Different clinical course of BPPV according to the medical conditions.

Dizziness is one of the most prevalent complaints in medicine, and benign paroxysmal positional vertigo (BPPV) accounts for one-third of all cases. The present study was aimed at identifying differences in the course and prognosis of BPPV depending on the patient's medical condition during hospitalization. Patients in group 1 were hospitalized due to trauma, those in group 2 for scheduled surgery, and those in group 3 for medical treatment. The intervals from admission to symptom onset, surgery to symptom onset, and symptom onset to ENT department referral were compared. The interval from admission to symptom onset was shortest in group 1 (3.1 ± 8.0 days) and differed significantly from that in group 3 (20.0 ± 35.0 days, p < 0.001). The interval from surgery to symptom onset for group 2 was 5.6 ± 5.8 days and was significantly shorter than that from admission to symptom onset for group 3 (p = 0.014). The interval from symptom onset to ENT referral in group 3 (2.0 ± 2.8 days) was significantly shorter than in groups 1 and 2 (4.1 ± 5.1 and 4.0 ± 3.6 days, p = 0.008 and p = 0.002, respectively). The findings imply that the course of BPPV differed according to the patients' medical condition.

An imbalance between proliferation and differentiation underlies the development of microRNA-defective pineoblastoma.

Mutations in the microRNA processing genes DICER1 and DROSHA drive several cancers that resemble embryonic progenitors. To understand how microRNAs regulate tumorigenesis, we ablated Drosha or Dicer1 in the developing pineal gland to emulate the pathogenesis of pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. Accordingly, these mice develop pineal tumors marked by loss of microRNAs, including the let-7/miR-98-5p family, and de-repression of microRNA target genes. Pineal tumors driven by loss of Drosha or Dicer1 mimic tumors driven by Rb1 loss, as they exhibit upregulation of S-phase genes and homeobox transcription factors that regulate pineal development. Blocking proliferation of these tumors facilitates expression of pinealocyte maturation markers, with a concomitant reduction in embryonic markers. Select embryonic markers remain elevated, however, as the microRNAs that normally repress these target genes remain absent. One such microRNA target gene is the oncofetal transcription factor Plagl2, which regulates expression of pro-growth genes, and inhibiting their signaling impairs tumor growth. Thus, we demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation.

Double Primary Cancers of Earlobe Merkel Cell Carcinoma and Lung Adenocarcinoma.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma with a high rate of metastasis. MCC is rarely suspected during clinical examination, thus requiring biopsy to establish a pathologic diagnosis. In addition, MCC sometimes occurs in double primary cancers. Although there have been reviews on double primary cancers, only a few cases involving MCC have been described. Herein, we report a case of a 54-year-old female patient who presented to our clinic with a diagnosis of earlobe MCC following an excisional biopsy performed by another clinic. Further evaluation, including chest imaging, revealed a mass in the lung. The patient underwent a wide excision of the right earlobe, and video-assisted thoracic surgery on the lung. Pathology confirmed MCC in the right earlobe and adenocarcinoma in the lung. The patient underwent postoperative adjuvant chemotherapy followed by radiotherapy. Up to this point, 3 years after the surgery, there has been no evidence of recurrence.

Intronic Germline DICER1 Variants in Patients With Sertoli-Leydig Cell Tumor.

Germline pathogenic loss-of-function (pLOF) variants in DICER1 are associated with a predisposition for a variety of solid neoplasms, including pleuropulmonary blastoma and Sertoli-Leydig cell tumor (SLCT). The most common DICER1 pLOF variants include small insertions or deletions leading to frameshifts, and base substitutions leading to nonsense codons or altered splice sites. Larger deletions and pathogenic missense variants occur less frequently. Identifying these variants can trigger surveillance algorithms with potential for early detection of DICER1-related cancers and cascade testing of family members. However, some patients with DICER1-associated tumors have no pLOF variants detected by germline or tumor testing. Here, we present two patients with SLCT whose tumor sequencing showed only a somatic missense DICER1 RNase IIIb variant. Conventional exon-directed germline sequencing revealed no pLOF variants. Using a custom capture panel, we discovered novel intronic variants, ENST00000343455.7: c.1752+213A>G and c.1509+16A>G, that appear to interfere with normal splicing. We suggest that when no DICER1 pLOF variants or large deletions are discovered in exonic regions despite strong clinical suspicion, intron sequencing and splicing analysis should be performed.

Glucocorticoid Receptor Activation in Lobular Breast Cancer Is Associated with Reduced Cell Proliferation and Promotion of Metastases.

Estrogen receptor-positive (ER+) invasive lobular breast cancer (ILC) comprises about ~15% of breast cancer. ILC's unique genotypic (loss of wild type E-cadherin expression) and phenotypic (small individual round cancer cells that grow in discontinuous nests) are thought to contribute to a distinctive pattern of metastases to serosal membranes. Unlike invasive ductal carcinoma (IDC), ILC metastases often intercalate into the mesothelial layer of the peritoneum and other serosal surfaces. While ER activity is a known driver of ILC proliferation, very little is known about how additional nuclear receptors contribute to ILC's distinctive biology. In ER+ IDC, we showed previously that glucocorticoid receptor (GR) activity inhibits pro-proliferative gene expression and cell proliferation. Here we examined ER+ ILC models and found that GR activation similarly reduces S-phase entry gene expression and ILC proliferation. While slowing tumor growth rate, our data also suggest that GR activation results in an enhanced metastatic phenotype through increasing integrin-encoding gene expression, extracellular matrix protein adhesion, and mesothelial cell clearance. Moreover, in an intraductal mouse mammary gland model of ILC, we found that GR expression is associated with increased bone metastases despite slowed primary mammary tumor growth. Taken together, our findings suggest GR-mediated gene expression may contribute to the unusual characteristics of ILC biology.

Primary Bilateral Tuberculous Otitis Media After Kidney Transplantation: A Case Report.

We report a case of primary bilateral tuberculous otitis media in a patient who underwent kidney transplantation. This case presents unusual clinical features and histopathology from those of classical tuberculous otitis media. A 75-year-old woman presented at the clinic with purulent ear discharge and hearing loss in both ears. She had undergone kidney transplantation 6 years prior and had been taking immunosuppressant medications. Otoscopic examination and imaging studies suggested acute otitis media, which was irresponsive to antibiotics. The patient underwent surgery to eradicate the disease, and histopathologic examination revealed multifocal granulomas with Langhans giant cells without caseous changes. Ziehl-Neelsen staining and polymerase chain reaction confirmed the diagnosis of tuberculous otitis media. While tuberculous otitis media is a very rare manifestation of extrapulmonary tuberculosis, this case is more noteworthy in that it occurred as a primary infection rather than as a reactivation of a prior infection. In addition, it did not show the classical triad of clinical manifestations, which occurred bilaterally, and its histopathology was different from those of classical tuberculous otitis media. This case presents a new clinical variation in tuberculous otitis media.

Objective Tinnitus of Nasopharyngeal Origin.

We report a rare case of objective tinnitus induced by nasopharyngeal muscle constriction. A 49-year-old female patient presented at the clinic with unintentional sounds coming from the nasal cavity while talking or swallowing, which were similar to the lip-smacking sound. Physical examination revealed a hypertrophic posterior nasopharyngeal wall and torus tubarius at rest. With voluntary effort, the posterior pharyngeal wall protruded prominently and collided with the torus tubarius on either side, generating a sound when they were separated. Botox injection was recommended but the patient refused. The diagnosis and treatment of objective tinnitus are well established, but in some cases, it may occur under unexpected conditions. We report a novel type of objective tinnitus. A thorough physical examination for tinnitus could reveal the cause.

Is sleep apnea truly associated with hearing loss? A nationwide, population-based study with STOP-BANG questionnaire.

Objectives: We aimed to investigate the effect of obstructive sleep apnea (OSA) on hearing ability. Methods: We retrospectively reviewed the population-based survey data collected by the Korean National Health and Nutrition Examination Survey between January 1, 2019 and December 31, 2020. The data included 3,575 participants who completed the STOP-BANG questionnaire (SBQ) and pure-tone audiometry. OSA risk was assessed using the SBQ, and the hearing level was compared between the risk groups. Results: Among the 3,575 participants, 2,152 (60.2%), 891 (24.9%), and 532 (14.9%) were classified as being low, intermediate, and high risk, respectively. The intermediate- and high-risk groups showed significantly worse hearing levels than the low-risk group. When age and sex were adjusted, the hearing level did not differ between the risk groups. Conclusion: The study found that the presence of OSA minimally affected hearing level. Because hearing loss due to hypoxic damage develops over a long period of time, further research on the association between the duration of OSA, rather than the presence or severity of OSA, and hearing loss is needed.

Ectopic PLAG1 induces muscular dystrophy in the mouse.

Even though various genetic mutations have been identified in muscular dystrophies (MD), there is still a need to understand the biology of MD in the absence of known mutations. Here we reported a new mouse model of MD driven by ectopic expression of PLAG1. This gene encodes a developmentally regulated transcription factor known to be expressed in developing skeletal muscle, and implicated as an oncogene in certain cancers including rhabdomyosarcoma (RMS), an aggressive soft tissue sarcoma composed of myoblast-like cells. By breeding loxP-STOP-loxP-PLAG1 (LSL-PLAG1) mice into the MCK-Cre line, we achieved ectopic PLAG1 expression in cardiac and skeletal muscle. The Cre/PLAG1 mice died before 6 weeks of age with evidence of cardiomyopathy significantly limiting left ventricle fractional shortening. Histology of skeletal muscle revealed dystrophic features, including myofiber necrosis, fiber size variation, frequent centralized nuclei, fatty infiltration, and fibrosis, all of which mimic human MD pathology. QRT-PCR and Western blot revealed modestly decreased Dmd mRNA and dystrophin protein in the dystrophic muscle, and immunofluorescence staining showed decreased dystrophin along the cell membrane. Repression of Dmd by ectopic PLAG1 was confirmed in dystrophic skeletal muscle and various cell culture models. In vitro studies showed that excess IGF2 expression, a transcriptional target of PLAG1, phenocopied PLAG1-mediated down-regulation of dystrophin. In summary, we developed a new mouse model of a lethal MD due to ectopic expression of PLAG1 in heart and skeletal muscle. Our data support the potential contribution of excess IGF2 in this model. Further studying these mice may provide new insights into the pathogenesis of MD and perhaps lead to new treatment strategies.

Neuromuscular retraining therapy combined with preceding botulinum toxin A injection for chronic facial paralysis.

BACKGROUND: Neuromuscular retraining therapy (NMRT) is the central treatment for synkinesis. The efficacy of botulinum toxin type A (BTX-A) may be enhanced with the addition of physical therapy. OBJECTIVES: To investigate the effects of NMRT combined with preceding BTX-A injection (NMRT-B) on facial synkinesis and asymmetry in chronic facial paralysis. MATERIALS AND METHODS: We recruited 99 patients with unilateral facial paralysis and no recovery for > 6 months who underwent NMRT-B for > 1 year. The patients were scheduled to receive NMRT after 1-2 weeks of BTX-A injection. We used a computer-based numerical scoring system to evaluate the facial functions. Primary, secondary, and final facial movement scores were evaluated before and after 1 year of treatment. RESULTS: Patients with chronic facial paralysis who underwent NMRT-B exhibited improved facial movement after 1 year of treatment. NMRT-B provided satisfactory control of synkinesis and improved the primary movements. The mean primary and final facial movement scores were significantly increased after treatment, while the mean secondary facial movement scores were significantly decreased. CONCLUSIONS AND SIGNIFICANCE: NMRT-B improved the final facial movement in patients with chronic facial paralysis and synkinesis, regardless of the degrees of facial synkinesis and asymmetry before treatment.

In vivo screening identifies SPP2, a secreted factor that negatively regulates liver regeneration.

BACKGROUND AND AIMS: The liver is remarkably regenerative and can completely recover even when 80% of its mass is surgically removed. Identification of secreted factors that regulate liver growth would help us understand how organ size and regeneration are controlled but also provide candidate targets to promote regeneration or impair cancer growth. APPROACH AND RESULTS: To enrich for secreted factors that regulate growth control, we induced massive liver overgrowth with either YAP or MYC . Differentially expressed secreted factors were identified in these livers using transcriptomic analysis. To rank candidates by functionality, we performed in vivo CRISPR screening using the Fah knockout model of tyrosinemia. We identified secreted phosphoprotein-2 (SPP2) as a secreted factor that negatively regulates regeneration. Spp2 -deficient mice showed increased survival after acetaminophen poisoning and reduced fibrosis after repeated carbon tetrachloride injections. We examined the impact of SPP2 on bone morphogenetic protein signaling in liver cells and found that SPP2 antagonized bone morphogenetic protein signaling in vitro and in vivo. We also identified cell-surface receptors that interact with SPP2 using a proximity biotinylation assay coupled with mass spectrometry. We showed that SPP2's interactions with integrin family members are in part responsible for some of the regeneration phenotypes. CONCLUSIONS: Using an in vivo CRISPR screening system, we identified SPP2 as a secreted factor that negatively regulates liver regeneration. This study provides ways to identify, validate, and characterize secreted factors in vivo.

Characterization of Primary Muscle Tension Dysphonia Using Acoustic and Aerodynamic Voice Metrics.

OBJECTIVES/HYPOTHESIS: The objectives of this study were to (1) identify optimal clusters of 15 standard acoustic and aerodynamic voice metrics recommended by the American Speech-Language-Hearing Association (ASHA) to improve characterization of patients with primary muscle tension dysphonia (pMTD) and (2) identify combinations of these 15 metrics that could differentiate pMTD from other types of voice disorders. STUDY DESIGN: Retrospective multiparametric METHODS: Random forest modeling, independent t-tests, logistic regression, and affinity propagation clustering were implemented on a retrospective dataset of 15 acoustic and aerodynamic metrics. RESULTS: Ten percent of patients seen at the New York University (NYU) Voice Center over two years met the study criteria for pMTD (92 out of 983 patients), with 65 patients with pMTD and 701 of non-pMTD patients with complete data across all 15 acoustic and aerodynamic voice metrics. PCA plots and affinity propagation clustering demonstrated substantial overlap between the two groups on these parameters. The highest ranked parameters by level of importance with random forest models-(1) mean airflow during voicing (L/sec), (2) mean SPL during voicing (dB), (3) mean peak air pressure (cmH2O), (4) highest F0 (Hz), and (5) CPP mean vowel (dB)-accounted for only 65% of variance. T-tests showed three of these parameters-(1) CPP mean vowel (dB), (2) highest F0 (Hz), and (3) mean peak air pressure (cmH2O)-were statistically significant; however, the log2-fold change for each parameter was minimal. CONCLUSION: Computational models and multivariate statistical testing on 15 acoustic and aerodynamic voice metrics were unable to adequately characterize pMTD and determine differences between the two groups (pMTD and non-pMTD). Further validation of these metrics is needed with voice elicitation tasks that target physiological challenges to the vocal system from baseline vocal acoustic and aerodynamic ouput. Future work should also place greater focus on validating metrics of physiological correlates (eg, neuromuscular processes, laryngeal-respiratory kinematics) across the vocal subsystems over traditional vocal output measures (eg, acoustics, aerodynamics) for patients with pMTD. LEVEL OF EVIDENCE: II.

Multiple Pyogenic Granulomas in the External Auditory Canal.

Pyogenic granuloma is a benign vascular tumor of the skin or mucous membrane. One-third of pyogenic granulomas have been reported in the head and neck, but it is rarely present in the external auditory canal. Pyogenic granuloma mostly presents as a solitary granuloma, and only a few cases of multiple forms have been reported. This report describes a rare case of multiple pyogenic granulomas in the external auditory canal of a 36-year-old man along with a review of the literatures. Although it is very rare for PGs to occur in the EAC, it can be suspected in conditions such as after acute and/or chronic trauma, hormonal changes or systemic drug administration, rapid growth, and easy bleeding tendency with a friable surface. Some PGs may spontaneously resolve, but when they cause symptoms, excision is recommended for treatment and diagnosis. In the case of excision, the tumor should be excised down to the perichondrium level to prevent recurrence. Although PG mainly occurs in a solitary form, the present case shows a new clinical variation where multiple PGs were present in the EAC.

Sinonasal Manifestations of Severe Cherubism: A Case with 11-year Follow-up.

Cherubism, a type of fibroosteodysplasia, is a rare hereditary disease that causes variable degrees of facial deformity in children. Hypertrophy of the mandible is the most common symptom, but in severe cases, the disease affects the eyes, teeth, and sinonasal cavity. There have been few reports regarding sinonasal complications and no standard treatment has been established. This paper reports long-term treatment of severe cherubism that invaded the sinonasal cavity treated with consecutive endoscopic sinonasal surgeries.

High-throughput functional annotation of natural products by integrated activity profiling.

Determining mechanism of action (MOA) is one of the biggest challenges in natural products discovery. Here, we report a comprehensive platform that uses Similarity Network Fusion (SNF) to improve MOA predictions by integrating data from the cytological profiling high-content imaging platform and the gene expression platform Functional Signature Ontology, and pairs these data with untargeted metabolomics analysis for de novo bioactive compound discovery. The predictive value of the integrative approach was assessed using a library of target-annotated small molecules as benchmarks. Using Kolmogorov-Smirnov (KS) tests to compare in-class to out-of-class similarity, we found that SNF retains the ability to identify significant in-class similarity across a diverse set of target classes, and could find target classes not detectable in either platform alone. This confirmed that integration of expression-based and image-based phenotypes can accurately report on MOA. Furthermore, we integrated untargeted metabolomics of complex natural product fractions with the SNF network to map biological signatures to specific metabolites. Three examples are presented where SNF coupled with metabolomics was used to directly functionally characterize natural products and accelerate identification of bioactive metabolites, including the discovery of the azoxy-containing biaryl compounds parkamycins A and B. Our results support SNF integration of multiple phenotypic screening approaches along with untargeted metabolomics as a powerful approach for advancing natural products drug discovery.

Host Cell Redox Alterations Promote Latent HIV-1 Reactivation through Atypical Transcription Factor Cooperativity.

Immune cell state alterations rewire HIV-1 gene expression, thereby influencing viral latency and reactivation, but the mechanisms are still unfolding. Here, using a screen approach on CD4+ T cell models of HIV-1 latency, we revealed Small Molecule Reactivators (SMOREs) with unique chemistries altering the CD4+ T cell state and consequently promoting latent HIV-1 transcription and reactivation through an unprecedented mechanism of action. SMOREs triggered rapid oxidative stress and activated a redox-responsive program composed of cell-signaling kinases (MEK-ERK axis) and atypical transcription factor (AP-1 and HIF-1α) cooperativity. SMOREs induced an unusual AP-1 phosphorylation signature to promote AP-1/HIF-1α binding to the latent HIV-1 proviral genome for its activation. Consistently, latent HIV-1 reactivation was compromised with pharmacologic inhibition of oxidative stress sensing or of cell-signaling kinases, and transcription factor's loss of expression, thus functionally linking the host redox-responsive program to viral transcriptional rewiring. Notably, SMOREs induced the redox program in primary CD4+ T cells and reactivated latent HIV-1 in aviremic patient samples alone and in combination with known latency-reversing agents, thus providing physiological relevance. Our findings suggest that manipulation of redox-sensitive pathways could be exploited to alter the course of HIV-1 latency, thus rendering host cells responsive to help achieve a sterilizing cure.

FOXM1 Inhibition Enhances the Therapeutic Outcome of Lung Cancer Immunotherapy by Modulating PD-L1 Expression and Cell Proliferation.

Programmed death-ligand 1 (PD-L1) is a major target to cancer immunotherapy, and anti-PD-L1 and anti-PD-1 antibody-mediated immunotherapy are being increasingly used. However, immune checkpoint inhibitors (ICIs) are ineffective in treating large tumors and cause various immune-related adverse events in nontarget organs, including life-threatening cardiotoxicity. Therefore, the development of new therapeutic strategies to overcome these limitations is crucial. The focus of this study is the forkhead box protein M1 (FOXM1), which is identified as a potential therapeutic target for cancer immunotherapy and is associated with the modulation of PD-L1 expression. Selective small interfering RNA knockdown of FOXM1 or treatment with thiostrepton (TST) significantly reduces PD-L1 expression in non-small-cell lung cancer (NSCLC) cells and inhibits proliferation. Chromatin immunoprecipitation-PCR reveals that FOXM1 selectively upregulates PD-L1 expression by binding directly to the PD-L1 promoter. In vivo animal studies have shown that TST treatment significantly downregulates PD-L1 expression in human NSCLC tumors, while greatly reducing tumor size without side effects on normal tissues. Combined treatment with TST and anti-4-1BB antibody in the LLC-1 syngeneic tumor model induces synergistic therapeutic outcomes against immune resistant lung tumors as well as 2.72-folds higher CD3+ T cells in tumor tissues compared to that in the anti-4-1BB antibody treatment group.

Surgical Reconsideration of Traumatic Facial Paralysis.

INTRODUCTION: Despite the different pathophysiological mechanisms underlying Bell's palsy, in assessing severe traumatic facial paralysis, many surgeons rely on electrophysiological criteria to determine whether facial nerve exploration is warranted. To assess the value of preoperative electroneurography (ENoG) and the time of surgery, we analyzed data from three tertiary medical centers. MATERIALS AND METHODS: The records of 517 patients with a degenerative ratio (DR) greater than 80% on ENoG were collected, and two groups were defined: group A (90% DR ≤ ENoG) and group B (80% DR ≤ ENoG < 90% DR). The difference in effectiveness of surgery versus conservative treatment was analyzed based on the postoperative outcome determined by the House-Brackmann grading system. The independent-samples t test was used to compare surgery with conservative treatment for each day of surgical exploration. RESULT: In groups A and B, the average recovery time from facial paralysis was better in patients who had undergone surgical exploration than in those who had been treated conservatively. In group A, the difference was significant only for patients who underwent surgery within 8 days. In group B, a significant difference was found for patients who underwent surgery within 16 days but also for surgery performed 20 and 30 days after the onset of facial paralysis. DISCUSSION: In the surgical treatment of facial paralysis, the criteria for trauma patients should be distinguished from those of patients with Bell's palsy. In traumatic facial paralysis, some axons are more vulnerable to external collapse, and the degree of Wallerian degeneration of the peripheral nervous system will vary depending on the type of injury. The results of this study will help to identify those patients with traumatic facial paralysis who should be treated surgically and when they should be treated.

Surface ECG-based complexity parameters for predicting outcomes of catheter ablation for nonparoxysmal atrial fibrillation: efficacy of fibrillatory wave amplitude.

Catheter ablation (CA) is a well-established therapy for rhythm control in atrial fibrillation (AF). However, CA outcomes for persistent AF remain unsatisfactory because of the high recurrence rate despite time-consuming efforts and the latest ablation technology. Therefore, the selection of good responders to CA is necessary. Surface electrocardiography (sECG)-based complexity parameters were tested for the predictive ability of procedural termination failure during CA and late recurrence of atrial arrhythmias (AA) after CA. A total of 130 patients with nonparoxysmal AF who underwent CA for the first time were investigated. A 10-second sECG of 4 leads (leads I, II, V1, and V6) was analyzed to compute the fibrillatory wave amplitude (FWA), dominant frequency (DF), spectral entropy (SE), organization index (OI), and sample entropy (SampEn). The study endpoints were procedural termination failure during CA and late (≥1 year) AA recurrence after CA. In the multivariate analysis, FWA in lead V1 and DF in lead I were independent predictors of successful AF termination during CA (P <.05). The optimal cut-off values for FWA in lead V1 and DF in lead I were 60.38 µV (area under the curve [AUC], 0.672; P = .001) and 5.7 Hz (AUC, 0.630; P = .016), respectively. The combination of FWA of lead V1 and DF of lead I had a more powerful odds ratio for predicting procedural termination failure (OR, 8.542; 95% CI, 2.938-28.834; P < .001). FWA in lead V1 was the only independent predictor of late recurrence after CA. The cut-off value is 65.73 µV which was 0.634 of the AUC (P = .009). These sECG parameters, FWA in lead V1 and DF in lead I, predicted AF termination by CA in patients with nonparoxysmal AF. In particular, FWA in lead V1 was an independent predictor of late recurrence of AA after CA.