Gestational paracetamol exposure induces core behaviors of neurodevelopmental disorders in infant rats and modifies response to a cannabinoid agonist in females.

Paracetamol (PAR) is an over-the-counter analgesic/antipyretic used during pregnancy worldwide. Epidemiological studies have been associating gestational PAR exposure with neurobehavioral alterations in the progeny resembling autism spectrum disorders and attention-deficit hyperactivity disorder symptoms. The endocannabinoid (eCB) dysfunction was previously hypothesized as one of the modes of action by which PAR may harm the developing nervous system. We aimed to evaluate possible effects of gestational exposure to PAR on male and female rat's offspring behavior and if an acute injection of WIN 55,212-2 (WIN, 0.3 mg/kg), a non-specific cannabinoid agonist, prior to behavioral tests, would induce different effects in PAR exposed and non-exposed animals. Pregnant Wistar rats were gavaged with PAR (350 mg/kg/day) or water from gestational day 6 until delivery. Nest-seeking, open field, apomorphine-induced stereotypy, marble burying and three-chamber tests were conducted in 10-, 24-, 25- or 30-days-old rats, respectively. PAR exposure resulted in increased apomorphine-induced stereotyped behavior and time spent in the central area of the open field in exposed female pups. Additionally, it induced hyperactivity in the open field and increased marble burying behavior in both male and female pups. WIN injection modified the behavioral response only in the nest seeking test, and opposite effects were observed in control and PAR-exposed neonate females. Reported alterations are relevant for the neurodevelopmental disorders that have been associated with maternal PAR exposure and suggest that eCB dysfunction may play a role in the action by which PAR may harm the developing brain.

Blood tests and use of nutritional supplements in a cohort of Brazilian children with trisomy 21.

OBJECTIVE: To describe the use of nutritional supplements and blood status (hemogram, lipidogram, hepatic function, inflammatory markers, minerals, and homocysteine) in a sample of Brazilian T21 children with private health support before their first consultation with a T21 expert. METHOD: This descriptive cross-sectional study enrolled 102 participants. Brazilian families with a T21 member under 18 years old were contacted and those that consented answered a survey regarding socio-demographics and the use of nutritional supplements and shared the blood tests that their T21 members have collected for the first consultation with a T21 expert. RESULTS: Frequencies and percentages were used to describe the variables. The most used supplements included vitamins (A, C and D), minerals (zinc and iron), omega-3, and antioxidants (curcumin). Hypothyroidism was observed in 56.9% of the participants. Hemogram alterations (increased hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and red cell distribution width, leukopenia, and lymphocytopenia), dyslipidemia, altered hepatic and inflammatory blood markers were frequently found. CONCLUSIONS: Nutritional supplements (mainly vitamins, minerals, omega-3 and antioxidants) are frequently used by Brazilian T21 children independently of professional counseling and/or supervision and should be a question to be raised during the clinical anamnesis since some of them may impact medical conduct. Moreover, many blood tests are altered in this population and clinicians should be aware of them in order to warrant an appropriate screening and the implementation of risk management measures as soon as possible and improve the general health of these persons.

Blood tests and use of nutritional supplements in a cohort of Brazilian children with trisomy 21

Abstract Objective: To describe the use of nutritional supplements and blood status (hemogram, lipidogram, hepatic function, inflammatory markers, minerals, and homocysteine) in a sample of Brazilian T21 children with private health support before their first consultation with a T21 expert. Method: This descriptive cross-sectional study enrolled 102 participants. Brazilian families with a T21 member under 18 years old were contacted and those that consented answered a survey regarding socio-demographics and the use of nutritional supplements and shared the blood tests that their T21 members have collected for the first consultation with a T21 expert. Results: Frequencies and percentages were used to describe the variables. The most used supplements included vitamins (A, C and D), minerals (zinc and iron), omega-3, and antioxidants (curcumin). Hypothyroidism was observed in 56.9% of the participants. Hemogram alterations (increased hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and red cell distribution width, leukopenia, and lymphocytopenia), dyslipidemia, altered hepatic and inflammatory blood markers were frequently found. Conclusions: Nutritional supplements (mainly vitamins, minerals, omega-3 and antioxidants) are frequently used by Brazilian T21 children independently of professional counseling and/or supervision and should be a question to be raised during the clinical anamnesis since some of them may impact medical conduct. Moreover, many blood tests are altered in this population and clinicians should be aware of them in order to warrant an appropriate screening and the implementation of risk management measures as soon as possible and improve the general health of these persons.

Water reuse in the post-tanning process: minimizing environmental impact of leather production.

Post-tanning wastewater is very diversified, as the post-tanning stage should meet the desirable properties of the leather for the final product, with low standardization of the process (compared to beamhouse and tanning). This makes post-tanning effluent reuse less feasible, and reuse in the post-tanning stage still needs to be explored. This work aims to evaluate the reuse of liquid effluents in the post-tanning process. The work methodology consisted of (i) characterization of water streams (groundwater, liquid effluent after primary treatment, and liquid effluent after secondary treatment); (ii) pilot-scale post-tanning tests using groundwater, primary effluent, and secondary effluent; (iii) characterization of the residual baths from pilot-scale tests (pH, conductivity, total solids, chemical oxygen demand, biochemical oxygen demand, chloride, hardness and oil and grease); and (iv) testing the leather obtained for total sulfated ash and organoleptic properties. Results showed that the primary effluent and the secondary effluent could be reused in pilot-scale post-tanning tests. There was an increase in the conductivity of the residual baths when liquid effluents were reused, which confirms the accumulation of salts in the effluents after their reuse.

Intrauterine and Lactational Exposure to Paracetamol: Cardiometabolic Evaluation in Adult Female and Male Offspring.

ABSTRACT: Paracetamol (PAR) is the most common over-the-counter drug recommended by physicians for treatment of pain and fever during gestation. This drug is not teratogenic, being considered safe for fetus; however, PAR crosses the blood-placental barrier. Considering that, the present study aimed to evaluate the vascular and metabolic safety of PAR exposure during intrauterine and neonatal development in adult male and female-exposed offspring. Wistar female rats were gavaged, with PAR (350 mg/kg/d), from gestational day 6-21 or from gestational day 6 until postnatal day 21. Control dams received water by gavage at the same periods. The male and female offspring were evaluated at adulthood (80 days of life). The thoracic aorta reactivity to acetylcholine, sodium nitroprusside, and phenylephrine was evaluated in male and female adult offspring. It was observed that aortic relaxation was similar between the PAR and control offspring. In addition, the contraction to phenylephrine was similar between the groups. Further, the insulin sensitivity, adipose tissue deposition and blood pressure were not different between PAR and control adult offspring. These results suggest that the protocol of PAR exposure used in the present study did not program vascular and metabolic alterations that would contribute to the development of cardiometabolic diseases in adult life, being safe for the exposed offspring.

Perinatal exposure to paracetamol: Dose and sex-dependent effects in behaviour and brain's oxidative stress markers in progeny.

Paracetamol (PAR) has been employed worldwide for pain and fever treatment during pregnancy and lactation. Epidemiologic studies have shown that exposure to PAR can increase the risk for developmental disorders, such as attention-deficit hyperactive disorder and autism spectrum disorder. This study aimed to investigate if gestational and lactational exposure to human-relevant doses of PAR could alter behavioural and brain oxidative stress parameters in the rat`s offspring. Wistar dams were gavaged daily with water or PAR (35 mg/kg/ or 350 mg/kg) during gestational day 6 to weaning (postnatal day 21). Behavioural assessments occurred at post-natal days 10 (nest seeking test), 27 (behavioural stereotypy) and 28 (three chamber sociability test and open field). Concentration of advanced oxidation protein products (AOPP), reduced glutathione (GSH), lipid hydroperoxides (LOOH) and activity of superoxide dismutase (SOD) were estimate in prefrontal cortex, hippocampus, striatum and cerebellum of 22-day-old rats. Compared to CON animals, males exposed to PAR during pregnancy and lactation augmented apomorphine-induced stereotyped behaviour (350 mg/kg) and ambulation in open-field test (35 mg/kg). Reduced exploratory behaviour in three chamber sociability test was observed in pups exposed to PAR at 350 mg/kg in both sexes. PAR treatment decreased hippocampal GSH level and striatal SOD activity in males exposed to 35 mg/kg, suggesting the vulnerability of these areas in PAR-induced developmental neurotoxicity. Findings suggest PAR use during pregnancy and lactation as a potential risk factor for neurodevelopmental disorders with males being more susceptible.

Evaluation of hepatic and renal effects in rat dams and their offspring after exposure to paracetamol during gestation and lactation.

Paracetamol (PAR) is the analgesic and antipyretic of choice for pregnant and nursing women. PAR may reach the fetus and/or neonate through the placenta and/or milk and effect development. This study evaluated possible hepatic and renal effects in rat dams and their offspring exposed to PAR using a human-relevant route of administration and doses from Gestational Day 6 to Postnatal Day (PND) 21. Dams were gavaged daily with PAR (35 or 350mg kg-1) or water (CON). Dams and pups were killed on PND21 and 22 respectively, and blood was collected for biochemical analysis (aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine). The kidneys and liver were isolated and processed for histopathological assessment and evaluation of oxidative stress markers. Compared with the CON groups, pups exposed to 350mg kg-1 PAR had increased renal reduced glutathione (GSH), whereas dams exposed to both doses of PAR increased serum AST. PAR administration did not affect parameters of general toxicity or renal and hepatic oxidative stress. In conclusion, maternal exposure to human-relevant doses of PAR by gavage was not associated with hepatic or renal toxicity in the pups or dams, but PAR was not devoid of effects. Exposure to PAR increased renal GSH in pups, which could suggest an adaptive antioxidant response, and affected maternal serum AST activity.

Gestational exposure to paracetamol in rats induces neurofunctional alterations in the progeny.

Paracetamol (PAR) is an over-the-counter medicine used as analgesic or antipyretic by 40-50% of the pregnant women in different countries. Epidemiologic studies have been associating maternal use of PAR with neurodevelopmental disruption and special attention has been given to its potential to increase the odds for neurodevelopmental disorders, such as attention-deficit hyperactive disorder and autism spectrum disorder. Population-based research do not allow the establishment of causal relationships because variable control is weak. We aimed to evaluate the potential of PAR to induce developmental neurotoxicity in rats. Pregnant Wistar rats were gavaged with PAR (350 mg/kg/day) or water from gestational day 6 until delivery. General toxicity endpoints included dams' body weight and food intake as well as pups' body weight until weaning. Behavioral evaluation occurred at post-natal days 10 (nest seeking test), 27 (behavioral stereotypy), 28 (three chamber sociability test and open field) and 29 (hot plate and elevated plus-maze). Moreover, lipid hidroperoxide (LOOH), reduced glutathione (GSH) and brain derived neurotrophic factor (BDNF) levels were quantified in prefrontal cortex and hippocampus of 22-days-old rats. Gestational exposure to PAR impaired nest seeking behavior, augmented apomorphine-induced behavioral stereotypy and decreased rostral grooming in the elevated plus maze. Exposed female pups presented elevated vertical exploration in the open field test. No alterations were observed in LOOH, GSH or BDNF levels in the prefrontal cortex or hippocampus. Exposure regimen did not affect general toxicity parameters or pups' behavior in the hot plate and sociability tests. These data suggest PAR as a developmental neurotoxicant. Observed alterations may be relevant for neurodevelopmental disorders.

Rat self-grooming and its relationships with anxiety, dearousal and perseveration: Evidence for a self-grooming trait.

Rodent self-grooming is a behavior that, besides its cleaning function, can be led by arousing experiences. A putative trait-like nature of this behavior was studied. With the aim of providing information about how grooming behavior can reflect different behavioral processes, an individual differences approach was adopted. Fifty nine male Wistar-derived rats were submitted to five 30-min long behavioral tests. These tests were selected based on the behavioral processes they entangle. Elevated plus-maze (EPM): anxiety, exploration/habituation, arousal/dearousal; Marble burying (MB): active/passive coping; Operant extinction (EXT): frustration, perseveration; Conditioned fear context (CFC): fearfulness, active/passive coping; Novelty after restraint (NAR): stress induced behavior. Orthogonal (Varimax) factor analyses were performed within each test in order to select the most representative measures. To the selected variables from all tests a Direct Oblimin factor analysis was applied. A three factor solution was found after the application of the Cattell's scree test. This solution accounted for 44.2% of the variance. By looking at the loading variables, some conclusions could be drawn. On Factor 1 loaded time spent grooming in three tests and the measure of extinction resistance. We considered this factor to evidence a trait-like nature of grooming and a relationship between it and perseveration. On Factor 2 loaded freezing in the CFC, SAPs in the EPM and grooming duration in the EXT. We considered this factor to correspond to anxiety. On Factor 3, moderate to high loadings were found for crossings in the NAR test and for grooming duration in this test and in the EPM. A lower loading on this factor was also found for the number of buried marbles. We considered this factor as related to dearousal. The present results suggest important relationships both (1) within grooming measures recorded in different behavioral tests and (2) among grooming and other behaviors observed in the tests. These relationships are in accordance with a trait-like nature for self-grooming and shed some light to how grooming behavior interplays with anxiety, dearousal and perseveration.

Transplantation with kidneys retrieved from deceased donors with acute renal failure.

BACKGROUND: The discard rate of kidneys recovered from deceased donors with acute renal failure (ARF) is higher compared with those without ARF mainly due to the uncertainty regarding short-term and long-term outcomes. METHODS: We retrospectively analyzed 1-year patient, graft, and rejection-free survivals and renal function of transplantations performed with kidneys recovered from deceased donors with or without ARF, defined as serum creatinine level of more than 1.5 mg/dL. We performed multivariable analysis to evaluate whether ARF was an independent risk factor associated with inferior outcomes. RESULTS: Of a total of 1518 patients, 253 received kidneys from expanded-criteria donors (ECD; with ARF [n=116] and without ARF [n=137]) and 1265 from standard-criteria donors (SCD; with ARF [n=369] and without ARF [n=896]). The incidence of delayed graft function was higher in ECD (68.1% vs. 58.4%; P=0.072) and SCD (69.9% vs. 50.6%; P<0.001) recipients of kidneys with ARF compared with those without ARF, respectively. At 1 year, patient, graft, and rejection-free survivals were not statistically different in SCD or ECD recipients with or without ARF. Renal function at 1 year was similar in recipients of ECD (41.9±26.3 vs. 40.1±21.7 mL/min; P=0.565) or SCD (50.9±29.9 vs. 53.6±28.5 mL/min; P=0.131) kidneys with and without ARF, respectively. Compared with kidneys without ARF, receiving a kidney allograft with ARF was not associated with increased risk of death, graft lost, or inferior renal function 1 year after transplantation. CONCLUSION: In this cohort of patients, kidneys from deceased donors with ARF provided graft survival and renal function comparable with kidneys from donors without ARF 1 year after transplantation.

Transpondo limites com doadores falecidos: transplantes bem-sucedidos com rins de doador com creatinina sérica igual a 13,1 mg/dL / Overcoming limits with deceased donors: successful renal transplantations from a donor with serum creatinine of 13.1 mg/dL

Doadores falecidos não limítrofes com insuficiência renal aguda podem ser uma opção segura para aumentar a oferta de rins para transplante. a avaliação histológica é fundamental para o estabelecimento do prognóstico funcional desses enxertos. Dois transplantes renais foram realizados com rins provenientes de um doador falecido jovem com insuficiência renal aguda severa sem comprometimento estrutural do parêquima renal. Ambos os enxertos apresentaram atraso de funcionamento no período pós-operatório, embora um deles com boa diurese inicial não tenha necessitado diálise. Função renal adequada foi observada a partir do 30º dia após o transplante. A insuficiência renal aguda severa no doador falecido não é fator de risco independente para a evolução em curto prazo do enxerto renal e não deve ser considerada contra-indicação absoluta para a realização do transplante.

Deceased donors not bordering with acute renal failure can be a safe option to increase the supply of kidneys for transplantation. histological evaluation is essential to establish the functional prognosis of these grafts. Two kidney transplants were performed with kidneys from a deceased donor couple with acute renal failure without severe structural impairment of parenchymal kidney. Both grafts were functioning in the late postoperative period, although one with good initial diuresis has not required dialysis. Adequate renal function was observed from day 30 after transplantation. Acute renal failure in severe deceased donor is not an independent risk factor for the development in short-term renal graft and should not be considered an absolute contraindication for transplantation was performed.

[Overcoming limits with deceased donors: successful renal transplantations from a donor with serum creatinine of 13.1 mg/dL].

Non-expanded deceased donors with acute kidney failure can be a safe option to increase the number of kidneys for transplantation. Histological evaluation is fundamental to establish the functional prognosis of those grafts. Two kidney transplantations were performed from a young deceased donor with severe acute kidney failure and no structural change in the renal parenchyma. Both patients had postoperative delayed graft function, but one of them, who had good initial urinary volume, required no dialysis. Adequate renal function was present at day 30 after transplantation. Severe acute kidney failure in deceased donors is not an independent risk factor for short-term outcome of renal graft and should not be considered an absolute contraindication for transplantation.