Clinical Presentations of Patients with Chronic Rhinosinusitis

Purpose of Review: Chronic rhinosinusitis (CRS) is denoted as the symptomatic inflammations of sin nasal mucosa persists for ≥12 weeks. The purpose of this study was to review the recent literatures for digging out a clear concept on the clinical presentations of patients with chronic rhinosinusitis and assess the potentialities of the features. Recent Findings: According to the findings, descriptions and discussions of several recent studies it was observed that, a package of clinical features and presentations are associated with chronic rhinosinusitis. Some are major and some are minor potentials. The frequencies and severities of symptoms and features are directly dependent on the duration of that disease. Summary: Basically, rhinosinusitis or CRS is an inflammatory and infectious disease which affects the nasal cavities as well as the paranasal sinuses of patients. Rhinosinusitis with polyps is more common in male than that in female. There are many possible clinical features of CRS. But as per the frequencies, duration and effects nasal congestion, nasal discharge (Anterior/posterior nasal drip), pain/pressure on the face, impaired ability to smell (Hyposmia/anosmia), dizziness, fever and cough are the most common clinical features of chronic rhinosinusitis.

Modulation of Glucose Production by Central Insulin Requires IGF-1 Receptors in AgRP Neurons

Similar to insulin, central administration of insulin-like Growth Factor-1 (IGF-1) can suppress hepatic glucose production (HGP), but it is unclear if this effect is mediated via insulin receptors (InsRs) or IGF-1 receptors (IGF-1Rs) in the brain. To this end, we utilized pharmacologic and genetic approaches in combination with hyperinsulinemic-euglycemic clamps to decipher the role of these receptors in mediating central effects of IGF-1 and insulin on HGP. In rats, we observed that intracerebroventricular (ICV) administration of IGF-1 or insulin markedly increased the glucose infusion rate (GIR) by >50% and suppressed HGP (<i>P</i><0.001). However, these effects were completely prevented by preemptive ICV infusion with an IGF-1R and InsR/IGF-1R Hybrid (HybridRs) blocking antibody.<a> Likewise, ICV infusion of the InsR antagonist, S961, which also can bind HybridRs, interfered with the ability of central insulin, but not IGF-1 to increase the GIR. </a>Furthermore, hyperinsulinemic clamps in mice lacking IGF-1Rs in AgRP neurons revealed ~30% reduction in the GIR in KO animals, which was explained by an impaired ability of peripheral insulin to completely suppress HGP (<i>P</i><0.05). Signaling studies further revealed an impaired ability of peripheral insulin to trigger ribosomal S6 phosphorylation or PIP3 production in AgRP neurons lacking IGF-1Rs. In summary, these data suggest that attenuation of IGF-1Rs signaling in the MBH, and specifically in AgRP neurons, can phenocopy impaired regulation of HGP as previously demonstrated in mice lacking InsRs in these cells, suggesting a previously unappreciated role for IGF-1Rs and/or HybridRs in the regulation of central insulin/IGF-1 signaling on glucose metabolism.

Modulation of Glucose Production by Central Insulin Requires IGF-1 Receptors in AgRP Neurons

Similar to insulin, central administration of insulin-like Growth Factor-1 (IGF-1) can suppress hepatic glucose production (HGP), but it is unclear if this effect is mediated via insulin receptors (InsRs) or IGF-1 receptors (IGF-1Rs) in the brain. To this end, we utilized pharmacologic and genetic approaches in combination with hyperinsulinemic-euglycemic clamps to decipher the role of these receptors in mediating central effects of IGF-1 and insulin on HGP. In rats, we observed that intracerebroventricular (ICV) administration of IGF-1 or insulin markedly increased the glucose infusion rate (GIR) by >50% and suppressed HGP (<i>P</i><0.001). However, these effects were completely prevented by preemptive ICV infusion with an IGF-1R and InsR/IGF-1R Hybrid (HybridRs) blocking antibody.<a> Likewise, ICV infusion of the InsR antagonist, S961, which also can bind HybridRs, interfered with the ability of central insulin, but not IGF-1 to increase the GIR. </a>Furthermore, hyperinsulinemic clamps in mice lacking IGF-1Rs in AgRP neurons revealed ~30% reduction in the GIR in KO animals, which was explained by an impaired ability of peripheral insulin to completely suppress HGP (<i>P</i><0.05). Signaling studies further revealed an impaired ability of peripheral insulin to trigger ribosomal S6 phosphorylation or PIP3 production in AgRP neurons lacking IGF-1Rs. In summary, these data suggest that attenuation of IGF-1Rs signaling in the MBH, and specifically in AgRP neurons, can phenocopy impaired regulation of HGP as previously demonstrated in mice lacking InsRs in these cells, suggesting a previously unappreciated role for IGF-1Rs and/or HybridRs in the regulation of central insulin/IGF-1 signaling on glucose metabolism.

EPISODES OF HEARTBURN AND BLOATING IN MEDICAL PRACTICE

The aim of the study was to study the frequency and nature of episodes of heartburn and bloating in patients with duodenal and gastric ulcers in the Georgian population, considering the histomorphological and morphometric changes of the gastric mucosa and the parameters of gastric secretion. At the same time, we were interested in analyzing patients' anamnesis before being hospitalized for the last 2 months. The analysis of the material showed that incidence of heartburn episodes in the Georgian population is clearly higher in patients with peptic ulcer disease 12 - (79.9%) than in patients with gastric ulcer (9 - 31.9%). Episodes of heartburn in these patients are characterized not only by increasing of rate (more than 50 episodes), both day and night, but the intensity and duration (which is due to abnormal gastroesophageal reflux). This is a high risk for the occurrence of heartburn episodes. As for bloating, it was detected in patients with duodenal ulcer (11–26.2%), in gastric ulcer 11– (32.9%). The main pathogenetic aspects of heartburn episodes were found to be diffuse fundal glands hyperplasia and high acidity (duodenal ulcer and pyloric anterior ulcer). It was also found that a large percentage of patients were not treated properly, leading to impaired ability to work and changes in quality of life and disease progression.

H3K9 tri-methylation at Nanog times differentiation commitment and enables the acquisition of primitive endoderm fate

Mouse Embryonic Stem (ES) cells have an inherent propensity to explore distinct gene-regulatory states associated with either self-renewal or differentiation. This property is largely dependent on ERK activity, which promotes silencing of pluripotency genes, most notably of the transcription factor Nanog. Here, we aimed at identifying repressive histone modifications that would mark the Nanog locus for inactivation in response to ERK activity. We found histone H3 lysine 9 tri-methylation (H3K9me3) focally enriched between the Nanog promoter and its -5kb enhancer. While in undifferentiated ES cells H3K9me3 at Nanog depends on ERK activity, in somatic cells it becomes ERK-independent. Moreover, upon deletion of the region harbouring H3K9me3, ES cells display reduced heterogeneity of NANOG expression, delayed commitment into differentiation and impaired ability to acquire a primitive endoderm fate. We suggest that establishment of irreversible H3K9me3 at specific master regulators allows the acquisition of particular cell fates during differentiation.

Body Language as a Communicative Aid amongst Language Impaired Students: Managing Disabilities

Language impairment is a condition of impaired ability in expressing ideas, information, needs and in understanding what others say. In the teaching and learning of English as a second language, this disability poses a lot of difficulties for impaired students as well as the teacher in the pedagogic process. Pathologies and other speech/language interventions have aided such students in coping with language learning; however, this study explores another dimension of aiding impaired students in an ESL situation: the use of body language. The study adopts a quantitative methodology in assessing the role of body language as a learning tool amongst language/speech impaired students. It was discovered that body language aids students to manage speech disabilities and to achieve effective communication; this helps in making the teaching and learning situation less cumbersome.

Neuregulin-1-dependent control of amygdala microcircuits is critical for fear extinction

Anxiety disorders, especially posttraumatic stress disorder, are marked by an impaired ability to understand that a conditioned stimulus previously paired with a noxious stimulus is no longer noxious. Although previous studies suggest that fear extinction depends on the function of the amygdala, the underlying mechanisms are unclear. We found that NRG1 receptors (ErbB4) were abundantly expressed in the intercalated amygdala (ITC). The NRG1-ErbB4 pathway in the ITC promotes fear extinction. The NRG1-ErbB4 pathway in the ITC did not affect excitatory input to ITC neurons from BLA neurons but increased feed-forward inhibition of CeM neurons through increased GABAergic neurotransmission of ITC neurons. We also found that the NRG1-ErbB4 signaling pathway in ITC might regulate fear extinction through P/Q-type voltage-activated Ca2+ channels (VACCs) but not through L- or N-type VACCs. Overall, our results suggest that the NRG1-ErbB4 signaling pathway in the ITC might represent a potential target for the treatment of anxiety disorders.

The Mechanism by Which LiCl Attenuates the Impaired Ability of Learning and Memory of APP/PS1 Double Transgenic Mice May Involve Elevating the Expression of a7 Nicotinic Acetylcholine Receptors via Regulation of the Wnt/β-catenin Pathway

BackgroundWe examined the mechanism by which lithium chloride (LiCl) attenuates the impaired learning and memory of APP/PS1 double transgenic (APP/PS1) mice. MethodsSix- or twelve-month-old APP/PS1 and wild-type (WT) mice were divided randomly into 4 groups: WT, WT+Li (100 mg LiCl/kg body weight, gavage once daily), APP/PS1 and APP/PS1+Li. Primary rat hippocampal neurons were exposed to β-amyloid peptide oligomers (AβOs), LiCl and/or XAV939 (inhibitor of Wnt/β-catenin) or transfected with small interfering RNA against the β-catenin gene. Phosphor-glycogen synthase kinase-3β (GSK3β) (ser9), total GSK3β, β-catenin, cyclin D1, and α7 nAChR protein and mRNA were quantified by Western blotting or real-time PCR, respectively; senile plaques and α7 protein by immunohistochemical or immunofluorescent staining; Aβ 42 by ELISA; and cell viability by CCK8. Learning and memory were assessed utilizing the Morris water maze test. ResultsIn the brains of APP/PS1 mice, the level of Aβ was increased and those of α7 nAChR, phosphor-GSK3β (ser9), β-catenin, and cyclin D1 (at the protein and/or mRNA level) reduced. Treatment with LiCl for 2 months at 4 or 10 months of age attenuated all of these effects. Similar changes in the levels of these proteins were observed in primary neurons exposed to AβOs and these effects were attenuated by LiCl and aggravated by XAV939. Inhibition of β-catenin expression lowered the level of α7 nAChR protein in these cells. ConclusionLiCl attenuates the impaired ability of learning and memory of APP/PS1 mice via a mechanism that might involve elevation of the level of α7 nAChR as a result of altered Wnt/β-catenin signaling.

The fatty acid elongase ELOVL6 regulates bortezomib resistance in multiple myeloma

Resistance to the proteasome inhibitor bortezomib (BTZ) represents a major obstacle in the treatment of multiple myeloma (MM). The contribution of lipid metabolism in the resistance of MM cells to BTZ is mostly unknown. Here we report that levels of fatty acid elongase 6 (ELOVL6) were lower in MM cells from BTZ-nonresponsive vs BTZ-responsive patients and in cultured MM cells selected for BTZ resistance compared with parental counterparts. Accordingly, depletion of ELOVL6 in parental MM cells suppressed BTZ-induced endoplasmic reticulum (ER) stress and cytotoxicity, whereas restoration of ELOVL6 levels in BTZ-resistant MM cells sensitized them to BTZ in tissue culture settings and, as xenografts, in a plasmacytoma mouse model. Furthermore, for the first time, we identified changes in the BTZ-induced lipidome between parental and BTZ-resistant MM cell lines underlying a functional difference in their response to BTZ. We demonstrated that restoration of ELOVL6 levels in BTZ-resistant MM cells resensitized them to BTZ largely via upregulation of ELOVL6-dependent ceramide species, which was a prerequisite for BTZ-induced ER stress and cell death in these cells. Our data characterize ELOVL6 as a major clinically relevant regulator of MM cell resistance to BTZ, which can emerge from the impaired ability of these cells to alter ceramide composition in response to BTZ.