ResearchPad - neurochemicals https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[The Childbirth Experience Questionnaire (CEQ)—Validation of its use in a Danish-speaking population of new mothers stimulated with oxytocin during labour]]> https://www.researchpad.co/article/elastic_article_14579 When determining optimal treatment regimens, patient reported outcomes including satisfaction are increasingly appreciated. It is well established that the birth experience may affect the postnatal attachment to the newborn and the management of subsequent pregnancies and deliveries. As we have no robust validated Danish tool to evaluate the childbirth experience exists, we aimed to perform a transcultural adaptation of the Childbirth Experience Questionnaire (CEQ) to a Danish context.MethodsIn accordance with the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN), we translated the Swedish-CEQ to Danish. The Danish-CEQ was tested for content validity among 10 new mothers. In a population of women who have had their labour induced, we then assessed the electronic questionnaire for validity and reliability using factor analytical design, hypothesis testing, and internal consistency. Based on these data, we determined criterion and construct responsiveness in addition to floor and ceiling effects.ResultsThe content validation resulted in minor adjustments in two items. This improved the comprehensibility. The electronic questionnaire was completed by 377 of 495 women (76.2%). The original Swedish-CEQ was four-dimensional, however an exploratory factor analysis revealed a three-dimensional structure in our Danish population (Own capacity, Participation, and Professional support). Parous women, women who delivered vaginally, and women with a labour duration <12 hours had a higher score in each domain. The internal consistency (Cronbach’s alpha) ranged between 0.75 and 0.89 and the ICC between 0.68–0.93. We found ceiling effects of 57.6% in the domain Professional support and of 25.5% in the domain Participation.ConclusionThis study offers transcultural adaptation of the Swedish-CEQ to a Danish context. The 3-dimensional Danish-CEQ demonstrates construct validity and reliability. Our results revealed significant ceiling effect especially in the domain Professional support, which needs to be acknowledged when considering implementing the Danish-CEQ into trials and clinical practice. ]]> <![CDATA[Bilateral Parkinson’s disease model rats exhibit hyperalgesia to subcutaneous formalin administration into the vibrissa pad]]> https://www.researchpad.co/article/Nc1e56242-0f9e-4dec-b14c-0acf3482ec2d

We bilaterally injected 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of rats and developed bilateral Parkinson’s disease (PD) model rats in order to experimentally investigate the neural mechanisms underlying the alteration of nociception in the orofacial region of patients with PD. We explored the effects of dopamine depletion on nociception by investigating behavioral responses (face rubbing) triggered by subcutaneous administration of formalin into the vibrissa pad. We also assessed the number of c-Fos–immunoreactive (c-Fos-IR) cells in the superficial layers of the trigeminal spinal subnucleus caudalis (Vc). Subcutaneous formalin administration evoked a two-phase increase in face rubbing. We observed the first increase 0–5 min after formalin administration (first phase) and the second increase 10–60 min after administration (second phase). The number of face rubbing behaviors of 6OHDA–injected rats did not significantly change compared with saline–injected rats in both phases. Significant increase of c-Fos-IR cells in the Vc was found in 6-OHDA–injected rats after formalin administration compared with those in saline–injected rats after formalin administration. We also assessed expression of c-Fos-IR cells in the paraventricular nucleus (PVN), and significant decrease of c-Fos-IR cells in the PVN of 6-OHDA–injected rats was found. Taken together, these findings suggest that bilateral dopaminergic denervation evoked by 6-OHDA administration causes hyperalgesia in the trigeminal region and the PVN may be involved in the hyperalgesia.

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<![CDATA[Predicting resource-dependent maternal health outcomes at a referral hospital in Zanzibar using patient trajectories and mathematical modeling]]> https://www.researchpad.co/article/5c8823d5d5eed0c4846390ee

Poor intra-facility maternity care is a major contributor to maternal mortality in low- and middle-income countries. Close to 830 women die each day due to preventable maternal complications, partly due to the increasing number of women giving birth in health facilities that are not adequately resourced to manage growing patient populations. Barriers to adequate care during the ‘last mile’ of healthcare delivery are attributable to deficiencies at multiple levels: education, staff, medication, facilities, and delays in receiving care. Moreover, the scope and multi-scale interdependence of these factors make individual contributions of each challenging to analyze, particularly in settings where basic data registration is often lacking. To address this need, we have designed and implemented a novel systems-level and dynamic mathematical model that simulates the impact of hospital resource allocations on maternal mortality rates at Mnazi Mmoja Hospital (MMH), a referral hospital in Zanzibar, Tanzania. The purpose of this model is to provide a rigorous and flexible tool that enables hospital administrators and public health officials to quantitatively analyze the impact of resource constraints on patient outcomes within the maternity ward, and prioritize key areas for further human or capital investment. Currently, no such tool exists to assist administrators and policy makers with effective resource allocation and planning. This paper describes the structure and construct of the model, provides validation of the assumptions made with anonymized patient data and discusses the predictive capacity of our model. Application of the model to specific resource allocations, maternal treatment plans, and hospital loads at MMH indicates through quantitative results that medicine stocking schedules and staff allocations are key areas that can be addressed to reduce mortality by up to 5-fold. With data-driven evidence provided by the model, hospital staff, administration, and the local ministries of health can enact policy changes and implement targeted interventions to improve maternal health outcomes at MMH. While our model is able to determine specific gaps in resources and health care delivery specifically at MMH, the model should be viewed as an additional tool that may be used by other facilities seeking to analyze and improve maternal health outcomes in resource constrained environments.

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<![CDATA[Citrulline protects mice from experimental cerebral malaria by ameliorating hypoargininemia, urea cycle changes and vascular leak]]> https://www.researchpad.co/article/5c8c194bd5eed0c484b4d370

Clinical and model studies indicate that low nitric oxide (NO) bioavailability due in part to profound hypoargininemia contributes to cerebral malaria (CM) pathogenesis. Protection against CM pathogenesis may be achieved by altering the diet before infection with Plasmodium falciparum infection (nutraceutical) or by administering adjunctive therapy that decreases CM mortality (adjunctive therapy). This hypothesis was tested by administering citrulline or arginine in experimental CM (eCM). We report that citrulline injected as prophylaxis immediately post infection (PI) protected virtually all mice by ameliorating (i) hypoargininemia, (ii) urea cycle impairment, and (iii) disruption of blood brain barrier. Citrulline prophylaxis inhibited plasma arginase activity. Parasitemia was similar in citrulline- and vehicle control-groups, indicating that protection from pathogenesis was not due to decreased parasitemia. Both citrulline and arginine administered from day 1 PI in the drinking water significantly protected mice from eCM. These observations collectively indicate that increasing dietary citrulline or arginine decreases eCM mortality. Citrulline injected ip on day 4 PI with quinine-injected ip on day 6 PI partially protected mice from eCM; citrulline plus scavenging of superoxide with pegylated superoxide dismutase and pegylated catalase protected all recipients from eCM. These findings indicate that ameliorating hypoargininemia with citrulline plus superoxide scavenging decreases eCM mortality.

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<![CDATA[Impulsivity across reactive, proactive and cognitive domains in Parkinson's disease on dopaminergic medication: Evidence for multiple domain impairment]]> https://www.researchpad.co/article/5c6dc9fad5eed0c48452a639

Impulse control disorders (ICD) may occur in Parkinson’s disease (PD) although it remains to be understood if such deficits may occur even in the absence of a formal ICD diagnosis. Moreover, studies addressing simultaneously distinct neurobehavioral domains, such as cognitive, proactive and reactive motor impulsivity, are still lacking. Here, we aimed to investigate if reactive, proactive and cognitive impulsivity involving risk taking are concomitantly affected in medicated PD patients, and whether deficits were dependent on response strategies, such as speed accuracy tradeoffs, or the proportion of omission vs. commission errors. We assessed three different impulsivity domains in a sample of 21 PD patients and 13 matched controls. We found impaired impulsivity in both reactive (p = 0.042) and cognitive domains (p = 0.015) for the PD patients, irrespective of response strategy. For the latter, effect sizes were larger for the actions related with reward processing (p = 0.017, dCohen = 0.9). In the proactive impulsivity task, PD patients showed significantly increased number of omissions (p = 0.041), a response strategy which was associated with preserved number of commission errors. Moreover, the number of premature and proactive response errors were correlated with disease stage. Our findings suggest that PD ON medication is characterized compared to healthy controls by impairment across several impulsivity domains, which is moderated in the proactive domain by the response strategy.

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<![CDATA[A combined computational strategy of sequence and structural analysis predicts the existence of a functional eicosanoid pathway in Drosophila melanogaster]]> https://www.researchpad.co/article/5c6c7583d5eed0c4843cfe40

This study reports on a putative eicosanoid biosynthesis pathway in Drosophila melanogaster and challenges the currently held view that mechanistic routes to synthesize eicosanoid or eicosanoid-like biolipids do not exist in insects, since to date, putative fly homologs of most mammalian enzymes have not been identified. Here we use systematic and comprehensive bioinformatics approaches to identify most of the mammalian eicosanoid synthesis enzymes. Sensitive sequence analysis techniques identified candidate Drosophila enzymes that share low global sequence identities with their human counterparts. Twenty Drosophila candidates were selected based upon (a) sequence identity with human enzymes of the cyclooxygenase and lipoxygenase branches, (b) similar domain architecture and structural conservation of the catalytic domain, and (c) presence of potentially equivalent functional residues. Evaluation of full-length structural models for these 20 top-scoring Drosophila candidates revealed a surprising degree of conservation in their overall folds and potential analogs for functional residues in all 20 enzymes. Although we were unable to identify any suitable candidate for lipoxygenase enzymes, we report structural homology models of three fly cyclooxygenases. Our findings predict that the D. melanogaster genome likely codes for one or more pathways for eicosanoid or eicosanoid-like biolipid synthesis. Our study suggests that classical and/or novel eicosanoids mediators must regulate biological functions in insects–predictions that can be tested with the power of Drosophila genetics. Such experimental analysis of eicosanoid biology in a simple model organism will have high relevance to human development and health.

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<![CDATA[The availability, prices and affordability of essential medicines in Malawi: A cross-sectional study]]> https://www.researchpad.co/article/5c6c75d2d5eed0c4843d025a

Introduction

The Malawian government recently introduced cost-covering consultation fees for self-referral patients in tertiary public hospitals. Previously, patients received medicines free of charge in government-owned health facilities, but must pay elsewhere. Before the government implements a payment policy in other areas of health care, it is important to investigate the prices, affordability and availability of essential medicines in Malawi.

Methods

Data on availability and prices of 50 essential medicines were collected in 44 health facilities in two major cities and two districts. These included 12 public facilities, 11 facilities of the Christian Health Association of Malawi (CHAM), nine retail pharmacies, eight wholesalers and four private clinics/hospitals. Price, availability and affordability were assessed based on the methodology developed by the World Health Organization and Health Action International, which compares local prices to international reference prices.

Results and discussion

The overall availability of medicines was 48.5% in public facilities, 71.1% in retail pharmacies, 62.9% in CHAM facilities and 57.5% in private clinics. The availability of essential medicines varied from 0% for ethosuximide to 100% for amoxicillin and cotrimoxazole tablets. Antibiotic formulations for adults were widely available, in contrast to the low availability of pediatric formulations. Several medicines for non-communicable diseases like sodium valproate, phenytoin, paraldehyde, captopril and simvastatin showed poor availability and affordability. The overall median price ratio compared to the international reference price was 1.11 for wholesalers, 2.54 in CHAM facilities, 2.70 in retail pharmacies, and 4.01 in private clinics, which is low compared to other countries. But nevertheless, for 18 out of 32 medicines assessed, the cost of one course exceeded the statutory minimum daily wage, making them unaffordable to a majority of the population. Therefore, continued provision of free public health care is still of critical importance for the foreseeable future until other financing mechanisms have been explored.

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<![CDATA[The influence of a hot environment on physiological stress responses in exercise until exhaustion]]> https://www.researchpad.co/article/5c648d4dd5eed0c484c824d1

Exhaustive exercise in a hot environment can impair performance. Higher epinephrine plasma levels occur during exercise in heat, indicating greater sympathetic activity. This study examined the influence of exercise in the heat on stress levels. Nine young healthy men performed a maximal progressive test on a cycle ergometer at two different environmental conditions: hot (40°C) and normal (22°C), both between 40% and 50% relative humidity. Venous blood and saliva samples were collected pre-test and post-test. Before exercise there were no significant changes in salivary biomarkers (salivary IgA: p = 0.12; α-amylase: p = 0.66; cortisol: p = 0.95; nitric oxide: p = 0.13; total proteins: p = 0.07) or blood lactate (p = 0.14) between the two thermal environments. Following exercise, there were significant increases in all variables (salivary IgA 22°C: p = 0.04, 40°C: p = 0.0002; α-amylase 22°C: p = 0.0002, 40°C: p = 0.0002; cortisol 22°C: p = 0.02, 40°C: p = 0.0002; nitric oxide 22°C: p = 0.0005, 40°C: p = 0.0003, total proteins 22°C: p<0.0001, 40°C: p<0.0001 and; blood lactate 22°C: p<0.0001, 40°C: p<0.0001) both at 22°C and 40°C. There was no significant adjustment regarding IgA levels between the two thermal environments (p = 0.74), however the levels of α-amylase (p = 0.02), cortisol (p<0.0001), nitric oxide (p = 0.02) and total proteins (p = 0.01) in saliva were higher in the hotter conditions. Blood lactate was lower under the hot environment (p = 0.01). In conclusion, enduring hot temperature intensified stressful responses elicited by exercise. This study advocates that hot temperature deteriorates exercise performance under exhaustive stress and effort conditions.

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<![CDATA[Serotonin and neuropeptides are both released by the HSN command neuron to initiate Caenorhabditis elegans egg laying]]> https://www.researchpad.co/article/5c536ad5d5eed0c484a479f2

Neurons typically release both a small-molecule neurotransmitter and one or more neuropeptides, but how these two types of signal from the same neuron might act together remains largely obscure. For example, serotonergic neurons in mammalian brain express the neuropeptide Substance P, but it is unclear how this co-released neuropeptide might modulate serotonin signaling. We studied this issue in C. elegans, in which all serotonergic neurons express the neuropeptide NLP-3. The serotonergic Hermaphrodite Specific Neurons (HSNs) are command motor neurons within the egg-laying circuit which have been shown to release serotonin to initiate egg-laying behavior. We found that egg-laying defects in animals lacking serotonin were far milder than in animals lacking HSNs, suggesting that HSNs must release other signal(s) in addition to serotonin to stimulate egg laying. While null mutants for nlp-3 had only mild egg-laying defects, animals lacking both serotonin and NLP-3 had severe defects, similar to those of animals lacking HSNs. Optogenetic activation of HSNs induced egg laying in wild-type animals, and in mutant animals lacking either serotonin or NLP-3, but failed to induce egg laying in animals lacking both. We recorded calcium activity in the egg-laying muscles of animals lacking either serotonin, NLP-3, or both. The single mutants, and to a greater extent the double mutant, showed muscle activity that was uncoordinated and unable to expel eggs. Specifically, the vm2 muscles cells, which are direct postsynaptic targets of the HSN, failed to contract simultaneously with other egg-laying muscle cells. Our results show that the HSN neurons use serotonin and the neuropeptide NLP-3 as partially redundant co-transmitters that together stimulate and coordinate activity of the target cells onto which they are released.

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<![CDATA[Kami-shoyo-san improves ASD-like behaviors caused by decreasing allopregnanolone biosynthesis in an SKF mouse model of autism]]> https://www.researchpad.co/article/5c5ca2dcd5eed0c48441ebe8

Dysfunctions in the GABAergic system are associated with the pathogenesis of autism spectrum disorder (ASD). However, the mechanisms by which GABAergic system dysfunctions induce the pathophysiology of ASD remain unclear. We previously demonstrated that a selective type I 5α-reductase inhibitor SKF105111 (SKF) induced ASD-like behaviors, such as impaired sociability-related performance and repetitive grooming behaviors, in male mice. Moreover, the effects of SKF were caused by a decrease in the endogenous levels of allopregnanolone (ALLO), a positive allosteric modulator of the GABAA receptor. In this study, we used SKF-treated male mice as a putative animal model of ASD and examined the effects of Kami-shoyo-san (KSS) as an experimental therapeutic strategy for ASD. KSS is a traditional Kampo formula consisting of 10 different crude drugs and has been used for the treatment of neuropsychiatric symptoms. KSS dose-dependently attenuated sociability deficits and suppressed an increase in grooming behaviors in SKF-treated mice without affecting ALLO content in the prefrontal cortex. The systemic administration of the dopamine D1 receptor antagonist SCH23390 reversed the ameliorative effects of KSS. On the other hand, the dopamine D2 receptor antagonist sulpiride and GABAA receptor antagonist bicuculline only attenuated the ameliorative effect of KSS on repetitive self-grooming behaviors. The present results indicate that KSS improves SKF-induced ASD-like behaviors by facilitating dopamine receptor-mediated mechanisms and partly by neurosteroid-independent GABAA receptor-mediated neurotransmission. Therefore, KSS is a potential candidate for the treatment of ASD.

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<![CDATA[Resilient hepatic mitochondrial function and lack of iNOS dependence in diet-induced insulin resistance]]> https://www.researchpad.co/article/5c61e8b8d5eed0c48496f037

Obesity-derived inflammation and metabolic dysfunction has been related to the activity of the inducible nitric oxide synthase (iNOS). To understand the interrelation between metabolism, obesity and NO., we evaluated the effects of obesity-induced NO. signaling on liver mitochondrial function. We used mouse strains containing mitochondrial nicotinamide transhydrogenase activity, while prior studies involved a spontaneous mutant of this enzyme, and are, therefore, more prone to oxidative imbalance. Wild-type and iNOS knockout mice were fed a high fat diet for 2, 4 or 8 weeks. iNOS knockout did not protect against diet-induced metabolic changes. However, the diet decreased fatty-acid oxidation capacity in liver mitochondria at 4 weeks in both wild-type and knockout groups; this was recovered at 8 weeks. Interestingly, other mitochondrial functional parameters were unchanged, despite significant modifications in insulin resistance in wild type and iNOS knockout animals. Overall, we found two surprising features of obesity-induced metabolic dysfunction: (i) iNOS does not have an essential role in obesity-induced insulin resistance under all experimental conditions and (ii) liver mitochondria are resilient to functional changes in obesity-induced metabolic dysfunction.

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<![CDATA[Omega-3 and -6 fatty acid plasma levels are not associated with liver cirrhosis-associated systemic inflammation]]> https://www.researchpad.co/article/5c5ca296d5eed0c48441e70f

Background

Liver cirrhosis is associated with profound immunodysfunction, i.e. a parallel presence of chronic systemic inflammation and immunosuppression, which can result in acute-on-chronic liver failure (ACLF). Omega-3 fatty acids are precursors of pro-resolving mediators and support the resolution of inflammation.

Objective

The aim of this study was to determine plasma levels of omega-3 fatty acids in patients with liver cirrhosis and ACLF.

Methods

Patients with liver cirrhosis with and without ACLF were enrolled in a prospective cohort study and analyzed post-hoc for the present sub-study. Clinical data and biomaterials were collected at baseline and at day 7, 28 and after 3 months of follow-up. Plasma concentrations of arachidonic acid (ARA) and docosahexaenoic acid (DHA), which represent key omega-6 and -3 fatty acids, respectively, were quantified and associated with markers of systemic inflammation and severity of liver cirrhosis.

Results

A total of 117 patients were included in the present analyses. Of those, 26 (22.2%), 51 (43.6%) and 40 (34.2%) patients had compensated or decompensated liver cirrhosis, and ACLF. Plasma levels of ARA and DHA were similar in patients with compensated cirrhosis, decompensated cirrhosis, and ACLF. Furthermore, no significant association between plasma ARA or DHA and C-reactive protein or peripheral blood leukocytes were observed (P>0.05).

Conclusion

In our study plasma levels of key omega-3 and omega-6 fatty acid are neither associated with the severity of liver cirrhosis nor with liver-cirrhosis-associated systemic inflammation.

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<![CDATA[Cell type-specific differences in redox regulation and proliferation after low UVA doses]]> https://www.researchpad.co/article/5c57e6d0d5eed0c484ef3ec4

Ultraviolet A (UVA) radiation is harmful for living organisms but in low doses may stimulate cell proliferation. Our aim was to examine the relationships between exposure to different low UVA doses, cellular proliferation, and changes in cellular reactive oxygen species levels. In human colon cancer (HCT116) and melanoma (Me45) cells exposed to UVA doses comparable to environmental, the highest doses (30–50 kJ/m2) reduced clonogenic potential but some lower doses (1 and 10 kJ/m2) induced proliferation. This effect was cell type and dose specific. In both cell lines the levels of reactive oxygen species and nitric oxide fluctuated with dynamics which were influenced differently by UVA; in Me45 cells decreased proliferation accompanied the changes in the dynamics of H2O2 while in HCT116 cells those of superoxide. Genes coding for proteins engaged in redox systems were expressed differently in each cell line; transcripts for thioredoxin, peroxiredoxin and glutathione peroxidase showed higher expression in HCT116 cells whereas those for glutathione transferases and copper chaperone were more abundant in Me45 cells. We conclude that these two cell types utilize different pathways for regulating their redox status. Many mechanisms engaged in maintaining cellular redox balance have been described. Here we show that the different cellular responses to a stimulus such as a specific dose of UVA may be consequences of the use of different redox control pathways. Assays of superoxide and hydrogen peroxide level changes after exposure to UVA may clarify mechanisms of cellular redox regulation and help in understanding responses to stressing factors.

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<![CDATA[Chemical composition, antioxidant, anti-inflammatory, and cytotoxic activities of Opuntia stricta cladodes]]> https://www.researchpad.co/article/5c59feb5d5eed0c48413531a

Background

The Opuntia spp. have been used in traditional medicine for many centuries. It is used in the management of diseases that involves oxidative stress, especially diabetes, obesity and cancer. Opuntia stricta (Haw) is one of the relatively unknown species in South Africa where it is regarded more as a weed. Because of this, not much is known about its chemical composition.

Aim

To determine the chemical composition, antioxidant, anti-inflammatory, and cytotoxic activities of Opuntia stricta cladodes.

Methods

The phytochemical composition of acetone, aqueous and ethanol extract of cladodes of Opuntia stricta (Haw), as well as the vitamins A, C and E of its dried weight cladodes and the antioxidant activities, were evaluated using standard in vitro methods. The anti-inflammatory and cytotoxic activities were evaluated using cell-based assays. The phytochemical composition and vitamins were determined spectrophotometrically, while the antioxidant activities were determined by DPPH, nitric oxide, hydrogen peroxide scavenging activity and phosphomolybdenum (total) antioxidant activity. Anti-inflammatory activity was determined using RAW 264.7 cells, while cytotoxicity was determined using U937 cells.

Results

The phytochemical composition showed a significant difference in the various extracts. The total phenolics were higher than other phytochemicals in all the extracts used. All the extracts displayed antioxidant activity, while most of the extracts showed anti-inflammatory activity. Only one extract showed cytotoxicity, and it was mild.

Conclusion

The results show that the Opuntia stricta is rich in polyphenolic compounds and has good antioxidant activity as well as anti-inflammatory activities.

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<![CDATA[Lithium is able to minimize olanzapine oxidative-inflammatory induction on macrophage cells]]> https://www.researchpad.co/article/5c59ff0bd5eed0c4841359bf

Background

Olanzapine (OLZ) is a second-generation antipsychotic drug used for treatment of schizophrenia, bipolar disorder, and other neuropsychiatric conditions. Undesirable side effects of OLZ include metabolic alterations associated with chronic oxidative-inflammation events. It is possible that lithium (Li), a mood modulator that exhibits anti-inflammatory properties may attenuate OLZ-induced oxi-inflammatory effects.

Methodology

To test this hypothesis we activated RAW 264.7 immortalized macrophages with OLZ and evaluated oxidation and inflammation at the gene and protein levels. Li and OLZ concentrations were determined using estimated plasma therapeutic concentrations.

Results

OLZ triggered a significant increase in macrophage proliferation at 72 h. Higher levels of oxidative markers and proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, with a concomitant reduction in IL-10, were observed in OLZ-exposed macrophages. Lithium (Li) exposure triggered a short and attenuated inflammatory response demonstrated by elevation of superoxide anion (SA), reactive oxygen species (ROS), IL-1β, and cellular proliferation followed by elevation of anti-inflammatory IL-10 levels. Li treatment of OLZ-supplemented macrophages was able to reverse elevation of oxidative and inflammatory markers and increase IL-10 levels.

Conclusions

Despite methodological limitations related to in vitro protocols, results suggested that Li may attenuate OLZ-induced oxidative and inflammatory responses that result from metabolic side effects associated with OLZ.

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<![CDATA[Interactive effects of OXTR and GAD1 on envy-associated behaviors and neural responses]]> https://www.researchpad.co/article/5c4243a2d5eed0c4845e0913

Inequity aversion (negative feelings induced by outcome differences between the self and other) plays a key role in human social behaviors. The neurotransmitters oxytocin and GABA have been implicated in neural responses to inequity. However, it remains poorly understood not only how individual genetic factors related to oxytocin and GABA affect the neural mechanisms behind inequity aversion, but also how these genes interact. To address these issues, we examined relationships between genotypes, behavioral decisions and brain activities during the ultimatum game. We identified interactive effects between the polymorphisms of the oxytocin receptor gene (OXTR) and glutamate decarboxylase 1 gene for GABA synthesis (GAD1) on envy aversion (i.e., disadvantageous inequity aversion) and on envy-induced activity in the dorsal ACC (dACC). Thus, our integrated approach suggested interactive genetic effects between OXTR and GAD1 on envy aversion and the underlying neural substrates.

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<![CDATA[Melanotan-II reverses autistic features in a maternal immune activation mouse model of autism]]> https://www.researchpad.co/article/5c40f77dd5eed0c48438626a

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social interactions, difficulty with communication, and repetitive behavior patterns. In humans affected by ASD, there is a male pre-disposition towards the condition with a male to female ratio of 4:1. In part due to the complex etiology of ASD including genetic and environmental interplay, there are currently no available medical therapies to improve the social deficits of ASD. Studies in rodent models and humans have shown promising therapeutic effects of oxytocin in modulating social adaptation. One pharmacological approach to stimulating oxytocinergic activity is the melanocortin receptor 4 agonist Melanotan-II (MT-II). Notably the effects of oxytocin on environmental rodent autism models has not been investigated to date. We used a maternal immune activation (MIA) mouse model of autism to assess the therapeutic potential of MT-II on autism-like features in adult male mice. The male MIA mice exhibited autism-like features including impaired social behavioral metrics, diminished vocal communication, and increased repetitive behaviors. Continuous administration of MT-II to male MIA mice over a seven-day course resulted in rescue of social behavioral metrics. Normal background C57 male mice treated with MT-II showed no significant alteration in social behavioral metrics. Additionally, there was no change in anxiety-like or repetitive behaviors following MT-II treatment of normal C57 mice, though there was significant weight loss following subacute treatment. These data demonstrate MT-II as an effective agent for improving autism-like behavioral deficits in the adult male MIA mouse model of autism.

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<![CDATA[Growth factors expression and ultrastructural morphology after application of low-level laser and natural latex protein on a sciatic nerve crush-type injury]]> https://www.researchpad.co/article/5c3fa5aad5eed0c484ca713c

The effects of low-level laser therapy (LLLT) and natural latex protein (F1, Hevea brasiliensis) were evaluated on crush-type injuries (15kg) to the sciatic nerve in the expressions of nerve growth factor (NGF) and vascular endothelium growth factor (VEGF) and ultrastructural morphology to associate with previous morphometric data using the same protocol of injury and treatment. Thirty-six male rats were allocated into six experimental groups (n = 6): 1-Control; 2-Exposed nerve; 3-Injured nerve; 4-LLLT (15J/cm2, 780nm, 30mW, Continuous Wave) treated injured nerve; 5-F1 (0,1mg) treated injured nerve; and 6-LLLT&F1 treated injured nerve. Four or eight weeks after, sciatic nerve samples were processed for analysis. NGF expression were higher (p<0.05) four weeks after in all injured groups in comparison to Control (Med:0.8; Q1:0; Q3:55.5%area). Among them, the Injured (Med:70.7; Q1:64.4; Q3:77.5%area) showed the highest expression, and F1 (Med:17.3; Q1:14.1; Q3:21.7%area) had the lowest. At week 8, NGF expressions decreased in the injured groups. VEGF was expressed in all groups; its higher expression was observed in the injured groups 4 weeks after (Injured. Med:29.5; F1. Med:17.7 and LLLT&F1. Med:19.4%area). At week 8, a general reduction of VEGF expression was noted, remaining higher in F1 (Med:35.1; Q1.30.6; Q3.39.6%area) and LLLT&F1 (Med:18.5; Q1:16; Q3:25%area). Ultrastructural morphology revealed improvements in the treated groups; 4 weeks after, the F1 group presented greater quantity and diameter of the nerve fibers uniformly distributed. Eight weeks after, the F1 and LLLT&F1 showed similar characteristics to the non-injured groups. In summary, these results and our previous studies indicated that F1 and LLLT may favorably influence the healing of nerve crush injury. Four weeks after nerve injury F1 group showed the best results suggesting recovery acceleration; at 8th week F1 and LLLT&F1 groups presented better features and higher vascularization that could be associated with VEGF maintenance.

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<![CDATA[Coherency of circadian rhythms in the SCN is governed by the interplay of two coupling factors]]> https://www.researchpad.co/article/5c18139dd5eed0c4847755e7

Circadian clocks are autonomous oscillators driving daily rhythms in physiology and behavior. In mammals, a network of coupled neurons in the suprachiasmatic nucleus (SCN) is entrained to environmental light-dark cycles and orchestrates the timing of peripheral organs. In each neuron, transcriptional feedbacks generate noisy oscillations. Coupling mediated by neuropeptides such as VIP and AVP lends precision and robustness to circadian rhythms. The detailed coupling mechanisms between SCN neurons are debated. We analyze organotypic SCN slices from neonatal and adult mice in wild-type and multiple knockout conditions. Different degrees of rhythmicity are quantified by pixel-level analysis of bioluminescence data. We use empirical orthogonal functions (EOFs) to characterize spatio-temporal patterns. Simulations of coupled stochastic single cell oscillators can reproduce the diversity of observed patterns. Our combination of data analysis and modeling provides deeper insight into the enormous complexity of the data: (1) Neonatal slices are typically stronger oscillators than adult slices pointing to developmental changes of coupling. (2) Wild-type slices are completely synchronized and exhibit specific spatio-temporal patterns of phases. (3) Some slices of Cry double knockouts obey impaired synchrony that can lead to co–existing rhythms (“splitting”). (4) The loss of VIP-coupling leads to desynchronized rhythms with few residual local clusters. Additional information was extracted from co–culturing slices with rhythmic neonatal wild-type SCNs. These co–culturing experiments were simulated using external forcing terms representing VIP and AVP signaling. The rescue of rhythmicity via co–culturing lead to surprising results, since a cocktail of AVP-antagonists improved synchrony. Our modeling suggests that these counter-intuitive observations are pointing to an antagonistic action of VIP and AVP coupling. Our systematic theoretical and experimental study shows that dual coupling mechanisms can explain the astonishing complexity of spatio-temporal patterns in SCN slices.

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<![CDATA[Variation in severe postpartum hemorrhage management: A national vignette-based study]]> https://www.researchpad.co/article/5c1c0ac6d5eed0c484426a7b

Objectives

To assess variations in management of severe postpartum hemorrhage: 1) between obstetricians in the same situation 2) by the same obstetrician in different situations.

Study design

A link to a vignette-based survey was emailed to obstetricians of 215 maternity units; the questionnaire asked them to report how they would manage the PPH described in 2 previously validated case-vignettes of different scenarios of severe PPH. Vignette 1 described a typical immediate, severe PPH, and vignette 2 a less typical case of severe but gradual PPH. They were constructed in 3 successive steps and included multiple-choice questions proposing several types of clinical practice options at each step. Variations in PPH were assessed in a descriptive analysis; agreement about management and its timing between vignette 1 and vignette 2 was assessed with the Kappa coefficient.

Results

Analysis of complete responses from 119 (43.4%) obstetricians from 53 (24.6%) maternity units showed delayed or inadequate management in both vignettes. While 82.3% and 83.2% of obstetricians (in vignettes 1 and 2, respectively) would administer oxytocin 15 minutes after PPH diagnosis, only 52.9% and 29.4% would alert other team members. Management by obstetricians of the two vignette situations was inconsistent in terms of choice of treatment and timing of almost all treatments.

Conclusion

Case vignettes demonstrated inadequate management as well as variations in management between obstetricians and in different PPH situations. Protocols or procedures are necessary in all maternity units to reduce the variations in practices that may explain a part of the delay in management that leads to PPH-related maternal mortality and morbidity.

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