisms in the effects of varenicline. The present results support previous findings showing that an nAChR agonist can serve as an adjuvant for MOR antinociception and, based on results with U69,593, further indicate that the adjuvant effects of nAChR drugs may also apply to antinociception produced by KOR. Our findings support the further evaluation of nAChR agonists as adjuvants of opioid pharmacotherapy for pain management and point out the need for further investigation into the mechanisms by which they produce opioid-adjuvant effects. SIGNIFICANCE STATEMENT: Nicotine has been shown to augment the antinociceptive effects of µ-opioid receptor analgesics without exacerbating their effects on operant performance. The present study demonstrates that the nicotinic acetylcholine receptor (nAChR) agonist epibatidine and partial α4ß2 nAChR agonist varenicline can also augment the antinociceptive effects of nalbuphine, as well as those of a κ-opioid receptor agonist, without concomitantly exacerbating their behaviorally disruptive effects. These findings support the view that nAChR agonists and partial agonists may have potential as adjuvant therapies for opioid-based analgesics.

Reinforcing effects of synthetic cathinones in rhesus monkeys: Dose-response and behavioral economic analyses.

The abuse of synthetic cathinones ("bath salts") with psychomotor stimulant and/or entactogenic properties emerged as a public health concern when they were introduced as "legal" alternatives to drugs of abuse such as cocaine or MDMA. In this study, experiments were conducted in nonhuman primates to examine how differences in transporter selectivity might impact the reinforcing effects of synthetic cathinones. Rhesus monkeys (N = 5) were trained to respond for intravenous injections under a fixed-ratio (FR) 30, timeout 60-s schedule of reinforcement. The reinforcing effects of selected cathinones (e.g., MDPV, αPVP, MCAT, and methylone) with a range of pharmacological effects at dopamine and serotonin transporters were compared to cocaine and MDMA using dose-response analysis under a simple FR schedule and behavioral economic procedures that generated demand curves for two doses of each drug. Results show that one or more doses of all drugs were readily self-administered in each subject and, excepting MDMA (21 injections/session), peak levels of self-administration were similar across drugs (between 30 and 40 injections/session). Demand elasticity for the peak and the peak + 1/2-log dose of each drug did not significantly differ, and when data for the two doses were averaged for each drug, the following rank-order of reinforcing strength emerged: cocaine > MCAT = MDPV = methylone > αPVP = MDMA. These results indicate that the reinforcing strength of synthetic cathinones are not related to their selectivity in binding dopamine or serotonin transporter sites.

The discriminative stimulus effects of epibatidine in C57BL/6J mice.

The α4ß2* nicotinic acetylcholine receptor (nAChR) subtypes are targeted for the development of smoking cessation aids, and the use of drug discrimination in mice provides a robust screening tool for the identification of drugs acting through nAChRs. Here, we established that the α4ß2* nAChR agonist epibatidine can function as a discriminative stimulus in mice. Male C57BL/6J mice discriminated epibatidine (0.0032 mg/kg, subcutaneously) and were tested with agonists varying in selectivity and efficacy for α4ß2* nAChRs. The discriminative stimulus effects of epibatidine were characterized with the nonselective, noncompetitive nicotinic antagonist mecamylamine, with the selective ß2-substype-containing nAChR antagonist dihydro-ß-erythroidine hydrobromide (DHßE), and the α7 antagonist methyllycaconitine (MLA). Nicotine (0.32-1.0 mg/kg, subcutaneously), the partial nAChR agonist cytisine (1.0-5.6 mg/kg, subcutaneously), and the α7 nAChR agonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide (10-56 mg/kg, intraperitoneally) produced no more than 33% epibatidine-appropriate responding. The partial α4ß2* nAChR agonists varenicline and 2'-fluoro-3'-(4-nitro-phenyl)deschloroepibatidine produced 61 and 69% epibatidine-appropriate responding, respectively. DHßE and mecamylamine, but not MLA, significantly antagonized the discriminative stimulus effects of epibatidine. These results show that epibatidine may be trained as a discriminative stimulus in mice and has utility in elucidating the in-vivo pharmacology of α4ß2* nAChR ligands.