Changes in tongue morphology predict responses in pharyngeal patency to selective hypoglossal nerve stimulation.

STUDY OBJECTIVES: The major goal of the study was to determine whether changes in tongue morphology under selective hypoglossal nerve therapy for obstructive sleep apnea were associated with alterations in airway patency during sleep when specific portions of the hypoglossal nerve were stimulated. METHODS: This case series was conducted at the Johns Hopkins Sleep Disorders Center at Johns Hopkins Bayview Medical Center. Twelve patients with apnea implanted with a multichannel targeted hypoglossal nerve-stimulating system underwent midsagittal ultrasound tongue imaging during wakefulness. Changes in tongue shape were characterized by measuring the vertical height and polar dimensions between tongue surface and genioglossi origin in the mandible. Changes in patency were characterized by comparing airflow responses between stimulated and adjacent unstimulated breaths during non-rapid eye movement sleep. RESULTS: Two distinct morphologic responses were observed. Anterior tongue base and hyoid-bone movement (5.4 [0.4] to 4.1 [1.0] cm (median and [interquartile range]) with concomitant increases in tongue height (5.0 [0.9] to 5.6 [0.7] cm) were associated with decreases in airflow during stimulation. In contrast, comparable anterior hyoid movement (tongue protrusion from 5.8 [0.5] to 4.5 [0.9] cm) without significant increases in height (5.2 [1.6] to 4.6 [0.8] cm) were associated with marked increases in airflow during sleep. CONCLUSIONS: Tongue protrusion with preservation of tongue shape predicted increases in patency, whereas anterior movement with concomitant increases in height were associated with decreased pharyngeal patency. These findings suggest that pharyngeal patency can be best stabilized by stimulating lingual muscles that maintain tongue shape while protruding the tongue, thereby preventing it from prolapsing posteriorly during sleep. CITATION: Fleury Curado T, Pham L, Otvos T, et al. Changes in tongue morphology predict responses in pharyngeal patency to selective hypoglossal nerve stimulation. J Clin Sleep Med. 2023;19(5):947-955.

A Novel Non-invasive Approach for Measuring Upper Airway Collapsibility in Mice.

Introduction: Invasive procedures were previously developed for measuring pharyngeal collapsibility in rodents during expiration, when declining neuromuscular activity makes the airway unstable. We developed a non-invasive approach for streamlining collapsibility measurements by characterizing responses in physiologic markers of dynamic expiratory airflow obstruction to negative nasal pressure challenges. Methods: Anesthetized mice were instrumented to monitor upper airway pressure-flow relationships with head-out plethysmography while nasal pressure was ramped down from ~ +5 to -20 cm H2O over several breaths. Inspiratory and expiratory flow, volume, and timing characteristics were assessed breath-wise. Pcrit was estimated at transitions in expiratory amplitude and timing parameters, and compared to gold standard PCRIT measurements when nasal and tracheal pressures diverged during expiration. Predictions equations were constructed in a development data set (n = 8) and applied prospectively to a validation data set (n = 16) to estimate gold standard PCRIT. Results: The development data demonstrated that abrupt reversals in expiratory duration and tidal volume during nasal pressure ramps predicted gold standard PCRIT measurements. After applying regression equations from the development to a validation dataset, we found that a combination of expiratory amplitude and timing parameters proved to be robust predictors of gold standard PCRIT with minimal bias and narrow confidence intervals. Conclusions: Markers of expiratory airflow obstruction can be used to model upper airway collapsibility, and can provide sensitive measures of changes in airway collapsibility in rodents. This approach streamlines repeated non-invasive PCRIT measurements, and facilitates studies examining the impact of genetic, environmental, and pharmacologic factors on upper airway control.

Mechanisms Underlying Improvement in Obstructive Sleep Apnea Syndrome by Uvulopalatopharyngoplasty.

In a previous case report, we determined for the first time that uvulopalatopharyngoplasty (UPPP) does not change the volume of the upper airway but causes morphological changes in the entire upper airway. The objective of this study is to elucidate the mechanisms underlying the improvement in obstructive sleep apnea syndrome (OSAS) by UPPP. We present an additional case involving a patient with OSAS treated using UPPP. Morphological and numerical parameter changes after surgery were compared with the corresponding preoperative values. Anatomically accurate upper airway computational models were reconstructed from computed tomographic imaging data. In addition, computed fluid dynamics analysis was performed to reveal inhalation flow characteristics before and after UPPP and clearly assess the effect of UPPP on airflow patterns in the patient's upper airway. An important benefit of UPPP is the morphological changes in the entire upper airway, in addition to widening the restricted area. These morphological changes induce laminarization of the pharyngeal jet. To obtain sufficient efficacy of UPPP in OSAS, the morphological changes in the upper airway and the airflow pattern after the surgery must be controlled.

Cytokeratin 13, Cytokeratin 17, and Ki-67 Expression in Human Acquired Cholesteatoma and Their Correlation With Its Destructive Capacity.

OBJECTIVES: Cholesteatoma is a nonneoplastic destructive lesion of the temporal bone with debated pathogenesis and bone resorptive mechanism. Both molecular and cellular events chiefly master its activity. Continued research is necessary to clarify factors related to its aggressiveness. We aimed to investigate the expression of Ki-67, cytokeratin 13 (CK13) and cytokeratin 17 (CK17) in acquired nonrecurrent human cholesteatoma and correlate them with its bone destructive capacity. METHODS: A prospective quantitative immunohistochemical study was carried out using fresh acquired cholesteatoma tissues (n=19), collected during cholesteatoma surgery. Deep meatal skin tissues from the same patients were used as control (n=8). Cholesteatoma patients were divided into 2 groups and compared (invasive and noninvasive) according to a grading score for bone resorption based upon clinical, radiologic and intraoperative findings. To our knowledge, the role of CK17 in cholesteatoma aggressiveness was first investigated in this paper. RESULTS: Both Ki-67 and CK17 were significantly overexpressed in cholesteatoma than control tissues (P<0.001 for both Ki-67 and CK17). In addition, Ki-67 and CK17 were significantly higher in the invasive group than noninvasive group of cholesteatoma (P=0.029, P=0.033, respectively). Furthermore, Ki-67 and CK17 showed a moderate positive correlation with bone erosion scores (r=0.547, P=0.015 and r=0.588, P=0.008, respectively). In terms of CK13, no significant difference was found between cholesteatoma and skin (P=0.766). CONCLUSION: Both Ki-67 and CK17 were overexpressed in cholesteatoma tissue and positively correlated with bone resorption activity. The concept that Ki-67 can be a predictor for aggressiveness of cholesteatoma was supported. In addition, this is the first study demonstrating CK17 as a favoring marker in the aggressiveness of acquired cholesteatoma.

Pathogenesis and Bone Resorption in Acquired Cholesteatoma: Current Knowledge and Future Prospectives.

Cholesteatoma is a cystic non tumorous lesion of the temporal bone that has the ability to destroy nearby structures by its power to cause bone resorption and as a result, fatal complications prevail. We aimed to conduct a comprehensive review for pathogenesis of acquired cholesteatoma, bone resorption mechanisms, and offer a future vision of this serious disease. We have reviewed different theories for pathogenesis of acquired cholesteatoma including the most relevant and updated ones with special emphasis on the mechanisms of bone resorption through Medline/PubMed research using the keywords 'aetiopathogenesis, bone resorption, acquired cholesteatoma, temporal bone, and cytokines.' In order to strengthen our study, we searched the reference lists of identified reviews. Cholesteatoma is a subject of debate among otolaryngologists since it was prescribed firstly. Over many decades, several theories were postulated for aetiopathogenesis of cholesteatoma with a tendency to follow more than one theory to explain the proper nature of that disease. Until now, the mechanism of bone resorption has yet to be more clarified. In the last century, a leap has occurred in the field of biomolecular cholesteatoma research which improved our knowledge about its pathophysiology and bone destructive mechanism. However, surgery is still the only available treatment. We conclude that discovery of new therapeutic choices for cholesteatoma other than surgery by the use of anti-growth, anti-proliferative, apoptotic agents as well as medications that antagonize osteoclastogenesis should be the main concern in the future clinical and experimental research work. Also, searching for predictors of the aggressiveness of cholesteatoma can affect the timing of intervention and prevent occurrence of complications.

Volumes of Velopharyngeal and Glossopharyngeal Airway Were Not Changed after Uvulopalatopharyngoplasty: Report of Three Cases.

Objective. The aim of this study was to investigate the changes in velopharyngeal and glossopharyngeal airway morphology and volume after uvulopalatopharyngoplasty in three adult obstructive sleep apnea syndrome patients who had bilateral large tonsils using three-dimensional computed tomography. Case Report. All three patients (one male and two females) who presented with a history of heavy snoring and excessive daytime sleepiness were examined with overnight nocturnal polysomnography, which indicated moderate-to-severe obstructive sleep apnea syndrome. Because all patients had large tonsils, uvulopalatopharyngoplasty was expected to enlarge the pharyngeal airway. Polysomnography and three-dimensional computed tomography scanning were performed and compared, both before and 3 months after uvulopalatopharyngoplasty. Results. Unexpectedly, although the morphology of the glossopharyngeal airway clearly changed after UPPP, the volume changes in the velopharyngeal and glossopharyngeal airways were negligible.

Studies on therapeutic effects and pathological features of an antithrombin preparation in septic disseminated intravascular coagulation patients.

PURPOSE: Few reports have been made on the therapeutic effects as well as pathological features of an antithrombin preparation in patients diagnosed with septic disseminated intravascular coagulation (DIC) by the diagnostic criteria for acute DIC. MATERIALS AND METHODS: A total of 88 sepsis patients who had received inpatient hospital care during the period from January 2000 through December 2008 were divided into two groups, an antithrombin group and a non-antithrombin group, to study the outcomes. Furthermore, the relationship between sepsis-related factors and DIC in 44 patients was studied. RESULTS: The antithrombin group contained 34 patients, and the non-antithrombin group contained 54 patients. The outcomes were significantly better in the antithrombin group. The levels of protein C were low in DIC patients. CONCLUSION: Our results suggest that early administration of antithrombin might improve outcomes of septic DIC patients in the diagnostic criteria for Japanese Association for Acute Medicine acute DIC.

A functional variation in the hypocretin neuropeptide precursor gene may be associated with obstructive sleep apnea syndrome in Japan.

OBJECTIVES/HYPOTHESIS: To evaluate the association of hypocretin neuropeptide precursor gene (HCRT) variations with obstructive sleep apnea syndrome (OSAS) in a cohort of Japanese patients and to further evaluate whether the significant HCRT variations have potential functional consequences on HCRT expression. STUDY DESIGN: Case-control genetic association study. METHODS: We studied the genetic variations within the HCRT gene. The study population consisted of 100 OSAS patients and 100 control subjects. The HCRT gene was amplified by polymerase chain reaction in all study subjects followed by direct sequencing and analysis of sequencing data. RESULTS: Two genetic variations within the HCRT intron, IVS1+16T>C (rs9902709) and IVS1-69G>C, were identified with significant differences between patients and controls (P < .05). A reporter gene assay using HeLa cells showed that the construct containing the C allele of the rs9902709 variation had significantly higher luciferase activity compared with the construct containing the T allele (P = .002). Furthermore, enzyme immunoassay revealed that subjects with T/C and C/C genotypes for rs9902709 had 1.4-fold and 1.5-fold increases in sera levels of orexin-A, respectively. CONCLUSIONS: Our genetic association study, followed by functional and quantitative phenotyping assays, demonstrated a functional locus within the HCRT gene, which may act to increase HCRT expression and lead to a protective effect against the development of OSAS.

Pathologic evaluation of primary laryngeal anterior commissure carcinoma both in patients who have undergone open surgery as initial treatment and in those who have undergone salvage surgery after irradiation failure.

Laryngeal anterior commissure (AC) cancer has been the subject of much controversy. Our study was aimed at pathologically evaluating the tendency of AC cancer to invade the thyroid cartilage and analyzing the role of thyroid cartilage invasion by tumor cells at the AC as an anatomic cause for irradiation failure. Our study included 36 patients with glottic cancer involving AC. Patients with recurrent or persistent disease after radiotherapy underwent salvage surgery. Surgical specimens from 22 patients who had open surgery, either as primary or salvage surgery, were available for pathologic examination to identify the presence of cartilage invasion. We found microscopic invasion of the thyroid cartilage in 40.9% of the studied tumors. Only 21.4% of patients who had open salvage surgery showed evidence of cartilage invasion at the AC. We concluded that laryngeal AC cancers are more likely to invade the cartilage, and that anatomic risk factors are not the main cause of irradiation failure.

Selection of behaviors and segmental coordination during larval locomotion is disrupted by nuclear polyglutamine inclusions in a new Drosophila Huntington's disease-like model.

Huntington's disease is an autosomal dominant neurodegenerative disorder that is caused by abnormal expansion of a polyglutamine tract in the huntingtin protein, resulting in intracellular aggregate formation and neurodegeneration. How neuronal cells are affected by such a polyglutamine tract expansion remains obscure. To dissect the ways in which polyglutamine expansion can cause neural dysfunction, the authors generated Drosophila transgenic strains expressing either a nuclear targeted or cytoplasmic form of pathogenic (NHtt-152Q(NLS), NHtt-152Q), or nonpathogenic (NHtt-18Q(NLS), NHtt-18Q) N-terminal human huntingtin. These proteins were expressed in the dendritic arborization neurons of the larval peripheral nervous system and their effects on neuronal survival, morphology, and larval locomotion were examined. The authors found that NHtt-152Q(NLS) larvae had altered dendrite morphology and larval locomotion, whereas NHtt-152Q, NHtt-18Q(NLS), and NHtt-18Q larvae did not. Furthermore, the authors examined the physiological defect underlying this disrupted larval locomotion in detail by recording spontaneous ongoing segmental nerve activity. NHtt-152Q(NLS) larvae displayed uncoordinated activity between anterior and posterior segments. Moreover, anterior segments had shorter bursts and longer interburst intervals in NHtt-152Q(NLS) larvae than in NHtt-18Q(NLS) larvae, whereas posterior segments had longer bursts and shorter interburst intervals. These results suggest that the pathogenic protein disrupts neuron function without inducing cell death, and describe how this dysfunction leads to a locomotor defect. These results also suggest that sensory inputs are necessary for the coordination of anterior and posterior body parts during locomotion. From these analyses the authors show that examination of motor behaviors in the Drosophila larvae is a powerful new model to dissect non-cell-lethal mechanisms of mutant Htt toxicity.

Protein-losing gastroenteropathy and retinitis associated with cytomegalovirus infection in an immunocompetent infant: a case report.

UNLABELLED: A 6-week-old immunocompetent girl developed protein-losing gastroenteropathy (PLGE) and retinitis associated with cytomegalovirus (CMV) infection. At presentation, CMV antigenaemia (6 cells/46,000 white blood cells) and its DNA were detected in the patient's blood and in the mother's milk. Intravenous ganciclovir and gamma-globulin rapidly ameliorated all symptoms and CMV antigenaemia disappeared. No immunological defects were identified in this patient. To the best of our knowledge, this case involves the youngest known immunocompetent patient demonstrating CMV-induced PLGE and retinitis. CONCLUSION: breast-feeding by a cytomegalovirus-positive mother can be a primary cause of early onset cytomegalovirus infection in infants.

Obesity and obstructive sleep apnea syndrome.

We investigated the influence of obesity on upper airway obstruction, especially the relationship between obesity and the type of obstruction. The site of obstruction was identified by means of endoscopic examination and dynamic MRI during sleep. Many obese patients have the circumferential type of obstruction.

Application of lingual tonsillectomy to sleep apnea syndrome involving lingual tonsils.

In sleep apnea syndrome, surgical treatment is applied in obstructive-type cases and some mixed-type cases. If the obstructive part is in the root of the tongue, forward transfer of the tongue, lingual tonsillectomy and laser midline glossectomy are applied. In this study, we demonstrate the surgical technique of lingual tonsillectomy using an ultrasonic coagulating dissector (SonoSurg) with a blade tip shape developed in our department. We conclude that lingual tonsillectomy using SonoSurg, which we have frequently used, should be the first choice of treatment for snoring and sleep apnea caused by hypertrophy of the lingual tonsils from the viewpoints of effectiveness, prevention of hemorrhage, safety and handling.