Evolutionary Selection and Constraint on Human Knee Chondrocyte Regulation Impacts Osteoarthritis Risk.

During human evolution, the knee adapted to the biomechanical demands of bipedalism by altering chondrocyte developmental programs. This adaptive process was likely not without deleterious consequences to health. Today, osteoarthritis occurs in 250 million people, with risk variants enriched in non-coding sequences near chondrocyte genes, loci that likely became optimized during knee evolution. We explore this relationship by epigenetically profiling joint chondrocytes, revealing ancient selection and recent constraint and drift on knee regulatory elements, which also overlap osteoarthritis variants that contribute to disease heritability by tending to modify constrained functional sequence. We propose a model whereby genetic violations to regulatory constraint, tolerated during knee development, lead to adult pathology. In support, we discover a causal enhancer variant (rs6060369) present in billions of people at a risk locus (GDF5-UQCC1), showing how it impacts mouse knee-shape and osteoarthritis. Overall, our methods link an evolutionarily novel aspect of human anatomy to its pathogenesis.

Cochlear implantation using the underwater technique: long-term results.

INTRODUCTION: The opening of the round window and the insertion of the electrode array into the scala tympani during cochlear implant surgery can lead to a pressure shock of the delicate inner ear structures. By filling the tympanic cavity with Ringer Solution during these surgical steps (underwater technique), the hydrostatic pressure of the fluid acts as a smooth pressure stabilizer, avoiding a pressure shock of the inner ear structures. The aim of this retrospective study was to present long-term results of this new method of cochlear implantation in underwater technique. METHODS: Altogether, 47 implantations in 43 patients with residual hearing at the frequencies 250, 500 and 1000 Hz in the unaided preoperative pure tone audiometry were included. A cochlear implantation via round window with a conventional full-length electrode was performed in underwater technique. Changes of residual hearing 7 weeks and 24 months after surgery were analyzed. RESULTS: Overall postimplant hearing preservation 7 weeks after implantation was achieved in 22 ears (47%). Subsequent follow-up was performed on average 24 months after surgery (range 12 months-4.2 years) in all patients. At this late postoperative evaluation, preservation of hearing was recorded in 18 ears (38%). Neither the follow-up time nor the type of electrode had a significant impact on the postoperative hearing loss. CONCLUSION: The underwater technique is an atraumatic cochlear implantation technique with hearing preservation rates comparable to results in literature and a very small hearing preservation decline rate over time even when using full-length CI electrodes.

The Positive Effect of Sialendoscopy with Irrigation Lavage for Sialadenitis without Sialolithiasis or Stenosis.

AIMS: The aim of the study was to evaluate different irrigation solutions during sialendoscopy to reduce complaints caused by sialodochitis. METHODS: The investigators designed and implemented a retrospective study composed of 94 patients with sialodochitis but no sialolithiasis or relevant stenosis of the salivary duct system. Three different irrigations (normal saline, cortisone single-shot, and cortisone) were used. After the sialendoscopy, the patients were asked about the current status of the affected salivary gland, and the quantity and quality of the gland swelling/inflammation over a follow-up period of 11.6 months (6-24 months). RESULTS: At the time of follow-up, 41 patients (43.6%) no longer had any complaints with the salivary gland in question. In 75.5% of the patients, a satisfying result was achieved. In total, only 3 patients needed submandibulectomy in the course of the study due to persistent complaints. The outcome showed no statistical differences between the mean of the 3 groups (p = 0.149). CONCLUSION: Sialendoscopy with flushing/lavage seems to be a good treatment option for patients with sialodochitis lacking sialolithiasis. The results of this study suggest that the type of irrigation used during sialendoscopy seems to be secondary.

The correlation between ECochG parameters and early auditory behavior after cochlear implantation in children.

OBJECTIVE: The individual outcome after cochlear implantation in children with auditory synaptopathy/neuropathy (AS/AN) is difficult to predict. A tool for preoperative assessment would be helpful for counseling parents. This study evaluates the outcome after CI in children with AS/AN and with sensorineural hearing loss (SNHL), and correlates it with the preoperative ECochG results in order to find specific parameters of prognostic value. DESIGN: The improvement of auditory behavior after CI was retrospectively assessed using the LittlEARS questionnaire and quantified in a score (LS). This score was correlated with the CAP/SP ratio in the preoperative ECochG. The score was further correlated with the patient's age six months following CI. STUDY SAMPLE: Nine children with AS/AN were compared to nine children with SNHL. RESULTS: Both groups showed a significant improvement in LS following CI. There was a significant positive correlation between the CAP/SP ratio and the improvement in LS in all children. The correlation between age and LS was significantly negative in the SNHL group and positive in the AS/AN group. CONCLUSION: All children with AS/AN and SNHL benefit to a similar extent from CI. The preoperatively assessed CAP/SP ratio has a prognostic value for the development of auditory behavior following CI.

Hazard of CO2 laser-induced airway fire in laryngeal surgery: experimental data of contributing factors.

In carbon dioxide (CO2) laser surgery of the larynx, the potentially dangerous combination of laser-induced heat in an oxygen-enriched atmosphere typically occurs when jet ventilation is used or due to an insufficiently blocked endotracheal tube. Until now, no limitations for safe oxygen concentrations or laser intervals have been established. The aim of this study was to investigate and quantify the factors that may contribute to an airway fire in laryngeal laser surgery. Fat, muscle and cartilage were irradiated with a CO2 laser at 2, 4, 6 and 8 W in five different oxygen concentrations with and without smoke exhaustion. The time to ignition was recorded for each different experimental setup. Fat burnt fastest, followed by cartilage and muscle. The elevation of laser energy or oxygen concentration reduced the time to inflammation of any tissue. The elevation of oxygen by 10 % increases the risk of inflammation more than the elevation of laser power by 2 W. Under smoke exhaustion, inflammation and burning occurred delayed or were even inhibited at lower oxygen concentrations. Lasing in more than 50 % oxygen is comparatively dangerous and can cause airway fire in less than 5 s, especially when laser energies of more than 5 W are applied. In equal or lower than 50 % oxygen, an irradiation interval of 5 s can be considered a comparatively safe time limit to prevent inflammation in laryngeal laser surgery. Smoke exhaustion should always be applied.

Aspartame and Its Metabolites Cause Oxidative Stress and Mitochondrial and Lipid Alterations in SH-SY5Y Cells.

Due to a worldwide increase in obesity and metabolic disorders such as type 2 diabetes, synthetic sweeteners such as aspartame are frequently used to substitute sugar in the diet. Possible uncertainties regarding aspartame's ability to induce oxidative stress, amongst others, has led to the recommendation of a daily maximum dose of 40 to 50 mg per kg. To date, little is known about the effects of this non-nutritive sweetener on cellular lipid homeostasis, which, besides elevated oxidative stress, plays an important role in the pathogenesis of various diseases, including neurodegenerative diseases such as Alzheimer's disease. In the present study, treatment of the human neuroblastoma cell line SH-SY5Y with aspartame (271.7 µM) or its three metabolites (aspartic acid, phenylalanine, and methanol (271.7 µM)), generated after digestion of aspartame in the human intestinal tract, resulted in significantly elevated oxidative stress associated with mitochondrial damage, which was illustrated with reduced cardiolipin levels, increased gene expression of SOD1/2, PINK1, and FIS1, and an increase in APF fluorescence. In addition, treatment of SH-SY5Y cells with aspartame or aspartame metabolites led to a significant increase in triacylglycerides and phospholipids, especially phosphatidylcholines and phosphatidylethanolamines, accompanied by an accumulation of lipid droplets inside neuronal cells. Due to these lipid-mediating properties, the use of aspartame as a sugar substitute should be reconsidered and the effects of aspartame on the brain metabolism should be addressed in vivo.

Vitamin B12 Attenuates Changes in Phospholipid Levels Related to Oxidative Stress in SH-SY5Y Cells.

Oxidative stress is closely linked to Alzheimer's disease (AD), and is detected peripherally as well as in AD-vulnerable brain regions. Oxidative stress results from an imbalance between the generation and degradation of reactive oxidative species (ROS), leading to the oxidation of proteins, nucleic acids, and lipids. Extensive lipid changes have been found in post mortem AD brain tissue; these changes include the levels of total phospholipids, sphingomyelin, and ceramide, as well as plasmalogens, which are highly susceptible to oxidation because of their vinyl ether bond at the sn-1 position of the glycerol-backbone. Several lines of evidence indicate that a deficiency in the neurotropic vitamin B12 is linked with AD. In the present study, treatment of the neuroblastoma cell line SH-SY5Y with vitamin B12 resulted in elevated levels of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and plasmalogens. Vitamin B12 also protected plasmalogens from hydrogen peroxide (H2O2)-induced oxidative stress due to an elevated expression of the ROS-degrading enzymes superoxide-dismutase (SOD) and catalase (CAT). Furthermore, vitamin B12 elevates plasmalogen synthesis by increasing the expression of alkylglycerone phosphate synthase (AGPS) and choline phosphotransferase 1 (CHPT1) in SH-SY5Y cells exposed to H2O2-induced oxidative stress.

Impact of the Vestibular System on the Formation and Progression to Idiopathic Scoliosis: A Review of Literature.

The physiopathogenesis of adolescent idiopathic scoliosis remains unknown. However, a multifactorial pathogenesis is being assumed. Besides biomechanical, biochemical, and genetic factors, some studies have focused on congenital or acquired abnormalities in the vestibular organ with consecutive development of scoliosis. This study aims to analyze a possible correlation between any vestibular organ congenital or acquired pathologies and scoliosis based on the current literature. Therefore, we conducted a literature search in three databases, with search terms such as "scoliosis," "organ of balance," "idiopathic scoliosis," "vestibular organ," "spine," and "balance." Fifteen studies were selected and used for research. The relationship between scoliosis and vestibular organ abnormalities was recorded from all included works. Seven studies demonstrated a direct correlation between vestibular organ anatomical abnormalities and the form of the scoliotic spine. Another study confirmed the influence of the pathology of the vestibular organ on scoliosis but questioned whether it had an impact on the formation or the progression of the curvature. Others demonstrated a temporal overlap of the embryonic development of the vestibular organ and the beginning of pre-scoliotic characteristics, but their relationship remained questionable. In three studies, the correlation remained unclear, and any context has been denied. It seems unlikely that an isolated vestibular disorder can trigger structural scoliosis. However, the vestibular system pathologies may certainly occur in the multifactorial genesis of idiopathic scoliosis. Whether the correlation refers to the expression or the progression of scoliosis or may even have an influence on both remains unclear. New treatment options could be derived from these findings with a positive influence on the course of the deformity.

The Titanium Angular Clip Prosthesis for Ossicular Chain Reconstruction: Long-Term Results.

OBJECTIVES: To describe the long-term results of the titanium angular clip prosthesis 10 years after its initial description. STUDY DESIGN: Clinical retrospective study. SETTING: Tertiary referral center. PATIENTS: Sixty three patients with isolated defects of the long process of the incus where the ossicular chain was reconstructed by a titanium angular clip prosthesis. INTERVENTIONS: Therapeutic. MAIN OUTCOME MEASURES: The mean air-bone gap was calculated over the frequencies of 0.5, 1, 2, 3, and 4 kHz. RESULTS: The placement of the prosthesis was straightforward in all patients, without any complication. During the first follow-up visit after 3 weeks (n = 61) the mean air-bone gap (ABG) was reduced by 10 dB HL, and from 24 dB HL preoperatively to 14 dB HL. At the long-term follow-up appointment-4 years after implantation (n = 29)-the mean ABG was still reduced by 8 dB HL, from a mean of 26 dB HL preoperatively to 18 dB HL. CONCLUSION: The use of the titanium angular clip prosthesis is a safe and reliable way to bridge an isolated erosion of the long process of the incus, leading to significant and long-lasting improvement of the ABG both in the short and long-term follow-up. A similarly large improvement of the sound transmission can be achieved both in patients with a Type A and a Type B/C tympanogram.

Influence of ambient air pressure changes on vestibular symptoms after stapes surgery.

OBJECTIVE: To examine if vestibular irritation after stapes surgery may be provoked by pressure changes across the tympanic membrane, which consecutively results in displacements of the ossicular chain and the piston prosthesis suspended to it. METHODS: In this prospective study 15 patients (13 female, 2 male) received unilateral stapes surgery (4 left, 11 right ear) with stapedotomy (n=14) or stapedectomy (n=1) at an academic tertiary referral center. Surgery was performed under local anesthesia via a transmeatal approach with a piston prosthesis 0.4×4.5mm. The fixation of the stapes, the exclusion of a malleus head fixation, and the gliding capacity of the malleus-incus joint were examined intraoperatively. A pure tone audiogram at four frequencies, a tympanometry with simultaneous video-oculography (VOG), caloric testing, and posturography with and without simultaneous tympanometry were performed six days before surgery, six weeks and three months after surgery, respectively. RESULTS: The mean air bone gap improved significantly from 25 (±8) dB preoperatively to 10 (±6) dB after surgery. In the tympanometry with simultaneous VOG only two patients showed nystagmus beats into the operated ears during only one of the two follow-up appointments. All other patients did not show any vestibular symptoms or nystagmus during any of the follow-up appointments. In the combined testing of posturography and tympanometry no patient showed any pathological findings. CONCLUSION: In patients who underwent stapes surgery with a piston prosthesis no vestibular symptoms can be provoked by pressure changes in the external auditory canal.

Preservation of Vestibular Function and Residual Hearing After Round Window Cochlear Implantation.

OBJECTIVE: To examine the possible correlation between the loss of short-term residual hearing and vestibular function after cochlear implantation (CI). STUDY DESIGN: Retrospective patient review. SETTING: Academic tertiary referral center. PATIENTS: One hundred twenty patients with normal vestibular function (VF) in the caloric testing and residual hearing (RH) at the frequencies 250, 500, and 1000 Hz on the surgery side between 2008 and 2016 were included in the study. INTERVENTION: Primary CI on the first side via round window with a conventional full-length electrode. MAIN OUTCOME MEASURES: Changes of RH and VF 7 weeks after surgery were analyzed. Preservation of RH was defined as measurable postoperative thresholds at the frequencies 250, 500, and 1000 Hz in the pure-tone audiogram. Preservation of the VF after CI was assessed both by an absolute and relative threshold in the caloric testing. RESULTS: Seven weeks after implantation, the preservation of RH was achieved in 52 (43.3 %) patients and the preservation of VF in 95 (79.2 %) patients on the operated side. There was no significant statistical correlation between these two parameters. CONCLUSION: The loss of RH was more than twice as frequent as the loss of VF. However, no statistical correlation between the failure of the two inner ear functions was found. The exact causes are still unknown, but our data could give an indication that there may be different underlying pathomechanisms.

Acquired stenosis of the external auditory canal - long-term results and patient satisfaction.

BACKGROUND: The surgical treatment of acquired post-inflammatory atresia of the external auditory canal (EAC) is challenging. Based on the long-term surgical experience, a modified split skin graft technique has been established at our clinic. AIMS/OBJECTIVES: The aim was to evaluate the clinical and audiological data and patient satisfaction after performing meatoplasty. MATERIAL AND METHODS: In total, 16 patients were included who underwent intraoperative enlargement of the bony EAC, resection of the fibrotic scar tissue, reconstruction with split skin grafts and splinting of the anterior tympanomeatal angle in the period of 2004-2016. Patients presented at a long-term follow-up appointment for reevaluation. RESULTS: The mean follow-up time was 52 months after surgery. The pure-tone average (52 dB vs. 31 dB) and the air-bone gap (27 dB vs. 11 dB) decreased significantly compared to the preoperative status. The grade of stenosis also showed a significant improvement during the follow-up visit. Complete re-atresia was observed only in two patients (10.5%). CONCLUSION: The applied surgical technique is a safe and successful treatment option for acquired atresia of the EAC. SIGNIFICANCE: The study provides important data for the surgical treatment of acquired atresia of the EAC and corroborates the significance of intensive aftercare.

Transcriptional profiling of synovium in a porcine model of early post-traumatic osteoarthritis.

To determine the transcriptional profile of synovium during the molecular phase of post-traumatic osteoarthritis, anterior cruciate ligament transections (ACL) were performed in 36 Yucatan minipigs. Equal numbers were randomly assigned to no further treatment, ACL reconstruction or repair. Perimeniscal synovium for histopathology and RNA-sequencing was harvested at 1 and 4 weeks post-operatively and from six healthy control animals. Microscopic synovitis scores significantly worsened at 1 (p < 0.001) and 4 weeks (p = 0.003) post-surgery relative to controls, and were driven by intimal hyperplasia and increased stromal cellularity without inflammatory infiltrates. Synovitis scores were similar between no treatment, reconstruction, and repair groups (p ≥ 0.668). Relative to no treatment at 1 week, 88 and 367 genes were differentially expressed in the reconstruction and repair groups, respectively (227 and 277 at 4 weeks). Relative to controls and with the treatment groups pooled, 1,683 transcripts were concordantly differentially expressed throughout the post-surgery time-course. Affected pathways included, proteolysis_connective tissue degradation (including upregulations of protease-encoding MMP1, MMP13, and ADAMTS4), and development_cartilage development (including upregulations of ACAN, SOX9, and RUNX2), among others. Using linear regression, significant associations of post-surgery synovial expression levels of 20 genes with the articular cartilage glycosaminoglycan loss were identified. These genes were predominantly related to embryonic skeletal system development and included RUNX2. In conclusion, this study confirmed an increased synovial expression of genes that may serve as targets to prevent cartilage degradation, including MMP1, MMP13, and ADAMTS4, in knees with microscopic synovitis and cartilage proteoglycan loss. Attractive novel targets include regulators of embryonic developmental processes in synovium. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Transcriptional profiling of articular cartilage in a porcine model of early post-traumatic osteoarthritis.

To identify the molecular pathophysiology present in early post-traumatic osteoarthritis (PTOA), the transcriptional profile of articular cartilage and its response to surgical PTOA induction were determined. Thirty six Yucatan minipigs underwent anterior cruciate ligament (ACL) transection and were randomly assigned in equal numbers to no further treatment, reconstruction or ligament repair. Cartilage was harvested at 1 and 4 weeks post-operatively and histology and RNA-sequencing were performed and compared to controls. Microscopic cartilage scores significantly worsened at 1 (p = 0.028) and 4 weeks (p = 0.001) post-surgery relative to controls, but did not differ between untreated, reconstruction or repair groups. Gene expression after ACL reconstruction and ACL transection were similar, with only 0.03% (including SERPINB7 and CR2) and 0.2% of transcripts (including INHBA) differentially expressed at 1 and 4 weeks respectively. COL2A1, COMP, SPARC, CHAD, and EF1ALPHA were the most highly expressed non ribosomal, non mitochondrial genes in the controls and remained abundant after surgery. A total of 1,275 genes were differentially expressed between 1 and 4 weeks post-surgery. With the treatment groups pooled, 682 genes were differentially expressed at both time-points, with the most significant changes observed in MMP1, COCH, POSTN, CYTL1, and PTGFR. This study confirmed the development of a microscopic PTOA stage after ACL surgery in the porcine model. Upregulation of multiple proteases (including MMP1 and ADAMTS4) were found; however, the level of expression remained orders of magnitude below that of extracellular matrix protein-coding genes (including COL2A1 and ACAN). In summary, genes with established roles in PTOA as well as novel targets for specific intervention were identified. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:318-329, 2018.

Maturation of auditory brainstem responses in young children with congenital monaural atresia.

OBJECTIVE: To date, the impact of conductive hearing loss on the auditory pathway at brainstem level has only been investigated in animal studies, which showed a species-specific delay of maturation. In this study, the functional maturation of auditory brainstem response (ABR) parameters in humans with unilateral atresia of the external auditory canal was investigated. METHODS: 42 newborns and toddlers ranging in age from 13 days to 11 months were included. The click-evoked ABR interpeak latencies (IPL) of the atretic ears and the contralateral ears with normal hearing were evaluated. The children had no comorbidities and had never been fitted with any kind of hearing aid. The absolute latencies (AL) and IPL of a matched control group were compared to the contralateral normally hearing ears of the children with unilateral atresia. RESULTS: The mean air-bone gap in the ears with atresia was 44 dB HL. Despite this partial acoustic deprivation, no significant difference between the IPLs of normal ears and ears with atresia could be detected. Both for AL and IPL, the differences between the normal ears and the control group were all within 1 standard deviation to the mean. CONCLUSION: The data showed that the monaural acoustic deprivation by a block of sound conduction does not produce any delay of functional maturation at brainstem level in this group of patients. With regard to the AL and IPL on brainstem level, no differences between the normal ears of children with unilateral atresia and children with bilateral normal hearing could be detected.

Impact of the Vestibular System on the Formation and Progression to Idiopathic Scoliosis: A Review of Literature

The physiopathogenesis of adolescent idiopathic scoliosis remains unknown. However, a multifactorial pathogenesis is being assumed. Besides biomechanical, biochemical, and genetic factors, some studies have focused on congenital or acquired abnormalities in the vestibular organ with consecutive development of scoliosis. This study aims to analyze a possible correlation between any vestibular organ congenital or acquired pathologies and scoliosis based on the current literature. Therefore, we conducted a literature search in three databases, with search terms such as “scoliosis,” “organ of balance,” “idiopathic scoliosis,” “vestibular organ,” “spine,” and “balance.” Fifteen studies were selected and used for research. The relationship between scoliosis and vestibular organ abnormalities was recorded from all included works. Seven studies demonstrated a direct correlation between vestibular organ anatomical abnormalities and the form of the scoliotic spine. Another study confirmed the influence of the pathology of the vestibular organ on scoliosis but questioned whether it had an impact on the formation or the progression of the curvature. Others demonstrated a temporal overlap of the embryonic development of the vestibular organ and the beginning of pre-scoliotic characteristics, but their relationship remained questionable. In three studies, the correlation remained unclear, and any context has been denied. It seems unlikely that an isolated vestibular disorder can trigger structural scoliosis. However, the vestibular system pathologies may certainly occur in the multifactorial genesis of idiopathic scoliosis. Whether the correlation refers to the expression or the progression of scoliosis or may even have an influence on both remains unclear. New treatment options could be derived from these findings with a positive influence on the course of the deformity.

Electrocochleography in children with auditory synaptopathy/neuropathy: diagnostic findings and characteristic parameters.

INTRODUCTION: The early diagnosis of AS/AN in children remains challenging because it exclusively relies on the detection of OAE and/or CM, while ABR are pathologically changed or missing. The aim of our study was to ensure the diagnosis of AS/AN, demarcate it to an outer hair cell damage and possibly differentiate between pre- and postsynaptic pathologies. METHODS: We retrospectively evaluated the transtympanic ECochG results of ten children with AS/AN and compared them to a matched group with SNHL and without any signs of AS/AN. We analyzed the thresholds, latencies and - as a new parameter - the amplitude ratio between CAP and SP. RESULTS: CM and SP thresholds were significantly lower than CAP thresholds in AS/AN patients and significantly lower than SP and CM thresholds in SNHL patients with comparable CAP thresholds. The CAP/SP ratio of amplitudes in SNHL children was more than three times (significantly) higher than in AS/AN children. The cutoff value was set at 1.0 in order to differentiate between both groups with a 80-90% sensitivity and specificity. It was not possible to differentiate between a pre- and postsynaptic type of AS/AN in our collective. SUMMARY AND CONCLUSION: The ECochG can add valuable information for a precise differential diagnosis of AS/AN, especially in babyhood. We identified the CAP/SP ratio as a new parameter for differentiation between AS/AN and SNHL. When the CAP/SP ratio falls below 1.0, patients can be diagnosed AS/AN with high specificity and sensitivity. Significantly smaller SPL are needed to evoke SP and CM in the AS/AN group, thus showing the preserved hair cell function.