Clinical Utility of Machine Learning Methods Using Regression Models for Diagnosing Eosinophilic Chronic Rhinosinusitis.

Objective: Machine learning methods using regression models can predict actual values of histological eosinophil count from blood eosinophil levels. Therefore, these methods might be useful for diagnosing eosinophilic chronic rhinosinusitis, but their utility still remains unclear. We compared 2 statistical approaches, and investigated the utility of machine learning methods for diagnosing eosinophilic chronic rhinosinusitis. Study Design: Retrospective study. Setting: Medical center. Methods: Data, including eosinophilic levels, obtained from blood and sinonasal samples of 264 patients with chronic rhinosinusitis (257 with and 57 without nasal polyps) were analyzed. We determined factors affecting histopathological eosinophil count in regression models. We also investigated optimal cutoff values for blood eosinophil percentages/absolute eosinophil counts (AECs) through receiver operating characteristic curves and machine-learning methods based on regression models. A histopathological eosinophil count ≥10/high-power field was defined as eosinophilic chronic rhinosinusitis. Results: Blood eosinophil levels, nasal polyp presence, and comorbid asthma were factors affecting histopathological eosinophil count. Cutoffs between the 2 statistical approaches differed in the group with nasal polyps, but not in one without nasal polyps. Machine-learning methods identified blood eosinophil percentages ≥1% or AEC ≥100/µL as cut-offs for eosinophilic chronic rhinosinusitis with nasal polyps, while ≥6% or ≥400/µL for one without nasal polyps. Conclusion: Cut-offs of blood eosinophil levels obtained by machine-learning methods might be useful when suspecting eosinophilic chronic rhinosinusitis prior to biopsy because of their ability to adjust covariates, dealing with overfitting, and predicting actual values of histological eosinophil count.

Pharmacokinetics of monoclonal antibodies locally-applied into the middle ear of guinea pigs.

Countless therapeutic antibodies are currently available for the treatment of a broad range of diseases. Some target molecules of therapeutic antibodies are involved in the pathogenesis of sensorineural hearing loss (SNHL), suggesting that SNHL may be a novel target for monoclonal antibody (mAb) therapy. When considering mAb therapy for SNHL, understanding of the pharmacokinetics of mAbs after local application into the middle ear is crucial. To reveal the fundamental characteristics of mAb pharmacokinetics following local application into the middle ear of guinea pigs, we performed pharmacokinetic analyses of mouse monoclonal antibodies to FLAG-tag (FLAG-mAbs), which have no specific binding sites in the middle and inner ear. FLAG-mAbs were rapidly transferred from the middle ear to the cochlear fluid, indicating high permeability of the round window membrane to mAbs. FLAG-mAbs were eliminated from the cochlear fluid 3 h after application, similar to small molecules. Whole-body autoradiography and quantitative assessments of cerebrospinal fluid and serum demonstrated that the biodistribution of FLAG-mAbs was limited to the middle and inner ear. Altogether, the pharmacokinetics of mAbs are similar to those of small molecules when locally applied into the middle ear, suggesting the necessity of drug delivery systems for appropriate mAb delivery to the cochlear fluid after local application into the middle ear.

Effects of Unrestricted Kinematically Aligned Total Knee Arthroplasty with a Modified Soft-Tissue Respecting Technique on the Deformity of Limb Alignment in Japanese Patients.

Background and Objectives: Unrestricted kinematic alignment total knee arthroplasty (KA-TKA) with a soft-tissue respecting technique (STRT) is a soft-tissue-dependent tibial resection entailing the restoration of the original soft-tissue tension using ligamentotaxis after resurfacing the femur, based on the concept of restoring the native or pre-osteoarthritis alignment in each patient. However, there is no consensus on the indications of unrestricted KA-TKA with the STRT. We modified the STRT, followed by an investigation of the effects of surgery on the postoperative hip-knee-ankle angle (HKAA). Materials and Methods: We retrospectively analyzed the clinical background data, including the preoperative and postoperative HKAA, of 87 patients who underwent unrestricted KA-TKA with the modified STRT. Univariate and multivariate analyses were performed to determine the factors affecting the postoperative HKAA. A receiver operating characteristic (ROC) curve was plotted to investigate the change in the cut-off values of preoperative HKAA with respect to the safe zone of the postoperative HKAA. We generated two regression models, the linear regression model and generalized additive model (GAM) using machine learning, to predict the postoperative HKAA. Results: Univariate and multivariate analyses revealed the preoperative HKAA as the factor most relevant to the postoperative HKAA. ROC analysis revealed that the preoperative HKAA exhibited a high predictive utility, with a cut-off value of -10°, when the safe range of postoperative HKAA was set at ±5°. The GAM was the superior machine learning model, indicating a non-linear association between the preoperative and postoperative HKAA. Patients with preoperative HKAAs ranging from -18° to 4° were more likely to fall within the ±5° safe range of the postoperative HKAA. Conclusions: The preoperative HKAA influences the postoperative HKAA in unrestricted KA-TKA with the modified STRT. Machine learning using the GAM may contribute to the selection of patients eligible for the surgical approach.

Comorbidity of eosinophilic chronic rhinosinusitis in chronic eosinophilic pneumonia.

We aimed to elucidate details of comorbid chronic rhinosinusitis (CRS) in chronic eosinophilic pneumonia (CEP) under the collaboration between otolaryngologists and pulmonologists in a prospective study. The CEP diagnosis was performed by pulmonologists based on clinical symptoms, laboratory findings, and/or eosinophilia detected in bronchoalveolar lavage. All patients were referred to otolaryngologists before undergoing oral corticosteroid treatment for CEP. Ten CEP cases visited to otolaryngologists. All cases showed bilateral sinonasal inflammation in computed tomography (CT), indicating comorbid CRS. Nasal polyps (NPs) were observed in 50% of patients on endoscopy. Eighty percent of patients were diagnosed with eosinophilic CRS. In blood eosinophil levels and the mucosal eosinophil count, there were no significant differences between CRS without and with NPs. In Lund-Mackay CT total scores, among-individual variability was observed in CRS with NPs. The collaboration revealed blood/sinonasal eosinophilia and the variability in Lund-Mackay CT total scores as remarkable findings about the comorbid CRS.

Psychological states affecting initial pupil size changes after olfactory stimulation in healthy participants.

Odor perception affects physiological and psychological states. Pupillary light reflex (PLR) parameters can be affected by olfactory stimulation and psychological states, although it remains unclear whether the olfactory stimulation-induced psychological changes can associate with PLR parameter changes. This study aimed to investigate effects of olfactory stimulation-induced psychological changes on PLR parameter changes with repeated measurements. We collected data on six mood subscales of the profile of mood states, and on five PLR parameter measurements from 28 healthy participants. Participants underwent a 10-min olfactory stimulation on different days with six odorants available with the T&T olfactometer. As obtained data were clustered, we used linear mixed-effects models for statistical analyses. The olfactory stimulation using the no-odor liquid did not affect mood states and the initial pupil size (INIT). The sweat odorant worsened all mood subscales including fatigue-inertia (Fatigue)/Vigor-Activity (Vigor), and decreased INIT compared to the no-odor liquid. When comparing INIT responses related to changes in mood subscales between the no-odor liquid and the sweat odorant, worsened states of Fatigue/Vigor were associated with decreased INIT in the sweat odorant. Fatigue/Vigor can be used as mental fatigue indicators. Thus, mental fatigue can be associated with decreased INIT in the olfactory stimulation.

Recommendation of using both initial pupil size and constriction latency in pupillary light reflex as objective indicators reflecting subacute pain-related mental fatigue.

A previous study examining clinical subacute pain models under different methodological conditions showed that pain-induced mental fatigue can be associated with decreased initial pupil size (INIT)/shortened constriction latency (LAT) in the pupillary light reflex (PLR). We aimed to investigate the potential of INIT/LAT as objective indicators reflecting mental fatigue under the same methodological conditions. We recruited 118 patients planning to undergo three types of representative otolaryngological head and neck surgery procedures. We used the numerical rating scale (NRS) to assess subjective pain intensity and two mental fatigue-related mood categories of the Profile of Mood States, as well as INIT and LAT measurements (1) in the afternoon one day before surgery (pre1-surgery), (2) in the morning of the day of surgery (pre2-surgery), and (3) in the morning of the day following surgery (post-surgery). We assessed time point-dependent changes using one- or two-way analysis of variance, as well as responses of PLR parameters to mental fatigue using linear mixed-effects models (LMMs). As a result, NRS scores, the two mood categories, as well as LAT and INIT, showed significant time point-dependent changes. In post-hoc analyses, only INIT showed significant changes between the two pre-surgery time points. Thus, INIT values fluctuated even under pain-free conditions due to differences in the time of the day. LMMs demonstrated decreased INIT/shortened LAT related to mental fatigue. All surgical groups showed similar associations between mental fatigue and INIT/LAT findings. As each parameter has advantages and disadvantages, it is recommended to use both INIT and LAT as the indicators.

Decreased initial pupil size and shortened constriction latency due to negative mood states and mental fatigue in clinical subacute pain models.

Previous clinical studies on pupillary light reflex parameters showed shortened constriction latency (LAT) and decreased initial pupil size (INIT) due to increased numeric rating scale (NRS) scores, reflecting subjective pain intensity, in subacute pain models. As noxious stimulation causes pupil dilation, decreased INIT (pupil constriction) was an unexpected finding. Pain-related negative moods and mental fatigue might have caused this finding. We aimed to investigate how psychological states affect LAT/INIT in two subacute pain models. For psychological assessment, we used the Profile of Mood States (POMS) and calculated the total mood disturbance (TMD) score using six mood categories. We collected data on NRS scores, POMS-related scores, LAT, and INIT through a longitudinal study. Using linear mixed-effects models, we evaluated the association of TMD scores with NRS scores, LAT, and INIT. Furthermore, we performed subanalyses targeting two mood categories that represent mental fatigue: Fatigue-Inertia (Fatigue) and Vigor-Activity (Vigor). We investigated whether obtained results can be identical in both models. In total, 141 patients were enrolled. Increased NRS scores were associated with increased TMD/Fatigue scores and decreased Vigor scores, being associated with shortened LAT/decreased INIT in both models. Score changes in NRS, TMD, Fatigue, and Vigor indicated that increased subjective pain intensity can be associated with negative mood states, especially mental fatigue. This study revealed that negative moods and mental fatigue induced by acute pain can be associated with shortened LAT/decreased INIT in both models, indicating clinical potential of LAT/INIT as objective indicators reflecting the psychological states for pain assessment.

Clinical potential of pupillary light reflex and heart rate variability parameters as objective indicators of tonsillectomy-induced pain.

Objective.Establishing objective indicators of subjective pain intensity is important in pain assessment. Pupillary light reflex (PLR) and heart rate variability (HRV) indicate autonomic nervous system (ANS) activity and may serve as pain indicators because pain can affect ANS activity. In this prospective longitudinal study, we aimed to investigate the potential of PLR/HRV parameters as objective indicators of subjective pain intensity after tonsillectomy.Approach.Sixty-seven patients undergoing tonsillectomy were enrolled. Subjective pain intensity based on a numeric rating scale (NRS) and eight PLR/HRV parameters were assessed at five time points. We investigated the changes in the NRS values over time. We estimated regression coefficients reflecting parameter changes per unit change in the NRS score using linear mixed-effects models.Main Results.The mean NRS score was 0 at two pre-surgery time points, 5 on postoperative days (PODs) 1 and 2, and 0 at postoperative week 3. Two parameters (initial pupil size [INIT] and constriction latency [LAT]) showed significant changes on POD1 and POD2 in comparison to baseline data measured at the pre-surgery time point. Among these parameters, only LAT showed no significant changes between POD1 and POD2. Significant regression coefficients with the narrowest 95% confidence intervals were observed for INIT and LAT. Increased NRS scores were associated with decreased INIT and shortened LAT.Significance.LAT was a robust indicator of subjective pain intensity. Our patients showed decreased INIT with increased NRS scores, indicating the predominance of the parasympathetic, not sympathetic, tone in pupils. Further studies are required to investigate factors causing this predominance.

Alterations in prefrontal cortical neuregulin-1 levels in post-pubertal rats with neonatal ventral hippocampal lesions.

Genetic studies in humans have implicated the gene encoding neuregulin-1 (NRG-1) as a candidate susceptibility gene for schizophrenia. Furthermore, it has been suggested that NRG-1 is involved in regulating the expression and function of the N-methyl-D-aspartate receptor and the GABAA receptor in several brain areas, including the prefrontal cortex (PFC), the hippocampus, and the cerebellum. Neonatal ventral hippocampal lesioned (NVHL) rats have been considered as a putative model for schizophrenia with characteristic post-pubertal alteration in response to stress and neuroleptics. In this study, we examined NRG-1, erb-b2 receptor tyrosine kinase 4 (erbB4), and phospho-erbB4 (p-erbB4) levels in the PFC and the distribution of NRG-1 in the NVHL rats by using immunoblotting and immunohistochemical analyses. Neonatal lesions were induced by bilateral injection of ibotenic acid in the ventral hippocampus of postnatal day 7 Sprague-Dawley (SD)-rats. NVHL rats showed significantly decreased levels of NRG-1 and p-erbB4 in the PFC compared to sham controls at post-pubertal period, while the level of erbB4 did not differ between sham and NVHL rats. Moreover, microinjection of NRG-1 into the mPFC improved NVHL-induced prepulse inhibition deficits. Our study suggests PFC NRG-1 alteration as a potential mechanism in schizophrenia-like behaviors in the NVHL model.

Clinical potential of pupillary light reflex parameters as objective indicators reflecting chronic rhinosinusitis-specific quality of life: a 12-month prospective longitudinal study.

Pupillary light reflex (PLR) and heart rate variability (HRV) parameters can be objective indicators of chronic rhinosinusitis (CRS) status from the viewpoint of autonomic nervous system activity. This study aimed to establish objective indicators for CRS using the 22-item Sino-Nasal Outcome Test (SNOT-22) and PLR/HRV parameters. Sixty-seven patients were prospectively and longitudinally followed up after surgical treatment. We investigated changes in SNOT-22 scores, representing CRS-specific quality of life (QOL). We prepared two models: linear regression model adjusting clinical factors as predictor variables (model 1) and linear mixed-effects model adjusting clinical factors and among-individual variability (model 2). We compared Akaike's information criterion (AIC) values and regression coefficients. The model with lower AIC values was defined as the better-fit model. Model 2 showed lower AIC values in all parameters (better-fit model). Three parameters showed opposite results between the two models. The better-fit models showed significances in the five PLR parameters but not in any HRV parameters. Among these PLR parameters, constriction latency can be the most robust indicator because of the narrowest 95% confidence intervals. Adjusting the among-individual variability while investigating clinical potential of PLR/HRV parameters to reflect CRS-specific QOL can improve the model fit, thereby reaching robust conclusions from obtained data.

Inverted papilloma originating from the lacrimal sac and the nasolacrimal duct with marked FDG accumulation.

Inverted papilloma originating from the lacrimal sac and the nasolacrimal duct is rare, although that in the sinonasal region is a relatively common lesion with local invasion, malignant potential and high recurrence rates after surgery. We report a 52-year-old woman with inverted papilloma of the right lacrimal sac and the nasolacrimal duct, who underwent CT, MR imaging and FDG-PET/CT preoperatively. In addition to CT and MR imaging features similar to those in previous reports, the inverted papilloma exhibited marked FDG accumulation with a maximum standardized uptake value of 7.34 and no other significant FDG accumulation was detected. In summary, our case of inverted papilloma originating from the right lacrimal sac and the nasolacrimal duct noted marked FDG accumulation on PET/CT, which enabled visualization of the localized tumor extension with no metastases.

Clinical factors affecting pupillary light reflex parameters: a single-centre, cross-sectional study.

PURPOSE: To evaluate the effects of stimulus intensity, aging, sex, smoking and eye symmetry on pupillary light reflex (PLR) parameters. METHODS: We evaluated 2812 eyes from 1406 subjects in a single-centre, cross-sectional study. PLR data were collected using four different stimulus intensities. We prepared two models for each of the eight PLR parameters, and defined the model with the lowest values of Akaike's information criterion (AIC) as being the best-fit. Model A was a linear regression model without adjustment for among-individual variability, while the Model B linear mixed-effects models (LMMs) were adjusted for among-individual variability. The regression coefficients of the two models were compared. RESULTS: Model B showed the lowest AIC values for all parameters and the best fit. For light stimulus intensity, age and eye symmetry, the two models yielded similar results for all PLR parameters. For sex and smoking index, some PLR parameters showed the opposite results, i.e., Model A showed significant effects while Model B did not. CONCLUSION: These results indicate that light stimulus intensity, aging, sex, smoking and eye symmetry are factors that affect PLR parameters. These should be adjusted when evaluating the clinical potential of PLR as a diagnostic tool. In addition, adjusting for among-individual variability due to LMMs can improve the model fit and reduce false positives. This can reveal the association between clinical factors and PLR parameters with increased accuracy.

Clinical potential of pupillary light reflex and heart rate variability parameters as biomarkers for assessing pain relief effects on autonomic function: a prospective longitudinal study.

OBJECTIVE: To investigate the association between subjective pain intensity and objective parameters obtained from two autonomic function tests in a longitudinal study targeting acute pain model in otolaryngology-head and neck region: pupillary light reflex (PLR) and heart rate variability (HRV). APPROACH: We enrolled 35 patients with acute otolaryngology-head and neck region inflammatory disorders at pre-treatment stage. The acute inflammatory disorders were defined as acute tonsillitis, peritonsillar abscess, acute epiglottitis, acute sinusitis, and deep neck space abscess. Patients underwent a numeric rating scale (NRS) to monitor subjective pain intensity, PLR, and HRV as objective tests at 4 time-points during the follow-up term. As main outcome variables, we used 15 analyzable PLR/HRV parameters. To improve robustness of conclusions about the association between NRS and PLR/HRV parameters, we prepared four linear mixed-effects models (LMMs) including predictor variables such as NRS, sociodemographic factors, and individual variability. And then, we selected the better-fit model based on the lowest Akaike's information criterion. MAIN RESULTS: NRS significantly decreased due to treatments. In 14 out of 15 parameters, better-fit models were models including not only sociodemographic factors but also individual variability. We observed significant parameter alterations to one unit change of NRS in five PLR and four HRV parameters. SIGNIFICANCE: The current study revealed that PLR/HRV parameters can be used as biomarkers reflecting pain relief effects. In addition, the findings suggest the importance of adjusting predictor variables, especially individual variability defined as random effects in LMMs, for obtaining more accurate parameter estimation in the longitudinal study.

Effective combination of pupil light reflex and heart rate variability to assess foot bath effects on autonomic function in healthy adults.

OBJECTIVES: To evaluate the effects of a foot bath on autonomic nervous system (ANS) activities as measured by pupil light reflex (PLR) and heart rate variability (HRV) in healthy adults. METHODS: PLR and HRV were assessed before and during a foot bath in healthy subjects (n = 110). The subjects dipped their feet in 40 °C water at a level below their knees for 15 min The light reflex in PLR was elicited at four ascending stimulus intensities. Linear-mixed effect models were fit with PLR parameters, and a Wilcoxon signed-rank test with HRV parameters. In PLR analysis, an interaction term between the foot bath intervention and the stimulus intensity was included as a fixed effect. RESULTS: The PLR analysis showed significant interactions in five out of seven parameters. The altered patterns indicated enhanced activity of the parasympathetic nervous system (PNS) due to the intervention. In contrast, the HRV analysis showed few alterations of PNS activities due to the intervention. CONCLUSIONS: The study results demonstrated differences in altered PNS activity during a foot bath, when assessed by PLR and HRV. In PLR, the stimulus intensity was a crucial factor for the evaluation of foot bath effects. Taken together, the combination of PLR and HRV effectively evaluates ANS activities during a foot bath.

Long-term olfactory function outcomes after pituitary surgery by endoscopic endonasal transsphenoidal approach.

OBJECTIVES: To evaluate long-term olfactory outcomes in patients who underwent pituitary surgery through the endoscopic endonasal transsphenoidal approach (EETSA) by T&T olfactometer. METHODS: We retrospectively reviewed 26 patients who underwent pituitary surgery via EETSA. Olfactory function was assessed by T&T olfactometer before and 6 months after surgery. The mean of recognition thresholds for five different odorants was used. The change in the mean recognition threshold values was evaluated in the entire cohort and the subgroup analysis was performed according to the age, sex, past history of pituitary surgery (primary surgery or revision surgery), histopathology (non-functioning adenoma (NFA) or functioning adenoma (FA)), reconstruction procedure (rescue flap or nasoseptal flap), and superior turbinate management (preserved or resected). RESULTS: Of the 26 patients (12 men and 14 women, median age 53 years), 21 patients were newly diagnosed with pituitary gland tumor (16 NFAs, 5 FAs) and the remaining 5 were diagnosed with recurrent pituitary gland tumor (4 NFAs and 1 FA). In the whole cohort, the mean recognition threshold values of T&T olfactometer significantly improved after surgery (P=0.01). Thirteen out of 26 patients (50%) showed olfactory improvement, whereas only 3 (12%) showed deterioration. In the subgroup analysis, olfactory function outcomes were not significantly different between the subgroups with respect to the age, sex, past history of pituitary surgery, histopathology, reconstruction procedure, or superior turbinate management. The olfactory function tended to worsen in the revision surgery group compared to that in the primary surgery group, but not significantly (P=0.06). CONCLUSIONS: The olfactory function was improved or maintained after pituitary surgery via EETSA in 88% of patients, indicating the benefits of low invasiveness of our surgical treatment. On the other hand, three patients (12%) demonstrated deterioration of olfactory function, suggesting that the risk of postoperative olfactory dysfunction should be informed to patients.

Lower ototoxicity and absence of hidden hearing loss point to gentamicin C1a and apramycin as promising antibiotics for clinical use.

Spread of antimicrobial resistance and shortage of novel antibiotics have led to an urgent need for new antibacterials. Although aminoglycoside antibiotics (AGs) are very potent anti-infectives, their use is largely restricted due to serious side-effects, mainly nephrotoxicity and ototoxicity. We evaluated the ototoxicity of various AGs selected from a larger set of AGs on the basis of their strong antibacterial activities against multidrug-resistant clinical isolates of the ESKAPE panel: gentamicin, gentamicin C1a, apramycin, paromomycin and neomycin. Following local round window application, dose-dependent effects of AGs on outer hair cell survival and compound action potentials showed gentamicin C1a and apramycin as the least toxic. Strikingly, although no changes were observed in compound action potential thresholds and outer hair cell survival following treatment with low concentrations of neomycin, gentamicin and paromomycin, the number of inner hair cell synaptic ribbons and the compound action potential amplitudes were reduced. This indication of hidden hearing loss was not observed with gentamicin C1a or apramycin at such concentrations. These findings identify the inner hair cells as the most vulnerable element to AG treatment, indicating that gentamicin C1a and apramycin are promising bases for the development of clinically useful antibiotics.

Optical coherence tomography for observation of the olfactory epithelium in mice.

OBJECTIVE: Optical coherence tomography (OCT) is an imaging tool that exploits the coherence of infrared light and is clinically utilized in the field of ophthalmology and dermatology. This study aimed to examine the feasibility of using OCT for diagnosing degeneration and regeneration of the olfactory epithelium in mice. METHODS: The olfactory and respiratory epithelia in excised nasal septa of adult mice were observed using OCT. Subsequently, histological assessments were performed with hematoxylin and eosin (H-E) staining. The thicknesses of the olfactory or respiratory epithelia were measured in both OCT images and H-E-stained paraffin sections. The ability of OCT to distinguish olfactory epithelia from respiratory epithelia in normal mice was compared with that of H-E staining. The feasibility of using OCT assessments for detecting changes in the thickness of olfactory epithelia was tested in a mouse model of the degeneration and regeneration of olfactory epithelia. RESULTS: OCT allowed visualization of the gross morphology of the olfactory and respiratory epithelium in normal mice, although it was limited in terms of visualizing cellular components. OCT-based measurements of epithelial thickness helped to distinguish olfactory epithelia from respiratory epithelia. Similar to H-E staining, OCT also clarified changes in the olfactory epithelium thickness after methimazole application. CONCLUSIONS: These findings indicate the utility of OCT for assessment of olfactory epithelial thickness and its potential for clinical evaluation of human olfactory epithelia.

NANOCI-Nanotechnology Based Cochlear Implant With Gapless Interface to Auditory Neurons.

: Cochlear implants (CI) restore functional hearing in the majority of deaf patients. Despite the tremendous success of these devices, some limitations remain. The bottleneck for optimal electrical stimulation with CI is caused by the anatomical gap between the electrode array and the auditory neurons in the inner ear. As a consequence, current devices are limited through 1) low frequency resolution, hence sub-optimal sound quality and 2), large stimulation currents, hence high energy consumption (responsible for significant battery costs and for impeding the development of fully implantable systems). A recently completed, multinational and interdisciplinary project called NANOCI aimed at overcoming current limitations by creating a gapless interface between auditory nerve fibers and the cochlear implant electrode array. This ambitious goal was achieved in vivo by neurotrophin-induced attraction of neurites through an intracochlear gel-nanomatrix onto a modified nanoCI electrode array located in the scala tympani of deafened guinea pigs. Functionally, the gapless interface led to lower stimulation thresholds and a larger dynamic range in vivo, and to reduced stimulation energy requirement (up to fivefold) in an in vitro model using auditory neurons cultured on multi-electrode arrays. In conclusion, the NANOCI project yielded proof of concept that a gapless interface between auditory neurons and cochlear implant electrode arrays is feasible. These findings may be of relevance for the development of future CI systems with better sound quality and performance and lower energy consumption. The present overview/review paper summarizes the NANOCI project history and highlights achievements of the individual work packages.

Transplantation of neurons derived from human iPS cells cultured on collagen matrix into guinea-pig cochleae.

The present study examined the efficacy of a neural induction method for human induced pluripotent stem (iPS) cells to eliminate undifferentiated cells and to determine the feasibility of transplanting neurally induced cells into guinea-pig cochleae for replacement of spiral ganglion neurons (SGNs). A stepwise method for differentiation of human iPS cells into neurons was used. First, a neural induction method was established on Matrigel-coated plates; characteristics of cell populations at each differentiation step were assessed. Second, neural stem cells were differentiated into neurons on a three-dimensional (3D) collagen matrix, using the same protocol of culture on Matrigel-coated plates; neuron subtypes in differentiated cells on a 3D collagen matrix were examined. Then, human iPS cell-derived neurons cultured on a 3D collagen matrix were transplanted into intact guinea-pig cochleae, followed by histological analysis. In vitro analyses revealed successful induction of neural stem cells from human iPS cells, with no retention of undifferentiated cells expressing OCT3/4. After the neural differentiation of neural stem cells, approximately 70% of cells expressed a neuronal marker, 90% of which were positive for vesicular glutamate transporter 1 (VGLUT1). The expression pattern of neuron subtypes in differentiated cells on a 3D collagen matrix was identical to that of the differentiated cells on Matrigel-coated plates. In addition, the survival of transplant-derived neurons was achieved when inflammatory responses were appropriately controlled. Our preparation method for human iPS cell-derived neurons efficiently eliminated undifferentiated cells and contributed to the settlement of transplant-derived neurons expressing VGLUT1 in guinea-pig cochleae. Copyright © 2015 John Wiley & Sons, Ltd.

Bladder recovery relates with increased mid-cingulate perfusion after shunt surgery in idiopathic normal-pressure hydrocephalus: a single-photon emission tomography study.

AIMS OF STUDY: It is reported that severe bladder disorder in idiopathic normal-pressure hydrocephalus (iNPH) is predicted by right frontal hypoperfusion. However, it is not known whether bladder recovery is predicted by brain perfusion change after shunt surgery. To address this issue, we compared bladder and brain function before and after shunt surgery in iNPH. METHODS: We enrolled 75 patients in the study. Before and 12 months after shunt surgery, we analyzed brain perfusion by SPECT and bladder disorder by a specialized grading scale. The scale consisted of grade 0, none; grade 1, urinary urgency and frequency; grade 2, urinary incontinence 1-3 times a week; grade 3, urinary incontinence >daily; and grade 4, loss of bladder control. More than one grade improvement is defined as improvement, and more than one grade decrement as worsening; otherwise no changes. RESULTS: Comparing before and after surgery, in the bladder-no-change group (32 cases) there was an increase in blood flow which is regarded as reversal of enlargement in the Sylvian fissure and lateral ventricles (served as control). In contrast, in the bladder-improved group (32 cases) there was an increase in bilateral mid-cingulate, parietal, and left frontal blood flow (p < 0.05). In the bladder-worsened group (11 cases) no significant blood flow change was observed. CONCLUSION: The present study showed that after shunt surgery, bladder recovery is related with mid-cingulate perfusion increase in patients with iNPH. The underlying mechanism might be functional restoration of the mid-cingulate that normally inhibits the micturition reflex.