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Eustachian tube dysfunction (ETD) is a common middle ear disorder in children that can have a significant impact on the quality of life. This review aims to provide an updated understanding of ETD and its clinical management. We will discuss the pathophysiology and diagnosis of ETD, as well as the medical and surgical treatment of ETD. We will also review studies of both adults and children with ETD, although special attention will be paid to children with ETD.

A highly diastereoselective total synthesis of several bis-THF C15 acetogenin natural products, chloroenyne from Laurencia majuscula, laurendecumenyne B, and laurefurenynes A/B, is reported. Additionally the synthesis of an advanced intermediate reported in the earlier total synthesis of (E/Z)-elatenynes (formal synthesis) is described. The salient features in the synthesis include epoxide opening, Birch reduction, Sharpless asymmetric dihydroxylation-cycloetherification, SN2 halo­genation, and a relay cross metathesis.

The total synthesis of (+)-petromyroxol (1) and its seven diastereomers including the (-)-iso-petromyroxol (2) is described. The employed strategy involves the use of easily available C5-epimeric epoxides 5 and 5' and nonselective anomeric C1-allylation, proceeding with or without inversion at C2, thereby giving the possibility of synthesizing all possible diastereomers. Extensive two-dimensional (2D) NMR analyses of all eight diastereomers have been carried out to assign the chemical shifts of the central carbons and the corresponding attached hydrogens and to learn how the C/H-chemical shifts of the tetrahydrofuran ring were influenced by the adjacent centers.

Telehealth in otolaryngology is gaining popularity as a potential tool for increased access for rural populations, decreased specialist wait times, and overall savings to the healthcare system. The adoption of telehealth has been dramatically increased by the COVID-19 pandemic limiting patients' physical access to hospitals and clinics. One of the key challenges to telehealth in general otolaryngology and otology specifically is the limited physical examination possible on the ear canal and middle ear. This is compounded in pediatric populations who commonly present with middle ear pathologies which can be challenging to diagnose even in the clinic. To address this need, various otoscopes have been designed to allow patients, their parents, or primary care providers to image the tympanic membrane and middle ear, and send data to otolaryngologists for review. Furthermore, the ability of these devices to capture images in digital format has opened the possibility of using artificial intelligence for quick and reliable diagnostic workup. In this manuscript, we provide a concise review of the literature regarding the efficacy of remote otoscopy, as well as recent efforts on the use of artificial intelligence in aiding otologic diagnoses.

BACKGROUND AND OBJECTIVES: Among people with diabetes mellitus, CKD may promote hypoglycemia through altered clearance of glucose-lowering medications, decreased kidney gluconeogenesis, and blunted counter-regulatory response. We conducted a prospective observational study of hypoglycemia among 105 individuals with type 2 diabetes treated with insulin or a sulfonylurea using continuous glucose monitors. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: We enrolled 81 participants with CKD, defined as eGFR

OBJECTIVE In chronic kidney disease, glycated albumin and fructosamine have been postulated to be better biomarkers of glycemic control than HbA1c. We evaluated the accuracy, variability, and covariate bias of three biomarkers (HbA1c, glycated albumin, and fructosamine) compared with continuous glucose monitoring (CGM)–derived measurement of glycemia across estimated glomerular filtration rate (eGFR) in type 2 diabetes. RESEARCH DESIGN AND METHODS A prospective cohort study was conducted of 104 participants with type 2 diabetes, 80 with eGFR RESULTS Within-person biomarker values were strongly correlated between the two CGM periods (r = 0.92–0.95), although no marker fully captured the within-person variability of mean CGM glucose. All markers were similarly correlated with mean CGM glucose (r = 0.71–77). Compared with mean CGM glucose, glycated albumin and fructosamine were significantly biased by age, BMI, serum iron concentration, transferrin saturation, and albuminuria; HbA1c was underestimated in those with albuminuria. CONCLUSIONS Glycated albumin and fructosamine were not less variable than HbA1c at a given mean CGM glucose level, with several additional sources of bias. These results support measuring HbA1c to monitor trends in glycemia among patients with eGFR

​ObjectiveCompared with hemoglobin A1c (HbA1c), continuous glucose monitoring (CGM) may better capture risk of diabetes complications in patients with chronic kidney disease (CKD), including diabetic peripheral neuropathy (DPN). We hypothesized that glucose time in range (TIR), measured by CGM, is associated with DPN symptoms among participants with type 2 diabetes mellitus (type 2 DM) and moderate-to-severe CKD.​Research design and methodsWe enrolled 105 people with type 2 DM treated with insulin or sulfonylurea, 81 participants with CKD (estimated glomerular filtration rate (eGFR) 2) and 24 matched control participants with eGFR ≥60 mL/min/1.73 m2. Each participant wore a CGM for two 6-day periods. Calculated glycemic measures included TIR (glucose 70–180 mg/dL) and glucose management indicator (GMI). DPN symptoms were assessed using the Michigan Neuropathy Screening Instrument (MNSI) questionnaire, with a positive MNSI score defined as ≥2 symptoms.​ResultsParticipants with CKD had a mean age of 68 years, diabetes duration 20 years, eGFR 38 mL/min/1.73 m2 and HbA1c 7.8%, 61 mmol/mol. Sixty-two participants reported ≥2 DPN symptoms, 51 (63%) with CKD and 11 (46%) controls. Less TIR and higher GMI were associated with higher risk of MNSI questionnaire score ≥2 (OR 1.25 (95% CI 1.02 to 1.52) per 10% lower TIR, and OR 1.79 (95% CI 1.05 to 3.04) per 1% higher GMI, adjusting for age, gender and race). Similar results were observed when analyses were restricted to participants with CKD. In contrast, there was no significant association of HbA1c with DPN symptoms.​ConclusionsSymptoms of DPN were common among participants with long-standing type 2 DM and CKD. Lower TIR and higher GMI were associated with DPN symptoms.

Insulin sensitivity can be measured by procedures such as the hyperinsulinemic euglycemic clamp or by using surrogate indices. Chronic kidney disease (CKD) and obesity may differentially affect these measurements because of changes in insulin kinetics and organ-specific effects on insulin sensitivity. In a cross-sectional study of 59 subjects with nondiabetic CKD [estimated glomerular filtration rate: (GFR) −1·1.73 m2] and 39 matched healthy controls, we quantified insulin sensitivity by clamp (SIclamp), oral glucose tolerance test, and fasting glucose and insulin. We compared surrogate insulin sensitivity indices to SIclamp using descriptive statistics, graphical analyses, correlation coefficients, and linear regression. Mean age was 62.6 yr; 48% of the participants were female, and 77% were Caucasian. Insulin sensitivity indices were 8–38% lower in participants with vs. without CKD and 13–59% lower in obese compared with nonobese participants. Correlations of surrogate indices with SIclamp did not differ significantly by CKD or obesity status. Adjusting for SIclamp in addition to demographic factors, Matsuda index was 15% lower in participants with vs. without CKD ( P = 0.09) and 36% lower in participants with vs. without obesity ( P = 0.0001), whereas 1/HOMA-IR was 23% lower in participants with vs. without CKD ( P = 0.02) and 46% lower in participants with vs. without obesity ( P < 0.0001). We conclude that CKD and obesity do not significantly alter correlations of surrogate insulin sensitivity indices with SIclamp, but they do bias surrogate measurements of insulin sensitivity toward lower values. This bias may be due to differences in insulin kinetics or organ-specific responses to insulin.

Key Clinical Message Some testosterone‐producing adrenal tumors can be successfully treated with long‐acting GnRH analogs and adrenal venous sampling can be useful to detect rare ectopic sex steroid‐producing tumors or confirm bilateral adrenal androgen hyperproduction in female hyperandrogenism.

After nerve injury, Schwann cells (SCs) dedifferentiate, proliferate, and support axon regrowth. If axons fail to regenerate, denervated SCs eventually undergo apoptosis due, in part, to increased expression of the low-affinity neurotrophin receptor, p75(NTR). Merlin is the protein product of the NF2 tumor suppressor gene implicated in SC tumorigenesis. Here we explore the contribution of merlin to SC responses to nerve injury. We find that merlin becomes phosphorylated (growth permissive) in SCs following acute axotomy and following gradual neural degeneration in a deafness model, temporally correlated with increased p75(NTR) expression. p75(NTR) levels are elevated in P0SchΔ39-121 transgenic mice that harbor an Nf2 mutation in SCs relative to wild-type mice before axotomy and remain elevated for a longer period of time following injury. Replacement of wild-type, but not phospho-mimetic (S518D), merlin isoforms suppresses p75(NTR) expression in primary human schwannoma cultures which otherwise lack functional merlin. Despite elevated levels of p75(NTR), SC apoptosis following axotomy is blunted in P0SchΔ39-121 mice relative to wild-type mice suggesting that loss of functional merlin contributes to SC resistance to apoptosis. Further, cultured SCs from mice with a tamoxifen-inducible knock-out of Nf2 confirm that SCs lacking functional merlin are less sensitive to p75(NTR)-mediated cell death. Taken together these results point to a model whereby loss of axonal contact following nerve injury results in merlin phosphorylation leading to increased p75(NTR) expression. Further, they demonstrate that merlin facilitates p75(NTR)-mediated apoptosis in SCs helping to explain how neoplastic SCs that lack functional merlin survive long-term in the absence of axonal contact.

Vestibular schwannomas (VSs) arise from Schwann cells (SCs) and result from the loss of function of merlin, the protein product of the NF2 tumor suppressor gene. In contrast to non-neoplastic SCs, VS cells survive long-term in the absence of axons. We find that p75(NTR) is overexpressed in VSs compared with normal nerves, both at the transcript and protein level, similar to the response of non-neoplastic SCs following axotomy. Despite elevated p75(NTR) expression, VS cells are resistant to apoptosis due to treatment with proNGF, a high affinity ligand for p75(NTR) . Furthermore, treatment with proNGF protects VS cells from apoptosis due to c-Jun N-terminal kinase (JNK) inhibition indicating that p75(NTR) promotes VS cell survival. Treatment of VS cells with proNGF activated NF-κB while inhibition of JNK with SP600125 or siRNA-mediated knockdown reduced NF-κB activity. Significantly, proNGF also activated NF-κB in cultures treated with JNK inhibitors. Thus, JNK activity appears to be required for basal levels of NF-κB activity but not for proNGF-induced NF-κB activity. To confirm that the increase in NF-κB activity contributes to the prosurvival effect of proNGF, we infected VS cultures with Ad.IκB.SerS32/36A virus, which inhibits NF-κB activation. Compared with control virus, Ad.IκB.SerS32/36A significantly increased apoptosis including in VS cells treated with proNGF. Thus, in contrast to non-neoplastic SCs, p75(NTR) signaling provides a prosurvival response in VS cells by activating NF-κB independent of JNK. Such differences may contribute to the ability of VS cells to survive long-term in the absence of axons.

Merlin is the protein product of the NF2 tumor suppressor gene. Germline NF2 mutation leads to neurofibromatosis type 2 (NF2), characterized by multiple intracranial and spinal schwannomas. Patients with NF2 also frequently develop peripheral neuropathies. While the role of merlin in SC neoplasia is well established, its role in SC homeostasis is less defined. Here we explore the role of merlin in SC responses to nerve injury and their ability to support axon regeneration. We performed sciatic nerve crush in wild-type (WT) and in P0SchΔ39–121 transgenic mice that express a dominant negative Nf2 isoform in SCs. Recovery of nerve function was assessed by measuring mean contact paw area on a pressure pad 7, 21, 60, and 90 days following nerve injury and by nerve conduction assays at 90 days following injury. After 90 days, the nerves were harvested and axon regeneration was quantified stereologically. Myelin ultrastructure was analyzed by electron microscopy. Functional studies showed delayed nerve regeneration in Nf2 mutant mice compared to the WT mice. Delayed neural recovery correlated with a reduced density of regenerated axons and increased endoneurial space in mutants compared to WT mice. Nevertheless, functional and nerve conduction measures ultimately recovered to similar levels in WT and Nf2 mutant mice, while there was a small (∼17%) reduction in the percent of regenerated axons in the Nf2 mutant mice. The data suggest that merlin function in SCs regulates neural ultrastructure and facilitates neural regeneration, in addition to its role in SC neoplasia.

In order to evaluate the phenotypic effects of implanted neural stem cells (NSCs) in the mouse model of Niemann-Pick C (NPC) disease, we injected a well-characterized clone of murine NSCs into the cerebella of neonatal Npc1(-/-) and control mice. The implanted cells survived and were abundant in some regions of the cerebellum. Life span was lengthened in NPC mice with the implanted NSCs. However, the rate of weight gain and subsequent weight loss, resulting from neurodegeneration, was not significantly different from un-injected controls. Ataxia was measured by Rota-Rod performance. The overall rate of decline in time on the Rota-Rod was not significantly slowed down. Thus, in this small group of NPC mice, a single administration in the neonatal period of the NSCs (which were not engineered to over-express the missing gene and not directed into the parenchyma) was only partially therapeutic.

Background: Alcoholic liver disease is associated with abnormalities of methionine metabolic enzymes that may contribute to glutathione depletion. Previously, we found that feeding micropigs a combination of ethanol with a folate-deficient diet resulted in the greatest decreases in S-adenosylmethionine and glutathione and increases in liver S-adenosylhomocysteine and oxidized disulfide glutathione. Methods: To study the mechanisms of glutathione depletion, we analyzed the transcripts and activities of enzymes involved in its synthesis and metabolism in liver and plasma specimens that were available from the same micropigs that receive folate-sufficient or folate-depleted diets with or without 40% of energy as ethanol for 14 weeks. Results: Ethanol feeding, folate deficiency, or their combination decreased liver and plasma glutathione and the activities of hepatic copper-zinc superoxide dismutase and glutathione peroxidase and increased the activity of manganese superoxide dismutase and glutathione reductase. Hepatic levels of cysteine and taurine were unchanged while plasma cysteine was increased in the combined diet group. Cystathionine β-synthase transcripts and activity were unaffected by ethanol feeding, while the activities of other transsulfuration enzymes involved in glutathione synthesis were increased. Glutathione transferase transcripts were increased 4-fold and its mean activity was increased by 34% in the combined ethanol and folate-deficient diet group, similar in magnitude to the observed 36% reduction in hepatic glutathione. Conclusions: Chronic ethanol feeding and folate deficiency acted individually or synergistically to affect methionine metabolism in the micropig by depleting glutathione pools and altering transcript expressions and activities of enzymes involved in its synthesis, utilization, and regeneration. The data suggest that the observed decrease in hepatic glutathione during ethanol feeding reflects its increased utilization to meet increased antioxidant demands, rather than reduction in its synthesis.

Niemann-Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is thought to result from deficient intracellular cholesterol and/or ganglioside trafficking. We have investigated the effects of allopregnanolone treatments on survival, weight loss, motor function, magnetic resonance imaging (MRI), and neuropathology in the mouse model of NPC (Npc1(-/-) mice). We confirmed previous results showing that a single injection of 250 microg of allopregnanolone on postnatal day 7 significantly extended the life span of Npc1(-/-) mice. This caused a marked difference in the weight curves of the treated mice but no statistical difference in the Rota-Rod performance. T2-weighted MRI and diffusion tensor imaging (DTI) of treated mice showed values of signal intensity and fractional anisotropy closer to those of wild-type mice than those of untreated Npc1(-/-) mice. Neuropathology showed that day-7 treatment markedly suppressed astrocyte reaction and significantly reduced microglial activation. Furthermore, the steroid treatment also increased myelination in brains of Npc1(-/-) mice. Similar effects of allopregnanolone treatment were observed in Npc1(-/-), mdr1a(-/-) double-mutant mice, which have a deficient blood-brain barrier, resulting in increased steroid uptake. The effects on survival and weight loss of a single injection on day 7 followed by injections every 2 weeks were also evaluated in Npc1(-/-) mice, and the beneficial effects were found to be greater than with the single injection at day 7. We conclude that allopregnanolone treatment significantly ameliorates several symptoms of NPC in Npc1(-/-) mice, presumably by effects on myelination or neuronal connectivity.

Vestibular schwannomas (VSs) arise from Schwann cells (SCs) and result from the loss of function of merlin, the protein product of the NF2 tumor suppressor gene. In contrast to non-neoplastic SCs, VS cells survive long-term in the absence of axons. We find that p75(NTR) is overexpressed in VSs compared with normal nerves, both at the transcript and protein level, similar to the response of non-neoplastic SCs following axotomy. Despite elevated p75(NTR) expression, VS cells are resistant to apoptosis due to treatment with proNGF, a high affinity ligand for p75(NTR) . Furthermore, treatment with proNGF protects VS cells from apoptosis due to c-Jun N-terminal kinase (JNK) inhibition indicating that p75(NTR) promotes VS cell survival. Treatment of VS cells with proNGF activated NF-κB while inhibition of JNK with SP600125 or siRNA-mediated knockdown reduced NF-κB activity. Significantly, proNGF also activated NF-κB in cultures treated with JNK inhibitors. Thus, JNK activity appears to be required for basal levels of NF-κB activity but not for proNGF-induced NF-κB activity. To confirm that the increase in NF-κB activity contributes to the prosurvival effect of proNGF, we infected VS cultures with Ad.IκB.SerS32/36A virus, which inhibits NF-κB activation. Compared with control virus, Ad.IκB.SerS32/36A significantly increased apoptosis including in VS cells treated with proNGF. Thus, in contrast to non-neoplastic SCs, p75(NTR) signaling provides a prosurvival response in VS cells by activating NF-κB independent of JNK. Such differences may contribute to the ability of VS cells to survive long-term in the absence of axons.

Vestibular schwannomas (VSs) represent benign Schwann cell (SC) neoplasms arising from the eighth cranial nerve and result from loss of function of the tumor suppressor gene, merlin. The mechanisms by which loss of merlin function promotes tumorigenesis in SCs is not well-defined. Denervation by axotomy leads to increased merlin inactivation by phosphorylation, increased p75NTR expression, JNK activation, and eventual death of normal SCs. In contrast to SCs, VS cells survive in the absence of axons. We found that p75NTR expression is elevated in sciatic nerves of mice harboring a SC specific dominant negative merlin mutation (P0SchΔ36-121) compared to nerves from wild-type mice suggesting that merlin status regulates p75NTR expression. Consistent with this we also find that p75NTR is over-expressed in primary human VS tissue compared with normal nerves. Treatment of normal rat SCs with proNGF, a high affinity p75NTR ligand, induces apoptosis by activating JNK. Primary cultured human VS cells, by contrast, display persistent JNK activity which promotes cell survival. Treatment of human primary VS cultures with the JNK inhibitors (I-JIP and SP600125) or JNK siRNA knock down results in decreased proliferation and increased apoptosis; treatment with proNGF protects cells from apoptosis due to JNK inhibition suggesting a p75NTR-mediated pro-survival signal in primary cultured VS cells. We explored the possibility that the pro-survival effect of p75NTR signaling results from activation of NF-κB. Indeed, proNGF treatment activated NF-κB in primary cultured VS cells while inhibition of JNK with SP600125 or siRNA-mediated JNK1/2 knockdown reduced NF-κB activity. Significantly, proNGF also activated NF-κB in primary cultured VS cells treated with JNK inhibitors. Thus, persistent JNK activity appears to be required for basal levels of NF-κB activity, but not for proNGF-induced NF-κB activity. To confirm that the increase in NF-κB activity by proNGF contributes to the prosurvival effect, we infected primary human VS cultures with Ad.IκB-SermutS32/36A virus which inhibits NF-κB activation. Compared to control virus, Ad.IκB-SermutS32/36A significantly increased VS cell apoptosis in VS cultures including those treated with proNGF. These results suggest that, in contrast to normal SCs which undergo apoptosis in response to p75NTR and JNK signaling, proNGF/p75NTR signaling provides a prosurvival response by activating NF-κB independent of JNK in merlin deficient VS cells. Such differences may account for the ability of human VS cells to proliferate and survive in the absence of axons. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1036. doi:10.1158/1538-7445.AM2011-1036