Repeated exposure to chlorpyrifos is associated with a dose-dependent chronic neurobehavioral deficit in adult rats

Organophosphate (OP) chemicals include commonly used pesticides and chemical warfare agents, and mechanistically they are potent inhibitors of the cholinesterase (ChE) enzyme. Epidemiological studies report long-term neuropsychiatric issues, including depression and cognitive impairments in OP-exposed individuals. Chlorpyrifos (CPF) is one of the most widely used pesticides worldwide. Multiple laboratory studies have reported on either the long-term behavioral effect of an acute high-dose CPF (30-250 mg/kg) or studied sub-chronic behavioral effects, particularly the motor and cognitive effects of repeated low-dose CPF. However, studies are lacking on chronic mood and depression-related morbidities following repeated CPF doses that would mimic occupationally relevant OP exposures. In this study, adult male rats were injected with CPF (1, 3, 5, or 10 mg/kg/d, s.c.) for 21 consecutive days. Dependent on the CPF dose, ChE activity was inhibited approximately 60-80% in the blood and about 20-50% in the hippocampus at 2-days after the end of CPF exposures. Following a 12-week washout period, a complete recovery of ChE activity was noted. However, CPF-treated rats exhibited a dose-dependent increase in signs related to anhedonia (sucrose preference test), anxiety (open-field and elevated plus-maze), and despair (forced swim test) at this stage. To the best of our knowledge, this could be the first laboratory study that demonstrates a cause-effect relationship between occupational-like CPF exposures in adult rats and the development of long-term depression-related outcomes and could provide an experimental system to study molecular mechanisms underlying environmental OP exposures and the elevated risk for chronic behavioral deficits

Analysis of the intraspinal calcium dynamics and its implications on the plasticity of spiking neurons

The influx of calcium ions into the dendritic spines through the N-metyl-D-aspartate (NMDA) channels is believed to be the primary trigger for various forms of synaptic plasticity. In this paper, the authors calculate analytically the mean values of the calcium transients elicited by a spiking neuron undergoing a simple model of ionic currents and back-propagating action potentials. The relative variability of these transients, due to the stochastic nature of synaptic transmission, is further considered using a simple Markov model of NMDA receptos. One finds that both the mean value and the variability depend on the timing between pre- and postsynaptic action-potentials. These results could have implications on the expected form of synaptic-plasticity curve and can form a basis for a unified theory of spike time-dependent, and rate based plasticity.Comment: 14 pages, 10 figures. A few changes in section IV and addition of a new figur

FK506 protects against articular cartilage collagenous extra-cellular matrix degradation

Objective: Osteoarthritis (OA) is a non-rheumatologic joint disease characterized by progressive degeneration of the cartilage extra-cellular matrix (ECM), enhanced subchondral bone remodeling, activation of synovial macrophages and osteophyte growth. Inhibition of calcineurin (Cn) activity through tacrolimus (FK506) in invitro monolayer chondrocytes exerts positive effects on ECM marker expression. This study therefore investigated the effects of FK506 on anabolic and catabolic markers of osteoarthritic chondrocytes in 2D and 3D invitro cultures, and its therapeutic effects in an invivo rat model of OA. Methods: Effects of high and low doses of FK506 on anabolic (QPCR/histochemistry) and catabolic (QPCR) markers were evaluated invitro on isolated (2D) and ECM-embedded chondrocytes (explants, 3D pellets). Severe cartilage damage was induced unilaterally in rat knees using papain injections in combination with a moderate running protocol. Twenty rats were treated with FK506 orally and compared to twenty untreated controls. Subchondral cortical and trabecular bone changes (longitudinal microCT) and macrophage activation (SPECT/CT) were measured. Articular cartilage was analyzed exvivo using contrast enhanced microCT and histology. Results: FK506 treatment of osteoarthritic chondrocytes invitro induced anabolic (mainly collagens) and reduced catabolic ECM marker expression. In line with this, FK506 treatment clearly protected ECM integrity invivo by markedly decreasing subchondral sclerosis, less development of subchondral pores, depletion of synovial macrophage activation and lower osteophyte growth. Conclusion: FK506 protected cartilage matrix integrity invitro and invivo. Additionally, FK506 treatment invivo reduced OA-like responses in different articular joint tissues and thereby makes Cn an interesting target for therapeutic intervention of OA

Circulating Cell-Free DNA in Dogs with Mammary Tumors: Short and Long Fragments and Integrity Index

Circulating cell-free DNA (cfDNA) has been considered an interesting diagnostic/prognostic plasma biomarker in tumor-bearing subjects. In cancer patients, cfDNA can hypothetically derive from tumor necrosis/apoptosis, lysed circulating cells, and some yet unrevealed mechanisms of active release. This study aimed to preliminarily analyze cfDNA in dogs with canine mammary tumors (CMTs). Forty-four neoplastic, 17 non-neoplastic disease-bearing, and 15 healthy dogs were recruited. Necrosis and apoptosis were also assessed as potential source of cfDNA on 78 CMTs diagnosed from the 44 dogs. The cfDNA fragments and integrity index significantly differentiated neoplastic versus non-neoplastic dogs (P<0.05), and allowed the distinction between benign and malignant lesions (P<0.05). Even if without statistical significance, the amount of cfDNA was also affected by tumor necrosis and correlated with tumor size and apoptotic markers expression. A significant (P<0.01) increase of Bcl-2 in malignant tumors was observed, and in metastatic CMTs the evasion of apoptosis was also suggested. This study, therefore, provides evidence that cfDNA could be a diagnostic marker in dogs carrying mammary nodules suggesting that its potential application in early diagnostic procedures should be further investigated

Sedentary behaviour and brain health in middle-aged and older adults: A systematic review

Sedentary behaviour may increase the risk of dementia. Studying physiological effects of sedentary behaviour on cerebral health may provide new insights into the nature of this association. Accordingly, we reviewed if and how acute and habitual sedentary behaviour relate to brain health factors in middle-aged and older adults (≥45 years). Four databases were searched. Twenty-nine studies were included, with mainly cross-sectional designs. Nine studies examined neurotrophic factors and six studied functional brain measures, with the majority of these studies finding no associations with sedentary behaviour. The results from studies on sedentary behaviour and cerebrovascular measures were inconclusive. There was a tentative association between habitual sedentary behaviour and structural white matter health. An explanatory pathway for this effect might relate to the immediate vascular effects of sitting, such as elevation of blood pressure. Nevertheless, due to the foremost cross-sectional nature of the available evidence, reverse causality could also be a possible explanation. More prospective studies are needed to understand the potential of sedentary behaviour as a target for brain health

Editorial note for the Geodesy and Geodynamics journal special issue Contemporary Research in Geodynamics and Earth Tides : An account of the 18th Geodynamics and Earth Tides Symposium 2016, Trieste, Italy

This volume aims at conveying the rich and interdisciplinary topics discussed at the 18th Geodynamics and Earth Tides Symposium, Trieste, 2016. For seventeen times the gathering was named the Earth Tides Symposium, when giving tribute to the evolution of the observed signals, the term geodynamics was added to the title.The present volume aims at a full coverage of the Symposium by including the entire list of abstracts that were presented either as oral or poster presentation

Clinical trials in vascular cognitive impairment following SPRINT-MIND: An international perspective

Summary A large interventional trial, the Systolic Blood Pressure Intervention Trial sub-study termed Memory and Cognition in Decreased Hypertension (SPRINT-MIND), found reduced risk of cognitive impairment in older adults with intensive, relative to standard, blood-pressure-lowering targets (systolic BP < 120 vs. <140 mm Hg). In this perspective, we discuss key questions and make recommendations for clinical practice and for clinical trials, following SPRINT-MIND. Future trials should embody cognitive endpoints appropriate to the participant group, ideally with adaptive designs that ensure robust answers for cognitive and cardiovascular endpoints. Reliable data from diverse populations, including the oldest-old (age > 80 years), will maximize external validity and global implementation of trial findings. New biomarkers will improve phenotyping to stratify patients to optimal treatments. Currently no antihypertensive drug class stands out for dementia risk reduction. Multi-domain interventions, incorporating lifestyle change (exercise, diet) alongside medications, may maximize global impact. Given the low cost and wide availability of antihypertensive drugs, intensive BP reduction may be a cost-effective means to reduce dementia risk in diverse, aging populations worldwide

Helping and Cooperation in Children with Autism

Helping and cooperation are central to human social life. Here, we report two studies investigating these social behaviors in children with autism and children with developmental delay. In the first study, both groups of children helped the experimenter attain her goals. In the second study, both groups of children cooperated with an adult, but fewer children with autism performed the tasks successfully. When the adult stopped interacting at a certain moment, children with autism produced fewer attempts to re-engage her, possibly indicating that they had not formed a shared goal/shared intentions with her. These results are discussed in terms of the prerequisite cognitive and motivational skills and propensities underlying social behavior

Glucosamine increases hyaluronic acid production in human osteoarthritic synovium explants

Background. Glucosamine (GlcN) used by patients with osteoarthritis was demonstrated to reduce pain, but the working mechanism is still not clear. Viscosupplementation with hyaluronic acid (HA) is also described to reduce pain in osteoarthritis. The synthesis of HA requires GlcN as one of its main building blocks. We therefore hypothesized that addition of GlcN might increase HA production by synovium tissue. Methods. Human osteoarthritic synovium explants were obtained at total knee surgery and pre-cultured for 1 day. The experimental conditions consisted of a 2 days continuation of the culture with addition of N-Acetyl-glucosamine (GlcN-Ac; 5 mM), glucosamine-hydrochloride (GlcN-HCl; 0.5 and 5 mM), glucose (Gluc; 0.5 and 5 mM). Hereafter HA production was measured in culture medium supernatant using an enzyme-linked binding protein assay. Real time RT-PCR was performed for hyaluronic acid synthase (HAS) 1, 2 and 3 on RNA isolated from the explants. Results. 0.5 mM