Developmental Exposure of Rats to Chlorpyrifos Leads to Behavioral Alterations in Adulthood, Involving Serotonergic Mechanisms and Resembling Animal Models of Depression

Developmental exposure to chlorpyrifos (CPF) causes persistent changes in serotonergic (5HT) systems. We administered 1 mg/kg/day CPF to rats on postnatal days 1–4, a regimen below the threshold for systemic toxicity. When tested in adulthood, CPF-exposed animals showed abnormalities in behavioral tests that involve 5HT mechanisms. In the elevated plus maze, males treated with CPF spent more time in the open arms, an effect seen with 5HT deficiencies in animal models of depression. Similarly, in an anhedonia test, the CPF-exposed group showed a decreased preference for chocolate milk versus water. Developmental CPF exposure also has lasting effects on cognitive function. We replicated our earlier finding that developmental CPF exposure ablates the normal sex differences in 16-arm radial maze learning and memory: during acquisition training, control male rats typically perform more accurately than do control females, but CPF treatment eliminated this normal sex difference. Females exposed to CPF showed a reduction in working and reference memory errors down to the rate of control males. Conversely, CPF-exposed males exhibited an increase in working and reference memory errors. After radial-arm acquisition training, we assessed the role of 5HT by challenging the animals with the 5HT(2) receptor antagonist ketanserin. Ketanserin did not affect performance in controls but elicited dose-dependent increases in working and reference memory errors in the CPF group, indicating an abnormal dependence on 5HT systems. Our results indicate that neonatal CPF exposures, classically thought to be subtoxic, produce lasting changes in 5HT-related behaviors that resemble animal models of depression

Comparative Developmental Neurotoxicity of Organophosphate Insecticides: Effects on Brain Development Are Separable from Systemic Toxicity

A comparative approach to the differences between systemic toxicity and developmental neurotoxicity of organophosphates is critical to determine the degree to which multiple mechanisms of toxicity carry across different members of this class of insecticides. We contrasted neuritic outgrowth and cholinergic synaptic development in neonatal rats given different organophosphates (chlorpyrifos, diazinon, parathion) at doses spanning the threshold for impaired growth and viability. Animals were treated daily on postnatal days 1–4 by subcutaneous injection so as to bypass differences in first-pass activation to the oxon or catabolism to inactive products. Evaluations occurred on day 5. Parathion (maximum tolerated dose, 0.1 mg/kg) was far more systemically toxic than was chlorpyrifos or diazinon (maximum tolerated dose, 1–5 mg/kg). Below the maximum tolerated dose, diazinon impaired neuritic outgrowth in the forebrain and brainstem, evidenced by a deficit in the ratio of membrane protein to total protein. Diazinon also decreased choline acetyltransferase activity, a cholinergic neuronal marker, whereas it did not affect hemicholinium-3 binding to the presynaptic choline transporter, an index of cholinergic neuronal activity. There was no m(2)-muscarinic acetylcholine receptor down-regulation, as would have occurred with chronic cholinergic hyper-stimulation. The same pattern was found previously for chlorpyrifos. In contrast, parathion did not elicit any of these changes at its maximum tolerated dose. These results indicate a complete dichotomy between the systemic toxicity of organophosphates and their propensity to elicit developmental neurotoxicity. For parathion, the threshold for lethality lies below that necessary for adverse effects on brain development, whereas the opposite is true for chlorpyrifos and diazinon

Socioeconomic inequalities in health among Swedish adolescents - adding the subjective perspective

Abstract Background Socioeconomic inequalities in adolescent health predict future inequalities in adult health. Subjective measures of socioeconomic status (SES) may contribute with an increased understanding of these inequalities. The aim of this study was to investigate socioeconomic health inequalities using both a subjective and an objective measure of SES among Swedish adolescents. Method Cross-sectional HBSC-data from 2002 to 2014 was used with a total sample of 23,088 adolescents aged 11–15 years. Three measures of self-rated health (dependent variables) were assessed: multiple health complaints, life satisfaction and health perception. SES was measured objectively by the Family Affluence Scale (FAS) and subjectively by “perceived family wealth” (independent variables). The trend for health inequalities was investigated descriptively with independent t-tests and the relationship between independent and dependent variables was investigated with multiple logistic regression analysis. Gender, age and survey year was considered as possible confounders. Results Subjective SES was more strongly related to health outcomes than the objective measure (FAS). Also, the relation between FAS and health was weakened and even reversed (for multiple health complaints) when subjective SES was tested simultaneously in regression models (FAS OR: 1.03, CI: 1.00;1.06 and subjective SES OR: 0.66, CI: 0.63;0.68). Conclusions The level of socioeconomic inequalities in adolescent health varied depending on which measure that was used to define SES. When focusing on adolescents, the subjective appraisals of SES is important to consider because they seem to provide a stronger tool for identifying inequalities in health for this group. This finding is important for policy makers to consider given the persistence of health inequalities in Sweden and other high-income countries

Overfeeding, Autonomic Regulation and Metabolic Consequences

The autonomic nervous system plays an important role in the regulation of body processes in health and disease. Overfeeding and obesity (a disproportional increase of the fat mass of the body) are often accompanied by alterations in both sympathetic and parasympathetic autonomic functions. The overfeeding-induced changes in autonomic outflow occur with typical symptoms such as adiposity and hyperinsulinemia. There might be a causal relationship between autonomic disturbances and the consequences of overfeeding and obesity. Therefore studies were designed to investigate autonomic functioning in experimentally and genetically hyperphagic rats. Special emphasis was given to the processes that are involved in the regulation of peripheral energy substrate homeostasis. The data revealed that overfeeding is accompanied by increased parasympathetic outflow. Typical indices of vagal activity (such as the cephalic insulin release during food ingestion) were increased in all our rat models for hyperphagia. Overfeeding was also accompanied by increased sympathetic tone, reflected by enhanced baseline plasma norepinephrine (NE) levels in both VMH-lesioned animals and rats rendered obese by hyperalimentation. Plasma levels of NE during exercise were, however, reduced in these two groups of animals. This diminished increase in the exercise-induced NE outflow could be normalized by prior food deprivation. It was concluded from these experiments that overfeeding is associated with increased parasympathetic and sympathetic tone. In models for hyperphagia that display a continuously elevated nutrient intake such as the VMH-lesioned and the overfed rat, this increased sympathetic tone was accompanied by a diminished NE response to exercise. This attenuated outflow of NE was directly related to the size of the fat reserves, indicating that the feedback mechanism from the periphery to the central nervous system is altered in the overfed state.

Organophosphate Insecticides Target the Serotonergic System in Developing Rat Brain Regions: Disparate Effects of Diazinon and Parathion at Doses Spanning the Threshold for Cholinesterase Inhibition

BACKGROUND: In the developing brain, serotonin (5HT) systems are among the most sensitive to disruption by organophosphates. OBJECTIVES: We exposed neonatal rats to daily doses of diazinon or parathion on postnatal days (PND)1–4 and evaluated 5HT receptors and the 5HT transporter in brainstem and forebrain on PND5, focusing on doses of each agent below the maximum tolerated dose and spanning the threshold for cholinesterase inhibition: 0.5, 1, or 2 mg/kg for diazinon, and 0.02, 0.05, and 0.1 mg/kg for parathion. RESULTS: Diazinon evoked up-regulation of 5HT(1A) and 5HT(2) receptor expression even at doses devoid of effects on cholinesterase activity, a pattern similar to that seen earlier for another organophosphate, chlorpyrifos. In contrast, parathion decreased 5HT(1A) receptors, again at doses below those required for effects on cholinesterase. The two agents also differed in their effects on the 5HT transporter. Diazinon evoked a decrease in the brainstem and an increase in the forebrain, again similar to that seen for chlorpyrifos; this pattern is typical of damage of nerve terminals and reactive sprouting. Parathion had smaller, nonsignificant effects. CONCLUSIONS: Our results buttress the idea that, in the developing brain, the various organophosphates target specific neurotransmitter systems differently from each other and without the requirement for cholinesterase inhibition, their supposed common mechanism of action

Mindfulness-based stress reduction in Parkinson’s disease: a systematic review

Background: Mindfulness based stress reduction (MBSR) is increasingly being used to improve outcomes such as stress and depression in a range of long-term conditions (LTCs). While systematic reviews on MBSR have taken place for a number of conditions there remains limited information on its impact on individuals with Parkinson’s disease (PD). Methods: Medline, Central, Embase, Amed, CINAHAL were searched in March 2016. These databases were searched using a combination of MeSH subject headings where available and keywords in the title and abstracts. We also searched the reference lists of related reviews. Study quality was assessed based on questions from the Cochrane Collaboration risk of bias tool. Results: Two interventions and three papers with a total of 66 participants were included. The interventions were undertaken in Belgium (n = 27) and the USA (n = 39). One study reported significantly increased grey matter density (GMD) in the brains of the MBSR group compared to the usual care group. Significant improvements were reported in one study for a number of outcomes including PD outcomes, depression, mindfulness, and quality of life indicators. Only one intervention was of reasonable quality and both interventions failed to control for potential confounders in the analysis. Adverse events and reasons for drop-outs were not reported. There was also no reporting on the costs/benefits of the intervention or how they affected health service utilisation. Conclusion: This systematic review found limited and inconclusive evidence of the effectiveness of MBSR for PD patients. Both of the included interventions claimed positive effects for PD patients but significant outcomes were often contradicted by other results. Further trials with larger sample sizes, control groups and longer follow-ups are needed before the evidence for MBSR in PD can be conclusively judged

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene

Marathon related death due to brainstem herniation in rehydration-related hyponatraemia: a case report

Introduction: Identifying marathon runners at risk of neurological deterioration at the end of the race (within a large cohort complaining of exhaustion, dehydration, nausea, headache, dizziness, etc.) is challenging. Here we report a case of rehydration-related hyponatraemia with ensuing brain herniation. Case presentation: We report the death of runner in his 30's who collapsed in the recovery area following a marathon. Following rehydration he developed a respiratory arrest in the emergency room. He was found to be hyponatraemic (130 mM). A CT brain scan showed severe hydrocephalus and brain stem herniation. Despite emergency insertion of an extraventricular drain, he was tested for brainstem death the following morning. Funduscopy demonstrated an acute-on-chronic papilledema; CSF spectrophotometry did not reveal any trace of oxyhemoglobin or bilirubin, but ferritin levels were considerably raised (530 ng/mL, upper reference value 12 ng/mL), consistent with a previous bleed. Retrospectively it emerged that the patient had suffered from a thunderclap headache some months earlier. Subsequently he developed morning headaches and nausea. This suggests that he may have suffered from a subarachnoid haemorrhage complicated by secondary hydrocephalus. This would explain why in this case the relatively mild rehydration-related hyponatremia may have caused brain swelling sufficient for herniation. Conclusion: Given the frequency of hyponatraemia in marathon runners (serum Na <135 mM in about 13%), and the non-specific symptoms, we discuss how a simple screening test such as funduscopy may help to identify those who require urgent neuroimaging

Inter-hemispheric EEG coherence analysis in Parkinson's disease : Assessing brain activity during emotion processing

Parkinson’s disease (PD) is not only characterized by its prominent motor symptoms but also associated with disturbances in cognitive and emotional functioning. The objective of the present study was to investigate the influence of emotion processing on inter-hemispheric electroencephalography (EEG) coherence in PD. Multimodal emotional stimuli (happiness, sadness, fear, anger, surprise, and disgust) were presented to 20 PD patients and 30 age-, education level-, and gender-matched healthy controls (HC) while EEG was recorded. Inter-hemispheric coherence was computed from seven homologous EEG electrode pairs (AF3–AF4, F7–F8, F3–F4, FC5–FC6, T7–T8, P7–P8, and O1–O2) for delta, theta, alpha, beta, and gamma frequency bands. In addition, subjective ratings were obtained for a representative of emotional stimuli. Interhemispherically, PD patients showed significantly lower coherence in theta, alpha, beta, and gamma frequency bands than HC during emotion processing. No significant changes were found in the delta frequency band coherence. We also found that PD patients were more impaired in recognizing negative emotions (sadness, fear, anger, and disgust) than relatively positive emotions (happiness and surprise). Behaviorally, PD patients did not show impairment in emotion recognition as measured by subjective ratings. These findings suggest that PD patients may have an impairment of inter-hemispheric functional connectivity (i.e., a decline in cortical connectivity) during emotion processing. This study may increase the awareness of EEG emotional response studies in clinical practice to uncover potential neurophysiologic abnormalities