Congenital metastatic neuroblastoma with placental involvement as a rare cause of non-immune fetal hydrops.

Non-immune hydrops fetalis represents the end-stage status of a variety of diseases, including metastatic tumors. We report a case of non-immune hydrops fetalis associated with multiple disseminated echogenic nodular lesions detected by ultrasound and confirmed by magnetic resonance. Cordocentesis demonstrated anemia and thrombopenia. Differential diagnosis included histiocytosis X, acute leukemia or metastatic disease. A stillbirth was diagnosed at week 25 + 6. The autopsy revealed hydrops fetalis, a right adrenal gland mass, multiple disseminated nodules histologically composed of small round blue cells positive for synaptophysin, and placental involvement, concordant findings with congenital undifferentiated neuroblastoma Stage M. No chromosomal abnormalities were associated, nor amplification abnormalities in MYCN and ALK genes. Metastatic neuroblastoma should be considered in the differential diagnosis of non-immune hydrops fetalis associated with multiple nodular lesions.

Therapeutic strategies and clinical evolution of patients with infantile fibrosarcoma: a unique paediatric case series

Background Infantile fibrosarcoma is the most frequent soft tissue sarcoma in newborns or children under one year of age. This tumour often implies high local aggressiveness and surgical morbidity. The large majority of these patients carry the ETV6–NTRK3 oncogenic fusion. Hence, the TRK inhibitor larotrectinib emerged as an efficacious and safe alternative to chemotherapy for NTRK fusion-positive and metastatic or unresectable tumours. However, real-world evidence is still required for updating soft-tissue sarcoma practice guidelines. Objective To report our experience with the use of larotrectinib in pediatric patients. Methods Our case series shows the clinical evolution of 8 patients with infantile fibrosarcoma under different treatments. All patients enrolled in this study received informed consent for any treatment. Results Three patients received larotrectinib in first line. No surgery was needed with larotrectinib, which led to the rapid and safe remission of tumours, even in unusual anatomical locations. No significant adverse effects were observed with larotrectinib. Conclusion Our case series supports that larotrectinib may be a therapeutic option for newborn and infant patients with infantile fibrosarcoma, especially in uncommon locations (AU)

Redescription of Brevimulticaecum baylisi () (Nematoda: Heterocheilidae), a parasite of Caiman crocodilus (Crocodylia: Alligatoridae) in the north-eastern Peruvian Amazon.

Caiman crocodilus is among the most abundant and widely distributed predators in the Neotropical region. These animals consume prey such as crustaceans, birds, small mammals, reptiles, amphibians, and fish, which can carry infective larval forms of nematodes. Brevimulticaecum has few studies on its morphology available, lacking detailed images. Therefore, the aim of this study was to redescribe Brevimulticaecum baylisi, stomach parasite of Caiman crocodilus, from subsistence hunting in the Yavari-Mirin River, Peruvian Amazon, using light and scanning electron microscopy. Four caimans were analyzed, and, macroscopically, all had ulcerative lesions in the stomach caused by this parasite. Histopathology showed an inflammatory infiltrate with a predominance of lymphocytes. Morphological characteristics of nematodes include the presence of three diamond-shaped lips wider than they are long, interlabia pyramidal, excretory pore located above the nerve ring, present intestinal cecum, ventriculus with five ventricular appendages, and long, winged spicules. These morphological characters, added to the number and distribution of the pre- and postcloacal papillae of the male specimens, allowed the identification of these parasites as B. baylisi. Scanning electron microscopy of these nematodes showed the presence of a dentigerous ridge on the inner surface of the lips in both sexes, while in males, the presence of a horseshoe-shaped median papilla was observed on the upper lip of the cloaca. Our research, therefore, adds these characteristics to the original description of B. baylisi, in addition to expanding the biogeographical distribution of this parasite.

Repeated Administration of the Cannabinoid WIN Alters the Isoflurane-Sparing Effect of Morphine and Dexmedetomidine.

The impacts of morphine and dexmedetomidine on the MAC of isoflurane were studied in rats constantly medicated with the cannabinoid WIN 55,212-2. METHODS: Prior to the administration of morphine, the MAC was measured in both untreated rats (MAC (ISO)) and those treated with a cannabinoid (MAC (ISO + CANN)). The effects of morphine (MAC (ISO + MOR)) and dexmedetomidine (MAC (ISO + DEX)) on untreated rats and rats treated for 21 days with the cannabinoids (MAC (ISO + CANN + MOR)) and (MAC (ISO + CANN + DEX) were also studied. RESULTS: MAC (ISO) was 1.32 ± 0.06, and MAC (ISO + CANN) was 1.69 ± 0.09. MAC (ISO + MOR) was 0.97 ± 0.02 (26% less than MAC (ISO)). MAC (ISO + CANN + MOR) was 1.55 ± 0.08 (8% less than MAC (ISO + CANN)), MAC (ISO + DEX) was 0.68 ± 0.10 (48% less than MAC (ISO)), and MAC (ISO + CANN + DEX) was 0.67 ± 0.08 (60% less than MAC (ISO + CANN)). CONCLUSIONS: Medication with a cannabinoid for 21 days augmented the MAC of isoflurane. The sparing effect of morphine on isoflurane is lower in rats constantly medicated with a cannabinoid. The sparing effect of dexmedetomidine on the minimum alveolar concentration of isoflurane is greater in rats repeatedly medicated with a cannabinoid.

Prospects and Advances in Adoptive Natural Killer Cell Therapy for Unmet Therapeutic Needs in Pediatric Bone Sarcomas.

Malignant bone tumors are aggressive tumors, with a high tendency to metastasize, that are observed most frequently in adolescents during rapid growth spurts. Pediatric patients with malignant bone sarcomas, Ewing sarcoma and osteosarcoma, who present with progressive disease have dire survival rates despite aggressive therapy. These therapies can have long-term effects on bone growth, such as decreased bone mineral density and reduced longitudinal growth. New therapeutic approaches are therefore urgently needed for targeting pediatric malignant bone tumors. Harnessing the power of the immune system against cancer has improved the survival rates dramatically in certain cancer types. Natural killer (NK) cells are a heterogeneous group of innate effector cells that possess numerous antitumor effects, such as cytolysis and cytokine production. Pediatric sarcoma cells have been shown to be especially susceptible to NK-cell-mediated killing. NK-cell adoptive therapy confers numerous advantages over T-cell adoptive therapy, including a good safety profile and a lack of major histocompatibility complex restriction. NK-cell immunotherapy has the potential to be a new therapy for pediatric malignant bone tumors. In this manuscript, we review the general characteristics of osteosarcoma and Ewing sarcoma, discuss the long-term effects of sarcoma treatment on bones, and the barriers to effective immunotherapy in bone sarcomas. We then present the laboratory and clinical studies on NK-cell immunotherapy for pediatric malignant bone tumors. We discuss the various donor sources and NK-cell types, the engineering of NK cells and combinatorial treatment approaches that are being studied to overcome the current challenges in adoptive NK-cell therapy, while suggesting approaches for future studies on NK-cell immunotherapy in pediatric bone tumors.

Therapeutic strategies and clinical evolution of patients with infantile fibrosarcoma: a unique paediatric case series.

BACKGROUND: Infantile fibrosarcoma is the most frequent soft tissue sarcoma in newborns or children under one year of age. This tumour often implies high local aggressiveness and surgical morbidity. The large majority of these patients carry the ETV6-NTRK3 oncogenic fusion. Hence, the TRK inhibitor larotrectinib emerged as an efficacious and safe alternative to chemotherapy for NTRK fusion-positive and metastatic or unresectable tumours. However, real-world evidence is still required for updating soft-tissue sarcoma practice guidelines. OBJECTIVE: To report our experience with the use of larotrectinib in pediatric patients. METHODS: Our case series shows the clinical evolution of 8 patients with infantile fibrosarcoma under different treatments. All patients enrolled in this study received informed consent for any treatment. RESULTS: Three patients received larotrectinib in first line. No surgery was needed with larotrectinib, which led to the rapid and safe remission of tumours, even in unusual anatomical locations. No significant adverse effects were observed with larotrectinib. CONCLUSION: Our case series supports that larotrectinib may be a therapeutic option for newborn and infant patients with infantile fibrosarcoma, especially in uncommon locations.

Effects of Microencapsulated Essential Oils on Equine Health: Nutrition, Metabolism and Methane Emission.

This review examines the available data regarding the positive effects of microencapsulated essential oils (EOs) on the nutrition, metabolism, and possibly the methane emission of horses. A literature review was conducted on the effect of microencapsulated (EOs) on the health of horses. The information comprises articles published in recent years in indexed journals. The results indicate that mixtures of microencapsulated EOs may be beneficial to equine health due to their antimicrobial and antioxidant activity, as well as their effects on enteric methane production, nutrient absorption, and immune system enhancement. Moreover, encapsulation stabilizes substances such as EOs in small doses, primarily by combining them with other ingredients.

Role of the MicroRNAs in the Pathogenic Mechanism of Painful Symptoms in Long COVID: Systematic Review.

The ongoing pandemic of COVID-19 has caused more than 6.7 million tragic deaths, plus, a large percentage of people who survived it present a myriad of chronic symptoms that last for at least 6 months; this has been named as long COVID. Some of the most prevalent are painful symptoms like headache, joint pain, migraine, neuropathic-like pain, fatigue and myalgia. MicroRNAs are small non-coding RNAs that regulate genes, and their involvement in several pathologies has been extensively shown. A deregulation of miRNAs has been observed in patients with COVID-19. The objective of the present systematic review was to show the prevalence of chronic pain-like symptoms of patients with long COVID and based on the expression of miRNAs in patients with COVID-19, and to present a proposal on how they may be involved in the pathogenic mechanisms of chronic pain-like symptoms. A systematic review was carried out in online databases for original articles published between March 2020 to April 2022; the systematic review followed the PRISMA guidelines, and it was registered in PROSPERO with registration number CRD42022318992. A total of 22 articles were included for the evaluation of miRNAs and 20 regarding long COVID; the overall prevalence of pain-like symptoms was around 10 to 87%, plus, the miRNAs that were commonly up and downregulated were miR-21-5p, miR-29a,b,c-3p miR-92a,b-3p, miR-92b-5p, miR-126-3p, miR-150-5p, miR-155-5p, miR-200a, c-3p, miR-320a,b,c,d,e-3p, and miR-451a. The molecular pathways that we hypothesized to be modulated by these miRNAs are the IL-6/STAT3 proinflammatory axis and the compromise of the blood-nerve barrier; these two mechanisms could be associated with the prevalence of fatigue and chronic pain in the long COVID population, plus they could be novel pharmacological targets in order to reduce and prevent these symptoms.

Chaperone-Mediated Autophagy Ablation in Pericytes Reveals New Glioblastoma Prognostic Markers and Efficient Treatment Against Tumor Progression.

Background: The lack of knowledge of the progression mechanisms of glioblastoma (GB), the most aggressive brain tumor, contributes to the absence of successful therapeutic strategies. Our team has recently demonstrated a crucial new role for chaperone-mediated autophagy (CMA) in pericytes (PC)-acquired immunosuppressive function, which prevents anti-tumor immune responses and facilitates GB progression. The possible impact that GB-induced CMA in PC has on other functions that might be useful for future GB prognosis/treatment, has not been explored yet. Thus, we proposed to analyze the contribution of CMA to other GB-induced changes in PC biology and determine if CMA ablation in PC is a key target mechanism for GB treatment. Methods: Studies of RNA-seq and secretome analysis were done in GB-conditioned PC with and without CMA (from knockout mice for LAMP-2A) and compared to control PC. Different therapeutic strategies in a GB mouse model were compared. Results: We found several gene expression pathways enriched in LAMP2A-KO PC and affected by GB-induced CMA in PC that correlate with our previous findings. Phagosome formation, cellular senescence, focal adhesion and the effector function to promote anti-tumor immune responses were the most affected pathways, revealing a transcriptomic profiling of specific target functions useful for future therapies. In addition, several molecules associated with tumor mechanisms and related to tumor immune responses such as gelsolin, periostin, osteopontin, lumican and vitamin D, were identified in the PC secretome dependent on GB-induced CMA. The CMA ablation in PC with GB cells showed an expected immunogenic phenotype able to phagocyte GB cells and a key strategy to develop future therapeutic strategies against GB tumor progression. A novel intravenous therapy using exofucosylated CMA-deficient PC was efficient to make PC reach the tumor niche and facilitate tumor elimination. Conclusion: Our results corroborate previous findings on the impaired immunogenic function of PC with GB-induced CMA, driving to other altered PC functions and the identifications of new target markers related to the tumor immune responses and useful for GB prognosis/therapy. Our work demonstrates CMA ablation in PC as a key target mechanism to develop a successful therapy against GB progression.

Minimum Alveolar Concentration of Isoflurane in Rats Chronically Treated with the Synthetic Cannabinoid WIN 55,212-2.

The minimum alveolar concentration MAC of isoflurane was measured in rats chronically treated with WIN 55,212-2. METHODS: The MAC of isoflurane was determined in 24 male rats from expiratory samples at time of tail clamping under the following conditions: without treatment MAC(ISO), in rats treated for 21 days with WIN 55,212-2 MAC(ISO + WIN55), and in rats 8 days after stopping treatment with WIN 55,212-2 (MACISO + WIN55 + 8D). RESULTS: The MAC(ISO) was 1.32 ± 0.06. In the MAC(ISO + WIN55) group, the MAC increased to 1.69 ± 0.09 (28%, p-value ≤ (0.0001). Eight days after stopping treatment with WIN55, the MAC did not decrease significantly, 1.67 ± 0.07 (26%, p-value ≤ 0.0001). CONCLUSIONS: The administration of WIN 55,212-2 for 21 days increases the MAC of isoflurane in rats. This effect does not disappear 8 days after discontinuation of treatment with the synthetic cannabinoid.

Lower ΔFosB expression in the dopaminergic system after stevia consumption in rats housed under environmental enrichment conditions.

Environmental enrichment (EE) has been proven to reduce drug seeking and the development of addiction-related behaviors in rodent models, but the effects of EE on natural reward acquisition in the form of sweet beverages are poorly understood. Accumulating evidence shows that the intake of sugar, the main ingredient of sweet beverages, alters the dopaminergic system, leading to addiction-related physiological and molecular changes. Sugar in sweet beverages has been replaced with natural sweeteners, such as stevia extract, which has greater sweetener potential but no energy content. Our research group found that sucralose consumption increased the expression of ΔFosB in reward-related nuclei, suggesting activation of the dopaminergic system. The present study assessed the effects of EE on stevia consumption and the expression of ΔFosB in the nucleus accumbens, caudate putamen, and prefrontal cortex. Sixteen male Wistar rats, 21 days old, were randomly assigned to an EE group (n = 8) or standard environment (SE) group (n = 8) and reared for 30 days. On postnatal day 52 (PND52), the brains of four animals in each housing condition were extracted to determine basal ΔFosB levels. Stevia consumption with intermittent access and ΔFosB immunoreactivity were measured for 21 days in the remainder of the rats. Compared with SE animals, EE animals exhibited a reduction of stevia consumption and alterations of ΔFosB immunoreactivity in the reward system. These results indicate that EE reduces stevia consumption and the stevia-induced ΔFosB expression, suggesting addiction-related changes in dopaminergic nuclei, which may be interpreted as a neuroprotective effect.

Control of Brain State Transitions with a Photoswitchable Muscarinic Agonist.

The ability to control neural activity is essential for research not only in basic neuroscience, as spatiotemporal control of activity is a fundamental experimental tool, but also in clinical neurology for therapeutic brain interventions. Transcranial-magnetic, ultrasound, and alternating/direct current (AC/DC) stimulation are some available means of spatiotemporal controlled neuromodulation. There is also light-mediated control, such as optogenetics, which has revolutionized neuroscience research, yet its clinical translation is hampered by the need for gene manipulation. As a drug-based light-mediated control, the effect of a photoswitchable muscarinic agonist (Phthalimide-Azo-Iper (PAI)) on a brain network is evaluated in this study. First, the conditions to manipulate M2 muscarinic receptors with light in the experimental setup are determined. Next, physiological synchronous emergent cortical activity consisting of slow oscillations-as in slow wave sleep-is transformed into a higher frequency pattern in the cerebral cortex, both in vitro and in vivo, as a consequence of PAI activation with light. These results open the way to study cholinergic neuromodulation and to control spatiotemporal patterns of activity in different brain states, their transitions, and their links to cognition and behavior. The approach can be applied to different organisms and does not require genetic manipulation, which would make it translational to humans.

Clinical Use of The Parasympathetic Tone Activity Index As a Measurement of Postoperative Analgaesia in Dogs Undergoing Ovariohysterectomy.

INTRODUCTION: While the current tools to assess canine postoperative pain using physiological and behavioural parameters are reliable, an objective method such as the parasympathetic tone activity (PTA) index could improve postoperative care. The aim of the study was to determine the utility of the PTA index in assessing postoperative analgaesia. MATERIAL AND METHODS: Thirty healthy bitches of different breeds were randomly allocated into three groups for analgaesic treatment: the paracetamol group (GPARAC, n = 10) received 15 mg/kg b.w., the carprofen group (GCARP, n = 10) 4 mg/kg b.w., and the meloxicam group (GMELOX, n = 10) 0.2 mg/kg b.w. for 48 h after surgery. GPARAC was medicated orally every 8 h, while GCARP and GMELOX were medicated intravenously every 24 h. The PTA index was used to measure the analgaesia-nociception balance 1 h before surgery (baseline), and at 1, 2, 4, 6, 8, 12, 16, 20, 24, 36, and 48 h after, at which times evaluation on the University of Melbourne Pain Scale (UMPS) was made. RESULTS: The baseline PTA index was 65 ± 8 for GPARAC, 65 ± 7 for GCARP, and 62 ± 5 for GMELOX. Postoperatively, it was 65 ± 9 for GPARAC, 63 ± 8 for GCARP, and 65 ± 8 for GMELOX. No statistically significant difference existed between baseline values or between values directly after treatments (P = 0.99 and P = 0.97, respectively). The PTA index showed a sensitivity of 40%, specificity of 98.46% and a negative predictive value of 99.07%. CONCLUSION: Our findings suggest that the PTA index measures comfort and postoperative analgaesia objectively, since it showed a clinical relationship with the UMPS.

Impact of GABAA and GABAB Inhibition on Cortical Dynamics and Perturbational Complexity during Synchronous and Desynchronized States.

Quantitative estimations of spatiotemporal complexity of cortical activity patterns are used in the clinic as a measure of consciousness levels, but the cortical mechanisms involved are not fully understood. We used a version of the perturbational complexity index (PCI) adapted to multisite recordings from the ferret (either sex) cerebral cortex in vitro (sPCI) to investigate the role of GABAergic inhibition in cortical complexity. We studied two dynamical states: slow-wave activity (synchronous state) and desynchronized activity, that express low and high causal complexity respectively. Progressive blockade of GABAergic inhibition during both regimes revealed its impact on the emergent cortical activity and on sPCI. Gradual GABAA receptor blockade resulted in higher synchronization, being able to drive the network from a desynchronized to a synchronous state, with a progressive decrease of complexity (sPCI). Blocking GABAB receptors also resulted in a reduced sPCI, in particular when in a synchronous, slow wave state. Our findings demonstrate that physiological levels of inhibition contribute to the generation of dynamical richness and spatiotemporal complexity. However, if inhibition is diminished or enhanced, cortical complexity decreases. Using a computational model, we explored a larger parameter space in this relationship and demonstrate a link between excitatory/inhibitory balance and the complexity expressed by the cortical network.SIGNIFICANCE STATEMENT The spatiotemporal complexity of the activity expressed by the cerebral cortex is a highly revealing feature of the underlying network's state. Complexity varies with physiological brain states: it is higher during awake than during sleep states. But it also informs about pathologic states: in disorders of consciousness, complexity is lower in an unresponsive wakefulness syndrome than in a minimally conscious state. What are the network parameters that modulate complexity? Here we investigate how inhibition, mediated by either GABAA or GABAA receptors, influences cortical complexity. And we do this departing from two extreme functional states: a highly synchronous, slow-wave state, and a desynchronized one that mimics wakefulness. We find that there is an optimal level of inhibition in which complexity is highest.

Treatment of infantile fibrosarcoma associated to an abdominal aortic aneurysm with larotrectinib: a case report.

Infantile fibrosarcoma (IFS) is a rare pediatric tumor which often presents the ETV6-NTRK3 gene fusion. NTRK3 encodes the neurotrophin-3 growth factor receptor tyrosine kinase, a druggable therapeutic target. Selective tropomyosin receptor kinase (TRK) inhibitors, such as larotrectinib, have shown efficacy and safety in the treatment of IFS. We report a case of an abdominal IFS diagnosed in a newborn associated with an aortic aneurysm that was successfully treated with larotrectinib without relevant adverse effects.

Astrocyte-mediated switch in spike timing-dependent plasticity during hippocampal development.

Presynaptic spike timing-dependent long-term depression (t-LTD) at hippocampal CA3-CA1 synapses is evident until the 3rd postnatal week in mice, disappearing during the 4th week. At more mature stages, we found that the protocol that induced t-LTD induced t-LTP. We characterized this form of t-LTP and the mechanisms involved in its induction, as well as that driving this switch from t-LTD to t-LTP. We found that this t-LTP is expressed presynaptically at CA3-CA1 synapses, as witnessed by coefficient of variation, number of failures, paired-pulse ratio and miniature responses analysis. Additionally, this form of presynaptic t-LTP does not require NMDARs but the activation of mGluRs and the entry of Ca2+ into the postsynaptic neuron through L-type voltage-dependent Ca2+ channels and the release of Ca2+ from intracellular stores. Nitric oxide is also required as a messenger from the postsynaptic neuron. Crucially, the release of adenosine and glutamate by astrocytes is required for t-LTP induction and for the switch from t-LTD to t-LTP. Thus, we have discovered a developmental switch of synaptic transmission from t-LTD to t-LTP at hippocampal CA3-CA1 synapses in which astrocytes play a central role and revealed a form of presynaptic LTP and the rules for its induction.

Challenges in Physiological Phenotyping of hiPSC-Derived Neurons: From 2D Cultures to 3D Brain Organoids.

Neurons derived from human induced pluripotent stem cells (hiPSC-derived neurons) offer novel opportunities for the development of preclinical models of human neurodegenerative diseases (NDDs). Recent advances in the past few years have increased substantially the potential of these techniques and have uncovered new challenges that the field is facing. Here, we outline and discuss challenges related to the functional characterization of hiPSC-derived neurons and propose ways to overcome current difficulties. In particular, the enormous variability among studies in the electrical properties of hiPSC-derived neurons and broad differences in cell maturation are factors that impair reproducibility. Furthermore, we discuss how the use of 3D brain organoids are of help in resolving some difficulties posed by 2D cultures. Finally, we elaborate on recent and future advances that may help to overcome the discussed challenges and speed-up progress in the field.

Clinical evaluation of postoperative analgesia, cardiorespiratory parameters and changes in liver and renal function tests of paracetamol compared to meloxicam and carprofen in dogs undergoing ovariohysterectomy.

BACKGROUND: In veterinary medicine, the administration of nonsteroidal anti-inflammatory analgesics (NSAIDs) for the control of postsurgical pain in dogs and cats is common given the anti-inflammatory, analgesic, and antipyretic effects of these drugs. This study compared the serum biochemical changes and postoperative analgesic effects of paracetamol, meloxicam, and carprofen in bitches submitted to an ovariohysterectomy using the Dynamic Interactive Visual Analog Scale (DIVAS) and Pain Scale of the University of Melbourne (UMPS) scoring systems. METHODS: Thirty bitches of different breeds underwent elective ovariohysterectomies and were randomly assigned to one of three treatment groups: a paracetamol group [15 mg kg-1 intravenous (IV)], a carprofen group (4 mg kg-1 IV), and a meloxicam group (0.2 mg kg-1 IV). All treatments were administered 30 minutes prior to surgery. Paracetamol was administered every 8 hours postoperatively for 48 hours total, while carprofen and meloxicam were intravenously administered every 24 hours. An evaluation of post-surgical pain was done with the DIVAS and the UMPS. The first post-surgical pain measurement was performed 1 hour after surgery and then 2, 4, 6, 8, 12, 16, 20, 24, 36, and 48 hours after surgery. RESULTS: All groups exhibited a gradual reduction in pain throughout the postoperative period in both scales; however, neither scale significantly differed between the three treatment groups (P > 0.05) during the 48 postoperative hours. CONCLUSIONS: Paracetamol was as effective as meloxicam and carprofen for post-surgical analgesia in bitches subjected to elective ovariohysterectomy. The present study demonstrates that paracetamol may be considered a tool for the effective treatment of acute perioperative pain in dogs. Furthermore, this drug led to no adverse reactions or changes in the parameters assessed in the present study, indicating its safety.