Genioglossus reflex responses to negative upper airway pressure are altered in people with tetraplegia and obstructive sleep apnoea.

KEY POINTS: Protective reflexes in the throat area (upper airway) are crucial for breathing. Impairment of these reflexes can cause breathing problems during sleep such as obstructive sleep apnoea (OSA). OSA is very common in people with spinal cord injury for unknown reasons. This study shows major changes in protective reflexes that serve to keep the upper airway open in response to suction pressures in people with tetraplegia and OSA. These results help us understand why OSA is so common in people with tetraplegia and provide new insight into how protective upper airway reflexes work more broadly. ABSTRACT: More than 60% of people with tetraplegia have obstructive sleep apnoea (OSA). However, the specific causes are unknown. Genioglossus, the largest upper-airway dilator muscle, is important in maintaining upper-airway patency. Impaired genioglossus muscle function following spinal cord injury may contribute to OSA. This study aimed to determine if genioglossus reflex responses to negative upper-airway pressure are altered in people with OSA and tetraplegia compared to non-neurologically impaired able-bodied individuals with OSA. Genioglossus reflex responses measured via intramuscular electrodes to ∼60 brief (250 ms) pulses of negative upper-airway pressure (∼-15 cmH2 O at the mask) were compared between 13 participants (2 females) with tetraplegia plus OSA and 9 able-bodied controls (2 females) matched for age and OSA severity. The initial short-latency excitatory reflex response was absent in 6/13 people with tetraplegia and 1/9 controls. Genioglossus reflex inhibition in the absence of excitation was observed in three people with tetraplegia and none of the controls. When the excitatory response was present, it was significantly delayed in the tetraplegia group compared to able-bodied controls: excitation onset latency (mean ± SD) was 32 ± 16 vs. 18 ± 9 ms, P = 0.045; peak excitation latency was 48 ± 17 vs. 33 ± 8 ms, P = 0.038. However, when present, amplitude of the excitation response was not different between groups, 195 ± 26 vs. 219 ± 98% at baseline, P = 0.55. There are major differences in genioglossus reflex morphology and timing in response to rapid changes in airway pressure in people with tetraplegia and OSA. Altered genioglossus function may contribute to the increased risk of OSA in people with tetraplegia. The precise mechanisms mediating these differences are unknown.

Nasal Resistance Is Elevated in People with Tetraplegia and Is Reduced by Topical Sympathomimetic Administration.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is common in individuals with tetraplegia and associated with adverse health outcomes. The causes of the high prevalence of OSA in this population are unknown, but it is important to understand as standard treatments are poorly tolerated in tetraplegia. Nasal congestion is common in tetraplegia, possibly because of unopposed parasympathetic activity. Further, nasal obstruction can induce OSA in healthy individuals. We therefore aimed to compare nasal resistance before and after topical administration of a sympathomimetic between 10 individuals with tetraplegia (T) and 9 able-bodied (AB) controls matched for OSA severity, gender, and age. METHODS: Nasal, pharyngeal, and total upper airway resistance were calculated before and every 2 minutes following delivery of ≈0.05 mL of 0.5% atomized phenylephrine to the nostrils and pharyngeal airway. The surface tension of the upper airway lining liquid was also assessed. RESULTS: At baseline, individuals with tetraplegia had elevated nasal resistance (T = 7.0 ± 1.9, AB = 3.0 ± 0.6 cm H2O/L/s), that rapidly fell after phenylephrine (T = 2.3 ± 0.4, p = 0.03 at 2 min) whereas the able-bodied did not change (AB = 2.5 ± 0.5 cm H2O/L/s, p = 0.06 at 2 min). Pharyngeal resistance was non-significantly higher in individuals with tetraplegia than controls at baseline (T = 2.6 ± 0.9, AB = 1.2 ± 0.4 cm H2O/L/s) and was not altered by phenylephrine in either group. The surface tension of the upper airway lining liquid did not differ between groups (T = 64.3 ± 1.0, AB = 62.7 ± 0.6 mN/m). CONCLUSIONS: These data suggest that the unopposed parasympathetic activity in tetraplegia increases nasal resistance, potentially contributing to the high occurrence of OSA in this population.

IRBIT Interacts with the Catalytic Core of Phosphatidylinositol Phosphate Kinase Type Iα and IIα through Conserved Catalytic Aspartate Residues.

Phosphatidylinositol phosphate kinases (PIPKs) are lipid kinases that generate phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), a critical lipid signaling molecule that regulates diverse cellular functions, including the activities of membrane channels and transporters. IRBIT (IP3R-binding protein released with inositol 1,4,5-trisphosphate) is a multifunctional protein that regulates diverse target proteins. Here, we report that IRBIT forms signaling complexes with members of the PIPK family. IRBIT bound to all PIPK isoforms in heterologous expression systems and specifically interacted with PIPK type Iα (PIPKIα) and type IIα (PIPKIIα) in mouse cerebellum. Site-directed mutagenesis revealed that two conserved catalytic aspartate residues of PIPKIα and PIPKIIα are involved in the interaction with IRBIT. Furthermore, phosphatidylinositol 4-phosphate, Mg2+, and/or ATP interfered with the interaction, suggesting that IRBIT interacts with catalytic cores of PIPKs. Mutations of phosphorylation sites in the serine-rich region of IRBIT affected the selectivity of its interaction with PIPKIα and PIPKIIα. The structural flexibility of the serine-rich region, located in the intrinsically disordered protein region, is assumed to underlie the mechanism of this interaction. Furthermore, in vitro binding experiments and immunocytochemistry suggest that IRBIT and PIPKIα interact with the Na+/HCO3- cotransporter NBCe1-B. These results suggest that IRBIT forms signaling complexes with PIPKIα and NBCe1-B, whose activity is regulated by PI(4,5)P2.

Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers.

Glioblastoma tumour cells release microvesicles (exosomes) containing mRNA, miRNA and angiogenic proteins. These microvesicles are taken up by normal host cells, such as brain microvascular endothelial cells. By incorporating an mRNA for a reporter protein into these microvesicles, we demonstrate that messages delivered by microvesicles are translated by recipient cells. These microvesicles are also enriched in angiogenic proteins and stimulate tubule formation by endothelial cells. Tumour-derived microvesicles therefore serve as a means of delivering genetic information and proteins to recipient cells in the tumour environment. Glioblastoma microvesicles also stimulated proliferation of a human glioma cell line, indicating a self-promoting aspect. Messenger RNA mutant/variants and miRNAs characteristic of gliomas could be detected in serum microvesicles of glioblastoma patients. The tumour-specific EGFRvIII was detected in serum microvesicles from 7 out of 25 glioblastoma patients. Thus, tumour-derived microvesicles may provide diagnostic information and aid in therapeutic decisions for cancer patients through a blood test.