The Kcna1 model of SUDEP exhibits progressive respiratory dysfunction, which suggests a potential increased susceptibility for respiratory failure during severe seizures that may result in sudden death.

Nucleocytoplasmic shuttling of macromolecules is a well-controlled process involving importins and exportins. These karyopherins recognize and bind to receptor-mediated intracellular signals through specific signal sequences that are present on cargo proteins and transport into and out of the nucleus through nuclear pore complexes. Nuclear localization signals (NLS) present on cargo molecules to be imported while nuclear export signals (NES) on the molecules to be exported are recognized by importins and exportins, respectively. The classical NLS are found on many transcription factors and molecules that are involved in the pathogenesis of allergic diseases. In addition, several immune modulators, including corticosteroids and vitamin D, elicit their cellular responses by regulating the expression and activity of importin molecules. In this review article, we provide a comprehensive list of importin and exportin molecules and their specific cargo that shuttled between cytoplasm and the nucleus. We also critically review the role and regulation of specific importin and exportin involved in the transport of activated transcription factors in allergic diseases, the underlying molecular mechanisms, and the potential target sites for developing better therapeutic approaches.

Objective Immediately preceding sudden unexpected death in epilepsy (SUDEP), patients experienced a final generalized tonic‐clonic seizure (GTCS), rapid ventilation, apnea, bradycardia, terminal apnea, and asystole. Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, we determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO2) in low‐risk and high‐risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high‐risk KO mice. Methods Heart rate and SaO2 were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100 mg/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry. Results Intermittent bradycardia was more prevalent in high‐risk KO mice, an effect that may be the result of increased parasympathetic drive. High‐risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild‐type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and/or hypopnea‐apnea. Blocking orexin receptors prevented the methacholine (MCh)–induced increase in breathing frequency in KO mice and reduced MCh‐induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high‐risk KO mice increased longevity. Significance High‐risk KO mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.

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INTRODUCTION:Clinicians should be aware of the potential adverse effects and complications that can occur with molecularly targeted agents for them to be able to diagnose and treat the condition.CASE PRESENTATION: 65-year-old female with stage IV epidermal growth factor receptor (EGFR) lung adenocarcinoma with metastases to the brain, spine, liver, and kidneys undergoing treatment with osimertinib for two months presented with a subjective fever of 102 F. On admission the patient was tachycardic with an elevated lactate warranting investigation and treatment of sepsis secondary to a UTI. Despite using broad spectrum antibiotics and proper fluid resuscitation, her hospital course was complicated with the development of a new onset dyspnea with exertion and insidious hypoxic respiratory failure. Computed tomography angiography (CTA) of the chest revealed an incidental sub segmental pulmonary embolism which was not treated with anticoagulation due to underlying hemorrhagic brain metastasis. More importantly, the CTA showed new ground glass opacities demonstrated on the upper lung fields concerning for interstitial lung disease (ILD). Osimertinib was discontinued and high-dose IV methylprednisolone was administered resulting in immediate relief of dyspnea and cessation of relapsing fever. There was also a significant improvement to the hypoxia within a 24-hour period. Patient was transitioned to oral prednisone and discharged home the following day.DISCUSSION: Anti-epidermal growth factor receptor agents, a class of small molecule kinase inhibitors, are primarily used for the treatment of advanced non-small cell lung cancer. Common side effects for this particular class of tyrosine kinase inhibitors (TKIs) include fatigue, rashes, and lymphopenia. The risk of ILD for patient's taking EGFR-TKIs is a rare incidence, occurring at a rate of 1-3%, within the first 2-3 months of initiating therapy. The exact mechanism of TKI induced lung injury remains unknown, the proposing theory is an interruption to the alveolar repair mechanism which potentiates lung injury to other causes, such as sepsis, medications, and prior radiation therapy. Discontinuation of EGFR-TKIs therapy is the primary modality to prevent worsening of ILD. Utilization of high-dose glucocorticoids is an additional measure that can be employed for the treatment of drug-induced ILD.CONCLUSIONS: Physicians must be vigilant, with a high degree of clinical suspicion, to discontinue the offending agent in the event that a patient on EGFR-TKIs therapy presents with fever, acute dyspnea with or without cough, tachycardia, and hypoxia. If symptoms of the adverse reaction are not recognized early enough, they may progress to other conditions, such as pulmonary fibrosis. In addition, there is an increased mortality ratewith the continuation of these agents once ILD develops.