Alienness parses BLAST results against public libraries to rapidly identify candidate HGT in any genome of interest. Alienness takes as input the result of a BLAST of a whole proteome of interest against any National Center for Biotechnology Information (NCBI) protein library. The user defines recipient  and donor  branches of interest in the NCBI taxonomy. Based on the best BLAST E-values of candidate donor and recipient taxa, Alienness calculates an Alien Index (AI) for each query protein. An AI > 0 indicates a better hit to candidate donor than recipient taxa and a possible HGT. Higher AI represent higher gap of E-values between candidate donor and recipient and a more likely HGT. We confirmed the accuracy of Alienness on phylogenetically confirmed HGT of non-metazoan origin in plant-parasitic nematodes. Alienness scans whole proteomes to rapidly identify possible HGT in any species of interest and thus fosters exploration of HGT more easily and largely across the tree of life.Horizontal gene transfer (HGT) is the transmission of genes between organisms by other means than parental to offspring inheritance. While it is prevalent in prokaryotes, HGT is less frequent in eukaryotes and particularly in Metazoa. Here, we propose Alienness, a taxonomy-aware web application available at  Horizontal gene transfer (HGT), is the transmission of genes between organisms by other way than direct  inheritance from parental lineages to their offspring. HGT is prevalent in prokaryotes , with suThese HGT challenge the view of a purely tree-like backbone underlying inheritance of genetic information across species . With thTwo classical ways to identify candidate HGT are (i) to study the intrinsic  and/or (ii) the extrinsic  is calculated to measure a difference of magnitude between the best non-metazoan and best metazoan E-value. If the best non-metazoan E-value is closer to 0 than the best metazoan E-value, the AI will be positive, if the AI is ≥45, it has been assumed that an HGT event is very likely. This AI method was used again to assess the total contribution of genes of non-metazoan origin in the whole genome of the bdelloid rotifer once it was sequenced [Globodera rostochiensis [Nacobbus aberrans [Xiphinema index [Methods in the extrinsic category do not suffer from undistinguishable GC content and codon usage as they rely only in a difference of magnitude in the BLAST or other similarity metrics between closely related and distant taxa. These methods are better suited to identify HGT between distant species  and require an as comprehensive as possible reference sequence library covering a diversity of species. One such method in the extrinsic category is the Alien Index metrics. It was first introduced by Gladyshev et al.  to identequenced . Using cchiensis , in the chiensis  as well aberrans , Xiphinema index  and othema index . It was ma index  and in sma index ,25,26. Ih), has been proposed [Adineta ricciae [To circumvent this difficulty of retrieving taxonomic information, it is tempting to divide the NCBI’s non-redundant protein library (NR) or other sequence libraries into taxonomic subsets  candidate donors). This approach has been implemented in a Perl software named alien_index . Howeverproposed . The priproposed ). Howeve ricciae  and late ricciae .A refined scoring method has been recently proposed that not only takes into account sequence similarity between receiver and candidate donors, measured in BLAST bit score, but also taxonomic distance measured as the number of step in the NCBI’s taxonomic lineage to reach the common ancestor of the query and subject species . The sofSimilarly, a method called DarkHorse and initially developed to identify HGT in bacteria is available as a software that can be downloaded and installed locally . This mePhylogenetic methods that compare a gene or protein tree to a reference species tree and identify inconsistencies are the gold standard to predict HGT. While such methods exist ,33,34,35As far as we know, there is currently no publicly available web tool that allows to easily and rapidly identify HGT from large datasets directly from a BLAST result.http://alienness.sophia.inra.fr. Alienness requires nothing else than BLAST results against any sequence library at the NCBI and a few parameters to calculate AI for a set of query sequences . Alienness can be applied to any genome of interest and to identify candidate HGT from any donor to any recipient taxonomic group.Here, we propose Alienness, a user-friendly web application that requires no installation of any software and that is publicly accessible at We tested the accuracy of Alienness on the genomes of two plant-parasitic nematodes, for which phylogenetically supported HGT of a whole series of genes involved in plant parasitism had been previously identified ,38. We fWe believe Alienness will promote a more rapid exploration of candidate HGT across the tree of life and will contribute to assessing more globally the evolutionary significance of HGT.Typically, Alienness takes as input a compressed BLAST result (in .zip or .gz format) of a proteome performed against any NCBI protein database . Currentftp://ftp.ncbi.nlm.nih.gov/pub/taxonomy/). This repository contains the full taxonomy database along with flat files associating nucleotide and protein sequence records with their TaxIDs. The challenge lies in reconstructing the taxonomic lineage of species just from GenBank identifier (GI) extracted from BLAST results. To perform this taxonomic identification, we use the files ‘gi_taxid_prot.dmp.gz’ and ‘taxdump.tar.gz’, both available for download at ftp://ftp.ncbi.nlm.nih.gov/pub/taxonomy/. The first file provides, for each GI of protein record, its corresponding TaxID) The second file contains NCBI Taxonomy database dump files, and more precisely nodes.dmp and names.dmp files. Alienness retrieves the parent node ID of each node ID in GenBank taxonomy database from nodes.dmp file and associates a name for each of them using names.dmp file. Thus, Alienness re-builds the lineage of species based on the GI accessions.The taxonomic assignment of BLAST hit sequences is performed using the taxonomic databases available on the NCBI FTP site  taxonomic groups.−3 and no filtering for low complexity regions. Based on the BLAST hits GI accession numbers and on the NCBI taxonomy, Alienness extracts the best metazoan and best non-metazoan E-values to calculate an AI, first defined in [Typically, Alienness takes as input the result of a BLASTp search of a whole set of predicted proteins of interest  against the NCBI’s NR library or any protein library available at NCBI. The BLAST result must be in tabular format and when performed against NR, we recommend using an E-value threshold of 1Efined in , with thWhen either no metazoan or non-metazoan significant BLAST hit is found, a penalty E-value of 1 is automatically assigned as the best metazoan or non-metazoan E-value, respectively. Hence, E-values of the best metazoan and non-metazoan hits vary between 0 and 1 and, consequently AI scores vary between −460.5 and 460.5. An AI > 0 indicates a better hit to a non-metazoan species than to a metazoan species and possible acquisition via HGT of non-metazoan origin. However, if the difference of magnitude between the best metazoan and non-metazoan E-values is low, this difference might not be significant and could just reflect a slight difference in the ranking of the best hits. For instance, a highly conserved protein between metazoan and non-metazoan species could by chance return a better hit to non-metazoan than metazoan. In the original publication of AI calculation, Gladyshev et al.  estimatehttp://alienness.sophia.inra.fr and does not require creation of an account or downloading any software. Alienness just requires a pre-computed BLAST result in tabular format (-outfmt 7) against a protein library. The BLAST result file must be compressed in .gz or .zip format. The protein library must have GI or accession numbers that exist in the NCBI taxonomy database to retrieve the taxonomic information necessary to calculate AI values . For a better coverage of the biodiversity, we recommend using the NCBI’s NR library. The Alienness web portal has been developed in HTML5 and CSS3 and launches a series of Perl programs via a CGI Perl module. Alienness is publicly and freely available at this URL: To run an Alienness analysis, click the ‘Alienness Tool’ tab and the following form will appear .Fill the following information . For instance, if you are interested in HGT of non-metazoan origin to a metazoan species, please input 33208 (NCBI TaxID for Metazoa) as recipient. If you are interested in HGT of non-green plant origin to a green plant species, please input 33090 (NCBI TaxID for Viridiplantae). This is valid for any TaxID and this information is necessary to retrieve the best ‘TaxID of recipient’ E-value and best ‘TaxID of candidate donor’ E-value for calculation of an Alien index.Mus musculus and you are looking for HGT of non-metazoan origin. Most of the best BLAST hits  will be self-hits of M. musculus against itself. Hence, there is no chance to identify a M. musculus protein that would return a better hit to a non-metazoan than to a metazoan species. It is thus necessary to ignore all self-hits to M. musculus for the calculation of AI values. In this case, you have to input 10090 (NCBI TaxID for M. musculus). If you suspect that some HGT may have arisen earlier, in an ancestor of the rodents, for instance, then you have to input 9989 (TaxID for Rodentia). This will ignore all BLAST hits to Rodentia. Note that you can input several TaxIDs separated by comma and no space in this field if you want to ignore several non-overlapping taxonomic groups. This is useful if there is no monophyletic group in the NCBI taxonomy corresponding to the ensemble of species you want to ignore. Because Alienness is fast, you can also run it several times with different ignored TaxIDs and check the effect of this parameter on the number of candidate HGT identified .Enter the NCBI TaxIDs  for the taxonomic groups you want to ignore in the calculation of the AI. You must at least input the TaxID of the query species you used to produce the BLAST result. For instance, imagine that your query proteome is from This field is optional and does not affect calculation of AI scores. This field controls the classification of the best BLAST hits in taxonomic categories in the output files. If left blank, the best hits are classified in the NCBI taxonomy basal categories Archaea, Bacteria, Eukaryota, Viroids and Viruses (the NCBI categories ‘Other’ and ‘Unclassified’ are ignored as they cannot be assigned to a species). If a user wants to further classify the best hits in other categories any additional TaxID can be entered. For instance, if you want to further categorize the Eukaryota into Fungi, Stramenopiles and Viridiplantae, you have to input 4751, 33634 and 33090 (separated by comma and no space).Input your e-mail address. Please double check that your e-mail is correct because the link to download the results will be sent to this address.Then click the submit button and wait for your compressed BLAST results to be uploaded to the server (do not refresh the page). Once the compressed BLAST result file is uploaded, a page will open and notify that the upload was successful and that you will receive two automatic e-mails. A first e-mail confirming the submission with a summary of the parameters selected by the user. A second one, a few minutes later, indicating that the job is finished and providing a summary of your job and a link to download a .zip archive with the results.So far, we have run a dozen of eukaryotic whole proteomes with Alienness, and on average, the whole process from retrieval of taxonomic information to calculation of AI scores and production of result files takes 10–15 min (excluding upload time for the compressed BLAST results).Project_name_HGT_ai_full.csv: table presenting AI values and taxonomic information for all the proteins that returned an AI value.Project_name_HGT_ai_junk.csv: all the proteins that have an AI ≤ 0 and are thus probably not originated by HGT.Project_name_HGT_ai_likely_contamination.csv: proteins with an AI > 0 and ≥70% identity to a protein from candidate donors .Project_name_HGT_ai_likely_contamination_stat.csv: statistics on the taxonomic distribution (species and kingdoms) of candidate donors for the possible contamination category.Project_name_HGT_ai_possible.csv: proteins with an AI > 0 and <70% identity to candidate donors constitute the pool of possible HGT.Project_name_HGT_ai_possible_stat.csv: statistics on the taxonomic distribution (species and kingdoms) of candidate donors for the possible HGT category.Project_name_HGT_ai_very_likely.csv: proteins with an AI > 30 and <70% identity to candidate donors constitute the pool of very likely HGT.Project_name_HGT_ai_very_likely_stat.csv: statistics on the taxonomic distribution (species and kingdoms) of candidate donors for the very likely HGT category.Project_name_HGT_blastp_no_hits.csv: proteins for which no AI could be calculated because they returned no significant BLAST hits.Project_name_index.html: an html file that allows visually exploring the BLAST results with a color code.Project_name_summary.txt: log file providing information on execution time, parameters selected by the user, etc.Once you download and uncompress the .zip result archive via the link in the automatic e-mail (Alienness_jobnumber.zip), the following result files will be available:Meloidogyne incognita [Note that the files Project_name_HGT_ai_full.csv, Project_name_HGT_ai_junk.csv, Project_name_HGT_ai_likely_contamination.csv, Project_name_HGT_ai_possible_stat.csv and Project_name_HGT_ai_very_likely.csv all have the same template (“Project_name” is substituted by the user-defined name set in the Alienness field number 2 in ncognita  (SupplemColumn 1 (AI): the Alien IndexColumn 2 (query hits number): the number of hits returned by the protein in consideration.Column 3 (query name): the query accession number.Columns 4–8: the best E-values for the basal NCBI taxonomy categories Archaea, Bacteria, Eukaryota, Viroids and Viruses. When the best E-value does not belong to the taxonomic category in consideration, a “-” character is present.Columns 9–10 : the best E-values for the user-defined additional taxonomic categories (field 5 of the form in M. incognita).Column 11: the best E-value for the user-defined taxonomic group of interest (recipient group). In this example, the group of interest is Metazoa as we are interested in candidate HGT of non-metazoan origin in a metazoan species (the root-knot nematode Column 12 (best hit GI) *: the NCBI GI accession of the best BLAST hit.Column 13 (best hit prct ident) *: the percent identity between the query sequence and the best hit.Column 14 (best hit org nickname) *: an abbreviated species name for the best hit.Column 15 (best hit org full name) *: full species name of the best hitColumn 16 (best hit taxo group) *: abbreviated taxonomic classification of the best hit.Column 17 (best hit taxid) *: NCBI TaxID of the best hit.Column 18 (best hit lineage): full taxonomic lineage for the best hit.* Note that hits to the user-defined excluded taxonomic groups . The first column contains names of kingdom or taxa and the second the occurrence of these taxa in the set of candidate donors or possible contaminants.The file “Project_name_index.html” allows exploring the BLAST results of interest regarding candidate HGT and candidate contaminants. By opening this file in a web browser, the following page will open .M. incognita protein  very likely HGT (AI > 30 and <70% identity to candidate donor); (ii) possible HGT (AI > 0 and <70% identity to candidate donor) and (iii) likely contamination (AI > 0 and ≥70% identity to candidate donor). For each category, a list of accession numbers from the query proteome as well as the AI value and the taxonomic category of the candidate donor are indicated. By clicking on any of these accession numbers, a color-coded BLAST result in .html format opens and allows exploring the results in more details. An example on a d by HGT ) is giveCellulophaga algicola with an E-value of 8E−81 The best hit that belongs to the taxonomic group of interest  and red (here best metazoan) E-values that are used to calculate the AI. Hits for which a taxonomic group could not be assigned are highlighted in light violet. This corresponds to protein that have either been removed from the NCBI or replaced by another protein with a different accession number. Hits that belong to the categories ‘other’ and ‘unclassified’ are highlighted in light grey. Note that no color code is given after the best green and best red taxonomic groups have been identified because these are necessary and sufficient to calculate an AI.In the BLAST result, the color code is as follows: hits that belong to the taxonomic group(s) to exclude are highlighted in blue. In this example, we chose to exclude the Tylenchida (TaxID: 6300) that include the root-knot nematodes and many other related plant-parasitic nematodes. The best ‘alien’ hit is indicated in green. In this example, we were interested in HGT of non-metazoan origin in a metazoan, so the alien taxon is anything but Metazoa. Here, the best alien taxon is from the bacterium M. incognita proteome [Meloidogyne proteins having no clear ortholog in Metazoa via an OrthoMCL analysis [M. incognita proteins for which an AI value could be calculated by Alienness and an automatic phylogenetic tree was previously reconstructed  on the 2008 version of the proteome . Some ofproteome . Brieflyanalysis . We usedanalysis  and thenanalysis . We idenstructed . To estistructed  for diff6 between the best non-metazoan and best metazoan hits. At this threshold, 34% and 17% of the A + B and A trees, respectively are still retrieved. At an AI threshold >26, only A + B phylogenetically supported proteins remain, the A-only supported cases are eliminated.At an AI value > −10 we recall 83% and 93% of HGT cases supported by automatic phylogenies with A + B and A support, respectively. However, at this AI value, 64% of the proteins that returned phylogenies without support for HGT are also retrieved. Note that the AI cut-off as to be set to >−37 to retrieve all phylogenetically supported proteins, but at this threshold, 93% of the proteins returning trees without support for HGT are also retrieved. At an E-value > 0; 63% of the HGT proteins with A + B phylogenetic support are retrieved and 68% of those with A support only. However, at this threshold, 21% of the proteins returning trees without support for HGT are also retrieved. From an AI threshold of >14, all proteins returning trees not supporting HGT are eliminated. An AI > 14 corresponds to a difference of magnitude >1ETo further measure the ability of Alienness to recall highly supported candidate HGT, we tested whether previously reported cases of HGT, supported by meticulous manual phylogenetic analysis were found by Alienness. From a survey of the literature, we identified 23 cases of HGT in plant-parasitic nematodes supported by manual phylogenetic analysis .M. incognita [G. rostochiensis [M. incognita and G. rostochiensis, respectively. We reported the AI scores for the proteins corresponding to these HGT cases  applicable to large datasets of thousands of genes. In this perspective, Alienness provides an efficient metrics to quickly reduce the number of candidates that can be further analyzed via phylogenetic analysis. For instance, in the case of the plant-parasitic nematodes 20,359 and 14,309 proteins were present in the predicted proteome of Alienness also provides a list of putative contaminants that can be useful for the user to prune the original dataset or even to identify possible endosymbiont. Any protein with an AI > 0 and ≥70% identity is put apart in a category of possible contaminants. In a recent paper, Ku and Martin  defined Although Alienness provides rapid identification of candidate HGT, some limitations should be kept in mind while interpreting the results. First, as discussed in the previous section, Alienness just predicts candidate HGT that ideally need to be further supported by additional sourced of evidence. Second, the ability to detect candidate HGT depends on the quality and coverage of the queried sequence library. Both the accuracy of the taxonomic assignment and the diversity of taxa covered by the reference library influence the calculation of AI or any other method based on BLAST hits. Third, because BLAST E-values and bit scores also depend on the length of the query protein and matching hits, metrics such as AI and HGT Index will necessarily return lower scores for short sequences as the difference of E-value or bit score between the best donor and recipient organisms will have less difference in magnitude.Overall, Alienness provides a fast and reliable service to rapidly detect candidate HGT in any genome of interest from any donor group. Although HGT is recognized as an evolutionary important and prevalent mechanism in prokaryotes, its importance and prevalence in eukaryotes remain actively debated and can be controversial . Explori


To assess the static and dynamic balance performance of students with normal hearing and with sensorineural hearing loss. A cross-sectional study assessing 96 students, 48 with normal hearing and 48 with sensorineural hearing loss of both sexes, aged 7 and 18 years. To evaluate static balance, Romberg, Romberg-Barré and Fournier tests were used; and for the dynamic balance, we applied the Unterberger test. Hearing loss students showed more changes in static and dynamic balance as compared to normal hearing, in all tests used (p<0.001). The same difference was found when subjects were grouped by sex. For females, Romberg, Romberg-Barré, Fournier and Unterberger test p values were, respectively, p=0.004, p<0.001, p<0.001 and p=0.023; for males, the p values were p=0.009, p<0.001, p<0.001 and p=0.002, respectively. The same difference was observed when students were classified by age. For 7 to 10 years old students, the p values for Romberg, Romberg-Barré and Fournier tests were, respectively, p=0.007, p<0.001 and p=0.001; for those aged 11 and 14 years, the p values for Romberg, Romberg-Barré, Fournier and Unterberger tests were p=0.002, p<0.001, p<0.001 and p=0.015, respectively; and for those aged 15 and 18 years, the p values for Romberg-Barré, Fournier and Unterberger tests were, respectively, p=0.037, p<0.001 and p=0.037. Hearing-loss students showed more changes in static and dynamic balance comparing to normal hearing of same sex and age groups. In static balance, the base of support remains fixed while the center of gravity moves. In this case, the sense of balance maintains the center of gravity within the base of support defined by the feet. Whereas, in dynamic balance, both the center of gravity and the base of support are in constant motion, and the center of gravity never aligns itself to the base of support during the stance phase of the movement.Body balance consists of maintaining the center of gravity within the base of support defined by the feet, and it may be static or dynamic.1 In s The vestibulo-cochlear system has a dual function — the cochlea is responsible for the auditory function, and the vestibular system is responsible for body balance. However, hearing ability is actually a secondary feature, because the primary function of the auditory organ is to maintain body balance.To maintain human body balance, anatomical and functional integrity of the vestibular system, located in the inner ear, is essential.3 The  As the vestibular system and the cochlea are anatomically very close to each other and may be vulnerable to the same harmful agents, children with internal ear injuries may present vestibular problems concomitant with sensorineural hearing loss.(-) Furthermore, several studies indicate that vestibular dysfunction is a frequent finding in the otoneurological evaluation of children with sensorineural hearing loss.However, when the vestibular system presents some type of disorder, body balance can be affected, as in some individuals with sensorineural hearing loss.6 As tVestibular disorders in childhood are not as rare as believed and may affect the acquisition of neuromotor skills, or interfere mainly in the sensory integration of the vestibular system. Children with vestibular disorders may report imbalance, dizziness, gait disorders and present with other manifestations, such as falls, dizziness, vertigo and frequent bumping into people/objects, which hinder the acquisition of motor skills typical of their age, such as riding a bicycle, skipping rope, playing “hopscotch” or even using playground toys.12 This condition may favor body balance changes in this population. In spite of these evidences, there are scarce data in the literature on balance in children with sensorineural hearing loss compared to normal-hearing children, particularly in relation to reporting the dynamic balance performance, which justifies the present study.In view of the above, children with sensorineural hearing loss appear to present alterations in sensory information provided by the vestibular system, possibly due to internal ear injury.13 ThiTo evaluate static and dynamic balance performance in normal-hearing students compared to children with sensorineural hearing loss.This is a cross-sectional study, in which a previous survey was carried out with the manager of a school dedicated to the education of children with special needs to delimit determine the sample size, to find out how many students with sensorineural hearing loss were enrolled in the age range covered by the study, and which of them fit the eligibility criteria. Normal hearing students were recruited from another educational institution. Both schools belonged to the state education network, had similar socioeconomic profiles, and were located in the city of Caruaru (PE).There was a predominance of female students and some age groups, which made it difficult to enlarge the study sample. Matching was possible for 48 students, by sex and age group. Thus, 96 students participated in this study, of which 48 in the Normal Hearing Group (NHG) and 48 in the Sensorineural Hearing Loss Group (SHLG), of both sexes, aged between 7 and 18 years.The students were recruited by sequential convenience sampling, matched by sex and age group, and selected by draws made by their teachers, who were not aware of the characteristics of this study. The draws took place in the classroom, in front of all the students and researchers of the study.The NHG was composed of 48 students, 24 male and 24 female, with two representatives of both sexes for each age group. The exclusion criteria adopted for this group were presence of neurological, physical, visual or mental deficiency, hearing complaint, and leg length discrepancy greater than 2cm, by actual measurement and apparent measurement of lower limbs.The SHLG comprised 48 students with sensorineural hearing loss, 24 male and 24 female, with two representatives of both sexes in each age group. The exclusion criteria for this group were presence of neurological, physical, visual or mental deficiency, and leg length discrepancy greater than 2cm, by actual measurement and apparent measurement of lower limbs conducted previously by the evaluators in each group. Other inclusion criteria for the SHLG were having received a clinical diagnosis of sensorineural hearing loss, issued by means of a medical report, and mastering the Brazilian Language of Signals (LIBRAS). This last criterion was employed to ensure that the commands related to the demands of the method would really be understood by all students with hearing loss. All students had access to learning LIBRAS in their school.The inclusion criteria for both groups were: to be regularly enrolled in one of the schools collaborating with the research and to be in the age group between 7 and 18 years.The information for the eligibility criteria of this study was obtained from the parents of the students, in interviews with the researchers; from the students’ school records, furnished by the school manager; and in the physical evaluation performed prior to the balance performance assessment.The procedures that preceded the static and dynamic balance evaluation were previously explained and demonstrated by the researchers to the normal hearing students, orally, and to the students with hearing loss, using LIBRAS, by one of the researchers who is an interpreter of this language.In both groups, the students were evaluated one by one by the same physical therapist in a reserved room of the school, using four clinical tests to detect changes in static and dynamic balance. To evaluate static balance, the Romberg, Romberg-Barré and Fournier tests were used, and the Unterberger test was used to evaluate dynamic balance. the volunteer remained standing up, barefoot, with the feet together in parallel position, the arms along the body, with the eyes closed, for one minute.In the Romberg test,14 the was performed similarly to the Romberg test, but with one foot directly in front of the other on the ground, in a straight line.The Romberg-Barré test14 wasA loss of balance and the inability to maintain the initial position of the test characterized a change in static balance for Romberg test and Romberg-Barré test. the volunteer remained standing up, barefoot, with unipodal support, standing up on the dominant leg, with the eyes closed, for 30 seconds. According to the test, those who could not remain in unipodal support during the established time were classified as having a change in static balance.In the Fournier test,14 the the students marched in place with their eyes closed, raising their knees up to approximately 45° and their hips up to 90°, performing 50 steps (one per second) with their arms extended in front of them at 90°. The volunteers who showed a right or left rotation equal or superior to 45° were classified as having a change in dynamic balance.In the Unterberger test,14 theStatic and dynamic balance data were recorded in a standardized card, containing the student’s identification, age, grade, school, lateral dominance and performance in all tests.2 test or Fisher’s exact test. The statistical significance level was set at p<0.05, and the Statistical Package for the Social Sciences (SPSS), version 18.0, was used to perform the statistical analysis of these data.Data were analyzed by Pearson’s χHospital da Restauração, according to the final protocol number CAAE: 1700.0.000.102-11, as provided by Resolution 466/12 of the National Health Council.This study was evaluated and approved by the Research Ethics Committee of the The present study evaluated static and dynamic balance in 48 normal hearing students and 48 students with sensorineural hearing loss, with mean age of 12.5±3.5 years in each group, as shown in Students with hearing loss showed greater occurrence of static and dynamic balance alterations than normal hearing children, with statistical differences in all the tests used, as shown in The same difference was observed when the students were grouped by sex . The samIn the present study, we observed differences between static and dynamic balances in the students evaluated, and the SHLG showed greater occurrence of alterations in this motor skill than the NHG. evaluated static balance in 60 children, 30 of whom were normal hearing children and 30 were children with sensorineural hearing loss, in the age group of 6 to 9 years, using six balance tests of the Bruininks-Oseretsky Test of Motor Proficiency, and found differences in static balance performance among the groups. Children with hearing loss also had poorer balance than normal hearing children.Likewise, Jafari et al.,15 eva analyzed static balance in 114 students, of which 57 were normal hearing children and 57 were children with sensorineural hearing loss, aged 4 to 14 years, using the unipodal support test. They concluded that children with hearing loss presented more static balance instability than normal hearing children, as we also observed in this study.An et al.,16 anaIn addition to the changes observed in the SHLG, related to static balance, in this study we also observed changes in dynamic balance performance. The SHLG presented more changes in dynamic balance than normal hearing children, taking into consideration the variables sex and age group 11 and 18 years. evaluated dynamic balance in 40 children, of which 20 were normal hearing children and 20 were children with sensorineural hearing loss, of both sexes and with a mean age of 12.3±5.6 years. In their study, children with hearing loss showed lower dynamic balance performance than normal hearing children, a fact also observed by the present study.Gayle et al.,17 evaThe scarcity of data on dynamic balance performance of children with sensorineural hearing loss made it difficult to discuss this finding, but results from other studies reinforce the findings of the present study, regarding dynamic balance in children and adolescents with sensorineural hearing loss. compared body balance and gait in students with hearing loss of both sexes, between 7 and 17 years. The authors did not find body balance differences in the evaluated students, unlike the findings of this study. However, differences were observed in gait performance, whose tests were conducted in dynamic situations. The authors believe that children with hearing loss cannot create posture strategies to circumvent the test when performed in dynamic situations, which could justify the findings of this study concerning changes in dynamic balance.Melo et al.,18 com evaluated the gait of 20 normal hearing children with mean age of 12.2±2.5 years and 20 children with hearing loss and mean age of 9.25±0.9 years. The gait evaluation was done by spraying the children’s feet and instructing them to walk across a dark platform in a straight line. By demarcating the children’s steps on the platform, the authors evaluated the length and width of the steps, the angle of the feet, the number of steps per minute, and the speed of the gait. In all these outcomes, children with hearing loss showed lower performance than normal hearing children, agreeing with the findings of this study.Likewise, Atasavun Uysal et al.,19 evaThe changes in static and dynamic balance found in students with hearing loss in this study may, if not treated, negatively influence the performance of motor skills that depend on an adequate body balance to be performed satisfactorily, such as walking, running and jumping, and this may interfere with the physical fitness and recreational and/or sports practices of these children. evaluated the sports participation of 42 children with hearing loss, and reported that they had greater limitation in manual dexterity (62%), ball skills (52%), and balance skills (45%). The authors believed that improving these motor skills, early in childhood, could contribute in a positive way in the school context and in the sports and social practices of these children.In this context, Hartman et al.,20 evaIn addition to the data obtained in the groups alone, some variables were also analyzed in this study, and one of the most relevant findings was observed in the variable age group. An extensive age group was employed to assess body balance performance in adolescence, given the scarce data in the literature. There was an improvement in body balance, in view of a lower frequency of body balance changes in older age groups, although differences among groups remained. This suggests that interventions in this population should be conducted not only in childhood but also in adolescence, and this may be incorporated into the school environment. who evaluated and compared body balance in healthy adolescents according to sex and observed that females had better body balance stability than males. In addition, the girls in this study were more focused on the tests than the boys, who showed more anxiety while performing the tests, which may justify the findings related to the variable sex in this study.The groups presented differences for both sexes. However, boys presented more changes in body balance than girls, corroborating the findings of Dorneles et al.,21 whoConsidering the above, this study identified static and dynamic balance changes in students with sensorineural hearing loss compared to normal hearing children of the same sex and age group. We suggest that such changes may occur due to an inadequate sensory organization in these children, due to the possible involvement of the vestibular system, caused by inner ear injury. reported that children with severe and profound hearing loss often had vestibular system hypoactivity. Similarly, Lavinsky described children with profound hearing loss and high prevalence of vestibular dysfunction in their study. These data could justify the findings of this study, considering that 91.7% of children with hearing loss in this study had severe and profound hearing loss. Other researches also reported that vestibular dysfunction is a frequent finding in otoneurological evaluations of children with sensorineural hearing loss.(-)Supporting this hypothesis, Guilder et al.,22 repIt is worth noting that the evaluation of the vestibular function was not performed in the hearing-loss students in this study, because a computerized vectoelectronystagmography is a high cost exam and is not available in the public health system of the city where the study was carried out, besides the fact that this project had no funding. This was, therefore, a limitation for any conclusions on the vestibular involvement in children and adolescents with hearing loss in this study.However, it is believed that every child with a clinical diagnosis of sensorineural hearing loss should undergo vestibular testing regardless of age and sex, and even in the absence of dizziness or vertigo.27Given the importance of examining the vestibular function, we suggest that future studies make this association between static and dynamic balance performance in children with hearing loss, with and without associated vestibular dysfunction, in order to identify the real influence of each of these systems (auditory and vestibular) in the balance performance of this population.One of the major contributions of this study was to provide data on dynamic balance performance of children and, especially, adolescents with hearing loss compared to normal hearing children, given the scarce data in the literature. In addition, it presented a homogeneous sample, which was pair-matched and much more representative than the study samples found in the literature.According to the findings of this study, students with sensorineural hearing loss presented more static and dynamic balance alterations than normal hearing students of the same sex and age group.This may be related to the involvement of the vestibular system due to inner ear injury. These changes may arise since early childhood, stressing the importance of raising awareness among health professionals and, above all, among hearing health and neuromotor development specialists, such as otolaryngologists , audiologists and speech therapists, and pediatricians, so that these professionals have a more general approach to children with hearing loss and exchange information, focusing not only on the hearing aspect, but also on the children’s neuromotor development and performance, in view of the observed alterations, which are often unknown by many of these professionals.Therefore, we stress the need of preventive programs in students health that reinforce the practice of specific physical exercises, with neuromotor evaluations of body balance and motor skills, in a periodic way, as well as early specific interventions, if necessary.All these tasks are physical therapy responsibilities, reflecting the importance of the physicalotherapist in the school environment. These interventions could be incorporated into the school daily routine, in institutions that serve this population and in multiprofessional teams, seeking to adapt and/or improve body balance, motor performance and quality of life of children and adolescents with sensorineural hearing loss.Students with sensorineural hearing loss had a higher occurrence of changes in static and dynamic balance than normal hearing students of the same sex and age group.


Hearing and touch represent two distinct sensory systems that both rely on the transformation of mechanical force into electrical signals. Here we used a battery of quantitative sensory tests to probe touch, thermal and pain sensitivity in a young control population (14–20 years old) compared to age-matched individuals with congenital hearing loss. Sensory testing was performed on the dominant hand of 111 individuals with normal hearing and 36 with congenital hearing loss. Subjects with congenital deafness were characterized by significantly higher vibration detection thresholds at 10 Hz  and 125 Hz (P < 0.05) compared to controls. These sensory changes were not accompanied by any major change in measures of pain perception. We also observed a highly significant reduction (30% compared to controls p < 0.001) in the ability of hearing impaired individual’s ability to detect cooling which was not accompanied by changes in warm detection. At least 60% of children with non-syndromic hearing loss showed very significant loss of vibration detection ability (at 10 Hz) compared to age-matched controls. We thus propose that many pathogenic mutations that cause childhood onset deafness may also play a role in the development or functional maintenance of somatic mechanoreceptors. Psychophysical testing reveals that human performance in specific sensory tasks is in part determined by the sensitivity of the sensory receptors activated by the stimulus7. The skin is equipped with a wide variety of mechanoreceptors and nociceptors that are tuned to respond optimally to different qualities of mechanical or thermal stimuli10. Using a classical twin study approach we and others have shown that human sensory performance is in large part genetically determined12. Thus in healthy subjects up to 67% of the variation in vibration detection threshold sensitivity measured for a 125 Hz stimulus could be shown to be due to genetic factors12. Similarly high heritability was also found for cold and warm detection thresholds12. Quantitative sensory testing for pain modalities like heat pain threshold, acid induced pain and hyperalgesia have also been shown to exhibit high levels of heritability11. It is well known that single gene defects can, in rare cases, lead to a complete loss of pain sensation in man14. More recently, it has been shown that single gene defects are also associated with loss and gain of function in human touch sensation18. For both pain and touch it is striking that mechanistic studies have revealed that often the genes associated with human sensory disorders code for ion channels involved in the transduction and transformation of sensory information at the peripheral endings of specific sensory neurons21. It is clear that there are probably still many genes and gene variants that influence somatosensory performance whether the stimuli are tactile, thermal or painful.The ability of humans to perceive different modalities of cutaneous sensory stimuli can be accurately assessed using quantitative sensory testing. Indeed, quantitative sensory testing is an integral part of the clinical examination in patients with sensory disorders including pain22. We have shown previously that there are likely common genetic factors that influence hearing and touch12. Thus measurements of vibration detection thresholds and tactile acuity showed a correlation with hearing sensitivity and acuity12. In addition, children with congenital hearing impairment performed on average worse than controls with higher vibration detection thresholds and poorer tactile acuity12. In our previous study we did not make any measurements of pain sensitivity in hearing impaired children. Vibration detection thresholds in humans are known to be dependent on the frequency of the vibrotactile stimulus15. In most studies a high frequency vibration is used (125 Hz) a stimulus that primarily probes sensations initiated by specialized rapidly-adapting mechanoreceptors that innervate Pacinian corpuscles23. In this study we also wished to probe tactile sensation mediated by mechanoreceptors that are selectively activated by low frequency vibration. Such receptors include rapidly-adapting mechanoreceptors innervating Meissner’s corpuscles in the glabrous skin, hair follicle afferents and slowly-adapting mechanoreceptors innervating Merkel cells15. Here we have used a broad battery of quantitative sensory tests, to probe variation in tactile, thermal and pain sensitivity in a highly homogenous population of adolescents (14–20 years old)  and 39 hearing impaired participants, aged between 14 and 20 years, underwent quantitative sensory testing. Data obtained from 14 healthy participants were excluded due to incomplete testing , technical problems, or due to inconsistencies (e.g. high performance variability) during testing. Three of 39 hearing impaired subjects were excluded; one due to insufficient information on the probable cause of the hearing impairment and the other two due to a non-genetic origin of the hearing deficit. Therefore, data obtained from 111 healthy subjects  and 36 hearing impaired subjects  were included in the study. Thirty-one subjects from the hearing impaired cohort had non-syndromic hearing loss, 4 had Usher’s syndrome (3 with type 2 and one with type 1), and one Alport syndrome . One hearing impaired subject had coeliac disease. Nine subjects had cochlear implants and 27 used hearing aids for moderate to severe hearing loss. Seven subjects had a positive family history of hearing loss. One hearing impaired subject reported difficulties perceiving wetness.24. We controlled for age by selecting a young adolescent population with a narrow age range. Gender was controlled for by balancing the proportion of males to females in both groups. Comparison of psychophysical parameters between males and females in the control cohort revealed statistically significant differences in vibration detection thresholds (VDT) at 10 Hz but not at 125 Hz; mean VDT  for females 3.68 ± 1.48 versus 4.28 ± 1.57 in males  = 4.2, P = 0.04). Mechanical detection thresholds (MDT) were also significantly lower in female subjects compared to males  = 16.2, P = 0.0001). Finally, warming detection thresholds were lower in control females  = 4.7, P = 0.03). There were no significant differences in performance between the two sexes for any of the other test parameters  = 68, P < 0.0001)  = 2.7, P = 0.09). Nevertheless, there was a small subset of hearing impaired individuals with z-scores less than −1.96 indicating loss of function for this test  = 4.5, P = 0.03), but not large; the mean VDT was increased in hearing impaired individuals by ~25%  below −1.96 . The difference in VDT at 125 Hz between hearing impaired and control individuals was also statistically significant  = 16.5, P < 0.0001). Post hoc Tukey tests revealed that the loss of cold detection was significant for hearing impaired male and females compared to controls . Examination of the distribution of z-scores for cold detection appeared to show two broad sub-groups: one group with z-values shifted to the loss-of-function direction and the other group with z scores around the control mean.Thermal detection thresholds for warming and cooling were also measured and we noted a strong and robust loss of function for cooling but not warm detection in the hearing impaired cohort Table , Fig. 4. = 4.7, P = 0.03). Four hearing impaired individuals had very low heat pain thresholds with z-scores that were above 1.96  had vibration detection thresholds that were more than two standard deviations higher than the control mean (z-score > −1.96), and subjects with similarly impaired vibration detection thresholds at 125 Hz, but not at 10 Hz appeared to represent an additional population (4/36) thus at least 22/36 (61%) of hearing impaired subjects exhibit a severe vibration detection deficit. Thus distinct patient groups were found with deficits in vibration detection threshold at 125 Hz and 10 Hz, respectively. This finding strongly suggests that the underlying pathophysiology is specific for the function or connectivity of distinct sets of mechanoreceptors. Thus it is known that a 10 Hz vibration is primarily detected by rapidly-adapting Meissner’s corpuscle receptors and slowly-adapting Merkel cell mechanoreceptors26. In contrast, the detection of high frequency vibration of 125 Hz primarily requires rapidly-adapting mechanoreceptors that innervate Pacinian corpuscles18. In this study we asked whether sensory deficits in subjects with hearing impairments extend to pain. We used a standardized testing protocol that included several elements of the QST of the German Research Network on Neuropathic Pain (DFNS)2. We found no clear deficits in pain sensitivity amongst hearing impaired individuals and this was especially clear for mechanical pain 32. Thus even if we had detailed genetic information on our hearing impaired study participants, it might be difficult to link a specific type of mutation to the touch phenotype in a cohort this size. However, our study shows that by measuring vibration detection thresholds with a 10 Hz stimulus we are likely to identify a very substantial number of hearing impaired individuals with touch deficits. We tested a small number of patients with Usher syndrome and it is known that many Usher genes are directly involved in mechanotransduction in hair cells36. Here we found that the small number of Usher syndrome patients all had poor vibration detection thresholds especially at 10 Hz  had non-syndromic forms of hearing loss. We assume that the vast majority of the study participants suffered from deafness with a genetic cause. It is known that there are well over 100 genes that when mutated can cause non-syndromic sensorineural deafness1/36 had 39. In general these studies did not examine perceptual thresholds but rather frequency discrimination (using frequencies > 100 Hz), but in contrast to data on blind individuals40, there was little evidence that hearing impaired subjects perform better on tactile tests. There is good evidence that auditory and tactile information may be processed in common cortical areas42, but interactions between auditory and tactile channels have been examined for high frequency channels ( > 100 Hz). It remains to be seen if there is significant cross-modality interactions for low frequency vibration which was most severely affected parameter in our hearing impaired cohort , and comorbidities.Two cohorts were studied one consisting of healthy high school children and one of high school children with congenital hearing loss. Adolescents were recruited from three Berlin high schools. Study participants were tested with a battery consisting of nine psychophysical tests applied to the skin. The hearing impaired cohort was recruited from the Margaretha-von-Witzleben School in Berlin (www.witzleben-schule.de). All subjects and their parents received written and oral information describing the study and signed an informed consent form. The subjects and schools were received compensation for taking part in the study. Because tactile sensitivity is known to change with age, we chose subjects with a narrow age range 14 to 20 yearsSubjects were seated comfortably in a quiet room at the school. Prior to testing, the participants were familiarized with the setup and their questions and concerns were addressed. Tests were completed in 2 sessions each of 45 minutes duration. Hearing impaired subjects were asked to switch off their hearing aids during the vibration detection threshold test. Sensory testing was done on the side of the dominant hand.44  whose widths are 0.75, 1.25, 1.75, 3.0, 4.5, and 6.0 mm. During the experiment the test subjects were blind-folded using shielded eyeglasses. The dominant hand is placed on a table with the palmar surface facing up. Starting with the widest width, the gratings of the Tactile Acuity Cube are applied in each trial for 2 s to the finger pad in one of the two orthogonal directions relative to the long axis of the finger , in a way that the cube exerts its whole weight on the finger (233 g). The subject indicated the perceived orientation of the alignment. The orientation of the cube was randomly selected by the experimenter. An adaptive method is used: a simple two-down (narrower grating when the subject answers correctly) and one-up (wider gratings when the subject answers incorrectly) procedure or algorithm is employed which converges to 71% correct response (the point at which the subject reliably perceives groove width). The test concluded after thirteen reversal points  were determined and the median of the last 10 were taken as threshold. Thresholds were determined for the little finger and the index finger and the mean of the two values taken as tactile acuity.Tactile acuity is determined with a two-alternative forced choice grating orientation test using the Tactile Acuity Cube (TAC) (MyNeurolab.com/Leica Microsystems) Fig. 44, 45. TMechanical detection threshold was determined with a standardized set of 23 von Frey filaments  Fig. . The filMechanical pain threshold was tested with a set of 7 weighted pinprick stimulators  Fig. . The tip2 and cut off temperatures between 0 °C and 50 °C. The thermode heats up or cools down at a rate of 1 °C/s. All thresholds were determined using the method of limits. The thermode was placed on the volar aspect of the mid-forearm region. Three consecutive trials were done for each thermal sensation with 30 seconds interstimulus interval in the following order: cold detection, warm detection, cold pain and heat pain threshold. Study participants are asked to indicate at what point they start experiencing cooling, warming, cold and heat pain while the thermode is still in contact with the skin. The average thermode temperature of the 3 trials constitutes the above mentioned thermal threshold.The thermal testing device, TSA II Thermosensory analyser , was employed to test for thermal detection and pain thresholds Fig. . The theDeaf − meanHC)/SDHC. The algebraic sign of z-score values for each parameter was adjusted so that it reflects the individual’s sensitivity for each parameter. Z-values above 0 indicate a gain of function, meaning the subject is more sensitive to the tested stimuli compared with HC; a z-value below 0 indicates as loss of function, meaning a reduced sensitivity. With this procedure sensory profiles could be generated where all the parameters had a standard normal distribution with a mean of 0 and standard deviation of 1 unit. Furthermore, individual z-scores lying outside of the 95% confidence interval  of our HC can be identified. Correlation analysis was done with spearman’s correlation test. A P value of less than 0.05 was considered statistically significant.The statistical analysis was done using R Software. Data were tested for normality and log-transformed when necessary before further statistical analysis except for raw data of CDT and HPT which were normally distributed. Test values were entered as dependent variables and group (hearing impaired and control) and gender  was entered as the independent variable. Differences in sensory parameter data between heraing and control groups were compared by a factorial analysis of variance (ANOVA) with the group  and gender . Assumptions for error  and homogeneity of variance (Levene’s test) were determined before conducting the ANOVA. The factorial ANOVAs were obtained with type II sum of squares for sex to test for differences in means between males and females in the control data. The main effect for group was studied with type III method because the sample sizes were unequal. This was followed with Tukey posthoc tests if significant effects are detected. Z-transformations were utilized to compare single individual data profiles with the healthy control (HC) mean. Z-scores for each single parameter referenced to gender was calculated using the following expression: Z-score = (mean


Morphologically congenital sensorineural hearing loss can be investigated under two categories. The majority of congenital hearing loss causes (80%) are membranous malformations. Here, the pathology involves inner ear hair cells. There is no gross bony abnormality and, therefore, in these cases high-resolution computerized tomography and magnetic resonance imaging of the temporal bone reveal normal findings. The remaining 20% have various malformations involving the bony labyrinth and, therefore, can be radiologically demonstrated by computerized tomography and magnetic resonance imaging. The latter group involves surgical challenges as well as problems in decision-making. Some cases may be managed by a hearing aid, others need cochlear implantation, and some cases are candidates for an auditory brainstem implantation (ABI). During cochlear implantation, there may be facial nerve abnormalities, cerebrospinal fluid leakage, electrode misplacement or difficulty in finding the cochlea itself. During surgery for inner ear malformations, the surgeon must be ready to modify the surgical approach or choose special electrodes for surgery. In the present review article, inner ear malformations are classified according to the differences observed in the cochlea. Hearing and language outcomes after various implantation methods are closely related to the status of the cochlear nerve, and a practical classification of the cochlear nerve deficiency is also provided. Inner ear malformations (IEM) represent approximately 20% of congenital hearing loss cases based on radiology ,2. MajorIt is very important to classify IEMs correctly and have a universally accepted system. There is a large variety of malformations which complicate diagnosis and management. Proper classification is as important as using a common language. If we do not have a common language, it is very difficult to understand the findings of another research group. Universally accepted classification of IEMs is particularly important in the field of CI. Surgeons, audiologists, speech and language specialists should be familiar with this system; otherwise, it will be very difficult to understand and compare the outcome after CI surgery in this particular patient group.There are certain challenges in the management of IEMs:1. Cerebrospinal fluid gusher and risk for meningitis2. Facial nerve anomalies3. Decision making for the surgical approach and the type of electrode4. Choosing the correct implantation method; CI vs ABI5. Timing of surgeryClassification of IEMs is based on differences in cochlear anatomy in various malformations. With this classification, cochlear anomalies with similar appearance are grouped together. They demonstrate similar clinical findings, and treatment options. This may not represent the functional outcome with CI, which is closely related to the situation of the cochlear nerve. If there is cochlear nerve deficiency, this will have a negative influence on the audiological and speech and language developmental after implantation. Therefore, during preoperative decision making for choosing the method of implantation, three factors should be considered: classification of IEMs, situation of the cochlear nerve and preoperative audiological findings. Only in this way, a clinician may have a better estimate of the audiological outcome in a given IEM. This is very important during preoperative counseling of the family. In the present paper, classification of cochlear nerve abnormalities is also provided.This review article describes the characteristics of anomalies in eight groups together with treatment options.It is important to become familiar with normal anatomy of the cochlea as seen on high resolution computerized tomography of the temporal bone. Temporal bone HRCT was performed on sections of 0.5 mm in thickness. The use of a 1.5- or 3-T MR imaging system is preferred for inner ear examinations, and it is strongly suggested to be done under general anesthesia. A thin-section gradient-echo sequence that is heavily T2 weighted is best suited for evaluation of the fluid-filled spaces of the membranous labyrinth and the eighth cranial nerve. A section thickness of as little as 0.4-0.7 mm is preferred for optimal delineation and to allow the generation of high-quality multiplanar reformatted images. Oblique sagittal reformatted images are obtained in planes perpendicular to the course of the seventh and eighth nerves in the internal auditory canal (IAC) and cerebellopontine angle. Routine axial T2-weighted imaging of the brain should be performed in all patients to exclude central nervous system causes of sensorineural hearing loss.Cochlea has 2½ or 2¾ turns . Mid-modSection inferior to the mid-modiolar view, passes through the area of the round window niche . This seAccording to present literature ,4, IEMs Complete labyrinthine aplasia (CLA) is the absence of the cochlea, vestibule, semicircular canals (SCCs), vestibular and cochlear aqueducts . The petAccording to radiological findings , three sIn these cases CLA is accompanied by hypoplasia or aplasia of the petrous bone. Middle ear may be adjacent to posterior fossa.In this group of CLA, formation of the petrous bone is normal, but the otic capsule is hypoplastic or aplastic.Formation of the petrous bone and the otic capsule is normal. Only in this group of CLA with otic capsule development, labyrinthine segment of the facial canal is in its normal location. This shows that otic capsule formation is essential for the facial canal to obtain its normal position.These patients either do not show a response during audiological evaluation or they may demonstrate profound sensorineural hearing loss on low frequencies which should be accepted as vibrotactile stimulation.It is not possible to perform CI surgery in these children as there is no inner ear development. In the first Consensus Meeting on ABI in Children , CLA togA rudimentary otocyst is used to define incomplete milimetric representations of the otic capsule (round or ovoid in shape) without an IAC . Parts oSimilar to CLA, either there is no response at all or profound loss on low frequency which is vibrotactile stimulation.The fact that there is no connection between the otocyst and the brainstem is a contraindication to CI surgery. Rudimentary otocyst is also a definite indication for ABI .Cochlear aplasia is the absence of the cochlea. The labyrinthine segment of the facial nerve is anteriorly displaced and occupies the normal location of the cochlea. Vestibule and SCCs are in their normal anatomic location; at the posterolateral part of IAC.There are two subgroups according to accompanying vestibular system:a- Cochlear aplasia with normal labyrinth : Vestibule and SCCs are normally developed.b- Cochlear aplasia with a dilated vestibule (CADV) : Vestibule and SCCs show dilatation. It is very important to differentiate CADV from a common cavity (CC) deformity. In the latter IAC is normally developed, and dilated vestibule occupies normal location at the posterolateral part of the fundus. CI surgery should not be done in CADV. In CC, however, IAC is usually posteriorly directed and opens into the center of CC. If cochleovestibular nerve (CVN) is present, CI can be done in CC. However, in some patients, it may be very difficult to distinguish between these entities. As in every CI candidate, during preoperative evaluation for implantation, audiological findings should be taken into account in choosing the right method of implantation.Cochlear aplasia with normal labyrinth is usually symmetric. Similar appearance is present in different individuals, suggesting a genetic etiology. In CADV, however, asymmetric development may be present; pathology may be due to genetic or environmental factors. Otic capsule development is always normal.These patients do not have a hearing level, the only stimulation can be vibrotactile.As there is no inner ear development, ABI is the only feasible surgical option to provide hearing in children with cochlear aplasia .A CC is defined as a single, ovoid or round chamber, representing cochlea and vestibule . TheoretCC needs to be differentiated from cochlear aplasia with dilated vestibule . CADV F has a diCorrect terminology for the nerve entering the CC is common CVN. CVN has to be demonstrated by 3 Tesla MRI in candidates undergoing evaluation for CI candidacy. Theoretically CVN contains cochlear and vestibular nerve fibers, however with the present radiological investigations, it is not possible to determine the percentage of cochlear fibers within the CVN. Audiological evaluation is very important to determine if hearing is present in CC, which indirectly gives an estimate of the cochlear fibers within the CVN. If a behavioral audiometric response or language development is present with hearing aid use, it can be assumed that a meaningful population of cochlear fibers exists and the patient may benefit from a CI. If the CVN cannot be demonstrated with MRI or there is a narrow or long IAC, where the presence of cochlear fibers is questionable, an ABI may be a more appropriate option from the outset. As the postoperative hearing cannot be accurately predicted before CI surgery, it is advisable to counsel the family that contralateral ABI may be necessary in case of limited language development with CI. These cases are regarded as “Possible Indications for an ABI”  5). Thi. Thi5). These patients usually have profound hearing loss.• For CI surgery, the surgical approach is via a transmastoid labyrinthotomy as described by McElveen et al.  with a s• Beltrame et al.  describe• In case of insufficient hearing and language development with CI use, ABI may be indicated on the contralateral side (possible ABI indication).• If CVN is absent or no IAC is present, ABI is the only option in the first place.In these two groups of malformations, there is a clear differentiation into a cochlea and vestibule.In this deformity, there is a clear differentiation between cochlea and vestibule. CH represents a group of cochlear malformations where external dimensions are less than those of a normal cochlea with various internal architecture deformities. In smaller cochlea, it is usually difficult to count the number of turns with CT and/or MRI. But the definition “cochlea with 1.5 turns” should be used for hypoplasia (particularly type III), rather than for IP-II cochlea. Four different types of CH have been defined :The cochlea is like a small bud, round or ovoid in shape, arising from the IAC . InternaThe cochlea has smaller dimensions with defective modiolus and interscalar septa, but with normal external outline . There mThe cochlea has fewer turns (less than 2 turns) with a short modiolus. The overall length of the interscalar septa is reduced. The internal  and external outline are similar to that of a normal cochlea, with fewer number of turns and smaller dimensions . The vesThe cochlea has a normal basal turn, but middle and apical turns are severely hypoplastic and located anterior and medially rather than in their normal central position . The labThese patients may demonstrate the full spectrum of hearing loss. They may have normal, mild or moderate hearing loss which can be rehabilitated with hearing aids only. Also pure conductive hearing loss is not uncommon which may benefit from stapes surgery. In the case of mixed hearing loss the patient benefit from stapes surgery and hearing aids. Profound hearing loss is also possible and can be rehabilated with CI and in the case of CN deficiency; with ABI. In conclusion CH patients represent the most interesting group of IEMs regarding clinical presentation and management.Decision making in patients with CH may be challenging. They may present with a range of different thresholds on audiometric testing; mild-profound sensorineural, conductive or mixed hearing loss. Decision making about the amplification options may be difficult, particularly in patients with a hypoplastic cochlear nerve.• Some cases of CH (particularly CH-III and CH-IV) may have pure conductive or mixed hearing loss where the conductive component is due to stapedial fixation. They may benefit from stapedotomy. This can be done in childhood and can result in better oral language development with or without hearing aid use, depending on the bone conduction levels.• Patients with mild to moderate SNHL can be habilitated with hearing aids and have near normal language development.• Majority of CH patients have severe to profound hearing loss where a CI would be a reasonable option, if they have a cochlear nerve. During surgery, facial nerve malposition is to be expected due to associated semicircular abnormalities . In hypoplastic cochlea, the promontory may not have the usual protuberance and it may be difficult to identify promontory and round window through the facial recess. In these situations, an additional transcanal approach may be necessary to expose the hypoplastic cochlea.• As the number of turns are smaller with narrower scalae, it is strongly advisable to use thin and shorter electrodes. Thick and long electrodes may not be inserted fully into the cochlea. Particularly important is CH II which has a potential for CSF leakage. FORM 19 (Med El) electrode is developed for these cases. It is 19 mm in length and makes one full turn around the hypoplastic and narrow basal turn in addition to providing effective sealing of the cochleostomy. If a longer electrode is chosen, it cannot be inserted up to the silicon stopper in case of gusher in CH-II.• Some patients with CH have CA aplasia with cochlear nerve aplasia and thus, an ABI would be the best hearing habilitative option.• Cochlear nerve deficiency is frequently observed in patients with CH. The best option in these cases is to perform CI in the side with better developed cochlear nerve or better audiological findings. If there is limited hearing and language development with CI, an ABI should be considered for the contralateral side. In certain cases, who are between 2-3 years of age, with barely visible cochlear nerves, CI and ABI can be done simultaneously; this is to avoid the loss of valuable time until ABI surgery if the chance of benefit from CI surgery is low. Simultaneous CI and ABI surgery has been performed in three patients in our department.Incomplete partition anomalies represent a group of cochlear malformations, where there is a clear differentiation between cochlea and vestibule, with normal external dimensions and various internal architecture defects. Incomplete partitions constitute 41% of IEMs according to the database of Hacettepe University Department of Otolaryngology. There are three different types of incomplete partition groups according to the defect in the modiolus and the interscalar septa.This type of incomplete partition anomaly was termed as “cystic cochleovestibular malformation” in 2002 by Sennaroglu and Saatci . These rRecurrent meningitis can occur in IP-I patients even prior to their CI surgery or in their non-operated ear. This is due to defective stapes footplate and CSF filling the cochlea. There is a cystic structure in the stapes footplate which is easily infected during an attack of otitis media. This is very characterstic for IP-I. Spontaneous CSF fistula and recurrent meningitis can be seen although less frequently in CH type II. This is because both IP-I and CH-II have endosteal developmental anomaly leading to defective footplate development . It is iAll patients with IP-I and recurrent meningitis who have normal tympanic membranes but fluid filling the middle ear and mastoid should have an exploration of the middle ear with special attention to the stapes footplate. Endaural incision was used, and after entering the middle ear, usually a large cyst coming from a defect at the stapes footplate was discovered and excised. After excising the cyst, a defect at the oval window was observed, and CSF gusher was encountered. If the defect is small it sould be enlarged with a 0.6 mm dimond bur for easier manipulation during plugging of the defect. It is also very important to keep stapes suprastructure and the ossicles intact in order to stabilize the fascia in place.• Majority of IP-I patients have severe to profound SNHL. They are almost always candidates for CI.• Size of the cochlea is normal. Therefore, straight electrode about 25 mm is preferred. Modiolar hugging electrode should not be used. FORM 24 (Med El) is developed for these cases. The length is 24 mm which makes a full turn around the basal turn. The conical stopper is used to stop CSF leakage around electrode . It is pDigisonic Classic and Digisonic Evo electrodes (Oticon) are also have a silicon stopper which might be useful for controlling gusher.• In case of gusher, it is most important to stop the CSF leakage from the cochleostomy. The surgeon should not leave operation room without controlling the leakage. After controlling the leakage, subtotal petrosectomy can be done as an additional measure. The benefit of subtotal petrosectomy in CI is to seal the middle ear space from the nasal passage. But if the leakage is not controlled and continues around the electrode, subtotal petrosectomy should not be performed. Most important issue is controlling the leakage from the cochleostomy.• As it is possible to have CN aplasia in IP-I, some patients may not be a candidate for CI surgery. Therefore, an ABI is indicated in IP-I patients with aplastic CN. Four patients with IP-I and an aplastic CN have received ABI in our department.• As in CC, an ABI may be indicated on the contralateral side in case of insufficient progress with CI as a possible indication for ABI .In IP-II, the apical part of the modiolus is defective . This anA recent study on histopathology demonstrated that modiolar defects may be due to high CSF pressure transmission into the inner ear as a result of EVA . An enlaThese patients do not have a characteristic hearing level, as their audiometric threshold testing varies from normal to profound. The hearing loss can be symmetric or asymmetric, but it is usually progressive. It is also possible to have sudden SNHL. In addition, there is an air bone gap particularly at low frequencies. Tympanometry is normal in the absence of otitis media and acoustic reflexes are generally present. Air bone gap in these children is likely to be due to a “third window” effect from the EVA, and may resemble the audiometric findings of superior canal dehiscence syndrome.• At a young age, these patients may have near normal hearing and may not require amplification initially. With fluctuations and progressive hearing loss, they become candidates for hearing aid.• Usually the progression in hearing loss continues, ultimately creating a need for CI at some point in the future. In our department we have also followed IP-II cases with profound SNHL since birth necessitating CI surgery at 1 year of age. High pulsating CSF pressure may be responsible for the progression of hearing loss. A role for head trauma has been suggested, and these patients are advised to wear helmets when playing sports and avoiding contact sports completely. As basal part of the modiolus is normal all kinds of electrodes can be used during surgery. Six of the 77 patients with IP-II had severe gusher during CI surgery. Oozing is also common in these patients. Therefore, electrode with silicon stopper is advisable in IP-II. FORM 24 makes one full turn around the basal turn and controls CSF leakage around the electrode. Digisonic Classic and Digisonic Evo electrodes (Oticon) are also have a silicon stopper which might be useful for controlling gusher.• Stapedotomy should not be performed in these cases as air-bone gap is most probably due to third window effect of EVA.• As all cases of IP-II have cochlear nerve, ABI is not indicated.Cochlea in IP-III has interscalar septa but the modiolus is completely absent . IP-III This anomaly is the rarest form of incomplete partition cases. IP-III constitutes 2% of the IEMs in the database in Hacettepe University Department of Otolaryngology.In IP-III cochlear otic capsule around the membranous labyrinth is thinner when compared to that in a normal cochlea. HRCT demonstrates that in IP-III, the otic capsule around the cochlea is thin and follows the outline of the membranous labyrinth as if it is formed by a thick endosteal layer. Instead of the usual three layers, probably the second and third layers are either absent or very thin. Innermost endosteal layer appears to be thickened without enchondral and outer periosteal layers .Phelps et al.  reportedIn IP-III there may be mixed type HL or profound SNHL. Conductive component may be due to thin otic capsule. Stapes surgery is contraindicated in this group as it may lead to gusher and further SNHL.Mixed hearing loss gives the impression of stapedial fixation. Stapedotomy results in severe gusher and further SNHL, and thus, should be avoided.• Patients with moderate to severe mixed or SNHL can be managed with hearing aids.• Patients with severe HL are candidates for CI. Because of the absent modiolous and large defect at the cochlear base, all patients with IP-III have severe gusher during CI surgery and there is a very high chance of electrode misplacement into IAC. The position of the electrode should be checked intraoperatively in all cases of IP-III. Modiolar hugging electrodes are to be avoided in IP-III. FORM 24 electrodes make one full turn around the cochlear base and also control CSF leakage around the electrode. If the interscalar septa are thick they reduce intracochlear volume and a long electrode may be misdirected into IAC. In such a case FORM 19 is advisable. Digisonic Classic and Digisonic Evo electrodes (Oticon) are also have a silicon stopper which might be useful for controlling gusher but they are longer than FORM electrodes, and they might go into the IAC. Spontaneous CSF fistula through the stapes footplate and recurrent meningitis is very rare in IP-III in spite of high volume CSF leak during CI surgery. This is most probably due to normal endosteal development  in IP-III.• All IP-III cases have excellent cochlear nerves. Therefore, ABI is not indicated in this group of incomplete partitions.This describes the presence of an enlarged vestibular aqueduct (i.e. the midpoint between posterior labyrinth and operculum is larger than 1.5 mm) in the presence of a normal cochlea, vestibule and SCCs . DiffereIn a previous study EVA is thought to be responsible for the transmission of CSF pressure into the inner ear causing progressive or sudden SNHL . It appeClassically EVA is described when the midpoint between posterior labyrinth and operculum is larger than 1.5 mm on axial sections. In our department, we have made the observation that EVA can be observed in a number of successive axial images. It may therefore, not be correct to evaluate EVA only on axial sections. We have to take vertical dimension of EVA into account as well. More correct definition of EVA may be “vertical and axial width larger than 1.5 mm on the midpoint between labyrinth and operculum” .Audiological presentation and management is similar to that of IP-II.The CA, cochlear fossette, or bony cochlear nerve canal transmits the cochlear nerve from the cochlea to IAC. This can be visualized in the mid-modiolar view as well as coronal sections on HRCT .The CA is considered hypoplastic  if the wCA abnormalities may be accompanied by a narrow IAC on HRCT . The IACOn axial section CN is followed until modiolus . On sagiSevere to profound SNHL is usually present. As the cochlea is normal, otoacoustic emissions (OAE) may be present and the child may pass newborn hearing screening if automated ABR is not obtained. Their hearing loss is typically discovered later on in childhood based on the family’s concerns of lack of sound awareness and language development. If the newborn screening protocol involves OAE and automated ABR, this malformation can be diagnosed during infancy. Diagnostic audiological evaluation will reveal profound hearing loss.Hearing aids usually do not provide sufficient amplification in patients with CA hypoplasia and aplasia. In patients with bilateral hypoplastic CA with hypoplastic cochlear nerve, hearing aid trial is necessary. If this does not provide adequate functional hearing, these patients usually become candidates for CI. The family should be counseled that if CI does not provide sufficient hearing in terms of auditory perception, contralateral ABI may be necessary to achieve improved audiologic and language outcomes.In CA aplasia, ABI is indicated as a first-line therapy.The classification of CVN is also important in the management of IEMs.It is important to trace the CN until it enters the cochlea on lower axial sections passing through the IAC . On paraThere is a separate CN but the size is less than the contralateral normal CN or ipsilateral normal facial nerve , 9g.There is no nerve in the anteroinferior part of the IAC , 9ı. ThiNormally cochlear and vestibular nerves originate at the brainstem together forming the CVN. CVN then separates into CN and superior and inferior vestibular nerves in the IAC. In cases of CC CVN enters the cavity without separating into individual nerves . With raIf CVN is smaller than contralateral CVN or ipsilateral FN, it can be accepted as hypoplastic . CVN hypIn case of Michel deformity with absent IAC, CVN is also absent . Only faSevere to profound SNHL is usually present. As the cochlea is normal, OAE may be present and the child may pass newborn hearing screening if automated ABR is not obtained. The amount of cochlear nerve fibers determine the hearing level and management strategy. However, for the present time there’s no spesific auditory profile characteristics for different CVN subgroups. It’s advisable to evaluate the candidate with the full audiological test battery.After a hearing aid trial, initial approach is a trial with CI. If the progress of the patient is insufficient, it is advisable to progress with ABI. This procedure is suitable if the initial CI surgery was done around the age of 6 months; ABI can then be done between 1-1.5 years old with acceptable language development. However if the patient comes in around the age of 2, the time delay between two surgeries increases hence the outcome of ABI decreases. Therefore, simultaneous CI and ABI maybe a better option in selected cases. In our department simultanous CI and ABI have been performed in three such cases.IEMs is a special group of patients. Unfortunately, until recent years the term “Mondini” has been used to describe many different anomalies. There are variety of IEMs and they all present in a different way. As can be seen easily each group has different characteristics in terms of presentation, radiology, hearing and surgical findings. Proper classification is very important in the management of IEMs. If the anomaly is correctly classified, appropriate treatment can be decided more correctly. Finally, proper classification also will create a common language around the world, where clinicians can understand each other better.


Overweight is believed to be associated with colorectal cancer risk. Adipose tissue is loose connective tissue composed of adipocytes. It is now recognized as a major endocrine organ, secreting humoral factors collectively called adipokines. Aberrant hormonal systems consisting of modulated adipokines and their receptors are thought to play a role in colorectal carcinogenesis and cancer progression in obese conditions. However, it is still unclear whether and how each adipokine relates to colorectal carcinogenesis. Notably, a couple of molecules that were initially proposed to be obesity-related adipokines were disqualified by subsequent studies. The adipokines, adiponectin, and intelectin-1 , whose levels are decreased in obesity, act as tumor suppressor factors in various cancers. Numerous studies have demonstrated a link between the insufficient expression and function of adiponectin and its receptor, T-cadherin, in colorectal carcinogenesis. Moreover, our recent study indicated that loss of TMEM207, which is critical for the proper processing of intelectin-1 in the colon mucosa, leads to insufficient intelectin-1 production, thus participating in colorectal carcinogenesis. Here, we discuss the recent understanding of the role of adipokines in colorectal carcinogenesis and subsequently describe the potent tumor suppressor roles of intelectin-1 and TMEM207 in colorectal cancer. Various epidemiological studies have demonstrated that overweight/obesity is a contributing factor to higher incidence and mortality of colorectal cancer ,2. Data Adipocytes are critical for maintaining biological homeostasis as they constitute storage depots for triglycerides and secrete humoral factors . AdipocyAdiponectin is the most abundant circulating peptide hormone, accounting for approximately 0.01% of total plasma protein ,9,10,11.Wei et al. reported that low plasma adiponectin levels were associated with the risk of colorectal cancer in men . MoreoveT-cadherin gene is frequently found in colorectal cancers and adenomas [T-cadherin methylation [The canonical adiponectin receptors, AdipoR1 and AdipoR2, are expressed in both normal colon epithelium and colorectal cancer . By contadenomas . Subsequhylation . Intereshylation . The dowIn conclusion, the insufficient expression and/or function of the adiponectin-T-cadherin axis may lead to colorectal carcinogenesis.Leptin  is a 16 kDa protein hormone. It was the first adipokine to be identified ,29. LeptThere are contradictory reports on the pathobiological properties of leptin in the onset and progression of colorectal cancer. In several studies, a significant increase in colon cancer risk with higher serum leptin concentration was observed , while oMin/+Apc mice, which harbor a point mutation at the Apc gene and are a well-established model for human familial adenomatous polyposis [Molecular biology experiments in vitro and animal model experiments also failed to reach a conclusion. Aparicio et al. reported that leptin significantly stimulated DNA synthesis in colon cancer cells, but did not promote the growth of colon cancer cells in a xenograft assay . Moreoveolyposis , did notolyposis .Two critical points must be further examined to determine whether the leptin-OBRb axis plays a role in colorectal carcinogenesis. First, the detailed expression status of OBRb should be evaluated in human colorectal cancer tissue specimens. OBRb is expressed in human colon cancer cell lines and adenoma tissue specimens . A previIn summary, whether the leptin-OBRb axis plays a role in colorectal carcinogenesis remains unclear.Resistin is a 12.5 kDa cysteine-rich peptide that induces low-grade inflammation by stimulating monocytes in humans. It owes its name to its ability to abrogate insulin function (resulting in resistance to insulin) . AccordiHowever, recent reassessments have shown that resistin seems to be of greater relevance in relation to the immune stress response than in the regulation of glucose homeostasis . SurprisThe pathobiological role of the resistin-CAP1 axis in obesity-related colorectal carcinogenesis remains largely unknown. Notably, Huang et al. reported that treatment of both HCT-116 and SW-48 colon cancer cells with resistin increased the adhesion of both cells to human umbilical vein endothelial cells . FurtherVisfatin is a highly-conserved 52 kDa protein found in living species from bacteria to humans. It was initially reported to be expressed in the visceral adipose tissue, with its expression correlating with the body mass index and commonly increasing in metabolic disease [Yang et al. reported that visfatin can trigger the epithelia-mesenchymal transition of colorectal cancer cells through Akt/GSK-3β/β-catenin signaling and suggested that increased expression of visfatin results in more aggressive colorectal cancer .However, the contribution of adipose tissue to circulating visfatin levels was not established. Recent studies, which prefer referring to this protein as nicotinamide phosphoribosyltransferase (NAMPT), characterized it as a cytoplasmic enzyme that regulates intracellular NAD levels—the cellular redox state—and histone deacetylases, in addition to promoting cell proliferation and inhibiting apoptosis . In the The pathobiological properties of visfatin in obesity-related colorectal carcinogenesis remain unclear. Examining the role of resistin in obesity-related colorectal carcinogenesis remains difficult.angiotensin-type 1 receptor but does not bind angiotensin II) [Initially, apelin was identified as the ligand of an “orphan” G protein-coupled receptor, designated the APJ receptor (a putative receptor protein that is related to the nsin II) . Apelin Apelin is upregulated in the adipose tissues of obese subjects; thus, plasma apelin concentration is increased in obesity and metabolic disease . PicaultThese findings imply that antagonists of the apelin/APJ system can prevent the progression of colorectal cancer by impairing tumor cell growth and/or inhibiting tumor neovascularization.Human intelectin-1  is a 34-kDa secretory protein that was first identified by its ability to bind galactofuranose units in the carbohydrate chains of bacterial cell walls . It was Janus-faced” pathobiological properties of intelectin-1 in various types of carcinogenesis.A series of reports indicated the potential role of intelectin-1 in carcinogenesis ,69,70,71Intelectin-1 was identified as a human intestinal lactoferrin receptor . HoweverTMEM207 was identified by researchers in a comprehensive project called the Secreted Protein Discovery Initiative, which was aimed at finding novel secretory and transmembrane proteins . SubsequRecently, we found that a transmembrane protein, designated TMEM207, facilitated the proper processing of intelectin-1 . The siRp = 0.01). Specifically, TMEM207 was expressed in 24 of 34 mucinous colon cancers but only in 10 of 178 non-mucinous cancer tissue specimens.TMEM207 expression was detected in 38 of 216 colorectal cancer tissue samples and displayed a significant inverse correlation with lymph node metastatic status. Its expression also significantly correlated with the mucinous phenotype of colorectal carcinoma (p = 0.014)  . Thus, tFurther examination to unravel the pathobiological property of intelectin-1/TMEM207 axis in mucinous carcinoma of the colorectum is now underway.We summarized studies of aberrant adipokines/receptors in colorectal carcinogenesis in Thus, a possible replacement therapy for adiponectin, particularly for KRAS-muted colorectal cancer and the development and application of apelin/APJ antagonists, should be pursued. Further studies are needed to determine whether intelectin-1 acts as a tumor suppressor or promoter in colorectal carcinogenesis.