CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses.

Infection with human and simian immunodeficiency viruses (HIV/SIV) requires binding of the viral envelope glycoprotein (Env) to the host protein CD4 on the surface of immune cells. Although invariant in humans, the Env binding domain of the chimpanzee CD4 is highly polymorphic, with nine coding variants circulating in wild populations. Here, we show that within-species CD4 diversity is not unique to chimpanzees but found in many African primate species. Characterizing the outermost (D1) domain of the CD4 protein in over 500 monkeys and apes, we found polymorphic residues in 24 of 29 primate species, with as many as 11 different coding variants identified within a single species. D1 domain amino acid replacements affected SIV Env-mediated cell entry in a single-round infection assay, restricting infection in a strain- and allele-specific fashion. Several identical CD4 polymorphisms, including the addition of N-linked glycosylation sites, were found in primate species from different genera, providing striking examples of parallel evolution. Moreover, seven different guenons (Cercopithecus spp.) shared multiple distinct D1 domain variants, pointing to long-term trans-specific polymorphism. These data indicate that the HIV/SIV Env binding region of the primate CD4 protein is highly variable, both within and between species, and suggest that this diversity has been maintained by balancing selection for millions of years, at least in part to confer protection against primate lentiviruses. Although long-term SIV-infected species have evolved specific mechanisms to avoid disease progression, primate lentiviruses are intrinsically pathogenic and have left their mark on the host genome.

High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress resistance.

Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in Caenorhabditis elegans, although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells.

Flipping the Classroom in Otolaryngology Residencies.

Objective To understand the use of the flipped classroom (FC) - learning core content prior to an academic session, with class time devoted to applying this content - in otolaryngology residency education. Methods An electronic survey of 107 otolaryngology program directors (PDs), including demographic details, the flipped classroom perception instrument (FCPI), and the otolaryngology programs' current use of FC. Results Forty-four (41%) PDs completed the FCPI. Seventy-one point one (71.1%) of respondents were male, 60% were 30-49 years, and the remainder were older. Sixty-two percent (62%) had fellowships associated with their program, 21.7% of programs used the FC model Very Often, 17.4% Somewhat Often, 28.3% Sometimes, 17.4% Somewhat Rarely, 8.7% Very Rarely, and 6.5% Never. Attitudes toward FC principles were positive with modes "strongly agree" for all, except for "online modules enhance learning" where the mode was "slightly agree" with significantly higher scores for PDs over age 50 than for those younger (4.17 vs. 3.63, p=0.033). There were no other significant differences comparing male vs. female PDs, younger vs. older PDs, smaller vs. larger programs, programs with or without fellowships, programs with 100% vs. <100% board exam pass rates, or programs in different geographical regions. The pre-class activity mean score was 4.34 (95% CI 4.12-4.56) and the in-class mean score was 4.18 (95% CI 3.99-4.37). There was no significant correlation between the likelihood of using a flipped classroom and attitude scores. Conclusion PDs value both the pre-class and interactive in-class principles of FCs but only 37.8% of programs use FC often, suggesting that practical approaches to implementation in this group could improve education in this population.

Hypomethylating Agent Azacitidine Is Effective in Treating Brain Metastasis Triple-Negative Breast Cancer Through Regulation of DNA Methylation of Keratin 18 Gene.

Breast cancer patients presenting with symptomatic brain metastases have poor prognosis, and current chemotherapeutic agents are largely ineffective. In this study, we evaluated the hypomethylating agent azacitidine (AZA) for its potential as a novel therapeutic in preclinical models of brain metastasis of breast cancer. We used the parental triple-negative breast cancer MDA-MB-231 (231) cells and their brain colonizing counterpart (231Br) to ascertain phenotypic differences in response to AZA. We observed that 231Br cells have higher metastatic potential compared to 231 cells. With regard to therapeutic value, the AZA IC50 value in 231Br cells is significantly lower than that in parental cells (P < .01). AZA treatment increased apoptosis and inhibited the Wnt signaling transduction pathway, angiogenesis, and cell metastatic capacity to a significantly higher extent in the 231Br line. AZA treatment in mice with experimental brain metastases significantly reduced tumor burden (P = .0112) and increased survival (P = .0026) compared to vehicle. Lastly, we observed a decreased expression of keratin 18 (an epithelial maker) in 231Br cells due to hypermethylation, elucidating a potential mechanism of action of AZA in treating brain metastases from breast cancer.

eHealth Literacy in Otolaryngology Patients.

OBJECTIVES: The aim of this study was to compare eHealth literacy-one's perception of one's ability to use the Internet for health care-among otolaryngology patients in 3 geographic settings of the same department. SETTING: An academic otolaryngology department. METHOD: Patients' opinions and perceptions of their eHealth literacy were assessed with a validated paper survey administered in the summer of 2017. RESULTS: Of 381 asked, 351 people completed the survey, 149 at a university town teaching hospital clinic (group A), 101 at a nearby rural clinic (group B), and 101 at a remote rural clinic (group C). Mean scores were 30.80, 28.97, and 29.03 for groups A, B, and C, respectively. The overall mean was 29.76 ± 5.97. Three surveys reported the minimum score of 8, and 26 reported the maximum score of 40. Results were statistically significantly different among all sites (P = .001), between groups A and B (P = .027), and between groups A and C (P = .0175). Women reported higher eHealth literacy (30.13 ± 6.27) than men (28.87 ± 5.11) (P = .045). Participant age and role (patient or parent of a patient) were statistically insignificant. Mean scores were similar to those previously reported in other patient populations. CONCLUSIONS: Otolaryngology patients in a university town had better eHealth literacy than patients in more rural settings, suggesting that online medical resources and access points are less likely to be useful in rural populations.

Adenoid size by drug induced sleep endoscopy compared to nasopharyngeal mirror exam.

OBJECTIVE: To establish how assessment of adenoid size is correlated between drug-induced sleep endoscopy (DISE) with indirect mirror nasopharyngoscopy (IMN). STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care academic hospital. METHODS: Over a 6-year period, 154 pediatric patients underwent DISE for obstructive sleep apnea and had IMN. DISE videos were assessed by one reviewer, blinded to results of mirror exams. IMN findings were taken from operative notes recorded by one attending physician. Demographic data, co-morbidities, and sleep study results were also recorded. RESULTS: Ninety-three (58.5%) males and 66 (41.5%) females were included. Mean age at DISE was 7.34 ± 3.99 years, with an average of 29 days after DISE until nasopharyngeal mirror examination. The mean initial adenoid size based on DISE assessment was 2.62 + 0.99, and on nasopharyngeal mirror assessment was 2.56 + 0.97. DISE and IMN assessment of adenoid size correlated well (Spearman's Rho = 0.82, P < 0.00001; Kendal tau = 0.764, P < 0.00001). CONCLUSIONS: DISE has proven to be an excellent tool to assess adenoid size prior to adenoidectomy in children with OSA.

In Vivo Evaluation of the Visual Pathway in Streptozotocin-Induced Diabetes by Diffusion Tensor MRI and Contrast Enhanced MRI.

Visual function has been shown to deteriorate prior to the onset of retinopathy in some diabetic patients and experimental animal models. This suggests the involvement of the brain's visual system in the early stages of diabetes. In this study, we tested this hypothesis by examining the integrity of the visual pathway in a diabetic rat model using in vivo multi-modal magnetic resonance imaging (MRI). Ten-week-old Sprague-Dawley rats were divided into an experimental diabetic group by intraperitoneal injection of 65 mg/kg streptozotocin in 0.01 M citric acid, and a sham control group by intraperitoneal injection of citric acid only. One month later, diffusion tensor MRI (DTI) was performed to examine the white matter integrity in the brain, followed by chromium-enhanced MRI of retinal integrity and manganese-enhanced MRI of anterograde manganese transport along the visual pathway. Prior to MRI experiments, the streptozotocin-induced diabetic rats showed significantly smaller weight gain and higher blood glucose level than the control rats. DTI revealed significantly lower fractional anisotropy and higher radial diffusivity in the prechiasmatic optic nerve of the diabetic rats compared to the control rats. No apparent difference was observed in the axial diffusivity of the optic nerve, the chromium enhancement in the retina, or the manganese enhancement in the lateral geniculate nucleus and superior colliculus between groups. Our results suggest that streptozotocin-induced diabetes leads to early injury in the optic nerve when no substantial change in retinal integrity or anterograde transport along the visual pathways was observed in MRI using contrast agent enhancement. DTI may be a useful tool for detecting and monitoring early pathophysiological changes in the visual system of experimental diabetes non-invasively.

Fibroblasts From Longer-Lived Species of Primates, Rodents, Bats, Carnivores, and Birds Resist Protein Damage.

Species differ greatly in their rates of aging. Among mammalian species life span ranges from 2 to over 60 years. Here, we test the hypothesis that skin-derived fibroblasts from long-lived species of animals differ from those of short-lived animals in their defenses against protein damage. In parallel studies of rodents, nonhuman primates, birds, and species from the Laurasiatheria superorder (bats, carnivores, shrews, and ungulates), we find associations between species longevity and resistance of proteins to oxidative stress after exposure to H(2)O(2) or paraquat. In addition, baseline levels of protein carbonyl appear to be higher in cells from shorter-lived mammals compared with longer-lived mammals. Thus, resistance to protein oxidation is associated with species maximal life span in independent clades of mammals, suggesting that this cellular property may be required for evolution of longevity. Evaluation of the properties of primary fibroblast cell lines can provide insights into the factors that regulate the pace of aging across species of mammals.

Fibroblasts from long-lived rodent species exclude cadmium.

Resistance to the lethal effects of cellular stressors, including the toxic heavy metal cadmium (Cd), is characteristic of fibroblast cell lines derived from long-lived bird and rodent species, as well as cell lines from several varieties of long-lived mutant mice. To explore the mechanism of resistance to Cd, we used inductively coupled plasma mass spectroscopy to measure the rate of Cd uptake into primary fibroblasts of 15 rodent species. These data indicate that fibroblasts from long-lived rodent species have slower rates of Cd uptake from the extracellular medium than those from short-lived species. In addition, fibroblasts from short-lived species export more zinc after exposure to extracellular Cd than cells from long-lived species. Lastly, fibroblasts from long-lived rodent species have lower baseline concentrations of two redox-active metals, iron and copper. Our results suggest that evolution of longevity among rodents required adjustment of cellular properties to alter metal homeostasis and to reduce the toxic effects of heavy metals that accumulate over the course of a longer life span.

A Case of Successful Use of Hypnosis in the Treatment of Parasomnia Overlap Disorder.

A young male patient was successfully treated for parasomnia overlap disorder (POD) using hypnosis. In 2006, this 16-year-old patient underwent a clinical evaluation for episodes of sleep talking, sleepwalking, and dream enactment. This initial assessment was followed by polysomnographic evaluation, a brain MRI, and three sessions of treatment using hypnosis. From the beginning, until the last contact in December 2011, benefits from the hypnotic suggestions were noted and documented.

Resistance of skin fibroblasts to peroxide and UV damage predicts hearing loss in aging mice.

Those mice whose skin-derived primary fibroblast cell lines resist lethal injury induced by hydrogen peroxide or UV light show lower age-related decline in hearing. Skin cell lines may provide an easily accessible surrogate index of intrinsic stress resistance that varies among individuals and influences the pace of neurosensory decline in aging mice.

Screening and evaluation of sleep disorders in children and adolescents.

Most pediatric professionals do not use a systematic screening, identification, or referral process to detect serious sleep problems and disorders in children and adolescents. Therefore, only 2% to 3% of children with sleep disorders are identified and treated. This article presents a screening, referral, and diagnostic process that helps detect and correct sleep disorders that impact children's learning, behavioral and emotional functioning, and health.

Insulin-dependent diabetes loci Idd5 and Idd9 increase sensitivity to experimental autoimmune encephalomyelitis.

The spontaneous development of autoimmune diabetes in NOD mice suggests that they are unable to establish and maintain immunologic self-tolerance. Congenic NOD mice expressing B10-derived alleles are protected from pancreatic beta cell destruction and autoimmune diabetes. To determine if the B10 alleles in loci Idd5 and Idd9 could influence susceptibility to autoimmunity in other organs, we compared MOG35-55-induced EAE in NOD mice to that of diabetes-resistant NOD.B10.Idd5 and NOD.B10.Idd9 mice. Surprisingly, the severity and chronicity of EAE were enhanced in the diabetes-resistant congenic mice. Our findings indicate that some alleles may influence susceptibility to immune-mediated damage in an organ or tissue-specific fashion, and highlight the necessity of disease-specific investigations.

Symptoms of depression in individuals with obstructive sleep apnea may be amenable to treatment with continuous positive airway pressure.

OBJECTIVE: To assess the reversibility of symptoms of depression using continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA). PATIENTS/METHODS: Patients referred to our center for evaluation of OSA who had a respiratory disturbance index (RDI) > or = 15 and who demonstrated a significant response to CPAP (> or = 50% drop in RDI) were evaluated for the symptoms of depression using the Beck Depression Inventory (BDI), and then reassessed after 4 to 6 weeks of treatment with CPAP at home. RESULTS: In this group of patients, the institution of CPAP therapy resulted in a significant (p < 0.0001) decrease in those symptoms of depression as assessed by the BDI (BDI at baseline, 4.1 +/- 3.7; BDI after CPAP, 1.0 +/- 2.0). This change in BDI was noted both in those individuals who had received an antidepressant prescription prior to referral, and in those who had not. An analysis of variance failed to reveal any effect on these data related to gender or baseline RDI. CONCLUSIONS: Patients with OSA may present to their primary care physician with symptoms suggesting a diagnosis of depression. In some of these individuals, the symptoms of depression may be ameliorated with CPAP.