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Preeclampsia (PE) is a complex pregnancy syndrome characterized by hypertension with or without proteinuria, affecting 2–6% of pregnancies globally. PE is characterized by excessive release of damage-associated molecular patterns (DAMPs) into the maternal circulation. This DAMP-rich milieu acts on innate immune cells, inducing a proinflammatory state characterized by elevated cytokines such as IL-1β and IL-18. This proinflammatory state in the mother and placenta results in the endothelial dysfunction strongly associated with cardiovascular disorders. While the immediate maternal and fetal risks of PE are well-documented, accumulating evidence indicates that PE also confers long-term cardiovascular risks to the mother, including hypertension, coronary heart disease, stroke, and heart failure. The underlying mechanisms connecting PE to these chronic cardiovascular conditions remain unclear. This article explores the potential role of trained innate immunity (TRIM) as a mechanistic link between PE and increased long-term cardiovascular risk. We propose that the persistent exposure to DAMPs during PE may epigenetically reprogram maternal innate immune cells and their progenitors, leading to TRIM. This reprogramming enhances the inflammatory response to subsequent stimuli, potentially contributing to endothelial dysfunction and chronic inflammation that predispose women to cardiovascular diseases later in life. Understanding the role of TRIM in PE could provide novel insights into the pathophysiology of PE-related cardiovascular complications and identify potential targets for therapeutic intervention. Further research is warranted to investigate the epigenetic and metabolic alterations in innate immune cells induced by PE and to determine how these changes may influence long-term maternal cardiovascular health. [ABSTRACT FROM AUTHOR]

Neural entrainment has become a popular technique to non-invasively manipulate brain rhythms via external, periodic stimulation. However, there is still debate regarding its underlying mechanisms and effects on brain activity. Here, we used EEG recordings during a visual entrainment paradigm to assess characteristic changes in the spectral content of EEG signals due to entrainment. Our results demonstrate that entrainment not only increases synchrony between neural oscillations and the entraining stimulus but also elicits previously unreported spectral tuning effects and long-lasting after-effects. These findings offer compelling evidence for the presence of dedicated, flexible, and adaptive mechanisms for neural entrainment, which may have key roles in adjusting the sensitivity and dynamic range of brain oscillators in response to environmental temporal structures. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a complex pregnancy syndrome characterized by hypertension with or without proteinuria, affecting 2–6% of pregnancies globally. PE is characterized by excessive release of damage-associated molecular patterns (DAMPs) into the maternal circulation. This DAMP-rich milieu acts on innate immune cells, inducing a proinflammatory state characterized by elevated cytokines such as IL-1β and IL-18. This proinflammatory state in the mother and placenta results in the endothelial dysfunction strongly associated with cardiovascular disorders. While the immediate maternal and fetal risks of PE are well-documented, accumulating evidence indicates that PE also confers long-term cardiovascular risks to the mother, including hypertension, coronary heart disease, stroke, and heart failure. The underlying mechanisms connecting PE to these chronic cardiovascular conditions remain unclear. This article explores the potential role of trained innate immunity (TRIM) as a mechanistic link between PE and increased long-term cardiovascular risk. We propose that the persistent exposure to DAMPs during PE may epigenetically reprogram maternal innate immune cells and their progenitors, leading to TRIM. This reprogramming enhances the inflammatory response to subsequent stimuli, potentially contributing to endothelial dysfunction and chronic inflammation that predispose women to cardiovascular diseases later in life. Understanding the role of TRIM in PE could provide novel insights into the pathophysiology of PE-related cardiovascular complications and identify potential targets for therapeutic intervention. Further research is warranted to investigate the epigenetic and metabolic alterations in innate immune cells induced by PE and to determine how these changes may influence long-term maternal cardiovascular health.

Lead (Pb), mercury (Hg), and cadmium (Cd) are prevalent and persistent environmental contaminants, causing detrimental effects on millions of individuals worldwide. Our previous research demonstrated that early-life exposure to low-level Pb, Hg, and Cd mixtures may lead to cognitive impairments. However, the association and interaction among low levels of Pb, Hg, or Cd exposure remains unclear. In this study, a two-level full factorial design (5.481, 0.036, and 2.132 mg/L for Pb, Hg, and Cd respectively) was conducted to assess the interplay among maternal Pb, Hg, and Cd exposure on offspring cognition. Following exposure during pregnancy and lactation, a competitive absorption among Pb, Hg, and Cd was observed. Maternal exposure to each metal alone resulted in higher blood and brain concentrations of Pb, Hg, and Cd in offspring compared to co-exposure at equivalent levels. However, behavioral experiments conducted in the Morris water maze and novel object recognition test revealed maternal Pb, Hg, and Cd exposure synergistically impaired offspring's spatial cognition and recognition memory. Importantly, this dysfunction persisted into middle age even without exposure after adulthood. Moreover, the open field test and elevated plus maze indicated maternal low-level Pb, Hg, and Cd co-exposure triggered risk-taking behavior in weaning offspring, with a significant main effect for Pb exposure. No long-lasting effect on risk-taking behavior was detected in middle-aged offspring. Further investigation into molecular mechanisms showed that the dysregulation of corticosterone reaction and immune response might be the potential mechanism underlying Pb, Hg, and Cd co-exposure-induced cognitive impairments. Our study highlights the synergistic and long-lasting effects of multiple heavy metal exposures,underscoring the urgency to prevent exposure to metal mixtures among children and women of childbearing age.

This qualitative study investigated the long-lasting effects of an average tour to the Holy Land on travellers of the same faith. Data were collected using written interviews, diary entries, observations and communications at least one year after Protestant travellers returned from their planned trip. Thematic analysis was used to analyse the data through the three phases of noting, encoding and then interpreting important aspects. The findings show these faith travellers invested themselves into the trip before, during and after, as part of their committed faith formation. Any faith-based reader would be interested in the results that evidence long-lasting effects for the participants through their actions and behaviours. All participants stated that this trip was a highlight, enhancing their personal connection with God and increasing their involvement in various faith events and activities. Since their return from the trip participants have initiated or contributed to multiple activities such as personal Bible study, storytelling, giving a particular book to others, starting Bible study groups and other personal faith formation behaviours within their work, home and community contexts.

This qualitative study investigated the long-lasting effects of an average tour to the Holy Land on travellers of the same faith. Data were collected using written interviews, diary entries, observations and communications at least one year after Protestant travellers returned from their planned trip. Thematic analysis was used to analyse the data through the three phases of noting, encoding and then interpreting important aspects. The findings show these faith travellers invested themselves into the trip before, during and after, as part of their committed faith formation. Any faith-based reader would be interested in the results that evidence long-lasting effects for the participants through their actions and behaviours. All participants stated that this trip was a highlight, enhancing their personal connection with God and increasing their involvement in various faith events and activities. Since their return from the trip participants have initiated or contributed to multiple activities such as personal Bible study, storytelling, giving a particular book to others, starting Bible study groups and other personal faith formation behaviours within their work, home and community contexts. [ABSTRACT FROM AUTHOR]

Tributyltin (TBT) is a typical organic pollutant that persists in aquatic sediments due to its wide usage as an antifouling fungicide during the past few decades. Despite increased awareness of the serious negative consequences of TBT on aquatic species, studies on the effects of TBT exposure on cephalopod embryonic development and juvenile physiological performance are scarce. To investigate the lasting effects of TBT toxicity on Sepia pharaonis from embryo to hatchling, embryos (gastrula stage, 3–5 h post fertilization) were exposed to four levels of TBT until hatching: 0 (control), 30 (environmental level), 60, and 120 ng/L. Subsequently, juvenile growth performance endpoints and behavioral alterations were assessed over 15 days post-hatching. Egg hatchability was significantly reduced and embryonic development (i.e., premature hatching) was accelerated in response to 30 ng/L TBT exposure. Meanwhile, TBT-induced alterations in embryonic morphology primarily included yolk-sac lysis, embryonic malformations, and uneven pigment distributions. During the pre-middle stage of embryonic development, the eggshell serves as an effective barrier to safeguard the embryo from exposure to 30–60 ng/L TBT, according to patterns of TBT accumulation and distribution in the egg compartment. However, even environmental relevant levels of TBT (30 ng/L) exposure during embryonic development had a negative impact on juvenile behavior and growth, including slowing growth, shortening eating times, causing more irregular movements, and increasing inking times. These findings indicate that after TBT exposure, negative long-lasting effects on S. pharaonis development from embryo to hatchling persist, suggesting that long-lasting toxic effects endure from S. pharaonis embryos to hatchlings.

Excessive neuronal synchrony is a hallmark of neurological disorders such as epilepsy and Parkinson's disease. An established treatment for medically refractory Parkinson's disease is high-frequency (HF) deep brain stimulation (DBS). However, symptoms return shortly after cessation of HF-DBS. Recently developed decoupling stimulation approaches, such as Random Reset (RR) stimulation, specifically target pathological connections to achieve long-lasting desynchronization. During RR stimulation, a temporally and spatially randomized stimulus pattern is administered. However, spatial randomization, as presented so far, may be difficult to realize in a DBS-like setup due to insufficient spatial resolution. Motivated by recently developed segmented DBS electrodes with multiple stimulation sites, we present a RR stimulation protocol that copes with the limited spatial resolution of currently available depth electrodes for DBS. Specifically, spatial randomization is realized by delivering stimuli simultaneously to L randomly selected stimulation sites out of a total of M stimulation sites, which will be called L/M-RR stimulation. We study decoupling by L/M-RR stimulation in networks of excitatory integrate-and-fire neurons with spike-timing dependent plasticity by means of theoretical and computational analysis. We find that L/M-RR stimulation yields parameter-robust decoupling and long-lasting desynchronization. Furthermore, our theory reveals that strong high-frequency stimulation is not suitable for inducing long-lasting desynchronization effects. As a consequence, low and high frequency L/M-RR stimulation affect synaptic weights in qualitatively different ways. Our simulations confirm these predictions and show that qualitative differences between low and high frequency L/M-RR stimulation are present across a wide range of stimulation parameters, rendering stimulation with intermediate frequencies most efficient. Remarkably, we find that L/M-RR stimulation does not rely on a high spatial resolution, characterized by the density of stimulation sites in a target area, corresponding to a large M. In fact, L/M-RR stimulation with low resolution performs even better at low stimulation amplitudes. Our results provide computational evidence that L/M-RR stimulation may present a way to exploit modern segmented lead electrodes for long-lasting therapeutic effects.

Excessive neuronal synchrony is a hallmark of neurological disorders such as epilepsy and Parkinson's disease. An established treatment for medically refractory Parkinson's disease is high-frequency (HF) deep brain stimulation (DBS). However, symptoms return shortly after cessation of HF-DBS. Recently developed decoupling stimulation approaches, such as Random Reset (RR) stimulation, specifically target pathological connections to achieve long-lasting desynchronization. During RR stimulation, a temporally and spatially randomized stimulus pattern is administered. However, spatial randomization, as presented so far, may be difficult to realize in a DBS-like setup due to insufficient spatial resolution. Motivated by recently developed segmented DBS electrodes with multiple stimulation sites, we present a RR stimulation protocol that copes with the limited spatial resolution of currently available depth electrodes for DBS. Specifically, spatial randomization is realized by delivering stimuli simultaneously to L randomly selected stimulation sites out of a total of M stimulation sites, which will be called L/M-RR stimulation. We study decoupling by L/M-RR stimulation in networks of excitatory integrate-and-fire neurons with spike-timing dependent plasticity by means of theoretical and computational analysis. We find that L/M-RR stimulation yields parameter-robust decoupling and long-lasting desynchronization. Furthermore, our theory reveals that strong high-frequency stimulation is not suitable for inducing long-lasting desynchronization effects. As a consequence, low and high frequency L/M-RR stimulation affect synaptic weights in qualitatively different ways. Our simulations confirm these predictions and show that qualitative differences between low and high frequency L/M-RR stimulation are present across a wide range of stimulation parameters, rendering stimulation with intermediate frequencies most efficient. Remarkably, we find that L/M-RR stimulation does not rely on a high spatial resolution, characterized by the density of stimulation sites in a target area, corresponding to a large M. In fact, L/M-RR stimulation with low resolution performs even better at low stimulation amplitudes. Our results provide computational evidence that L/M-RR stimulation may present a way to exploit modern segmented lead electrodes for long-lasting therapeutic effects. [ABSTRACT FROM AUTHOR]

Tumor antigen-targeting monoclonal antibodies (TA-targeting mAbs) are used as therapeutics in many malignancies and their capacity to mobilize the host immunity puts them at the forefront of anti-cancer immunotherapies. Both innate and adaptive immune cells have been associated with the therapeutic activity of such antibodies, but tumor escape from mAb-induced tumor immune surveillance remains one of the main clinical issues. In this preclinical study, we grafted immunocompetent and immunocompromised mice with the B16F10 mouse melanoma cell line and treated them with the TA99 TA-targeting mAb to analyze the immune mechanisms associated with the tumor response and resistance to TA99 monotherapy. In immunocompetent mice TA99 treatment strongly increased the fraction of CD8 and CD4 effector T cells in the tumor compared with isotype control, highlighting the specific immune modulation of the tumor microenvironment by TA99. However, in most mice, TA99 immunotherapy could not prevent immune effector exhaustion and the recruitment of regulatory CD4 T cells and consequently tumor escape from immune surveillance. Remarkably, anti-PD-1 treatment at the time of tumor emergence restored the Th1 effector functions of CD4 and CD8 T cells as well as of natural killer and γδT cells, which translated into a significant slow-down of tumor progression and extended survival. Our findings provide the first evidence that PD-1 blockade at the time of tumor emergence can efficiently boost the host anti-tumor immune response initiated several weeks before by the TA-targeting mAb. These results are promising for the design of combined therapies to sensitize non-responder or resistant patients.

Abtract Background Transcranial direct current stimulation (tDCS) is a non-invasive method increasingly popular for the treatment of several brain disorders, such as major depression. Despite great enthusiasm and promising results, some studies report discrepant findings and no consensus exists for the clinical use of tDCS. Objective The present study aims to (i) determine the most effective stimulation parameters to optimize antidepressant-like effect of tDCS in the forced-swim test in mice and (ii) identify brain regions recruited by tDCS and possibly involved in its behavioral effect using Fos immunohistochemistry. Results We reported that tDCS induced long-lasting antidepressant-like effect, which varied as a function of stimulation settings including number, duration, intensity and polarity of stimulation. Interestingly, the present study also demonstrated that tDCS reduced depressive-like behaviors induced by chronic corticosterone exposure. Furthermore, behavioral outcomes induced by a single stimulation were associated with neuronal activation in the prefrontal cortex, dorsal hippocampus, ventral tegmental area and nucleus accumbens, whereas no overexpression of c-fos was associated with 10 stimulations. Conclusion The strongest behavioral response was observed with an anodal stimulation of 200 μA during 20min. The repetition of this stimulation was necessary to induce long-lasting behavioral effects that are probably associated with plastic changes in the neuronal response. [ABSTRACT FROM AUTHOR]

Iron deficiency continues to be the most prevalent micronutrient deficit worldwide. Since iron is involved in several processes including myelination, dopamine neurotransmission and neuronal metabolism, the presence of iron deficiency anemia (IDA) in infancy relates to long-lasting neurofunctional effects. There is scarce data regarding whether these effects would extend to former iron deficient anemic human adults. Resting state functional magnetic resonance imaging (fMRI) is a novel technique to explore patterns of functional connectivity. Default Mode Network (DMN), one of the resting state networks, is deeply involved in memory, social cognition and self-referential processes. The four core regions consistently identified in the DMN are the medial prefrontal cortex, posterior cingulate/retrosplenial cortex and left and right inferior parietal cortex. Therefore to investigate the DMN in former iron deficient anemic adults is a particularly useful approach to elucidate de long term effects on functional brain. We conducted this research to explore the connection between IDA in infancy and altered patterns of resting state brain functional networks in young adults. Resting-state fMRI studies were performed to 31 participants that belong to a follow-up study since infancy. Of them, 14 participants were former iron deficient anemic in infancy and 17 were controls, with mean age of 21.5 years (±1.5) and 54.8% were males. Resting-state fMRI protocol was used and the data was analyzed using the seed based connectivity statistical analysis to assess the DMN. We found that compared to controls, former iron deficient anemic subjects showed posterior DMN decreased connectivity to the left posterior cingulate cortex (PCC), whereas they exhibited increased anterior DMN connectivity to the right PCC. Differences between groups were also apparent in the left medial frontal gyrus, with former iron deficient anemic participants having increased connectivity with areas included in DMN and dorsal attention networks. These preliminary results suggest different patterns of functional connectivity between former iron deficient anemic and control young adults. Indeed, IDA in infancy, a common nutritional problem among human infants, may turn out to be important for understanding the mechanisms of cognitive alterations, common in adulthood. [ABSTRACT FROM AUTHOR]

Tributyltin (TBT) is a typical organic pollutant that persists in aquatic sediments due to its wide usage as an antifouling fungicide during the past few decades. Despite increased awareness of the serious negative consequences of TBT on aquatic species, studies on the effects of TBT exposure on cephalopod embryonic development and juvenile physiological performance are scarce. To investigate the lasting effects of TBT toxicity on Sepia pharaonis from embryo to hatchling, embryos (gastrula stage, 3–5 h post fertilization) were exposed to four levels of TBT until hatching: 0 (control), 30 (environmental level), 60, and 120 ng/L. Subsequently, juvenile growth performance endpoints and behavioral alterations were assessed over 15 days post-hatching. Egg hatchability was significantly reduced and embryonic development (i.e., premature hatching) was accelerated in response to 30 ng/L TBT exposure. Meanwhile, TBT-induced alterations in embryonic morphology primarily included yolk-sac lysis, embryonic malformations, and uneven pigment distributions. During the pre-middle stage of embryonic development, the eggshell serves as an effective barrier to safeguard the embryo from exposure to 30–60 ng/L TBT, according to patterns of TBT accumulation and distribution in the egg compartment. However, even environmental relevant levels of TBT (30 ng/L) exposure during embryonic development had a negative impact on juvenile behavior and growth, including slowing growth, shortening eating times, causing more irregular movements, and increasing inking times. These findings indicate that after TBT exposure, negative long-lasting effects on S. pharaonis development from embryo to hatchling persist, suggesting that long-lasting toxic effects endure from S. pharaonis embryos to hatchlings. • TBT exposure was first introduced into cephalopods. • TBT exposure induced severe yolk sac lysis in embryos. • Long-lasting toxic effects endure from embryos to hatchlings. [ABSTRACT FROM AUTHOR]

• Late lactational 15 min/d MD induces antidepressant effects in male adult mice. • Late lactational 15 min/d MD increases the social dominance of male adult mice. • Late lactational 3 h/d MD decreases the social dominance of female adult mice. The lactation period is an important period for individual development and a sensitive period for the behavioral phenotypes and plasticity of individual offspring. Early life experiences (e.g., maternal deprivation (MD) and neglect) have significant long-lasting and dual effects on individual stress reactivities during adulthood. Theoretically, stress inoculation can improve the adaptive capacity of the body, but overstress can lead to dysfunction when adaptive mechanisms fail. To date, the potential effects of late lactational MD on the socioemotional behaviors of mouse offspring during adulthood are still not fully understood. In the present study, mice were subjected to early deprivation by individually separating pups from their dam for 0 min, 15 min, and 3 h per day from PND 13–25. The social dominance test (SDT), social interaction test (SI), open field test (OFT), and forced swim test (FST) were carried out during adulthood. The results showed that the social dominance of male mice in the 15 min/d MD group significantly increased, especially in low-rank mice. In the 3 h/d MD group, the social dominance of female mice was decreased, especially in the lower-rank mice. The anxiolytic and antidepressant-like effects of the 15 min/d MD group were significantly increased in male mice. Our study provides direct evidence that MD during late lactation period results in long-lasting effects on social dominance as well as on anxiety and depression phenotypes in a sex-dependent manner. [ABSTRACT FROM AUTHOR]

Adherence is a major issue in any medical treatment. Allergen immunotherapy (AIT) is particularly affected by a poor adherence because a flawed application prevents the immunological effects that underlie the clinical outcome of the treatment. Sublingual immunotherapy (SLIT) was introduced in the 1990s, and the early studies suggested that adherence and compliance to such a route of administration was better than the traditional subcutaneous route. However, the recent data from manufacturers revealed that only 13 % of patients treated with SLIT reach the recommended 3-year duration. Therefore, improved adherence to SLIT is an unmet need that may be achieved by various approaches. The utility of patient education and accurate monitoring during the treatment was demonstrated by specific studies, while the success of technology-based tools, including online platforms, social media, e-mail, and a short message service by phone, is currently considered to improve the adherence. This goal is of pivotal importance to fulfill the object of SLIT that is to modify the natural history of allergy, ensuring a long-lasting clinical benefit, and a consequent pharmaco-economic advantage, when patients complete at least a 3-year course of treatment. [ABSTRACT FROM AUTHOR]

Objective To show that neck proprioceptive input can induce long-term effects on vestibular-dependent self-motion perception. Methods Motion perception was assessed by measuring the subject’s error in tracking in the dark the remembered position of a fixed target during whole-body yaw asymmetric rotation of a supporting platform, consisting in a fast rightward half-cycle and a slow leftward half-cycle returning the subject to the initial position. Neck muscles were relaxed or voluntarily contracted, and/or vibrated. Whole-body rotation was administered during or at various intervals after the vibration train. The tracking position error (TPE) at the end of the platform rotation was measured during and after the muscle conditioning maneuvers. Results Neck input produced immediate and sustained changes in the vestibular perceptual response to whole-body rotation. Vibration of the left sterno-cleido-mastoideus (SCM) or right splenius capitis (SC) or isometric neck muscle effort to rotate the head to the right enhanced the TPE by decreasing the perception of the slow rotation. The reverse effect was observed by activating the contralateral muscle. The effects persisted after the end of SCM conditioning, and slowly vanished within several hours, as tested by late asymmetric rotations. The aftereffect increased in amplitude and persistence by extending the duration of the vibration train (from 1 to 10 min), augmenting the vibration frequency (from 5 to 100 Hz) or contracting the vibrated muscle. Symmetric yaw rotation elicited a negligible TPE, upon which neck muscle vibrations were ineffective. Conclusions Neck proprioceptive input induces enduring changes in vestibular-dependent self-motion perception, conditional on the vestibular stimulus feature, and on the side and the characteristics of vibration and status of vibrated muscles. This shows that our perception of whole-body yaw-rotation is not only dependent on accurate vestibular information, but is modulated by proprioceptive information related to previously experienced position of head with respect to trunk. Significance Tonic proprioceptive inflow, as might occur as a consequence of enduring or permanent head postures, can induce adaptive plastic changes in vestibular-dependent motion sensitiveness. These changes might be counteracted by vibration of selected neck muscles. [ABSTRACT FROM AUTHOR]

Abstract: Oxytocin (OXT) has been implicated in the regulation of social behaviors, including intermale offensive aggression. Recently, we showed that acute enhancement of brain OXT levels markedly suppressed offensive aggression and increased social exploration in resident rats confronted with an intruder in their home territory. Moreover, a different responsivity to the exogenous OXTergic manipulation was observed among individuals based on their baseline aggression. In this study we aimed at evaluating the behavioral response to chronically enhancing or attenuating central OXT levels, and at scrutinizing whether the trait-aggression moderates the treatment-induced behavioral changes. To this end, resident male wild-type Groningen rats were continuously (via osmotic minipumps) intracerebroventricularly infused with synthetic OXT or a selective OXT receptor (OXTR) antagonist for 7days. Changes in behavior were assessed performing a resident–intruder test before and at the end of the treatment period, as well as after 7days of withdrawal. Chronic infusion of OXT was found to selectively suppress aggression and enhance social exploration. Chronic blockage of OXTRs instead increased introductory aggressive behavior (i.e. lateral threat), yet without affecting the total duration of the aggression. The magnitude of the anti-aggressive changes correlated positively with the level of baseline aggression. Interestingly, OXT-induced behavioral changes persisted 7days after cessation of the treatment. In conclusion, these findings provide further evidence that enhanced functional activity of the central OXTergic system decreases social offensive aggression while it increases social explorative behavior. The data also indicate that chronically enhancing brain OXT levels may cause enduring anti-aggressive and pro-social explorative behavioral effects. [Copyright &y& Elsevier]

Despite some successful interventions and the large research efforts on this topic, iron deficiency and anemia remain the most common nutritional disorders in the world today. Recently, several researchers indicated that early, induced, iron deficiency produced a long-lasting effect even if the hemoglobin and iron levels returned to normal values. Recent human studies showed that 10–12-year-old children, who were iron deficient at age 1 year, showed lower IQ scores. In this study, we tried to imitate this condition by inducing iron deficiency in rats at age 21 days, for 28 days, and then tested the rats on day 120. The former iron-deficient rats had normal hematological and motor activity values, and normal thermoregulatory response, but they were very slow learners compared to the control rats. Treatment with a mixture of essential fatty acids improved their learning capacity. [ABSTRACT FROM AUTHOR]

Purpose: Some evidence suggests that levetiracetam (LEV) possesses antiepileptogenic characteristics. The purpose of this study was to investigate the time course of seizure protection by LEV compared with that of phenytoin (PHT), phenobarbital (PB), valproate (VPA), and carbamazepine (CBZ) in the spontaneously epileptic rat (SER). The SER is a double mutant ( tm/tm, zi/zi) showing both tonic convulsions and absence-like seizures. Methods: The effect of single (40, 80, and 160 mg/kg, i.p.) and 5-day (80 mg/kg/day, i.p.) administration of LEV on tonic convulsions and absence-like seizures in SERs were studied. Tonic convulsions induced by blowing air onto the animal's head at 5-min intervals for 30 min and spontaneous absence-like seizures characterized by 5- to 7-Hz spike–wave-like complexes in the cortical and hippocampal EEG were recorded for 30 min. In the single-administration study, observations for seizure activity were performed once before and 3 times (45, 75, and 135 min) after drug administration. In the 5-day administration study, seizure observation was performed 4 times for 30 min (once before and 3 times after drug administration) during the 5-day drug-administration period, and continued once a day until 8 days after the final administration. The antiepileptic effects of 5-day administration of conventional AEDs (PHT, PB, VPA, and CBZ) were examined by using similar methods. Results: Tonic convulsions and absence-like seizures were inhibited by a single administration of LEV at 80 and 160 mg/kg, i.p., but not significantly at 40 mg/kg, i.p. When LEV was repeatedly administered at 80 mg/kg/day, i.p., for 5 days to SERs, the inhibitory effects on seizures increased with administration time. The number of tonic convulsions and absence-like seizures were significantly reduced to 39.1% and 38.4% compared with previous values, respectively, after 5-day LEV administration. Furthermore, significant inhibition of tonic convulsions was detected ≤3 days after the final administration, and significant inhibition of absence-like seizures was still observed 8 days after the final injection of LEV. This demonstrates long-lasting seizure protection by LEV after cessation of treatment. PHT, PB, VPA, and CBZ inhibited tonic convulsions more potently compared with LEV in SERs. The maximal antiseizure effects of these drugs were reached after the initial administration, with almost the same antiseizure effects observed through day 5, despite continued drug administration. Moreover, a long-lasting treatment effect was not observed with any of these drugs except for PHT and CBZ, both of which showed moderately prolonged antiseizure effects. Conclusions: These results show that LEV is effective in the treatment of both convulsive and absence-like seizures in SERs after single- and multiple-dose administration. Interestingly, in the 5-day administration study, it was found that the antiepileptic effects for tonic convulsions and absence-like seizures were observed both during the drug-administration period and ≤8 days after the final administration of LEV. This long-lasting effect suggests that LEV may possess an antiepileptogenic effect that it does not share with PHT, PB, VPA, and CBZ. [ABSTRACT FROM AUTHOR]

Abstract: Single stress induces long-lasting changes in the hypothalamo-pituitary–adrenal (HPA) axis of adult animals. Selective oxytocin (OXT) receptor antagonist was administrated into the cerebroventricle of male rats to test its influence on plasma adrenocorticotropic hormone (ACTH) responses induced by immobilization stress. The ACTH level is significantly higher than the control level (P<0.05) up to 6 days after single stress. Although the OXT antagonist did not change the plasma ACTH level at the end of single stress (P=0.59), the antagonist significantly decreased the ACTH concentration at the end of repeated (3 days) stress and 2 days after single stress (P<0.05) compared with controls. The results suggest that endogenous brain OXT enhances the long-lasting but not immediate HPA axis response to stress. [Copyright &y& Elsevier]

Objective: We investigated whether the mid-term impact (1 week posttraining) of a "combined cognitive rehabilitation (CRP)/transcranial direct current stimulation (tDCS) program" on the performance of a Go/No-go task was enhanced compared with isolated CRP and whether it varied according to the stimulation site (right inferior frontal gyrus [rIFG] vs right dorsolateral prefrontal cortex [rDLPFC])., Methods: A total of 150 healthy participants were assigned to (1) an Inhibition Training (IT) group, (2) a group receiving active tDCS over the rIFG in combination with IT (IT + IF), (3) a group receiving active tDCS over the rDLPFC in combination with IT (IT + DL), (4) a group receiving IT with sham tDCS (ITsham), and (5) a No-Training (NT) group to control for test-retest effects. Each group undertook 3 sessions of a Go/No-go task concomitant with the recording of event-related potentials (T0, before training; T1, at the end of a 4-day training session [20 minutes each day]; T2, 1 week after T1)., Results: With the exception of the NT participants, all the groups exhibited improved performances at T2. The IT + DL group exhibited the best improvement profile, indexed by faster response times (RTs) (T0 > T1 = T2), with a reduced rate of errors at the posttraining sessions compared with both T0 and T1. This "inhibitory learning effect" was neurophysiologically indexed by shorter No-go N2d latencies and enhanced No-go P3d amplitudes., Conclusion: CRP combined with active tDCS over the rDLPFC appears to be optimal for boosting long-term (one week) inhibitory skills as it induced specific and robust neural changes.

Tumor antigen-targeting monoclonal antibodies (TA-targeting mAbs) are used as therapeutics in many malignancies and their capacity to mobilize the host immunity puts them at the forefront of anti-cancer immunotherapies. Both innate and adaptive immune cells have been associated with the therapeutic activity of such antibodies, but tumor escape from mAb-induced tumor immune surveillance remains one of the main clinical issues. In this preclinical study, we grafted immunocompetent and immunocompromised mice with the B16F10 mouse melanoma cell line and treated them with the TA99 TA-targeting mAb to analyze the immune mechanisms associated with the tumor response and resistance to TA99 monotherapy. In immunocompetent mice TA99 treatment strongly increased the fraction of CD8 and CD4 effector T cells in the tumor compared with isotype control, highlighting the specific immune modulation of the tumor microenvironment by TA99. However, in most mice, TA99 immunotherapy could not prevent immune effector exhaustion and the recruitment of regulatory CD4 T cells and consequently tumor escape from immune surveillance. Remarkably, anti-PD-1 treatment at the time of tumor emergence restored the Th1 effector functions of CD4 and CD8 T cells as well as of natural killer and γδT cells, which translated into a significant slow-down of tumor progression and extended survival. Our findings provide the first evidence that PD-1 blockade at the time of tumor emergence can efficiently boost the host anti-tumor immune response initiated several weeks before by the TA-targeting mAb. These results are promising for the design of combined therapies to sensitize non-responder or resistant patients. [ABSTRACT FROM AUTHOR]