Optimal Airway Management in the Treatment of Descending Necrotizing Mediastinitis Secondary to Deep Neck Infection.

PURPOSE: To review our experiences of descending necrotizing mediastinitis (DNM) secondary to deep neck infection (DNI) and determine appropriate airway management for decreasing mortality and morbidity of patients with DNM. METHODS: Medical records of 20 patients (8 women and 12 men) who had been managed for DNM secondary to DNI between March 2006 and December 2019 were analyzed. Diagnosis and extent of infection were confirmed by computed tomography of the neck and chest. The upper airway was closely monitored with a fiberoptic laryngoscope. Complications were evaluated according to various types of airway management in our serial cases. RESULTS: Five (25%) out of 20 patients died as a result of septic shock and multiorgan failure. None of these patients died of accidental airway obstruction or airway management mishaps. Keeping short-term orotracheal intubation was safe and adequate after the initial surgery. Early tracheotomy was performed for 4 patients and it was significantly associated with mortality (P = .032). Three patients who underwent late tracheotomy had no mortality. Patients with tracheotomy had longer duration of overall hospital stay than those without tracheotomy. CONCLUSIONS: Well-controlled airway management might decrease mortality, hospitalization, and airway complications in patients with DNM secondary to DNI. Keeping orotracheal intubation rather than upfront tracheotomy should be first considered when managing airway along with examination of the upper airway with a fiberoptic laryngoscope.

Oncological Outcomes after Pulmonary Metastasectomy for Head and Neck Squamous-Cell Carcinoma and Adenoid Cystic Carcinoma.

INTRODUCTION: Pulmonary metastatic head and neck cancer has a poor prognosis. Pulmonary metastasectomy has been performed but only in carefully selected patients. The aim of this study was to examine the clinical characteristics and oncological follow-up of patients who underwent pulmonary metastasectomy. METHODS: Data of 54 patients with squamous-cell carcinoma (SCC) or adenoid cystic carcinoma (ACC) who underwent metastasectomy between 2003 and 2019 at two tertiary referral centers were retrospectively reviewed. RESULTS: The 3-year and 5-year disease-free survival rates after metastasectomy were 49.9% and 39.9% for SCC and 38.9% and 32.4% for ACC, respectively. Univariate analysis revealed that a disease-free interval (DFI) less than 14 months and R1 resection (hazard ratio [HR] [95% confidence interval]: 2.95 [0.77-5.62], 4.64 [0.99-21.65], respectively) were risk factors for recurrence in SCC and that a high T stage (HR: 5.24 [1.22-22.58]) was a risk factor in ACC. In SCC, a DFI less than 14 months and R1 resection (hazard ratio: 6.35 [1.36-29.54], 12.79 [1.53-106.95], respectively) were risk factors in a multivariate analysis. CONCLUSION: Pulmonary metastasectomy had a fair effect on head and neck SCC and ACC, and the prognosis was better in SCC patients with a DFI greater than 14 months.

Oncological outcomes of preoperatively unexpected malignant tumors of the parotid gland.

PURPOSE: Unexpected parotid cancers are often encountered due to inaccuracies in the preoperative evaluation. This study aimed to examine the clinical characteristics and oncological outcomes of these cancers and to propose the appropriate management strategy. METHODS: This is a multicenter case series study in which a total of 302 patients were diagnosed postoperatively with parotid cancers between 2003 and 2017. Of these, 85 cases without evidence of malignancy prior to surgery but identified as malignant on postoperative pathology were included. RESULTS: Of 85 patients, 76 and 9 underwent superficial and total parotidectomy, respectively. A positive resection margin was present in 24.7% of the cases. Postoperative radiotherapy was administered to 43.6% of patients; 4.2% had a local recurrence, and no patients died of the disease. The 5-year overall and relapse-free survival rates were 100.0% and 95.2%, respectively. Patients who underwent piecemeal resection had significantly poorer oncologic outcomes. Age, sex, histologic grade, T stage, extracapsular extension, resection margin status, and postoperative radiotherapy did not affect recurrence and survival. CONCLUSION: Preoperatively unexpected parotid cancers had excellent local control and overall survival despite positive or close resection margin, with or without postoperative radiotherapy. Therefore, patients with unexpected parotid malignancies may benefit from less aggressive postoperative management option.

Functional Voice and Swallowing Outcome Analysis After Thyroid Lobectomy: Transoral Endoscopic Vestibular Versus Open Approach.

BACKGROUND: The transoral endoscopic thyroidectomy vestibular approach (TOETVA) is a scarless remote-access thyroidectomy technique. This study compared subjective and objective voice outcomes and swallowing outcomes of patients who underwent thyroid lobectomy using the TOETVA versus conventional open thyroidectomy (OT). METHODS: In addition to questionnaires, acoustic and aerodynamic analyses were performed to compare subjective and objective voice outcomes of the two groups. Swallowing outcome analyses were conducted using Swallowing Impairment Index-6 (SIS-6) scores. Assessments were performed preoperatively and 3 and 6 months after surgery. Propensity score matching was performed to compare the outcomes of the two groups. RESULTS: One hundred and two patients were included in this study (52 TOETVA and 50 OT). Excluding two patients who had vocal cord palsy and open conversion in the TOETVA group, 100 patients completed 3-month postoperative surveys. There were no significant differences between the groups in VAS, GRBAS, or VHI-10 scores at the preoperative and 3- and 6-month assessments. For both groups, there were no significant changes in acoustic or aerodynamic parameters during the 3-6-month postoperative period. The TOETVA group had lower SIS-6 scores at the postoperative 6-month assessment, but the SIS-6 scores after 12 months were similar between groups before and after propensity score matching. CONCLUSIONS: Following TOETVA lobectomy, there were no significant changes in voice outcomes 3 and 6 months after surgery, and the outcomes were comparable with those of OT. The TOETVA group also had swallowing outcomes that were comparable with the OT group.

Preservation of Salivary Function Following Extracapsular Dissection for Tumors of the Parotid Gland.

PURPOSE: This study evaluated salivary function after extracapsular dissection (ECD) compared with partial superficial parotidectomy (PSP) and classic superficial parotidectomy (CSP) of benign parotid gland tumors. The authors hypothesized that ECD would be superior to PSP and CSP in preserving postoperative salivary function. MATERIALS AND METHODS: Retrospective analyses were performed for 43 consecutive patients who underwent parotidectomies of benign parotid tumors performed by a single experienced surgeon. Clinical data and pre- and postoperative whole salivary flow rates were compared among the operative procedures. Pearson χ2 and Fisher exact tests were used to compare categorical variables. Kruskal-Wallis, Mann-Whitney U, and Wilcoxon signed rank tests were used to compare means. A P value less than .05 was considered significant throughout the study. RESULTS: Tumor sizes did not differ among groups. Operative times, amounts of drainage, and hospital days for ECD were markedly decreased compared with CSP and tended to be decreased compared with PSP. Resection margins were exposed in 0, 12.5, and 6.7% of patients who underwent ECD, PSP, and CSP, respectively. Postoperative complications occurred less often (but not meaningfully) after ECD. Postoperative basal salivary flow rates in the ECD, PSP, and CSP groups were 0.39, 0.32, and 0.14 mL/minute, respectively (P = .05). Stimulated salivary flow rates remained stable for the ECD and PSP groups but decreased in the CSP group. CONCLUSION: ECD is a safe and time-efficient surgical approach, offering early recovery from parotid tumors and better preservation of salivary function. ECD should be considered a surgical approach for parotid tumors, especially those in the parotid tail region, such as Warthin tumors.

Serendipitous discovery of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine derivatives as novel HIV-1 replication inhibitors.

We identified a novel class of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine compounds as potent HIV-1 replication inhibitors serendipitously during the process of evaluation of triazolothienopyrimidine (TTPM) compounds. Herein, we report synthesis and biological evaluation of 2-((phenylsulfonyl)methyl)-thieno[3,2-d]pyrimidine compounds using a cell-based full replication assay to identify thienopyrimidines 6 and 30, which could be further utilized as viable lead compounds.

Lipocalin-2 induces cardiomyocyte apoptosis by increasing intracellular iron accumulation.

Our objective was to determine whether lipocalin-2 (Lcn2) regulates cardiomyocyte apoptosis, the mechanisms involved, and the functional significance. Emerging evidence suggests that Lcn2 is a proinflammatory adipokine associated with insulin resistance and obesity-related complications, such as heart failure. Here, we used both primary neonatal rat cardiomyocytes and H9c2 cells and demonstrated for the first time that Lcn2 directly induced cardiomyocyte apoptosis, an important component of cardiac remodeling leading to heart failure. This was shown by detection of DNA fragmentation using TUNEL assay, phosphatidylserine exposure using flow cytometry to detect annexin V-positive cells, caspase-3 activity using enzymatic assay and immunofluorescence, and Western blotting for the detection of cleaved caspase-3. We also observed that Lcn2 caused translocation of the proapoptotic protein Bax to mitochondria and disruption of mitochondrial membrane potential. Using transient transfection of GFP-Bax, we confirmed that Lcn2 induced co-localization of Bax with MitoTracker® dye. Importantly, we used the fluorescent probe Phen Green SK to demonstrate an increase in intracellular iron in response to Lcn2, and depleting intracellular iron using an iron chelator prevented Lcn2-induced cardiomyocyte apoptosis. Administration of recombinant Lcn2 to mice for 14 days increased cardiomyocyte apoptosis as well as an acute inflammatory response with compensatory changes in cardiac functional parameters. In conclusion, Lcn2-induced cardiomyocyte apoptosis is of physiological significance and occurs via a mechanism involving elevated intracellular iron levels and Bax translocation.

Microarray analysis of Drosophila dicer-2 mutants reveals potential regulation of mitochondrial metabolism by endogenous siRNAs.

RNA interference is a eukaryotic regulatory mechanism by which small non-coding RNAs typically mediate specific silencing of their cognate genes. In Drosophila, the RNase III enzyme Dicer-2 (Dcr-2) is essential for biogenesis of endogenous small interfering RNAs (endo-siRNAs), which have been implicated in regulation of endogenous protein-coding genes. Although much is known about microRNA-based regulatory networks, the biological functions of endo-siRNAs in animals remain poorly understood. We performed gene expression profiling on Drosophila dcr-2 null mutant pupae to investigate transcriptional effects caused by a severe defect in endo-siRNA production, and found 306 up-regulated and 357 down-regulated genes with at least a twofold change in expression compared with the wild type. Most of these up-regulated and down-regulated genes were associated with energy metabolism and development, respectively. Importantly, mRNA sequences of 39% of the up-regulated genes were perfectly complementary to the sequences of previously reported endo-siRNAs, suggesting they may be direct targets of endo-siRNAs. We confirmed up-regulation of five selected genes matching endo-siRNAs and concomitant down-regulation of the corresponding endo-siRNAs in dcr-2 mutant pupae. Most of the potential endo-siRNA target genes were associated with energy metabolism, including the citric acid cycle and oxidative phosphorylation in mitochondria, implying that these are major metabolic processes directly affected by endo-siRNAs in Drosophila. Consistent with this finding, dcr-2 null mutant pupae had lower ATP content compared with controls, indicating that mitochondrial energy production is impaired in these mutants. Our data support a potential role for the endo-siRNA pathway in energy homeostasis through regulation of mitochondrial metabolism.

Synthesis and biological evaluation of triazolothienopyrimidine derivatives as novel HIV-1 replication inhibitors.

We identified a novel class of triazolothienopyrimidine (TTPM) compounds as potent HIV-1 replication inhibitors during a high-throughput screening campaign that evaluated more than 200,000 compounds using a cell-based full replication assay. Herein, we report the optimization of the antiviral activity in a cell-based assay system leading to the discovery of aryl-substituted TTPM derivatives (38, 44, and 45), which exhibited significant inhibition of HIV-1 replication with acceptable safety margins. These novel and potent TTPMs could serve as leads for further development.

Craniofacial Phenotype in Obstructive Sleep Apnea and Its Impact on Positive Airway Pressure (PAP) Adherence.

Positive airway pressure (PAP) is an important treatment tool for patients with moderate and severe obstructive sleep apnea (OSA), and adherence to PAP significantly affects treatment outcomes. Disease severity, adverse effects, and psychosocial factors are known to predict medication adherence. Cephalometric parameters have been reported to positively correlate with upper airway collapse. However, research on the correlation between these cephalometric parameters and PAP adherence remains insufficient. This study aimed to identify this relationship. This study included 185 patients with OSA who were prescribed PAP. Polysomnography (PSG) was performed to diagnose OSA, and paranasal sinus computed tomography (PNS CT) was performed to check for comorbidities of the upper airway. In addition, cephalometric parameters such as the hyoid-posterior nasal spine (H-PNS), posterior nasal spine-mandibular plane (PNS-MP), and hyoid-mandibular plane (H-MP) were measured in the midsagittal and axial CT views. Adherence was evaluated 3-12 months after the PAP prescription. A total of 136 patients were PAP-adherent, and 49 were nonadherent. There were more males in the adherent group and a higher average height in the adherent group. The PSG results showed that the apnea-hypopnea index (AHI), respiratory disturbance index (RDI), oxygen desaturation index (ODI), arousal index (AI), rapid eye movement (REM) AHI, and supine AHI were significantly higher, and the lowest oxygen saturation was lower in the adherent group. In the analysis of covariance (ANCOVA) model adjusted for sex and height, among the cephalometric parameters, H-MP was significantly longer in the adherent group (p = 0.027), and H-PNS showed a longer tendency (p = 0.074). In the logistic regression analysis model, the odds ratio (OR) and 95% confidence intervals (95% CI) of adherence and severe OSA in the third tertile compared to the first tertile of H-MP were 2.93 (1.25-6.86) and 4.00 (1.87-8.56). In the case of H-PNS, they were 2.58 (1.14-5.81) and 4.86 (2.24-10.54), respectively. This study concluded that an inferiorly placed hyoid bone in adult patients is associated with PAP adherence and disease severity.

Clinical Practice Guidelines for Oropharyngeal Dysphagia.

OBJECTIVE: Dysphagia is a common clinical condition characterized by difficulty in swallowing. It is sub-classified into oropharyngeal dysphagia, which refers to problems in the mouth and pharynx, and esophageal dysphagia, which refers to problems in the esophageal body and esophagogastric junction. Dysphagia can have a significant negative impact one's physical health and quality of life as its severity increases. Therefore, proper assessment and management of dysphagia are critical for improving swallowing function and preventing complications. Thus a guideline was developed to provide evidence-based recommendations for assessment and management in patients with dysphagia. METHODS: Nineteen key questions on dysphagia were developed. These questions dealt with various aspects of problems related to dysphagia, including assessment, management, and complications. A literature search for relevant articles was conducted using Pubmed, Embase, the Cochrane Library, and one domestic database of KoreaMed, until April 2021. The level of evidence and recommendation grade were established according to the Grading of Recommendation Assessment, Development and Evaluation methodology. RESULTS: Early screening and assessment of videofluoroscopic swallowing were recommended for assessing the presence of dysphagia. Therapeutic methods, such as tongue and pharyngeal muscle strengthening exercises and neuromuscular electrical stimulation with swallowing therapy, were effective in improving swallowing function and quality of life in patients with dysphagia. Nutritional intervention and an oral care program were also recommended. CONCLUSION: This guideline presents recommendations for the assessment and management of patients with oropharyngeal dysphagia, including rehabilitative strategies.

Discovery of 3,4-dihydropyrimidin-2(1H)-ones with inhibitory activity against HIV-1 replication.

3,4-Dihydropyrimidin-2(1H)-ones (DHPMs) were selected and derivatized through a HIV-1 replication assay based on GFP reporter cells. Compounds 14, 25, 31, and 36 exhibited significant inhibition of HIV-1 replication with a good safety profile. Chiral separation of each enantiomer by fractional crystallization showed that only the S enantiomer retained anti-HIV activity. Compound (S)-40, a novel and potent DHPM analog, could serve as an advanced lead for further development and the determination of the mechanism of action.

A novel 3,4-dihydropyrimidin-2(1H)-one: HIV-1 replication inhibitors with improved metabolic stability.

Following the previous SAR of a novel dihydropyrimidinone scaffold as HIV-1 replication inhibitors a detailed study directed towards optimizing the metabolic stability of the ester functional group in the dihydropyrimidinone (DHPM) scaffold is described. Replacement of the ester moiety by thiazole ring significantly improved the metabolic stability while retaining antiviral activity against HIV-1 replication. These novel and potent DHPMs with bioisosteres could serve as advanced leads for further optimization.

Neuronal M3 muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth.

The molecular pathways that promote the proliferation and maintenance of pituitary somatotrophs and other cell types of the anterior pituitary gland are not well understood at present. However, such knowledge is likely to lead to the development of novel drugs useful for the treatment of various human growth disorders. Although muscarinic cholinergic pathways have been implicated in regulating somatotroph function, the physiological relevance of this effect and the localization and nature of the receptor subtypes involved in this activity remain unclear. We report the surprising observation that mutant mice that selectively lack the M(3) muscarinic acetylcholine receptor subtype in the brain (neurons and glial cells; Br-M3-KO mice) showed a dwarf phenotype associated with a pronounced hypoplasia of the anterior pituitary gland and a marked decrease in pituitary and serum growth hormone (GH) and prolactin. Remarkably, treatment of Br-M3-KO mice with CJC-1295, a synthetic GH-releasing hormone (GHRH) analog, rescued the growth deficit displayed by Br-M3-KO mice by restoring normal pituitary size and normal serum GH and IGF-1 levels. These findings, together with results from M(3) receptor/GHRH colocalization studies and hypothalamic hormone measurements, support a model in which central (hypothalamic) M(3) receptors are required for the proper function of hypothalamic GHRH neurons. Our data reveal an unexpected and critical role for central M(3) receptors in regulating longitudinal growth by promoting the proliferation of pituitary somatotroph cells.

A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo.

One of the hallmarks of type 2 diabetes is that pancreatic beta cells fail to release sufficient amounts of insulin in the presence of elevated blood glucose levels. Insulin secretion is modulated by many hormones and neurotransmitters including acetylcholine, the major neurotransmitter of the peripheral parasympathetic nervous system. The physiological role of muscarinic acetylcholine receptors expressed by pancreatic beta cells remains unclear at present. Here, we demonstrate that mutant mice selectively lacking the M3 muscarinic acetylcholine receptor subtype in pancreatic beta cells display impaired glucose tolerance and greatly reduced insulin release. In contrast, transgenic mice selectively overexpressing M3 receptors in pancreatic beta cells show a profound increase in glucose tolerance and insulin release. Moreover, these mutant mice are resistant to diet-induced glucose intolerance and hyperglycemia. These findings indicate that beta cell M3 muscarinic receptors play a key role in maintaining proper insulin release and glucose homeostasis.

Use of a combination of N-acetylcysteine and clonazepam to treat burning mouth syndrome.

OBJECTIVE: This study was intended to evaluate the clinical efficacy of a combination of N-acetylcysteine (NAC) and clonazepam for treatment of burning mouth syndrome (BMS). STUDY DESIGN: A total of 160 patients with BMS were divided into 3 groups: group 1 received NAC (400 mg/d), group 2 received clonazepam (0.5 mg/d), and group 3 received both NAC and clonazepam. We evaluated symptom relief after 8 weeks of treatment using a visual analog scale (VAS). To assess oral health-related quality of life, we used the validated Korean version of an oral health impact profile (OHIP-14K). RESULTS: The overall response rates of the 3 groups were 60.3%, 51.3%, and 80.0%, respectively. The mean VAS and OHIP-14K scores significantly decreased in all groups after the 8-week treatments. The VAS score changes were -12.2 ± 19.5, -10.0 ± 14.1, and -21.0 ± 24.6, respectively (P = .001), in the 3 groups and the OHIP-14K changes were -2.3 ± 9.2, -4.4 ± 6.9, and -8.7 ± 10.3, respectively (P = .020). Group 3 showed significantly larger differences in VAS and OHIP-14K scores than group 2, before and after treatment. CONCLUSIONS: In the treatment of BMS, the NAC/clonazepam combination therapy was more effective than either monotherapy.

Possible association between oral health and sleep duration: A cross-sectional study based on the Korean National Health and Nutrition Examination Surveys from 2010 to 2015.

ABSTRACT: This study was performed to investigate the association between oral health and sleep duration in South Korean subjects using 2010-2015 data from the Korean National Health and Nutrition Examination Survey (KNHANES).Cross-sectional data on 35,599 adults over the age of 19 years who completed KNHANES were analyzed. All participants reported subjective oral health status and their daily average sleep duration using a self-reported questionnaire. Sleep duration and oral health status were divided into 3 categories: ≤5, 6-8, ≥9 h/day and good, fair, poor, respectively.The overall prevalence of poor oral health status was 43.8%. Univariate analysis demonstrated that poor oral health status was significantly associated with age, smoking, alcohol, diabetes, education, income, depression, marital status, and sleep duration. After adjusting for covariates (age, sex, diabetes mellitus, hypertension, obesity, smoking, income, education, marital status), sleep durations of ≤5 hours (OR = 1.42; 95% CI, 1.26-1.60) and ≥9 hours (OR = 1.21; 95% CI, 1.04-1.40) were significantly associated with poor oral health, compared to a sleep duration of 6-8 hours. Short or long sleep duration was more likely to have an impact on the development of poor oral health status in men than in women. A significant relationship between sleep duration and oral health status was found in participants younger than 60 years.This is the first report that both short and long sleep durations are significantly associated with the development of poor oral health status. The effect of short or long sleep duration on poor oral health was more significant in younger subjects and in men.

Feasibility of Brachial Plexus Schwannoma Enucleation With Intraoperative Neuromonitoring.

OBJECTIVES: To evaluate the feasibility of brachial plexus schwannoma enucleation under intraoperative neuromonitoring. METHODS: Five patients who were treated for brachial plexus schwannoma under intraoperative neuromonitoring from 2008 to 2018 were included in this retrospective review. Neuromonitoring was performed with a 100-µV event threshold of the neuromonitoring system (NIM-2 or 3) at the deltoid, biceps brachii, triceps brachii, and brachioradialis muscles. Patient characteristics, tumor size and location, intraoperative neuromonitoring findings, and postoperative function were evaluated. RESULTS: The intraoperative neuromonitoring findings were in accordance with the preoperative assessment of the included nerve root. Three patients had no postoperative morbidity, one patient had temporary paresthesia of the forearm for 2 months, and one patient mild loss of grip strength for 1 month. CONCLUSION: Intraoperative neuromonitoring of the arm and forearm muscles during enucleation of brachial plexus schwannoma promoted confident and successful surgery with minimal postoperative morbidity.

Conformational changes involved in G-protein-coupled-receptor activation.

Little is known about the nature of the conformational changes that convert G-protein-coupled receptors (GPCRs), which bind diffusible ligands, from their resting into their active states. To gain structural insight into this process, various laboratories have used disulfide cross-linking strategies involving cysteine-substituted mutant GPCRs. Several recent disulfide cross-linking studies using the M(3) muscarinic acetylcholine receptor as a model system have led to novel insights into the conformational changes associated with the activation of this prototypical class I GPCR. These structural changes are predicted to involve multiple receptor regions, primarily distinct segments of transmembrane helices III, VI and VII and helix 8. Given the high degree of structural homology found among most GPCRs, it is likely that these findings will be of considerable general relevance. A better understanding of the molecular mechanisms underlying GPCR activation might lead to novel strategies aimed at modulating GPCR function for therapeutic purposes.

An immune-responsive Serpin regulates the melanization cascade in Drosophila.

In arthropods, the melanization reaction is associated with multiple host defense mechanisms leading to the sequestration and killing of invading microorganisms. Arthropod melanization is controlled by a cascade of serine proteases that ultimately activates the enzyme prophenoloxidase (PPO), which, in turn, catalyzes the synthesis of melanin. Here we report the biochemical and genetic characterization of a Drosophila serine protease inhibitor protein, Serpin-27A, which regulates the melanization cascade through the specific inhibition of the terminal protease prophenoloxidase-activating enzyme. Our data demonstrate that Serpin-27A is required to restrict the phenoloxidase activity to the site of injury or infection, preventing the insect from excessive melanization.