Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria.

Inhibition of the biosynthesis of bacterial heptoses opens novel perspectives for antimicrobial therapies. The enzyme GmhA responsible for the first committed biosynthetic step catalyzes the conversion of sedoheptulose 7-phosphate into d-glycero-d-manno-heptose 7-phosphate and harbors a Zn2+ ion in the active site. A series of phosphoryl- and phosphonyl-substituted derivatives featuring a hydroxamate moiety were designed and prepared from suitably protected ribose or hexose derivatives. High-resolution crystal structures of GmhA complexed to two N-formyl hydroxamate inhibitors confirmed the binding interactions to a central Zn2+ ion coordination site. Some of these compounds were found to be nanomolar inhibitors of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity of their own, they demonstrated in vitro lipopolysaccharide heptosylation inhibition in Enterobacteriaceae as well as the potentiation of erythromycin and rifampicin in a wild-type Escherichia coli strain. These inhibitors pave the way for a novel treatment of Gram-negative infections.

Proof of concept of intracochlear drug administration by laser-assisted bioprinting in mice.

Transtympanic administration is used clinically for the injection of gentamicin and/or corticosteroids. This atraumatic route is based on passive diffusion through the round window membrane (RWM). The main limitation of this method is related to the clearance through the Eustachian tube, making the concentration of the therapeutic agent at the intracochlear level uncertain and limited. Moreover, this technique remains unsuitable for molecules of high molecular weight or in the case of gene therapies. The purpose was to study a new technique of intracochlear administration in an atraumatic, direct and controlled manner by laser-assisted bioprinting (LAB). LAB was used to deliver dexamethasone phosphate with thermosensitive hydrogel on the mouse RWM. After validation of the regularity and homogeneity of the pattern, the diffusion in vivo of the dexamethasone into the perilymph after LAB has been confirmed by ELISA. Auditory function measurements showed no hearing impairment suggesting that bioprinting does not induce significant cochlear damage. Hence, the present proof of concept study introduces a promising approach for inner ear drug delivery.

Biological and Structural Analyses of New Potent Allosteric Inhibitors of HIV-1 Integrase.

HIV-1 integrase-LEDGF allosteric inhibitors (INLAIs) share the binding site on the viral protein with the host factor LEDGF/p75. These small molecules act as molecular glues promoting hyper-multimerization of HIV-1 IN protein to severely perturb maturation of viral particles. Herein, we describe a new series of INLAIs based on a benzene scaffold that display antiviral activity in the single digit nanomolar range. Akin to other compounds of this class, the INLAIs predominantly inhibit the late stages of HIV-1 replication. A series of high-resolution crystal structures revealed how these small molecules engage the catalytic core and the C-terminal domains of HIV-1 IN. No antagonism was observed between our lead INLAI compound BDM-2 and a panel of 16 clinical antiretrovirals. Moreover, we show that compounds retained high antiviral activity against HIV-1 variants resistant to IN strand transfer inhibitors and other classes of antiretroviral drugs. The virologic profile of BDM-2 and the recently completed single ascending dose phase I trial (ClinicalTrials.gov identifier: NCT03634085) warrant further clinical investigation for use in combination with other antiretroviral drugs. Moreover, our results suggest routes for further improvement of this emerging drug class.

Early management of presbycusis: recommendations from the French Society of Otorhinolaryngology and Head and Neck Surgery, the French Society of Audiology, and the French Society of Geriatrics and Gerontology.

INTRODUCTION: Presbycusis is the physiological decrease in hearing due to advancing age and begins well before the sixth decade. These recommendations recall the principles of early diagnosis of presbycusis and the means of optimal rehabilitation as soon as the first symptoms appear. MATERIAL AND METHODS: The recommendations are based on a systematic analysis of the literature carried out by a multidisciplinary group of ENT physicians, audiologists, geriatricians and hearing specialists from all over France. They are classified as grade A, B, C or professional agreement according to a decreasing level of scientific evidence. RESULTS: The diagnosis of presbycusis is more difficult at the beginning of its evolution but a certain number of tools are available for its early diagnosis and its face-to-face or remote management. CONCLUSION: In the case of a clinical profile suggestive of presbycusis in a young subject, especially if there are several family cases, it is recommended to propose a genetic investigation. Free-field speech audiometry in noise is recommended to measure intelligibility in a realistic environment. Questionnaires in addition to audiometric tests would allow the best assessment of the patient's disability. Hearing rehabilitation with a hearing aid or cochlear implant may slow or prevent cognitive decline. Combined auditory and cognitive rehabilitation should be offered regardless of the time since the hearing was fitting. It is recommended to integrate programs accessible via smartphones, tablets or the Internet, that include different training domains to complement face-to-face sessions.

[Early management of presbycusis: recommendations from the French Society of Otorhinolaryngology and Head and Neck Surgery, the French Society of Audiology, and the French Society of Geriatrics and Gerontology]. / Recommandations de la Société française d'otorhinolaryngologie et de chirurgie de la face et du cou, la Société française d'audiologie et la Société française de gériatrie et gérontologie pour la prise en charge précoce de la presbyacousie.

INTRODUCTION: Presbycusis is the physiological decrease in hearing due to advancing age and begins well before the sixth decade. These recommendations recall the principles of early diagnosis of presbycusis and the means of optimal rehabilitation as soon as the first symptoms appear. MATERIAL AND METHODS: The recommendations are based on a systematic analysis of the literature carried out by a multidisciplinary group of doctors and audioprosthetists from all over France. They are graded A, B, C or expert opinion according to decreasing level of scientific evidence. RESULTS: The diagnosis of presbycusis is more difficult at the beginning of its evolution but a certain number of tools are available for its early diagnosis and its management in face-to-face or even distance learning. CONCLUSION: In case of a clinical profile suggestive of presbycusis in a young subject, especially if there are several family cases, it is recommended to propose a genetic investigation. It is recommended to perform free-field speech audiometry in noise to measure intelligibility in an environment as close as possible to reality. Questionnaires can be used in addition to audiometry to best assess the patient's disability. It is recommended that hearing rehabilitation with a hearing aid or cochlear implant may slow or prevent cognitive decline. Combined auditory and cognitive rehabilitation should be offered regardless of the time elapsed since the fitting. It is recommended to integrate programs accessible via smartphones, tablets or the Internet, integrating different training domains in addition to face-to-face sessions.

Structural Basis for E. coli Penicillin Binding Protein (PBP) 2 Inhibition, a Platform for Drug Design.

Penicillin-binding proteins (PBPs) are the targets of the ß-lactams, the most successful class of antibiotics ever developed against bacterial infections. Unfortunately, the worldwide and rapid spread of large spectrum ß-lactam resistance genes such as carbapenemases is detrimental to the use of antibiotics in this class. New potent PBP inhibitors are needed, especially compounds that resist ß-lactamase hydrolysis. Here we describe the structure of the E. coli PBP2 in its Apo form and upon its reaction with 2 diazabicyclo derivatives, avibactam and CPD4, a new potent PBP2 inhibitor. Examination of these structures shows that unlike avibactam, CPD4 can perform a hydrophobic stacking on Trp370 in the active site of E. coli PBP2. This result, together with sequence analysis, homology modeling, and SAR, allows us to propose CPD4 as potential starting scaffold to develop molecules active against a broad range of bacterial species at the top of the WHO priority list.

Long-Term Cognitive Prognosis of Profoundly Deaf Older Adults After Hearing Rehabilitation Using Cochlear Implants.

OBJECTIVES: To analyze long-term cognitive status and function after cochlear implantation in profoundly deaf individuals. DESIGN: Prospective observational longitudinal study. SETTING: Ten academic medical centers referent for cochlear implantation. PARTICIPANTS: Individuals aged 65 and older who qualified for cochlear implantation (N=70). MEASUREMENTS: Cognitive tests were administered before cochlear implantation and 1 and 5 or more years after cochlear implantation. Evaluation consisted of 6 tests assessing attention, memory, orientation, executive function, mental flexibility, and fluency. Cognitive status was determined as normal, mild cognitive impairment (MCI), or dementia. Speech perception in quiet and noisy conditions was assessed using disyllabic words, and quality of life was assessed using the Nijmegen Cochlear Implant Questionnaire. RESULTS: Mean follow-up was 6.8 years (range 5.5-8.5 years). Speech perception scores and quality of life remained stable from 1 to 7 years after cochlear implantation. Of 31 participants (45%) with MCI before cochlear implantation, 2 (6%) developed dementia during follow-up, 19 (61%) remained stable, and 10 (32%) returned to normal cognition. None of the 38 with normal cognition developed dementia during follow-up, although 12 (32%) developed MCI. CONCLUSION: MCI is highly prevalent in older adults with profound hearing loss. Nevertheless, we observed a low rate of progression to dementia, and cognitive function improved in some individuals with MCI at baseline. These results highlight that cochlear implantation should be strongly considered in profoundly deaf individuals, even those with MCI, who may have a specific subtype of MCI, with a possible positive effect of hearing rehabilitation on neurocognitive functioning.

Electric and acoustic harmonic integration predicts speech-in-noise performance in hybrid cochlear implant users.

BACKGROUND: Pitch perception of complex tones relies on place or temporal fine structure-based mechanisms from resolved harmonics and the temporal envelope of unresolved harmonics. Combining this information is essential for speech-in-noise performance, as it allows segregation of a target speaker from background noise. In hybrid cochlear implant (H-CI) users, low frequency acoustic hearing should provide pitch from resolved harmonics while high frequency electric hearing should provide temporal envelope pitch from unresolved harmonics. How the acoustic and electric auditory inputs interact for H-CI users is largely unknown. Harmonicity and inharmonicity are emergent features of sound in which overtones are concordant or discordant with the fundamental frequency. We hypothesized that some H-CI users would be able to integrate acoustic and electric information for complex tone pitch perception, and that this ability would be correlated with speech-in-noise performance. In this study, we used perception of inharmonicity to demonstrate this integration. METHODS: Fifteen H-CI users with only acoustic hearing below 500 Hz, only electric hearing above 2 kHz, and more than 6 months CI experience, along with eighteen normal hearing (NH) controls, were presented with harmonic and inharmonic sounds. The stimulus was created with a low frequency component, corresponding with the H-CI user's acoustic hearing (fundamental frequency between 125 and 174 Hz), and a high frequency component, corresponding with electric hearing. Subjects were asked to identify the more inharmonic sound, which requires the perceptual integration of the low and high components. Speech-in-noise performance was tested in both groups using the California Consonant Test (CCT), and perception of Consonant-Nucleus-Consonant (CNC) words in quiet and AzBio sentences in noise were tested for the H-CI users. RESULTS: Eight of the H-CI subjects (53%), and all of the NH subjects, scored significantly above chance level for at least one subset of the inharmonicity detection task. Inharmonicity detection ability, but not age or pure tone average, predicted speech scores in a linear model. These results were significantly correlated with speech scores in both quiet and noise for H-CI users, but not with speech in noise performance for NH listeners. Musical experience predicted inharmonicity detection ability, but did not predict speech performance. CONCLUSIONS: We demonstrate integration of acoustic and electric information in H-CI users for complex pitch sensation. The correlation with speech scores in H-CI users might be associated with the ability to segregate a target speaker from background noise using the speaker's fundamental frequency.

Structure-function analyses unravel distinct effects of allosteric inhibitors of HIV-1 integrase on viral maturation and integration.

Recently, a new class of HIV-1 integrase (IN) inhibitors with a dual mode of action, called IN-LEDGF/p75 allosteric inhibitors (INLAIs), was described. Designed to interfere with the IN-LEDGF/p75 interaction during viral integration, unexpectedly, their major impact was on virus maturation. This activity has been linked to induction of aberrant IN multimerization, whereas inhibition of the IN-LEDGF/p75 interaction accounts for weaker antiretroviral effect at integration. Because these dual activities result from INLAI binding to IN at a single binding site, we expected that these activities co-evolved together, driven by the affinity for IN. Using an original INLAI, MUT-A, and its activity on an Ala-125 (A125) IN variant, we found that these two activities on A125-IN can be fully dissociated: MUT-A-induced IN multimerization and the formation of eccentric condensates in viral particles, which are responsible for inhibition of virus maturation, were lost, whereas inhibition of the IN-LEDGF/p75 interaction and consequently integration was fully retained. Hence, the mere binding of INLAI to A125 IN is insufficient to promote the conformational changes of IN required for aberrant multimerization. By analyzing the X-ray structures of MUT-A bound to the IN catalytic core domain (CCD) with or without the Ala-125 polymorphism, we discovered that the loss of IN multimerization is due to stabilization of the A125-IN variant CCD dimer, highlighting the importance of the CCD dimerization energy for IN multimerization. Our study reveals that affinity for the LEDGF/p75-binding pocket is not sufficient to induce INLAI-dependent IN multimerization and the associated inhibition of viral maturation.

The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resistance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus immunoreactivity.

BACKGROUND: HIV-1 Integrase (IN) interacts with the cellular co-factor LEDGF/p75 and tethers the HIV preintegration complex to the host genome enabling integration. Recently a new class of IN inhibitors was described, the IN-LEDGF allosteric inhibitors (INLAIs). Designed to interfere with the IN-LEDGF interaction during integration, the major impact of these inhibitors was surprisingly found on virus maturation, causing a reverse transcription defect in target cells. RESULTS: Here we describe the MUT-A compound as a genuine INLAI with an original chemical structure based on a new type of scaffold, a thiophene ring. MUT-A has all characteristics of INLAI compounds such as inhibition of IN-LEDGF/p75 interaction, IN multimerization, dual antiretroviral (ARV) activities, normal packaging of genomic viral RNA and complete Gag protein maturation. MUT-A has more potent ARV activity compared to other INLAIs previously reported, but similar profile of resistance mutations and absence of ARV activity on SIV. HIV-1 virions produced in the presence of MUT-A were non-infectious with the formation of eccentric condensates outside of the core. In studying the immunoreactivity of these non-infectious virions, we found that inactivated HIV-1 particles were captured by anti-HIV-specific neutralizing and non-neutralizing antibodies (b12, 2G12, PGT121, 4D4, 10-1074, 10E8, VRC01) with efficiencies comparable to non-treated virus. Autologous CD4+ T lymphocyte proliferation and cytokine induction by monocyte-derived dendritic cells (MDDC) pulsed either with MUT-A-inactivated HIV or non-treated HIV were also comparable. CONCLUSIONS: Although strongly defective in infectivity, HIV-1 virions produced in the presence of the MUT-A INLAI have a normal protein and genomic RNA content as well as B and T cell immunoreactivities comparable to non-treated HIV-1. These inactivated viruses might form an attractive new approach in vaccine research in an attempt to study if this new type of immunogen could elicit an immune response against HIV-1 in animal models.

Transtympanic pseudoaneurysm of the internal carotid artery complicating a myringotomy in a four-year old child: Case report and literature review.

We report the first case of a transtympanic iatrogenic internal carotid artery (ICA) pseudoaneurysm diagnosed in a 4-year-old child following a myringotomy. An endovascular treatment with a covered-stent was decided; spontaneous thrombosis was found during the therapeutic arteriography, and the procedure was aborted. Otoscopy and computed tomography (CT) scan monitoring showed a prolonged thrombosis and the disappearance of the pseudoaneurysm 18months after the diagnostic arteriography. Based on literature review, endovascular techniques seem to be preferred to the surgical approach for treatment of intrapetrous ICA pseudoaneurysm, however clinical and CT scan monitoring may also be a valid option.

The Effect of Cochlear Damage on the Sensitivity to Harmonicity.

OBJECTIVES: A sum of simultaneous pure tones with harmonic relationships (i.e., simple frequency ratios) is normally heard as a single sound, with a single pitch, even when its components are fully resolved in the auditory periphery. This perceptual phenomenon called "harmonic fusion" is thought to play an important role in auditory scene analysis as listeners often have to segregate simultaneous harmonic sounds with different fundamental frequencies. The present study explored the consequences of mild or moderate cochlear hearing loss for the sensitivity to harmonicity and the detection of inharmonicity. DESIGN: The subjects were 12 normal-hearing (NH) listeners and 8 listeners with cochlear hearing loss amounting to 30 to 50 dB (mean: 42 dB) from 0.25 to 3 kHz. In each subject, thresholds for the detection of a change in the frequency ratio of simultaneous pure tones were measured with an adaptive forced-choice procedure. The standard frequency ratio was either harmonic (2:1, i.e., one octave) or inharmonic (0.8 or 1.2 octaves). The tones were presented at a low sensation level (at most 15 dB) within broadband noise, to minimize their cochlear interactions. In the main experimental conditions, the frequency register of the stimuli varied randomly within each trial, so that subjects were forced to process frequency ratios to achieve good performance; frequency discrimination was not sufficient. In other conditions, by contrast, frequency discrimination was sufficient to perform the task optimally. RESULTS: For both groups of subjects, thresholds in the main experimental conditions were lower (i.e., better) when the standard frequency ratio was harmonic than when it was inharmonic. This effect, revealing sensitivity to harmonicity, was weak for some members of the hearing-impaired group, but could be observed even in subjects showing a very poor frequency discrimination ability. The two groups, however, differed from each other with respect to the detection of inharmonicity: for the NH group, in agreement with previous results, negative deviations from one octave (i.e., compressions of this frequency ratio) were better detected than positive deviations (stretchings); for the hearing-impaired group, on the other hand, the sign of the deviations had no effect on performance. CONCLUSIONS: Sensitivity to harmonicity appears to be remarkably robust. However, it can be reduced in some listeners with mild or moderate cochlear damage. Moreover, as inharmonicity detection is asymmetric for NH listeners but apparently becomes symmetric in case of cochlear damage, it may be that listeners with cochlear damage do not detect inharmonicity in the same manner as NH listeners do. In some circumstances, inharmonicity can be detected on the basis of "beat" cues available in single frequency channels; however, the subjects tested here were unlikely to use cues of this type.

The Role of Electrode Placement in Bilateral Simultaneously Cochlear-Implanted Adult Patients.

OBJECTIVE: To evaluate the influence of the electrode placement on hearing performance in adult patients who were simultaneously and bilaterally cochlear implanted. STUDY DESIGN: Case series with planned data collection. SETTING: Tertiary referral university centers. SUBJECTS AND METHODS: The postoperative computed tomography scan was studied for 19 patients who were simultaneously and bilaterally implanted with a long straight electrode array. The size of the cochlea was measured in consideration of the major cochlear diameter and cochlear height. The electrode-to-modiolus distance for the electrodes positioned at 180 and 360 degrees and the angular depth of insertion of the array were also measured. Speech perception was assessed at 1 and 5 years postimplantation with disyllabic word lists in quiet and in noise, with the speech coming from the front and a background noise (cocktail party) coming from 5 loudspeakers. RESULTS: At 1 year postimplantation, the electrode-to-modiolus distance at 180 degrees was correlated with the speech perception scores in both quiet and noise. In patients with a full electrode insertion, no correlation was found between the angular depth of insertion and hearing performance. The speech perception scores in noise gradually declined as a function of the number of inserted and active electrodes. No relationship between electrode position and speech perception scores was found at 5 years postimplantation. CONCLUSION: In adult patients who were simultaneously and bilaterally implanted, the use of a long straight array, the full electrode array insertion, and the proximity to the modiolus might be determining factors to obtain the best speech performance at 1 year, without influence on the speech perception scores after long-term use.

Long-term results of middle fossa plugging of superior semicircular canal dehiscences: clinically and instrumentally demonstrated efficiency in a retrospective series of 16 ears.

The objective of this study is to report the surgical outcome after middle fossa approach (MFA) plugging in patients suffering from a superior semi-circular canal dehiscence (SCD) syndrome. This is a retrospective case review. Tertiary referral center. Sixteen ears in 13 patients with a SCD syndrome suffering from severe and disabling vestibular symptoms with a bony dehiscence on CT scan >3 mm and decreased threshold of cervical vestibular evoked potentials (cVEMPs). We assessed preoperatively: clinical symptoms, hearing, cVEMPs threshold, size of dehiscence and videonystagmography (VNG) with caloric and 100 Hz vibratory tests. Postoperatively, we noted occurrences of neurosurgical complication, evolution of audiological and vestibular symptoms, and evaluation of cVEMP data. Tullio's phenomenon was observed in 13 cases (81.3 %) and subjectively reported hearing loss in seven (43.7 %). All patients were so disabled that they had to stop working. No neurosurgical complications were observed in the postoperative course. In three cases (16.6 %), an ipsilateral and transitory immediate postoperative vestibular deficit associated with a sensorineural hearing loss (SNHL) was noted, which totally resolved with steroids and bed rest. All patients were relieved of audiological and vestibular symptoms and could return to normal activity with a mean follow-up of 31.1 months (range 3-95). No patient had residual SNHL. cVEMPs were performed in 14 ears postoperatively and were normalized in 12 (85.7 %). Two of the three patients operated on both sides kept some degree of unsteadiness and oscillopsia. MFA plugging of the superior semi-circular canal is an efficient and non-hearing deteriorating procedure.

Harmonic fusion and pitch affinity: Is there a direct link?

Simultaneous pure tones approximately one octave apart tend to be fused perceptually and to evoke a single pitch sensation. Besides, sequentially presented pure tones show a subjective "affinity" or similarity in pitch when their frequency ratio is close to one octave. The aim of the study reported here was to determine if these two perceptual phenomena are directly related. Each stimulus was a triplet of simultaneous or successive pure tones forming frequency ratios varying across stimuli between 0.96 and 1.04 octaves. The tones were presented at a low sensation level (15 dB) within broadband threshold-equalizing noise, in order to prevent them from interacting in the cochlea when they were simultaneous. A large set of stimulus comparisons made by 18 listeners indicated that: (1) when the tones were simultaneous, maximal fusion was obtained for a mean frequency ratio deviating by less than 0.2% from one octave, and fusion decreased less rapidly above this frequency ratio than below it; (2) when the tones were presented successively, maximal pitch affinity was obtained for a mean frequency ratio significantly larger than one octave, and pitch affinity decreased more rapidly above this frequency ratio than below it. The differences between the results obtained for simultaneous and successive tones suggest that harmonic fusion and pitch affinity are unrelated phenomena.

Prognostic Factors of Balance Quality After Transpetrosal Vestibular Schwannoma Microsurgery: An Instrumentally and DHI-based Prospective Cohort Study of 48 Patients.

OBJECTIVES: To evaluate short- and mid-term level of imbalance after vestibular schwannoma (VS) microsurgery by the transpetrosal approach, to search for factors predictive of vestibular compensation, and to determine which patient categories need a postoperative vestibular rehabilitation program. STUDY DESIGN: Prospective cohort study at a tertiary referral center. METHODS: Between 2010 and 2011, patients aged 18 to 75 operated on for VS by transpetrosal approaches were included. VS was characterized by its size (Koos classification) and the presence or not of a cystic component. Hearing was classified according to the Gardner Robertson grading. The preoperative workup included an audiogram, computerized video nystagmography (VNG) with caloric testing, gaze study, rotatory tests, click-evoked cervical vestibular evoked myogenic potential measurements (cVEMPs), and subjective visual vertical test. Patients were asked to complete a Dizziness Handicap Inventory (DHI). Postoperatively, patients were reevaluated on D7 (clinical status), D90 (VNG and DHI), and D180 (DHI). Timing and duration of vestibular rehabilitation were also recorded. RESULTS: Forty-eight patients were included. Preoperatively, 77% experienced mild instability problems with a mean DHI score of 14.1 (range 4-32). Postoperatively, 71% reported stable or even improved perceived stability. Mean DHI scores were 28.1 on D90 and 19.8 on D180. Serviceable hearing, cystic transformation, normal cVEMPs, diplopia, and vestibular syndrome on D7 were found to be predictive of worse equilibrium outcome than when absent. A preoperative caloric deficit greater than 75% seemed to be a good prognostic factor. Vestibular rehabilitation was conducted in 56% of patients. Starting it early (<1 mo) seemed to be beneficial for final equilibrium outcome. CONCLUSION: VS microsurgery provides good stability results. Some preoperative parameters may be predictive of worse or improved balance recovery, as is clinical status on D7.

Effects of body tilt on multifrequency admittance tympanometry.

INTRODUCTION: Hydrops and abnormalities of inner fluid pressure are involved in some otologic diseases such as Ménière's disease (MD). However, demonstrating abnormal perilymphatic or endolymphatic pressure is challenging. Multifrequency tympanometry studies in MD patients demonstrated an increase of the width of conductance tympanograms (outside an attack) compared with controls. To confirm that the increase in conductance width is caused by hyperpressure and not hypopressure in these patients tested outside an attack, we assessed the effect of changes in inner ear fluid pressure caused by body tilt on the results of multifrequency admittancemetry tympanograms. MATERIALS AND METHODS: A multifrequency tympanometry including conductance (G) tympanogram at 2 kHz and resonance frequency measurements were performed in 20 volunteers (40 ears) free of otologic or neurologic disease. The measures were collected in three different positions: vertical, supine, and Trendelenburg positions. RESULTS: Changes in inner ear fluid pressure caused by body tilt induced an increase in the width of G tympanograms. In the vertical position, the mean value was 141.7 ± 56.5 daPa; in the supine position, it increased to 158 ± 58.3 daPa; and increased even more in the Trendelenburg position (20 degrees), with a mean of 184 ± 69.6 daPa (p < 0.01). Resonance frequency also increased in the Trendelenburg position.We conclude that the increased width of G tympanograms in MD patients outside an attack may be caused by an increase in inner ear fluid pressure.

Stitchless fibrin glue-aided facial nerve grafting after cerebellopontine angle schwannoma removal: technique and results in 15 cases.

AIM OF THE STUDY: To evaluate the results of facial nerve (FN) grafting using great auricular cable graft and fibrin glue without suturing to palliate FN disruption after removal of large cerebellopontine angle (CPA) vestibular schwannoma (VS) or facial nerve schwannoma (FNS). To assess whether tumor size and origin influenced the results. STUDY DESIGN AND SETTING: Retrospective review of all patients having undergone removal of FNS/VS and needing intraoperative FN repair between 2001 and 2011. INTERVENTION: FN was rehabilitated using great auricular nerve cable graft and fibrin glue (Tisseal) without stitching suture. MAIN OUTCOME MEASURES: All data recorded were reviewed to access age, sex, tumor type, and tumor size according to the Koos classification and presenting symptoms. FN function was evaluated preoperatively and at 18 months using the House-Brackmann (HB) grading system. RESULTS: Among the 595 patients operated for CPA schwannomas in this period, 15 patients (2.5%) underwent FN repair, including 7 cases of FNS and 8 cases of VS. Tumor removal was total in all cases. FN recovery was HB3 in 13 cases (86.7%) and HB4 in 2. The mean time to the first clinical signs of facial reinnervation was 10 months (6-12 mo). No significant relation was found between postoperative facial function and tumor size or type, even if all cases of preoperative FP were noted in FNS. CONCLUSION: Immediate FN reconstruction with fibrin glue-aided greater auricular nerve graft can effectively restore FN function with excellent outcomes. The results seem better than those observed by other authors using sutured grafts or delayed hypoglossal-facial nerve anastomosis.

The allosteric HIV-1 integrase inhibitor BI-D affects virion maturation but does not influence packaging of a functional RNA genome.

The viral integrase (IN) is an essential protein for HIV-1 replication. IN inserts the viral dsDNA into the host chromosome, thereby aided by the cellular co-factor LEDGF/p75. Recently a new class of integrase inhibitors was described: allosteric IN inhibitors (ALLINIs). Although designed to interfere with the IN-LEDGF/p75 interaction to block HIV DNA integration during the early phase of HIV-1 replication, the major impact was surprisingly found on the process of virus maturation during the late phase, causing a reverse transcription defect upon infection of target cells. Virus particles produced in the presence of an ALLINI are misformed with the ribonucleoprotein located outside the virus core. Virus assembly and maturation are highly orchestrated and regulated processes in which several viral proteins and RNA molecules closely interact. It is therefore of interest to study whether ALLINIs have unpredicted pleiotropic effects on these RNA-related processes. We confirm that the ALLINI BI-D inhibits virus replication and that the produced virus is non-infectious. Furthermore, we show that the wild-type level of HIV-1 genomic RNA is packaged in virions and these genomes are in a dimeric state. The tRNAlys3 primer for reverse transcription was properly placed on this genomic RNA and could be extended ex vivo. In addition, the packaged reverse transcriptase enzyme was fully active when extracted from virions. As the RNA and enzyme components for reverse transcription are properly present in virions produced in the presence of BI-D, the inhibition of reverse transcription is likely to reflect the mislocalization of the components in the aberrant virus particle.