Dexmedetomidine as Conduit for Non-Invasive Ventilation (NIV) Compliance in COVID-19 and Chronic Obstructive Pulmonary Disease (COPD) Patients in Intensive Care Unit (ICU) Setting: Case Series.

Non-compliance to the non-invasive ventilation (NIV) mask in a distressed hypoxemic patient is not an unusual finding, especially in desaturated coronavirus disease (COVID-19) or chronic obstructive pulmonary disease (COPD) patients with respiratory distress who require ventilatory support to improve oxygenation. Failure to achieve success with the non-invasive ventilatory support with the tight-fitting mask led to emergent endotracheal intubation. This was in view to avert consequences such as severe hypoxemia and subsequent cardiac arrest.  Sedation is an important component of ICU management for noninvasive mechanical ventilation to improve NIV compliance/tolerance. Including the various sedatives used, such as fentanyl, propofol, or midazolam, the most suitable agent to be used as a primary/sole sedative still remains unclear. Dexmedetomidine providing analgosedation without significant respiratory depression facilitates better tolerance of NIV mask application. This case series is a retrospective analysis of patients in whom dexmedetomidine bolus followed by infusion was observed to facilitate compliance to NIV with the tight-fitting mask. Herein, a case summary of six patients with acute respiratory distress who were dyspnoic, agitated have severe hypoxemia were put on NIV with dexmedetomidine infusion is being reported. They were extremely uncooperative as their RASS score (Richmond Agitation-Sedation score) was + 1 to +3, not allowing the application of the NIV mask. Due to their poor compliance with to use of the NIV mask, proper ventilation could not be achieved. Dexmedetomidine infusion (0.3 to 0.4 mcg/kg/hr) was used after a bolus dose (0.2-0.3 mcg/kg). The RASS Score of our patients was +2 or +3 before this intervention which became -1 or -2 after including dexmedetomidine in the treatment protocol. The low dose dexmedetomidine bolus and infusion thereafter showed to improve the patient's acceptance of the device. Oxygen therapy with this was shown to improve patient oxygenation by allowing the acceptance of the tight-fitting NIV face mask. In conclusion, this case series serves as evidence of the use of dexmedetomidine as an effective therapy to calm the agitated desaturated patient, thereby facilitating non-invasive ventilation in COVID-19 and COPD patients and promoting better oxygenation. This may, in turn, avoid endotracheal intubation for invasive ventilation and the associated complications.

Leveraging Deep Learning Techniques and Integrated Omics Data for Tailored Treatment of Breast Cancer.

Multiomics data of cancer patients and cell lines, in synergy with deep learning techniques, have aided in unravelling predictive problems related to cancer research and treatment. However, there is still room for improvement in the performance of the existing models based on the aforementioned combination. In this work, we propose two models that complement the treatment of breast cancer patients. First, we discuss our deep learning-based model for breast cancer subtype classification. Second, we propose DCNN-DR, a deep convolute.ion neural network-drug response method for predicting the effectiveness of drugs on in vitro and in vivo breast cancer datasets. Finally, we applied DCNN-DR for predicting effective drugs for the basal-like breast cancer subtype and validated the results with the information available in the literature. The models proposed use late integration methods and have fairly better predictive performance compared to the existing methods. We use the Pearson correlation coefficient and accuracy as the performance measures for the regression and classification models, respectively.

Impaired neural stem cell expansion and hypersensitivity to epileptic seizures in mice lacking the EGFR in the brain.

Mice lacking the epidermal growth factor receptor (EGFR) develop an early postnatal degeneration of the frontal cortex and olfactory bulbs and show increased cortical astrocyte apoptosis. The poor health and early lethality of EGFR-/- mice prevented the analysis of mechanisms responsible for the neurodegeneration and function of the EGFR in the adult brain. Here, we show that postnatal EGFR-deficient neural stem cells are impaired in their self-renewal potential and lack clonal expansion capacity in vitro. Mice lacking the EGFR in the brain (EGFRΔbrain ) show low penetrance of cortical degeneration compared to EGFR-/- mice despite genetic recombination of the conditional allele. Adult EGFRΔ mice establish a proper blood-brain barrier and perform reactive astrogliosis in response to mechanical and infectious brain injury, but are more sensitive to Kainic acid-induced epileptic seizures. EGFR-deficient cortical astrocytes, but not midbrain astrocytes, have reduced expression of glutamate transporters Glt1 and Glast, and show reduced glutamate uptake in vitro, illustrating an excitotoxic mechanism to explain the hypersensitivity to Kainic acid and region-specific neurodegeneration observed in EGFR-deficient brains.

Maternal immune activation epigenetically regulates hippocampal serotonin transporter levels.

Major depressive disorder (MDD) is one of the most debilitating psychiatric diseases, affecting a large percentage of the population worldwide. Currently, the underlying pathomechanisms remain incompletely understood, hampering the development of critically needed alternative therapeutic strategies, which further largely depends on the availability of suitable model systems. Here we used a mouse model of early life stress - a precipitating factor for the development of MDD - featuring infectious stress through maternal immune activation (MIA) by polyinosinic:polycytidilic acid (Poly(I:C)) to examine epigenetic modulations as potential molecular correlates of the alterations in brain structure, function and behavior. We found that in adult female MIA offspring anhedonic behavior was associated with modulations of the global histone acetylation profile in the hippocampus. Morevoer, specific changes at the promoter and in the expression of the serotonin transporter (SERT), critically involved in the etiology of MDD and pharmacological antidepressant treatment were detected. Furthermore, an accompanying reduction in hippocampal levels of histone deacetylase (HDAC) 1 was observed in MIA as compared to control offspring. Based on these results we propose a model in which the long-lasting impact of MIA on depression-like behavior and associated molecular and cellular aberrations in the offspring is brought about by the modulation of epigenetic processes and consequent enduring changes in gene expression. These data provide additional insights into the principles underlying the impact of early infectious stress on the development of MDD and may contribute to the development of new targets for antidepressant therapy.

The brain-tumor related protein podoplanin regulates synaptic plasticity and hippocampus-dependent learning and memory.

INTRODUCTION: Podoplanin is a cell-surface glycoprotein constitutively expressed in the brain and implicated in human brain tumorigenesis. The intrinsic function of podoplanin in brain neurons remains however uncharacterized. MATERIALS AND METHODS: Using an established podoplanin-knockout mouse model and electrophysiological, biochemical, and behavioral approaches, we investigated the brain neuronal role of podoplanin. RESULTS: Ex-vivo electrophysiology showed that podoplanin deletion impairs dentate gyrus synaptic strengthening. In vivo, podoplanin deletion selectively impaired hippocampus-dependent spatial learning and memory without affecting amygdala-dependent cued fear conditioning. In vitro, neuronal overexpression of podoplanin promoted synaptic activity and neuritic outgrowth whereas podoplanin-deficient neurons exhibited stunted outgrowth and lower levels of p-Ezrin, TrkA, and CREB in response to nerve growth factor (NGF). Surface Plasmon Resonance data further indicated a physical interaction between podoplanin and NGF. DISCUSSION: This work proposes podoplanin as a novel component of the neuronal machinery underlying neuritogenesis, synaptic plasticity, and hippocampus-dependent memory functions. The existence of a relevant cross-talk between podoplanin and the NGF/TrkA signaling pathway is also for the first time proposed here, thus providing a novel molecular complex as a target for future multidisciplinary studies of the brain function in the physiology and the pathology. Key messages Podoplanin, a protein linked to the promotion of human brain tumors, is required in vivo for proper hippocampus-dependent learning and memory functions. Deletion of podoplanin selectively impairs activity-dependent synaptic strengthening at the neurogenic dentate-gyrus and hampers neuritogenesis and phospho Ezrin, TrkA and CREB protein levels upon NGF stimulation. Surface plasmon resonance data indicates a physical interaction between podoplanin and NGF. On these grounds, a relevant cross-talk between podoplanin and NGF as well as a role for podoplanin in plasticity-related brain neuronal functions is here proposed.

δ Subunit-containing GABAA receptors are preferred targets for the centrally acting analgesic flupirtine.

BACKGROUND AND PURPOSE: The Kv 7 channel activator flupirtine is a clinical analgesic characterized as 'selective neuronal potassium channel opener'. Flupirtine was found to exert comparable actions at GABAA receptors and Kv 7 channels in neurons of pain pathways, but not in hippocampus. EXPERIMENTAL APPROACH: Expression patterns of GABAA receptors were explored in immunoblots of rat dorsal root ganglia, dorsal horns and hippocampi using antibodies for 10 different subunits. Effects of flupirtine on recombinant and native GABAA receptors were investigated in patch clamp experiments and compared with the actions on Kv 7 channels. KEY RESULTS: Immunoblots pointed towards α2, α3, ß3 and γ2 subunits as targets, but in all γ2-containing receptors the effects of flupirtine were alike: leftward shift of GABA concentration-response curves and diminished maximal amplitudes. After replacement of γ2S by δ, flupirtine increased maximal amplitudes. Currents through α1ß2δ receptors were more enhanced than those through Kv 7 channels. In hippocampal neurons, flupirtine prolonged inhibitory postsynaptic currents, left miniature inhibitory postsynaptic currents (mIPSCs) unaltered and increased bicuculline-sensitive tonic currents; penicillin abolished mIPSCs, but not tonic currents; concentration-response curves for GABA-induced currents were shifted to the left by flupirtine without changes in maximal amplitudes; in the presence of penicillin, maximal amplitudes were increased; GABA-induced currents in the presence of penicillin were more sensitive towards flupirtine than K(+) currents. In dorsal horn neurons, currents evoked by the δ-preferring agonist THIP (gaboxadol) were more sensitive towards flupirtine than K(+) currents. CONCLUSIONS AND IMPLICATIONS: Flupirtine prefers δ-containing GABAA receptors over γ-containing ones and over Kv 7 channels.

STAT3 controls IL6-dependent regulation of serotonin transporter function and depression-like behavior.

Experimental evidence suggests a role for the immune system in the pathophysiology of depression. A specific involvement of the proinflammatory cytokine interleukin 6 (IL6) in both, patients suffering from the disease and pertinent animal models, has been proposed. However, it is not clear how IL6 impinges on neurotransmission and thus contributes to depression. Here we tested the hypothesis that IL6-induced modulation of serotonergic neurotransmission through the STAT3 signaling pathway contributes to the role of IL6 in depression. Addition of IL6 to JAR cells, endogenously expressing SERT, reduced SERT activity and downregulated SERT mRNA and protein levels. Similarly, SERT expression was reduced upon IL6 treatment in the mouse hippocampus. Conversely, hippocampal tissue of IL6-KO mice contained elevated levels of SERT and IL6-KO mice displayed a reduction in depression-like behavior and blunted response to acute antidepressant treatment. STAT3 IL6-dependently associated with the SERT promoter and inhibition of STAT3 blocked the effect of IL6 in-vitro and modulated depression-like behavior in-vivo. These observations demonstrate that IL6 directly controls SERT levels and consequently serotonin reuptake and identify STAT3-dependent regulation of SERT as conceivable neurobiological substrate for the involvement of IL6 in depression.

The poly(I:C)-induced maternal immune activation model in preclinical neuropsychiatric drug discovery.

Increasing epidemiological and experimental evidence implicates gestational infections as one important factor involved in the pathogenesis of several neuropsychiatric disorders. Corresponding preclinical model systems based upon maternal immune activation (MIA) by treatment of the pregnant female have been developed. These MIA animal model systems have been successfully used in basic and translational research approaches, contributing to the investigation of the underlying pathophysiological mechanisms at the molecular, cellular and behavioral levels. The present article focuses on the application of a specific MIA rodent paradigm, based upon treatment of the gestating dam with the viral mimic polyinosinic-polycytidilic acid (Poly(I:C)), a synthetic analog of double-stranded RNA (dsRNA) which activates the Toll-like receptor 3 (TLR3) pathway. Important advantages and constraints of this animal model will be discussed, specifically in light of gestational infection as one vulnerability factor contributing to the complex etiology of mood and psychotic disorders, which are likely the result of intricate multi-level gene×environment interactions. Improving our currently incomplete understanding of the molecular pathomechanistic principles underlying these disorders is a prerequisite for the development of alternative therapeutic approaches which are critically needed in light of the important drawbacks and limitations of currently available pharmacological treatment options regarding efficacy and side effects. The particular relevance of the Poly(I:C) MIA model for the discovery of novel drug targets for symptomatic and preventive therapeutic strategies in mood and psychotic disorders is highlighted in this review article.

Modafinil improves performance in the multiple T-Maze and modifies GluR1, GluR2, D2 and NR1 receptor complex levels in the C57BL/6J mouse.

Modafinil has been shown to modify behavioural and cognitive functions and to effect several brain receptors. Effects, however, were not observed at the receptor protein complex level and it was therefore the aim of the study to train mice in the multiple T-Maze (MTM) as a paradigm for spatial memory and to determine paralleling brain receptor complex levels. Sixty C57BL/6J mice were used in the study and divided into four groups (trained drug injected; trained vehicle injected; yoked drug injected; yoked vehicle injected). Animals obtained training for 4 days and were killed 6 h following the last training session on day 4. Hippocampi were dissected from the brain, membrane fractions were prepared by ultracentrifugation and were run on blue-native gels and immunoblotted with antibodies against major brain receptors. Modafinil treatment led to decreased latency and increased average speed, but not to changes in pathlength and number of correct decisions in the MTM. Drug effects were modifying receptor complexes of GluR1, GluR2, D2 and NR1. Training effects on receptor complex levels were observed for GluR3, D1 and nicotinic acetylcholine receptor alpha 7 (Nic7). GluR1 levels were correlating with GluR2 and D1 levels were correlating with D2 and NR1. Involvement of the glutamatergic, NMDA, dopaminergic and nicotinergic system in modafinil and memory training were herein described for the first time. A brain receptor complex pattern was revealed showing the concerted action following modafinil treatment.

Intraperitoneal injection of saline modulates hippocampal brain receptor complex levels but does not impair performance in the Morris Water Maze.

The involvement of the hippocampus in pain has been demonstrated but key players, i.e. the major brain receptors have not been shown to be modulated by pain. It was therefore the aim of the study to show the concerted action and pattern of brain receptor complex levels in a non-invasive model of moderate pain. C57BL/6J mice were divided into four groups of 14 animals each: trained injected, trained non-injected, yoked injected and yoked non-injected. Animals were tested in the open field and the elevated plus maze for behavioural evaluation and cognitive functions were tested using the Morris Water Maze. Hippocampi were taken 6 h following sacrification. Membrane proteins were prepared by ultracentrifugation and run on blue native gels to keep the native state, blotted to membranes and western blotting was carried out using the primary antibodies against serotonin receptor 5HT1A, muscarinic acetylcholine receptor M1 (mAChR-M1), nicotinic acetylcholine receptor alpha7 (nAChR-alpha7), glutamate (AMPA) receptor (GluR1) and neurokinin receptor 1 (NK-1). There was no difference between performance in behaviour or in the MWM between groups. Brain receptor level changes involved all receptors given above. Pain affected mAChR-M1, GluR1 and NK-1 complex levels when yoked-injected were compared with yoked non-injected animals. Memory mechanisms affected mAChR-M1 complex levels when trained non-injected animals were compared with yoked non-injected controls. Taken together, the neurochemical basis for testing receptor agonists/antagonists on the role of pain and the hippocampus was generated that may be useful for interpretations of the role of this complex area in moderate pain.

Classical presentation of Darier's disease: a rare disorder of keratinisation.

Keratosis follicularis or Darier's disease (DD), a rare autosomal dominant disorder is characterised clinically by appearance of multiple, prurutic, discrete, scaly papules affecting seborrheic areas coupled with palmar pits, nail changes and mucosal involvement. Histologicaly the lesions show suprabasal clefts with acantholytic and dyskeratotic cells. We report a case of 35 years old woman with typical clinical and histological features of Darier's disease.