'Seeing is believing' - gender disparities in otolaryngology-head and neck surgery in Africa: a narrative review.

PURPOSE OF REVIEW: Various factors affect otolaryngology - head and neck surgery (OHNS) services in low- and middle-income countries (LMICs); including inadequate infrastructure, limited academic positions, unfavorable hospital research policies, and traditional misconceptions about gender and surgery, among others. Although gender inequalities exist globally, they are particularly pronounced in LMICs, especially in Africa. RECENT FINDINGS: A comparative narrative literature review for relevant manuscripts from January 1, 2017 to through January 10th, 2024, using PubMed, Embase and Google Scholar for articles from the United States/Canada and Africa was done. 195 relevant articles were from the United States/Canada, while only 5 were from Africa and only 1 manuscript was relevant to OHNS. The reviewed articles reported that gender disparities exist in medical training, authorship, and career advancement. We highlight possible solutions to some of these disparities to promote a more gender-diversified workforce in OHNS in Africa as well as all over the world. SUMMARY: Additional studies on gender disparities in Africa, are needed. These studies will highlight need for inclusive policies, structured and accessible mentorship programs; through which these disparities can be highlighted and addressed. This will in the long run ensure sustainability of OHNS care in LMICs.

Protective Characteristics of Human Breast Milk on Early Childhood Otitis Media: A Narrative Review.

Introduction: Human breast milk (HBM) contains a complex and dynamically changing variety of factors that contribute to the infant's developing immune system's ability to fight upper respiratory tract infections, including otitis media (OM). We sought to summarize the current evidence on the protective characteristics of HBM, through direct or donated feeding, toward early childhood OM. Methods: For this narrative review, we performed a literature search on OM in the context of HBM feeding in the PubMed, Embase, and Google Scholar databases, between January 1, 2008, and July 1, 2023. Results: Immunoglobulin A (IgA) provides a short-term immunity of 2-3 days against otopathogens causing OM. IgA-mediated immunity is effective against OM up to 7 months of age if breastfeeding continues. The role of transferred IgM and IgG in HBM is unclear. Although there is a potential protective value of microRNA, hormones, oligosaccharides, stem cells, and interleukins present in HBM, their role is unclear. Any duration of breastfeeding is superior to no breastfeeding in OM risk reduction, with a big variability among studies (odds ratio 0.23-0.81, depending on the duration). Duration of breastfeeding ≥6 months was found to be the most effective in OM risk reduction, but there was no evidence of continued benefits after 2 years of age. Expressed breastfeeding was not shown to be more beneficial. The protective values of donor HBM against OM are still undetermined. Conclusion: HBM has numerous components that contribute to protection against early childhood OM.

Medical treatment does not reduce surgery rates in children with adenoid hypertrophy.

OBJECTIVE: We sought to study adenoidectomy rates in children with adenoid hypertrophy (AH) who were either treated with medical therapy or not during a 2-year follow-up period in a longitudinal population-based study. METHODS: We retrospectively identified healthy children aged 1-18 years between 2014 and 2020 with AH diagnosis from the Clalit Health Services database, the largest healthcare maintenance organization in Israel. The main outcome was adenoidectomy alone or in combination with other procedures performed within 2 years after diagnosis. The treatment group consisted of children who received medical therapy, defined as a pharmacy purchase of montelukast, nasal steroid sprays and/or antihistamines (medical therapy aimed to reduce AH) for ≥2 consecutive months, while the control group consisted of untreated children. RESULTS: We identified 68,356 unique children with AH, of them 56 % were boys, with a mean age of 4.9 ± 3.3 years. Of them, 5310 (7.7 %) received medical therapy. Overall, 6633 (9.7 %) underwent adenoidectomy within 2 years following diagnosis. There was no significant difference in surgery referral rates between the treatment and the control groups, 10 % vs. 9.7 %, respectively (p = 0.3). When adjusted for age and sex, the likelihood of undergoing adenoidectomy was similar in both groups (HR = 0.98, 95 % CI = 0.90-1.07, p = 0.6). Among operated children, the average time from diagnosis to surgery was statistically significantly longer in the treatment group than in the control group, 346 ± 180 vs 311 ± 175 days (p < 0.001). CONCLUSION: Prescribing montelukast, nasal steroids and/or oral antihistamines was not associated with a reduction in adenoidectomy rates and was associated with an average surgery delay of 35 days.

Sleep and Circadian Disturbances in Children With Neurodevelopmental Disorders.

Sleep problems are highly prevalent in those with neurodevelopmental disorders (NDDs). We propose this is secondary to multiple factors that directly and indirectly negatively impact sleep and circadian processes in those with NDDs, which in turn, further perturbs development, resulting in a "developmental and sleep/circadian-related encephalopathy." In this review, we discuss select NDDs with known or suspected sleep and circadian phenotypes. We also highlight important considerations when evaluating and treating sleep and circadian disorders in these populations.

ISOM 2023 research Panel 4 - Diagnostics and microbiology of otitis media.

OBJECTIVES: To identify and review key research advances from the literature published between 2019 and 2023 on the diagnosis and microbiology of otitis media (OM) including acute otitis media (AOM), recurrent AOM (rAOM), otitis media with effusion (OME), chronic suppurative otitis media (CSOM) and AOM complications (mastoiditis). DATA SOURCES: PubMed database of the National Library of Medicine. REVIEW METHODS: All relevant original articles published in Medline in English between July 2019 and February 2023 were identified. Studies that were reviews, case studies, relating to OM complications (other than mastoiditis), and studies focusing on guideline adherence, and consensus statements were excluded. Members of the panel drafted the report based on these search results. MAIN FINDINGS: For the diagnosis section, 2294 unique records screened, 55 were eligible for inclusion. For the microbiology section 705 unique records were screened and 137 articles were eligible for inclusion. The main themes that arose in OM diagnosis were the need to incorporate multiple modalities including video-otoscopy, tympanometry, telemedicine and artificial intelligence for accurate diagnoses in all diagnostic settings. Further to this, was the use of new, cheap, readily available tools which may improve access in rural and lowmiddle income (LMIC) settings. For OM aetiology, PCR remains the most sensitive method for detecting middle ear pathogens with microbiome analysis still largely restricted to research use. The global pandemic response reduced rates of OM in children, but post-pandemic shifts should be monitored. IMPLICATION FOR PRACTICE AND FUTURE RESEARCH: Cheap, easy to use multi-technique assessments combined with artificial intelligence and/or telemedicine should be integrated into future practice to improve diagnosis and treatment pathways in OM diagnosis. Longitudinal studies investigating the in-vivo process of OM development, timings and in-depth interactions between the triad of bacteria, viruses and the host immune response are still required. Standardized methods of collection and analysis for microbiome studies to enable inter-study comparisons are required. There is a need to target underlying biofilms if going to effectively prevent rAOM and OME and possibly enhance ventilation tube retention.

Newborn Hearing Screening: Early Ear Examination Improves the Pass Rate.

BACKGROUND: Temporary conductive hearing loss due to vernix accumulation in the external ear canal may lead to a false-positive result in newborn hearing screening tests. The aim of this study was to evaluate whether ear examination and intervention may reduce the false-positive rate prior to hospital discharge. METHODS: A case series of 42 newborns who failed initial otoacoustic emissions screening were studied in our institution between May and December 2020. RESULTS: During the study period, a total of 735 neonates (1470 ears) were screened by otoacoustic emissions in our hospital. Forty-two newborns who failed otoacoustic emissions were included in our study. They constituted 3.9% (n=58 ears) of the total number of ears screened. Forty-four ears (75.9%) passed and 14 ears (24.1%) failed otoacoustic emissions rescreening performed shortly following vernix cleaning. Twelve of the remaining 14 ears passed at 10-day rescreening. The remaining 2 ears presented true bilateral hearing loss. During the study period, the general false-positive rate decreased from 56/735 (7.61%) to 12/735(1.63%) (P < .00001). CONCLUSION: Cleaning the vernix of infants who failed otoacoustic emissions prior to hospital discharge lowers the false-positive rate of universal neonatal hearing screening. We may assume that vernix cleaning will reduce significant healthcare workload, costs of unnecessary investigations, as well as parental anxiety.

The Global Otolaryngology-Head and Neck Surgery Workforce.

Importance: A core component of delivering care of head and neck diseases is an adequate workforce. The World Health Organization report, Multi-Country Assessment of National Capacity to Provide Hearing Care, captured primary workforce estimates from 68 member states in 2012, noting that response rates were a limitation and that updated more comprehensive data are needed. Objective: To establish comprehensive workforce metrics for global otolaryngology-head and neck surgery (OHNS) with updated data from more countries/territories. Design, Setting, and Participants: A cross-sectional electronic survey characterizing the OHNS workforce was disseminated from February 10 to June 22, 2022, to professional society leaders, medical licensing boards, public health officials, and practicing OHNS clinicians. Main Outcome: The OHNS workforce per capita, stratified by income and region. Results: Responses were collected from 121 of 195 countries/territories (62%). Survey responses specifically reported on OHNS workforce from 114 countries/territories representing 84% of the world's population. The global OHNS clinician density was 2.19 (range, 0-61.7) OHNS clinicians per 100 000 population. The OHNS clinician density varied by World Bank income group with higher-income countries associated with a higher density of clinicians. Regionally, Europe had the highest clinician density (5.70 clinicians per 100 000 population) whereas Africa (0.18 clinicians per 100 000 population) and Southeast Asia (1.12 clinicians per 100 000 population) had the lowest. The OHNS clinicians deliver most of the surgical management of ear diseases and hearing care, rhinologic and sinus diseases, laryngeal disorders, and upper aerodigestive mucosal cancer globally. Conclusion and Relevance: This cross-sectional survey study provides a comprehensive assessment of the global OHNS workforce. These results can guide focused investment in training and policy development to address disparities in the availability of OHNS clinicians.

MitoTNT: Mitochondrial Temporal Network Tracking for 4D live-cell fluorescence microscopy data.

Mitochondria form a network in the cell that rapidly changes through fission, fusion, and motility. Dysregulation of this four-dimensional (4D: x,y,z,time) network is implicated in numerous diseases ranging from cancer to neurodegeneration. While lattice light-sheet microscopy has recently made it possible to image mitochondria in 4D, quantitative analysis methods for the resulting datasets have been lacking. Here we present MitoTNT, the first-in-class software for Mitochondrial Temporal Network Tracking in 4D live-cell fluorescence microscopy data. MitoTNT uses spatial proximity and network topology to compute an optimal tracking assignment. To validate the accuracy of tracking, we created a reaction-diffusion simulation to model mitochondrial network motion and remodeling events. We found that our tracking is >90% accurate for ground-truth simulations and agrees well with published motility results for experimental data. We used MitoTNT to quantify 4D mitochondrial networks from human induced pluripotent stem cells. First, we characterized sub-fragment motility and analyzed network branch motion patterns. We revealed that the skeleton node motion is correlated along branch nodes and is uncorrelated in time. Second, we identified fission and fusion events with high spatiotemporal resolution. We found that mitochondrial skeleton nodes near the fission/fusion sites move nearly twice as fast as random skeleton nodes and that microtubules play a role in mediating selective fission/fusion. Finally, we developed graph-based transport simulations that model how material would distribute on experimentally measured mitochondrial temporal networks. We showed that pharmacological perturbations increase network reachability but decrease network resilience through a combination of altered mitochondrial fission/fusion dynamics and motility. MitoTNT's easy-to-use tracking module, interactive 4D visualization capability, and powerful post-tracking analyses aim at making temporal network tracking accessible to the wider mitochondria research community.

Essential equipment and services for otolaryngology care: a proposal by the Global Otolaryngology-Head and Neck Surgery Initiative.

PURPOSE OF REVIEW: To highlight the need for comprehensive resource lists to provide baseline care of otolaryngologic conditions; to present a proposed list of essential equipment and services that may be applied toward surgical systems research, policymaking, and charitable efforts in global otolaryngology-head and neck surgery. RECENT FINDINGS: To provide effective and high-quality surgical care across care settings, there must be a global standard for equipment and ancillary services necessary to provide baseline care. Though there have been efforts to devise resource standards via equipment lists and appraisal tools, these have been limited in scope to general surgery, emergency care, and a few other subspecialty surgical contexts. Recent efforts have brought attention to the significant burden imposed by otolaryngologic conditions such as hearing loss, otitis media, head and neck cancer, head and neck trauma, and upper airway foreign bodies. Yet, there has not been a comprehensive list of resources necessary to provide baseline care for common otolaryngologic conditions. SUMMARY: Through an internal survey of its members, the Global Otolaryngology-Head and Neck Surgery Initiative has compiled a list of essential equipment and services to provide baseline care of otolaryngologic conditions. Our efforts aimed to address common otolaryngologic conditions that have been previously identified as high-priority with respect to prevalence and burden of disease. This expert-driven list of essential resources functions as an initial framework to be adapted for internal quality assessment, implementation research, health policy development, and economic priority-setting.

Audiometry-Confirmed Sudden Sensorineural Hearing Loss Incidence among COVID-19 Patients and BNT162b2 Vaccine Recipients.

OBJECTIVE: To compare sudden sensorineural hearing loss (SSNHL) incidence rates over the coronavirus disease 2019 (COVID-19) outbreak and the COVID-19 vaccination campaign periods to pre-COVID-19 periods. STUDY DESIGN: Retrospective cohort. SETTING: Secondary hospital. PATIENTS: Patients >12 years with auditory-confirmed SSNHL were enrolled. COVID-19 status and BNT162 inoculation records ≤28 days before SSNHL diagnosis were retrieved. Patients were categorized according to their date of presentation over four equal periods: 1) July 2018-April 2019 (first prepandemic period), 2) May 2019-February 2020 (second prepandemic period), 3) March 2020-December 2020 (COVID-19 outbreak), and 4) January 2021-October 2021 (BNT162b2 vaccinations campaign). INTERVENTIONS: Pre- and post-COVID-19 emergence; BNT162b2 vaccine. MAIN OUTCOME MEASURES: Incidence rate ratios (IRRs) were calculated to compare SSNHL cases during the COVID-19 and vaccination periods with pre-COVID-19 periods. RESULTS: Of the 100 patients with SSNHL over the four periods, 1 had COVID-19 and 8 were vaccinated. The annual SSNHL incidence was 12.87, 12.28, 13.45, and 19.89 per 100,000 over periods 1 to 4, respectively. SSNHL incidence over the third period was not significantly different than the first/second periods (IRR = 1.045, 95% confidence interval [CI] = 0.629-1.85, ρ = 0.788, and IRR = 1.095, 95% CI = 0.651-1.936, ρ = 0.683, respectively), whereas SSNHL incidence rate over the fourth period was higher (IRR = 1.545, 95% CI = 0.967-2.607, ρ = 0.068, and IRR = 1.619, 95% CI = 1-2.73, ρ = 0.05, respectively). SSNHL incidence in vaccine recipients was lower than prepandemic unvaccinated patients (IRR = 0.584, 95% CI =0.464-1.67, ρ = 0.984, and IRR = 0.612, 95% CI =0.48-1.744, ρ = 0.92, respectively). CONCLUSION: There were fewer SSNHL cases during the first COVID-19 months. Although the SSNHL rate over the COVID-19 vaccination campaign increased, it was not higher for patients who received the BNT162b2 vaccine.

Next-Generation SINE Compound KPT-8602 Ameliorates Dystrophic Pathology in Zebrafish and Mouse Models of DMD.

Duchenne muscular dystrophy (DMD) is a progressive, X-linked childhood neuromuscular disorder that results from loss-of-function mutations in the DYSTROPHIN gene. DMD patients exhibit muscle necrosis, cardiomyopathy, respiratory failure, and loss of ambulation. One of the major driving forces of DMD disease pathology is chronic inflammation. The current DMD standard of care is corticosteroids; however, there are serious side effects with long-term use, thus identifying novel anti-inflammatory and anti-fibrotic treatments for DMD is of high priority. We investigated the next-generation SINE compound, KPT-8602 (eltanexor) as an oral therapeutic to alleviate dystrophic symptoms. We performed pre-clinical evaluation of the effects of KPT-8602 in DMD zebrafish (sapje) and mouse (D2-mdx) models. KPT-8602 improved dystrophic skeletal muscle pathologies, muscle architecture and integrity, and overall outcomes in both animal models. KPT-8602 treatment ameliorated DMD pathology in D2-mdx mice, with increased locomotor behavior and improved muscle histology. KPT-8602 altered the immunological profile of the dystrophic mice, and reduced circulating osteopontin serum levels. These findings demonstrate KPT-8602 as an effective therapeutic in DMD through by promotion of an anti-inflammatory environment and overall improvement of DMD pathological outcomes.

Are Hounsfield Unit Measurements of Bony Absorption Changes in Cholesteatoma Helpful?

Abstract Introduction High-resolution computed tomography (HRCT) scans of the temporal bone are used to assess the bony erosion of the middle-ear structures whenever cholesteatoma is suspected. Objective To study the differences in HRCT Hounsfield unit (HU) index measurements of middle-ear bony structures between an ears with and without cholesteatoma. Methods A retrospective study of 59 patients who underwent surgery due to unilateral cholesteatoma. The HRCT HU index of the scutum, of three middle-ear ossicles, of the lateral semicircular canal (LSCC), and of the fallopian canal was measured in both ears. A comparison was made between the cholesteatoma and the non-cholesteatomatous ear (control). All measurements were conducted by an otolaryngologist. To assess the interobserver bias, 10% of the samples were randomly and independently assessed by another otolaryngologist and a neuroradiologist who were blinded. Results The average HU index was lower in the ear with cholesteatoma when compared with the non-cholesteatomatous ear. While the differences were statistically significant regarding the measurements of the scutum (516.02 ± 311.693 versus 855.64 ± 389.999; p = 0.001), the malleus (1049.44 ± 481.765 versus 1413.47 ± 313.376; p = 0.01), and the incus (498.03 ± 264.184 versus 714.25 ± 405.631; p = 0.001), the differences in the measurements of the LSCC (1042.34 ± 301.066 versus 1154.53 ± 359.609; p = 0.69) and of the fallopian canal (467.19 ± 221.556 versus 543.51 ± 263.573; p = 0.108) were not significantly different between both groups. The stapes was immeasurable in both groups due to its small size. Conclusion Hounsfield unit index measurements are a useful tool that may aid in the diagnosis of early-stage cholesteatoma.

Are Hounsfield Unit Measurements of Bony Absorption Changes in Cholesteatoma Helpful?

Introduction High-resolution computed tomography (HRCT) scans of the temporal bone are used to assess the bony erosion of the middle-ear structures whenever cholesteatoma is suspected. Objective To study the differences in HRCT Hounsfield unit (HU) index measurements of middle-ear bony structures between an ears with and without cholesteatoma. Methods A retrospective study of 59 patients who underwent surgery due to unilateral cholesteatoma. The HRCT HU index of the scutum, of three middle-ear ossicles, of the lateral semicircular canal (LSCC), and of the fallopian canal was measured in both ears. A comparison was made between the cholesteatoma and the non-cholesteatomatous ear (control). All measurements were conducted by an otolaryngologist. To assess the interobserver bias, 10% of the samples were randomly and independently assessed by another otolaryngologist and a neuroradiologist who were blinded. Results The average HU index was lower in the ear with cholesteatoma when compared with the non-cholesteatomatous ear. While the differences were statistically significant regarding the measurements of the scutum (516.02 ± 311.693 versus 855.64 ± 389.999; p = 0.001), the malleus (1049.44 ± 481.765 versus 1413.47 ± 313.376; p = 0.01), and the incus (498.03 ± 264.184 versus 714.25 ± 405.631; p = 0.001), the differences in the measurements of the LSCC (1042.34 ± 301.066 versus 1154.53 ± 359.609; p = 0.69) and of the fallopian canal (467.19 ± 221.556 versus 543.51 ± 263.573; p = 0.108) were not significantly different between both groups. The stapes was immeasurable in both groups due to its small size. Conclusion Hounsfield unit index measurements are a useful tool that may aid in the diagnosis of early-stage cholesteatoma.

Trends in Pediatric Acute Otitis Media Burden During the First COVID-19 Year.

OBJECTIVE: To study the changes in acute otitis media (AOM) pediatric emergency department (PED) visits and pediatric admission before and during the first coronavirus disease 2019 (COVID-19) year. STUDY DESIGN: Retrospective case review. SETTING: Secondary care center. PATIENTS: Children younger than 18 years with all-cause and AOM-related PED visits and pediatric admissions for 3 years (March 1, 2018-January 28, 2021) were identified. Children were categorized according to age (0-2, 2-6, and 6-18 yr) and their date of presentation: pre-COVID-19 (yearly average of visits/admissions during the 2 prepandemic years: March 1, 2018-February 28, 2019 and March 1, 2019-February 29, 2020) or COVID-19 year (visits/admissions between March 1, 2020-February 28, 2021). INTERVENTION: Pre- and post-COVID-19 emergence, alternating lockdowns, kindergarten and school closures, and increased hygiene measures. MAIN OUTCOME MEASURE: Post- versus pre-COVID-19 AOM PED visit and pediatric admission incidence rate ratios (IRRs), using a generalized estimating equation model with a negative binomial regression calculation, while controlling for monthly fluctuations. RESULTS: Annual AOM visits/admissions during the pre-COVID-19 and COVID-19 years were 517 and 192 and 256 and 94, respectively (p < 0.05 for both). For children aged 0 to 2 years, AOM visits/admissions significantly decreased during the first COVID-19 year, compared with the pre-COVID years (ß = -1.11 [IRR, 0.33; 95% confidence interval [CI], 0.26-0.42; p < 0.005] and ß = -1.12 [IRR, 0.33; 95% CI, 0.25-0.42; p < 0.005]). Relatively to all-cause of children aged 0 to 2 years, AOM visits/admissions decreased during the first COVID-19 year versus the pre-COVID-19 years (ß = -2.14 [IRR, 0.12; 95% CI, 0.08-0.17; p < 0.005] and ß = -1.36 [IRR, 0.26; 95% CI, 0.23-0.29; p < 0.005]) and had monthly fluctuations coinciding with the lockdown/relaxation measures. For children aged 2 to 6 years, the reduction in AOM admissions was significant (ß = -1.70, IRR, 0.18; 95% CI, 0.09-0.37; p < 0.005). No significant differences were observed for children aged 6 to 18 years because of the small sample size. CONCLUSION: Pediatric AOM burden substantially decreased during the first COVID-19 year.

What are the risk factors for acute otitis media treatment failure?

OBJECTIVE: To identify risk factors associated with acute otitis media treatment failure (AOMTF) among 13-valent pneumococcal conjugate vaccine (PCV) immunized children. METHODS: In this retrospective study, we identified children <12 years who were admitted to our hospital November 2017-October 2020. Children were categorized either as acute otitis media treatment failure (AOMTF), if they received adequate pre-admission antibiotics, or as AOM without treatment failure (AOMwTF), if they did not receive any pre-admission antibiotics. We collected demographics, clinical behavior, laboratory results, length and hospitalization course. Hospitalization was justified if previously treated properly. RESULTS: The AOMTF group included 84 children (43 boys, mean age: 1.30 ± 0.83 years), whereas the AOMwTF group included 251 children (132 boys, mean age: 1.20 ± 0.89 years). AOMTF accounted for 25% of all AOM admissions. Among the AOMTF group, 46 (54.8%) were treated with amoxicillin and 24 (28.6%) with amoxicillin/clavulanic acid. Risk factors for AOMTF included recurrent AOM episodes history (30.9% vs 5.5%, OR 7.6, 95%CI 3.5-15.4, p < 0.001), otorrhea (29.4% vs 9.5%, OR 4, 95%CI 2.1-7.5, p < 0.001), tympanic membrane perforation (14.2% vs 4.3%, OR 3.6, 95%CI 1.5-8.6, p < 0.0019). Children with AOMTF were treated more with 2nd- or 3rd-line antibiotics (90.2% vs 65.9%, OR 4, 95%CI 2.2-10.4, p < 0.001), and underwent more myringotomy/ventilation tube insertions (14.4% vs 6.9%, OR 2.3, 95%CI 1.0-5.0, p = 0.037). Mean admission durations were similar: 3.83 ± 1.6 days in the AOMTF group vs 3.37 ± 2.77 days in the AOMwTF group (p = 0.15). CONCLUSION: Risk factors associated with AOMTF should be identified early during the AOM course to reduce complication rates and surgery referral.

Increase in Haemophilus influenzae Detection in 13-Valent Pneumococcal Conjugate Vaccine Immunized Children With Acute Otitis Media.

NTHi was the predominant pathogen in ear cultures from severe acute otitis media (AOM) episodes in PCV-13 vaccinated children, more commonly in girls. NTHi-AOM episodes were associated with more myringotomies due to a higher treatment failure incidence. The low rate of ß-lactamase NTHi isolates in middle ear fluid cultures from PCV-13 vaccinated children presenting with AOM strengthens to still use amoxicillin as the first-line antibiotics.

Small Molecule Inhibitors of Nuclear Export and the Amelioration of Lupus by Modulation of Plasma Cell Generation and Survival.

OBJECTIVE: To investigate the hypothesis that selective inhibitors of nuclear export (SINE compounds), recently approved for treatment of refractory plasma cell (PC) malignancy, may have potential in the treatment of lupus. METHODS: Female NZB/NZW mice were treated with the SINE compound KPT-350 or vehicle control. Tissue specimens were harvested and analyzed by flow cytometry, using standard markers. Nephritis was monitored by determining the proteinuria score and by histologic analysis of kidney specimens. Serum anti-double-stranded DNA (anti-dsDNA) levels were measured by enzyme-linked immunosorbent assay, and total numbers of IgG-secreting and dsDNA-specific antibody-secreting cells were assessed by enzyme-linked immunospot assay. RESULTS: KPT-350 abrogated murine lupus nephritis at both early and late stages of the disease and rapidly impaired generation of autoreactive PCs in germinal centers (GCs). SINE compounds inhibited the production of NF-κB-driven homeostatic chemokines by stromal cells, altering splenic B and T cell strategic positioning and significantly reducing follicular helper T cell, GC B cell, and autoreactive PC counts. KPT-350 also decreased levels of cytokines and chemokines involved in PC survival and recruitment in the kidney of lupus-prone mice. Exportin 1, the target of SINE compounds, was detected in GCs of human tonsils, splenic B cells of lupus patients, and multiple B cell subsets in the kidneys of patients with lupus nephritis. CONCLUSION: Collectively, our results provide support for the therapeutic potential of SINE compounds, via their targeting of several molecular and cellular pathways critical in lupus pathogenesis, including autoantibody production by plasma cells.

[SENSORINEURAL HEARING LOSS AND VERTIGO DUE TO INTRA-COCHLEAR HEMORRHAGE].

INTRODUCTION: Intra-cochlear hemorrhage is a rare cause of sudden sensorineural hearing loss (SSNHL) which may be accompanied by diverse labyrinthine symptoms. In these cases, we expect magnetic resonance imaging (MRI) to demonstrate a high signal intensity in the labyrinth on unenhanced T1-weighted images as well as in fluid-attenuated inversion recovery (FLAIR) images. AIMS: To describe an experience with a case of intra-cochlear hemorrhage in a patient treated with anticoagulation, causing SSNHL and vertigo. METHODS: Case report and literature review. RESULTS: An 85-year old patient treated with anticoagulation therapy presented with right SSNHL, tinnitus and vertigo. Physical examination revealed: bilateral normal otoscopic examination, lateralized left Weber tuning fork test and a spontaneous left horizontal nystagmus. MRI performed demonstrated a high signal intensity inside the cochlea on unenhanced T1-weighted images. CONCLUSIONS: Performing an MRI is necessary in order to rule out frequent causes of SSNHL including benign as well as malignant tumors, malformations, trauma and more. The finding of an intra-labyrinthine hemorrhage causing SSNHL is rare, and should be taken into consideration when treated by anticoagulation therapy.