ResearchPad - neurochemistry https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Monitoring of cardiovascular physiology augmented by a patient-specific biomechanical model during general anesthesia. A proof of concept study]]> https://www.researchpad.co/article/elastic_article_14629 During general anesthesia (GA), direct analysis of arterial pressure or aortic flow waveforms may be inconclusive in complex situations. Patient-specific biomechanical models, based on data obtained during GA and capable to perform fast simulations of cardiac cycles, have the potential to augment hemodynamic monitoring. Such models allow to simulate Pressure-Volume (PV) loops and estimate functional indicators of cardiovascular (CV) system, e.g. ventricular-arterial coupling (Vva), cardiac efficiency (CE) or myocardial contractility, evolving throughout GA. In this prospective observational study, we created patient-specific biomechanical models of heart and vasculature of a reduced geometric complexity for n = 45 patients undergoing GA, while using transthoracic echocardiography and aortic pressure and flow signals acquired in the beginning of GA (baseline condition). If intraoperative hypotension (IOH) appeared, diluted norepinephrine (NOR) was administered and the model readjusted according to the measured aortic pressure and flow signals. Such patients were a posteriori assigned into a so-called hypotensive group. The accuracy of simulated mean aortic pressure (MAP) and stroke volume (SV) at baseline were in accordance with the guidelines for the validation of new devices or reference measurement methods in all patients. After NOR administration in the hypotensive group, the percentage of concordance with 10% exclusion zone between measurement and simulation was >95% for both MAP and SV. The modeling results showed a decreased Vva (0.64±0.37 vs 0.88±0.43; p = 0.039) and an increased CE (0.8±0.1 vs 0.73±0.11; p = 0.042) in hypotensive vs normotensive patients. Furthermore, Vva increased by 92±101%, CE decreased by 13±11% (p < 0.001 for both) and contractility increased by 14±11% (p = 0.002) in the hypotensive group post-NOR administration. In this work we demonstrated the application of fast-running patient-specific biophysical models to estimate PV loops and functional indicators of CV system using clinical data available during GA. The work paves the way for model-augmented hemodynamic monitoring at operating theatres or intensive care units to enhance the information on patient-specific physiology.

]]>
<![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[Disruption of genes associated with Charcot-Marie-Tooth type 2 lead to common behavioural, cellular and molecular defects in Caenorhabditis elegans]]> https://www.researchpad.co/article/N5d50b5cf-e057-490e-9c44-60569e9f28d4

Charcot-Marie-Tooth (CMT) disease is an inherited peripheral motor and sensory neuropathy. The disease is divided into demyelinating (CMT1) and axonal (CMT2) neuropathies, and although we have gained molecular information into the details of CMT1 pathology, much less is known about CMT2. Due to its clinical and genetic heterogeneity, coupled with a lack of animal models, common underlying mechanisms remain elusive. In order to gain an understanding of the normal function of genes associated with CMT2, and to draw direct comparisons between them, we have studied the behavioural, cellular and molecular consequences of mutating nine different genes in the nematode Caenorhabditis elegans (lin-41/TRIM2, dyn-1/DNM2, unc-116/KIF5A, fzo-1/MFN2, osm-9/TRPV4, cua-1/ATP7A, hsp-25/HSPB1, hint-1/HINT1, nep-2/MME). We show that C. elegans defective for these genes display debilitated movement in crawling and swimming assays. Severe morphological defects in cholinergic motors neurons are also evident in two of the mutants (dyn-1 and unc-116). Furthermore, we establish methods for quantifying muscle morphology and use these to demonstrate that loss of muscle structure occurs in the majority of mutants studied. Finally, using electrophysiological recordings of neuromuscular junction (NMJ) activity, we uncover reductions in spontaneous postsynaptic current frequency in lin-41, dyn-1, unc-116 and fzo-1 mutants. By comparing the consequences of mutating numerous CMT2-related genes, this study reveals common deficits in muscle structure and function, as well as NMJ signalling when these genes are disrupted.

]]>
<![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.

]]>
<![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.

]]>
<![CDATA[Microglia exit the CNS in spinal root avulsion]]> https://www.researchpad.co/article/5c79a3e5d5eed0c4841d1bf2

Microglia are central nervous system (CNS)-resident cells. Their ability to migrate outside of the CNS, however, is not understood. Using time-lapse imaging in an obstetrical brachial plexus injury (OBPI) model, we show that microglia squeeze through the spinal boundary and emigrate to peripheral spinal roots. Although both macrophages and microglia respond, microglia are the debris-clearing cell. Once outside the CNS, microglia re-enter the spinal cord in an altered state. These peripheral nervous system (PNS)-experienced microglia can travel to distal CNS areas from the injury site, including the brain, with debris. This emigration is balanced by two mechanisms—induced emigration via N-methyl-D-aspartate receptor (NMDA) dependence and restriction via contact-dependent cellular repulsion with macrophages. These discoveries open the possibility that microglia can migrate outside of their textbook-defined regions in disease states.

]]>
<![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.

]]>
<![CDATA[Association between sublingual microcirculation, tissue perfusion and organ failure in major trauma: A subgroup analysis of a prospective observational study]]> https://www.researchpad.co/article/5c8823c2d5eed0c484638f67

Introduction

Previous studies described impaired microvascular perfusion and tissue oxygenation as reliable predictors of Multiple Organ Failure in major trauma. However, this relationship has been incompletely investigated. The objective of this analysis is to further evaluate the association between organ dysfunction and microcirculation after trauma.

Materials and methods

This is a retrospective subgroup analysis on 28 trauma patients enrolled for the Microcirculation DAIly MONitoring in critically ill patients study (NCT 02649088). Patients were divided in two groups according with their Sequential Organ Failure Assessment (SOFA) score at day 4. At admission and every 24 hours, the sublingual microcirculation was evaluated with Sidestream Darkfield Imaging (SDF) and peripheral tissue perfusion was assessed with Near Infrared Spectroscopy (NIRS) and Vascular Occlusion Test (VOT). Simultaneously, hemodynamic, clinical/laboratory parameters and main organ supports were collected.

Results

Median SOFA score at Day 4 was 6.5. Accordingly, patients were divided in two groups: D4-SOFA ≤6.5 and D4-SOFA >6.5. The Length of Stay in Intensive Care was significantly higher in patients with D4-SOFA>6.5 compared to D4-SOFA≤6.5 (p = 0.013). Total Vessel Density of small vessels was significantly lower in patients with high D4-SOFA score at Day 1 (p = 0.002) and Day 2 (p = 0.006) after admission; the Perfused Vessel Density was lower in patients with high D4-SOFA score at Day 1 (p = 0.007) and Day 2 (p = 0.033). At Day 1, NIRS monitoring with VOT showed significantly faster tissue oxygen saturation downslope (p = 0.018) and slower upslope (p = 0.04) in patients with high D4-SOFA.

Discussion

In our cohort of major traumas, sublingual microcirculation and peripheral microvascular reactivity were significantly more impaired early after trauma in those patients who developed more severe organ dysfunctions. Our data would support the hypothesis that restoration of macrocirculation can be dissociated from restoration of peripheral and tissue perfusion, and that microvascular alterations can be associated with organ failure.

]]>
<![CDATA[Increased arterial pressure in mice with overexpression of the ADHD candidate gene calcyon in forebrain]]> https://www.researchpad.co/article/5c6c7585d5eed0c4843cfe50

The link between blood pressure (BP) and cerebral function is well established. However, it is not clear whether a common mechanism could underlie the relationship between elevated BP and cognitive deficits. The expression of calcyon, a gene abundant in catecholaminergic and hypothalamic nuclei along with other forebrain regions, is increased in the brain of the spontaneously hypertensive rat (SHR) which is a widely accepted animal model of essential hypertension and attention deficit hyperactivity disorder (ADHD). Previous studies demonstrated that mice with up-regulation of calcyon in forebrain (CalOE) exhibit deficits in working memory. To date, there is no evidence directly connecting calcyon to BP regulation. Here, we investigated whether forebrain up-regulation of calcyon alters BP using radiotelemetry. We found that CalOE mice exhibited higher mean arterial pressure (MAP) compared to tTA controls. Plasma norepinephrine levels were significantly higher in CalOE mice compared to tTA controls. Silencing the transgene with doxycycline normalized BP in CalOE mice, whereas challenging the mice with 4% high salt diet for 12 days exacerbated the MAP differences between CalOE and tTA mice. High salt diet challenge also increased proteinuria and urinary thiobarbituric acid reactive substances (TBARs) in tTA and CalOE; and the increases were more prominent in CalOE mice. Taken together, our data suggest that upregulation of calcyon in forebrain could increase BP via alterations in noradrenergic transmission and increased oxidative stress during high salt challenge. Overall, this study reveals that calcyon could be a novel neural regulator of BP raising the possibility that it could play a role in the development of vascular abnormalities.

]]>
<![CDATA[Fat cells gobbling up norepinephrine?]]> https://www.researchpad.co/article/5c65dcd9d5eed0c484dec37d

The sympathetic nervous system (SNS) controls key aspects of adipose tissue (AT) function through the release of norepinephrine (NE) and beta adrenergic signaling. Sympathetic tone is determined by NE release but also by the rate of extracellular NE clearance that historically has been believed to occur solely through solute carrier family 6 member 2 (SLC6A2) expressed on sympathetic neurons. Song and colleagues show that adipocytes can also clear NE through organic cation transporter 3 (Oct3). This contributes to our understanding of how adrenergic signaling is controlled in AT and also emphasizes the need to develop better methods to assess adrenergic signaling in vivo.

]]>
<![CDATA[The ovine hepatic mitochondrial proteome: Understanding seasonal weight loss tolerance in two distinct breeds]]> https://www.researchpad.co/article/5c76fe3cd5eed0c484e5b761

Seasonal weight loss (SWL) is a primary constraint for farmers in the Mediterranean and tropics. One cost-effective solution to SWL is utilizing breeds like the Damara sheep that have adapted to deal with nutritional stress. Previous studies concluded that one of the adaptation mechanisms of SWL is a specialized fatty acid metabolism. Accordingly, hepatic-mitochondrial proteomes were compared across two different breeds (24 sheep total, Merino, n = 12 and Damara, n = 12) and two different diets (restricted vs unrestricted diet, 6 per breed, per diet, 24 total). Mitochondrial-proteins were isolated and relatively quantified using Blue native PAGE / 2D-electrophoresis and then analyzed via mass spectrometry. The tool ReviGO summarized the proteomes’ gene-ontology terms. A total of 50 proteins were identified with 7 changing significantly in abundance (ANOVA p-value<0.05). Specific abundance patterns of corticosteroid and inflammatory response-associated proteins such as annexin and glutamate dehydrogenase suggests that the Damara has an unusual inflammation response when subjected to SWL in addition to its unique metabolism. All significant proteins warrant further study; Annexin in particular shows promise as a potentially useful biomarker.

]]>
<![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.

]]>
<![CDATA[Inward rectifier potassium (Kir) channels mediate salivary gland function and blood feeding in the lone star tick, Amblyomma americanum]]> https://www.researchpad.co/article/5c65dccbd5eed0c484dec23d

Background

Tick feeding causes extreme morbidity and mortality to humans through transmission of pathogens and causes severe economic losses to the agricultural industry by reducing livestock yield. Salivary gland secretions are essential for tick feeding and thus, reducing or preventing saliva secretions into the vertebrate host is likely to reduce feeding and hinder pathogen life cycles. Unfortunately, the membrane physiology of tick salivary glands is underexplored and this gap in knowledge limits the development of novel therapeutics for inducing cessation of tick feeding.

Methodology

We studied the influence of inward rectifier potassium (Kir) channel subtypes to the functional capacity of the isolated tick salivary gland through the use of a modified Ramsay assay. The secreted saliva was subsequently used for quantification of the elemental composition of the secreted saliva after the glands were exposed to K+ channel modulators as a measure of osmoregulatory capacity. Lastly, changes to blood feeding behavior and mortality were measured with the use of a membrane feeding system.

Principal findings

In this study, we characterized the fundamental role of Kir channel subtypes in tick salivary gland function and provide evidence that pharmacological inhibition of these ion channels reduces the secretory activity of the Amblyomma americanum salivary gland. The reduced secretory capacity of the salivary gland was directly correlated with a dramatic reduction of blood ingestion during feeding. Further, exposure to small-molecule modulators of Kir channel subtypes induced mortality to ticks that is likely resultant from an altered osmoregulatory capacity.

Conclusions

Our data contribute to understanding of tick salivary gland function and could guide future campaigns aiming to develop chemical or reverse vaccinology technologies to reduce the worldwide burden of tick feeding and tick-vectored pathogens.

]]>
<![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.

]]>
<![CDATA[Metabolomic profiling reveals correlations between spermiogram parameters and the metabolites present in human spermatozoa and seminal plasma]]> https://www.researchpad.co/article/5c76fe4fd5eed0c484e5b889

In 50% of all infertility cases, the male is subfertile or infertile, however, the underlying mechanisms are often unknown. Even when assisted reproductive procedures such as in vitro fertilization and intracytoplasmic sperm injection are performed, the causes of male factor infertility frequently remain elusive. Since the overall activity of cells is closely linked to their metabolic capacity, we analyzed a panel of 180 metabolites in human sperm and seminal plasma and elucidated their associations with spermiogram parameters. Therefore, metabolites from a group of 20 healthy donors were investigated using a targeted LC-MS/MS approach. The correlation analyses of the amino acids, biogenic amines, acylcarnitines, lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and sugars from sperm and seminal plasma with standard spermiogram parameters revealed that metabolites in sperm are closely related to sperm motility, whereas those in seminal plasma are closely related to sperm concentration and morphology. This study provides essential insights into the metabolome of human sperm and seminal plasma and its associations with sperm functions. This metabolomics technique could be a promising screening tool to detect the factors of male infertility in cases where the cause of infertility is unclear.

]]>
<![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.

]]>
<![CDATA[GluClR-mediated inhibitory postsynaptic currents reveal targets for ivermectin and potential mechanisms of ivermectin resistance]]> https://www.researchpad.co/article/5c59fee7d5eed0c484135792

Glutamate-gated chloride channel receptors (GluClRs) mediate inhibitory neurotransmission at invertebrate synapses and are primary targets of parasites that impact drastically on agriculture and human health. Ivermectin (IVM) is a broad-spectrum pesticide that binds and potentiates GluClR activity. Resistance to IVM is a major economic and health concern, but the molecular and synaptic mechanisms of resistance are ill-defined. Here we focus on GluClRs of the agricultural endoparasite, Haemonchus contortus. We demonstrate that IVM potentiates inhibitory input by inducing a tonic current that plateaus over 15 minutes and by enhancing post-synaptic current peak amplitude and decay times. We further demonstrate that IVM greatly enhances the active durations of single receptors. These effects are greatly attenuated when endogenous IVM-insensitive subunits are incorporated into GluClRs, suggesting a mechanism of IVM resistance that does not affect glutamate sensitivity. We discovered functional groups of IVM that contribute to tuning its potency at different isoforms and show that the dominant mode of access of IVM is via the cell membrane to the receptor.

]]>
<![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.

]]>
<![CDATA[Retraction: The Cellular Distribution of Serotonin Transporter Is Impeded on Serotonin-Altered Vimentin Network]]> https://www.researchpad.co/article/5c5df313d5eed0c484580c8c ]]> <![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.

]]>