The Effects of Burr-Assisted Rhinoplasty on Hearing.

AIM: The aim of this study is to examine the effects of the burr used for hump reduction and osteoplasty on cochlear function. MATERIALS AND METHODS: The design of this study was prospective, randomized, and controlled. Twenty patients who underwent burr-assisted septorhinoplasty were included in the study group. The control group consisted of 20 patients who underwent septoplasty. Pure tone audiometry, distortion product otoacoustic emission test, and tympanometry were performed to determine the auditory functions. RESULTS: No significant difference was observed between the bone conduction thresholds of the right and left ears in both groups, except for a single frequency (1000 Hz in the left ear) in the control group. There was no significant difference between the 2 groups' air conduction thresholds at frequencies of 500, 1000, 2000, 4000, 6000, and 8000 Hz preoperatively and postoperatively. In addition, the study and control group did not differ significantly in signal-to-noise ratio measurements at frequencies of 500, 1000, 2000, and 4000 Hz. The comparison of preoperative and postoperative otoacoustic emission measurement results of the study group revealed a statistically significant difference only at the frequencies of 2000 Hz in the right ear and 500 Hz in the left ear. Despite those differences, otoacoustic emissions were still present at those frequencies postoperatively. CONCLUSIONS: Our study showed that using burrs during rhinoplasty slightly impacts hearing, but it does not cause significant hearing loss. Burr-assisted rhinoplasty appears to be a safe operation regarding the auditory functions.

Surgical considerations and audiological results of cochlear implantation in patients with otosclerosis

Background/aim: To emphasize the role of cochlear implantation (CI) in the auditory rehabilitation of patients with otosclerosis (OS) and share our surgical experiences on this rare group of patients. Materials and methods: Retrospective analysis of the patients who have a diagnosis of otosclerosis and implanted between January 1998­May 2019 was performed. Preoperative and postoperative clinical, radiological, audiological and surgical findings are presented. Results: Among 2195 patients who have been implanted in our institution, 12 (0.54%) met the diagnostic criteria of OS according to their preoperative (clinical, radiological, audiological) and peroperative (surgical) findings. Electrode insertion was performed via "round window membrane and cochleostomy" in 8 and 4 patients, respectively. No major complications occured. All patients showed satisfactory performances by means of audiometric scores postoperatively. Nonauditory stimulation (NAS) which manifested as "facial twitching" was a challenging problem in one patient during the surgery and subsided after the operation. Conclusion: Our experience on CI in patients with OS revealed that the implantation was a relatively safe procedure and had satisfactory impact on audiological performances.

Anatomical and frequencies-specific hearing results of retrograde mastoidectomy.

PURPOSE: The aim of this study was to evaluate the long-term anatomical and frequency-specific hearing results of canal wall down (CWD) and canal wall up (CWU) mastoidectomy by retrograde mastoidectomy (RM) surgical method. MATERIALS AND METHODS: Patients underwent CWU and CWD procedures with method of RM, 53 and 59 patients between January 2010 and June 2015 were evaluated retrospectively. The pre- and post-operative pure tone average air-bone gap (ABG) values of these patients were recorded in detail at 0.5, 1, 2 and 4 kHz. Pre and post-operative ABG were evaluated in detail in each group in each frequency. In addition, at least two years follow-up recurrence rates were evaluated. RESULTS: In the CWU method, post-operative ABG decreased significantly at low-frequencies compared to pre-operative ABG (p < 0.05), especially at 2 kHz (p < 0.001). But, auditory improvement was not achieved at 4 kHz. In the CWD procedure, auditory improvement was not achieved both 1 kHz and 4 kHz. CWU and CWD recurrence rates were respectively 9.4% and 10.1%. CONCLUSION: Postoperative hearing results of both surgical methods provide good auditory outcome at low-frequencies. This improvement is evident in CWU especially at 2 kHz. This may be related to the protection of the external ear canal. In both surgical methods of RM, a satisfactory anatomical success was achieved with recurrence rates of around 10%. RM is a good surgical technique alternative to classical canal wall down procedure with both auditory results and low recurrence rates.

Cochlear Implantation in Postmeningitic Deafness.

PURPOSE: The aim of this study is to evaluate long-term outcomes of cochlear implantation (CI) in patients with postmeningitic deafness. METHODS: Twenty-seven patients with severe to profound hearing loss due to bacterial meningitis and received CI were the subjects of this study. Surgical findings and long-term audiological performances were evaluated. Speech perception and speech intelligibility of the implanted patients were evaluated with the categories of auditory performance-II (CAP-II) test and speech intelligibility rating (SIR) test, respectively. RESULTS: Eighteen of the 27 patients had received full electrode insertion through the patent cochlear lumen. Remaining 9 patients had varying degrees of ossification throughout the cochlea and needed to be drilled to achieve partial electrode insertion. None of the patients exhibited surgical complication. Scores in both test batteries (CAP-II and SIR) were comparable between patients who received full or partial electrode insertion (P > 0.05). CONCLUSION: Cochlear implantation after postmeningitic deafness has favorable outcomes especially in long term. Although this type of inner ear pathology may require special considerations during surgery, it is a relatively safe procedure.

Effects of nasal continuous positive airway pressure therapy on partners' sexual lives.

To assess sexual functioning in male and female partners before and after nasal continuous positive airway pressure (CPAP) therapy in men with obstructive sleep apnea (OSA). Twenty-one male patients with moderate to severe OSA and erectile dysfunction, and their female partner, were recruited into this prospective study. Males diagnosed with OSA were treated with nasal CPAP therapy for 12 weeks. Women were assessed for sexual functioning using the Female Sexual Function Index (FSFI), and for mood status using the Beck Depression Inventory (BDI), before and after their male partner underwent nasal CPAP therapy. Sexual functioning was assessed in men using the International Index of Erectile Function (IIEF), before and after nasal CPAP therapy. After nasal CPAP therapy for OSA in men, IIEF scores were significantly higher than pre-treatment scores. Total pre- and post-treatment IIEF scores (mean ± standard deviation) were 50.28 ± 15.88 and 65.42 ± 7.47, respectively, P < 0.01. Pre- and post-treatment FSFI scores in women were 21.54 ± 6.62 and 29.94 ± 3.76, respectively, P < 0.01. Pre- and post-treatment BDI scores in women were 14.61 ± 9.69 and 12.42 ± 8.92, respectively, P < 0.01. Following treatment of men with OSA, our data indicate benefits for nasal CPAP therapy on sexual functioning in both the male and female partners. Moreover, our findings indicate that improved sexual function in women after their male partner underwent nasal CPAP also had psychological benefits.

Speech and language development after cochlear implantation in children with bony labyrinth malformations: long-term results.

The aim of this study was to investigate speech and language development after long-term cochlear implantation in children with bony labyrinth malformations (BLMs) and to present the surgical findings in this group of patients. The auditory and linguistic skills of 21 children who had BLM were assessed in this study. They were implanted between 1998 and 2009. Twenty-two sex-matched and age-matched implantees without BLM were evaluated as the control group. To compare speech perception and speech intelligibility between the groups, the categories of auditory performance (CAP) test and speech intelligibility rating (SIR) test, respectively, were administered. The Turkish version of the Test of Early Language Development (TELD-3-T) was administered to evaluate and compare the linguistic skills of the groups. Surgical findings and complications were also analyzed. Implanted anomalies were common cavity in five patients, incomplete partition type 1 in 5 patients, and incomplete partition type 2 in 11 patients. The CAP and SIR scores were significantly higher in the control group (p < 0.05), but the TELD-3-T test scores were comparable among the groups (p > 0.05). Based on the specific type of malformation, the CAP and SIR scores were comparable between the subgroups (p > 0.05). No perioperative complications occurred in the control group. However, various perioperative complications (gusher, etc.) and surgical difficulty occurred in the anomaly group. The malformation group had unsatisfactory results with regard to speech perception skills; however, this group and the non-anomalous group exhibited comparable long-term results on linguistic development.

Rhinorrhoea in the elderly.

The ageing population has various medical problems, ranging from relatively minor to truly severe. The ageing process includes physiological changes that can also aggravate sinonasal problems such as rhinorrhoea. As one of the most troublesome condition of this population, the causes of rhinorrhea can be classified as "age related, medication induced, secondary to rhinitis and other causes (tumour, cerebrospinal fluid (CSF) leakage, etc.)". The underlying aetiology should be meticulously investigated. Although common conditions such as "allergic or infectious rhinitis" are relatively easy to diagnose and threat, more serious causes such as "primary spontaneous CSF rhinorrhea" are hard to manage. The treatment options should be individualised to the patient according to his or her metabolic, cardiac and central nervous system status. Rapid and accurate diagnosis and treatment of the pathology would not only increase the quality of life but also decrease morbidity and mortality of this population. As a conclusion, rhinorrhoea in the elderly is an important condition that should not be overlooked.

Analysis of acute impact of oleoresin capsicum on rat nasal mucosa using scanning electron microscopy.

Analysis of acute cellular changes seen in nasal mucosa of Wistar-Albino rats exposed to different doses of oleoresin capsicum for various time periods by means of scanning electron microscopy. Thirty-five Wistar-Albino rats were divided into five groups of seven rats each. 6-gram oleoresin capsicum per second was sprayed into cages of the groups except group 1. Spray times and duration of exposure to pepper gasses were different for each group. Thirty minutes after the exposure, the animals were killed and specimens from their nasal mucosas were harvested and examined under scanning electron microscope. Mucosal damage was scored from 0-4 points. Mean values of nasal mucosa damage scores of the groups were calculated and compared statistically. Average damage scores of the groups exposed to identical doses of oleoresin capsicum for various exposure times were compared and a statistically significant difference was seen between Groups 2 and 3 (p < 0.05), however the difference between Groups 4 and 5 was insignificant (p > 0.05). Average damage scores of the groups exposed to various doses for identical exposure times were compared, and statistically significant differences were observed between Groups 2 and 4 and also Groups 3 and 5 (p < 0.05). Outcomes of our study have demonstrated that pepper gas exerts destructive changes on rat nasal mucosa. The extent of these destructive changes increases with the prolonged exposure to higher doses. Besides, exposure time also stands out as an influential factor on the extent of the destructive changes.

Importance of yawning in the evaluation of excessive daytime sleepiness: a prospective clinical study.

As a dark and not fully understood side of human nature, yawning is believed to be a signs of various physiological or pathological behaviors of human. In this study, we aimed to investigate the importance of yawning in the evaluation of sleepiness. One hundred and twenty-nine snorers who were suspected to have obstructive sleep apnea syndrome underwent polysomnography and were asked to fill the Epworth sleepiness scale. The number of yawnings of patients was counted during the day following polysomnography. Patients were stratified into two groups: those have apnea hypopnea index <5 (n = 43, group 1) and those have apnea hypopnea index >30 (n = 86, group 2). Mean duration of sleep phases, oxygen saturations, sleep efficacies, yawning frequencies and Epworth scores of the groups were compared. Correlations of yawning frequency with Epworth scores, duration of sleep phases and mean oxygen saturations were investigated. Sleep efficacies were similar between the groups (p > 0.05). Yawning frequencies in group 1 and group 2 were 43.48 and 75.76 (mean rank), respectively (p < 0.01). Mean N1, N2, N3 phase durations and oxygen saturations were significantly lower in group 2 (p < 0.01). While there was a negative correlation between yawning frequency and duration of the non-REM phases and mean oxygen saturation (r = -0.53 and r = -0.31, respectively, p < 0.05), yawning frequency was positively correlated with Epworth scores (r = 0.46, p < 0.05). In addition to the shortened phases of sleep, increased Epworth score and decreased oxygen saturation, increased yawning frequency may indicate sleep deprivation.

Effects of surfactant on biofilm formation on silicone nasal splints.

Biofilms are sessile communities of bacteria embedded in self-produced extracellular polysaccharide matrix and are considered to be responsible for bacterial infections in humans. Topical surfactant use on silicone nasal splints may have a preventive effect on biofilm formation. The objective of this study is to investigate the effect of surfactant-containing nasal solutions on biofilm formation over the surface of silicone nasal splints. Forty patients were randomized after septoplasty to receive surfactant-containing saline solution (group 1) or saline without surfactant (group 2). At the postoperative 48th, 72th and 96th hours, pieces of splint samples were taken and prepared for scanning electron microscopic evaluation. Biofilm formation was observed in 3, 6 and 14 of 20 samples in group 1 (surfactant used) and 3, 14 and 20 of 20 samples in group 2 (control) at 48th, 72th and 96th hours, respectively. Biofilm formation incidences of groups at 48th hour were similar (p > 0.05), whereas it was significantly lower at group 1 regarding 72th and 96th hours (p < 0.05). Surfactant-containing nasal solutions have an inhibitory effect on biofilm formation over the surface of silicone nasal splints especially after 48 h. Surfactant-containing nasal solutions may have an important role in nasal septal dressing in the future.

Influence of surface properties of Merocel® (polyvinyl acetal) and silicone nasal splints on biofilm formation.

The objective of the study was to investigate biofilm formation on Merocel(®) and silicone nasal splint after nasal septal surgery. 50 patients who were scheduled to undergo nasal septal surgery were included in this study. The patients were randomized into receiving an insert of Merocel(®) or silicone splint after septoplasty. In group 1 (8 females, 17 males) and group 2 (10 females, 15 males), Merocel (®) packs or silicone splints were inserted into nasal cavities at the end of the procedures, respectively. All packs were removed 48 h after insertion, and samples were taken from the packs under sterilized conditions. Scanning electron microscopy was performed to observe biofilm formation on the surfaces of Merocel(®) and silicone splints. Biofilm formation was observed in 25 (100%) and 3 (12%) of the Merocel(®) and silicone splint samples, respectively. Our study revealed that biofilm formation on Merocel(®) packs is significantly higher than silicone splints, mainly due to the different texture and surface properties of these materials. Considering the hazardous effects of biofilm formation on humans, our observations in this study may guide surgeons to choose the most appropriate packing material after nasal septal surgery.

Quantitative measurement of m-RNA levels to assess expression of cyclooxygenase-II, inducible nitric oxide synthase and 12-lipoxygenase genes in middle ear cholesteatoma.

To assess expression of three main inflammatory genes, COX-II, ALOX-12 and i-NOS, quantitatively at transcriptional level in cholesteatoma matrix tissue. Ten patients who have chronic otitis media with primary acquired cholesteatoma were included in this study. Tissue samples obtained from cholesteatoma matrix and external ear canal skin (control tissue). Expression of the targeted genes (COX-II, i-NOS and LOX-12) was assessed using real-time quantitative polymerase chain reaction (RT-PCR) technique. The amount of COX2 mRNA was significantly higher in cholesteatoma matrix at transcriptional level (p = 0.038). There was no statistically significant difference regarding expression of iNOS and LOX12 mRNA levels (p > 0.05). There is a significant overexpression of the mRNA of COX-II in cholesteatoma matrix, which indicates a difference between the normal skin and cholesteatoma matrix at molecular level. COX-II gene overexpression seems to be associated with pathogenesis of cholesteatoma. This molecular change is similar to the molecular abnormalities observed in some benign and malignant neoplasms. Invasive and locally destructive nature of cholesteatoma may be due to COX-II overexpression. Absence of an increase in the gene expressions of i-NOS and LOX-12 in cholesteatoma matrix suggests that these mediators may not be related with the pathogenesis and evolution of cholesteatoma.

Epistaxis and Staphylococcus aureus colonization in the nasal vestibule: is it a cause or consequence?

The aim of this study was to investigate the relation between epistaxis and nasal colonization of Staphylococcus aureus in a population of patients with recurrent epistaxis. A total of 361 men and women were recruited, 245 patients with epistaxis (114 had crusting in the nasal vestibule; 131 did not) and 116 control subjects. A microbiology swab was taken from the anterior nasal cavity of each subject. Staphylococcus aureus was found to be more common in the epistaxis group when compared with the control group with a percentage of 31.8% and 4.3%, respectively (P < 0.05). There was no difference in the prevalence of S. aureus between the crust and non-crust groups (P > 0.05). When positive cultures were grouped and compared according to season, it was observed that the positive culture with epistaxis was much higher (44.82 %) in the autumn period. Staphylococcus aureus colonization in the nasal vestibule is more likely to be observed in individuals who have recurrent epistaxis than in those who do not have. It seems that this colonization may have a role in the etiology of epistaxis. However, with an altered medium of the nasal vestibule after each epistaxis period, it is also possible to speculate that this colonization is may be the consequence of epistaxis itself.

Microbial biofilm formation on silicone nasal splints: optimal time for splint removal.

OBJECTIVES: Biofilms are sessile communities associated with persistent infections and are resistant to conventional therapeutic strategies. They survive on the surface of various inorganic medical devices and cause serious medical problems. METHODS: We recruited 25 patients who underwent nasal surgery between January and May 2013. All patients received silicone splints at the conclusion of the procedure. Pieces of the splints were collected 48, 72 and 96 h post-surgery and prepared for scanning electron microscopy evaluation to assess biofilm formation. RESULTS: Biofilm was observed in 3, 14 and 25 of the 25 samples at 48, 72 and 96 h, respectively. The differences in the proportions of the samples with biofilm formation at each time point (48, 72, and 96 h) were statistically significant. CONCLUSION: Our data demonstrated that biofilm formation on silicone splints increases significantly after 48 h following placement. Although packing may reduce complications, surgeons must consider the potential hazards of packing materials, such as biofilm formation at 48 h post-surgery.

Occupational safety threats among dental personnel and related risk factors.

Occupational diseases are primarily considered to be important health problems for individuals with occupations in heavy industry fields. Although dentists work in very clean and elegant offices, they are frequently exposed to various chemicals and high-intensity, sound-producing instruments, such as compressors and aerators. In our study, we aimed to investigate the risk for occupational hearing loss of dental personnel, by performing pure-tone audiometry in 40 dentists and comparing the results with those of healthy individuals. We also sampled the nasal mucosa to investigate the effects of occupational chemicals on the nasal mucosa of the dentists. The pure-tone audiometric thresholds at 5 different frequencies (1000, 2000, 4000, 6000, and 8000 Hz) and working time were evaluated as potential risk factors. The pure-tone audiometric results (as decibels) at each frequency and the median values for each side (right and left ears) were significantly higher for dentists than for the control group (P < 0.05). The pure-tone audiometric results did not significantly differ between the women and men in the study group (P > 0.05). The findings in the nasal mucosa (goblet cell hyperplasia, neutrophil/eosinophil/basophil distribution, metaplasia, dysplasia, premalignant or malignant cells) were similar in the study and control groups (P > 0.05). In conclusion, our study indicated that high-intensity, sound-producing equipment is an important occupational threat for dentists, whereas chemical agents have minimal hazardous effects.

Phenotyping of allergic rhinitis.

Allergic rhinitis (AR) is characterized by immune-mediated inflammation of the nasal mucosal lining. Although this chronic disease is not fatal, it is associated with many debilitating symptoms. Like many other chronic diseases, AR has a wide range of clinical aspects, and comorbidities such as asthma, rhinosinusitis, dermatitis, and conjunctivitis may accompany the disease to different degrees. These comorbidities and features determine the clinical phenotypes of AR. Different phenotypes and other characteristics of AR are discussed in this review. It is important for clinicians to be aware of these variable clinical phenotypes of AR to diagnose and treat the disease properly.

Surgical Methods and Auditory Outcomes of Cochlear Implantation in Cochlear Ossification.

BACKGROUND: The aim of this study was to evaluate the surgical and auditory outcomes of cochlear implantation in patients with cochlear ossification. METHODS: This study comprised 54 patients with cochlear ossification who underwent cochlear implantation in the cochlear implant center of a tertiary care hospital between January 1998 and May 2019. Clinical data were evaluated including surgical findings and audiological performances. The auditory outcomes of the implanted patients were assessed through the Categories of Auditory Performance-II test and Speech Intelligibility Rating test, respectively. The outcomes of patients with cochlear ossification were compared with those of 54 patients selected for the control group who underwent implantation with no cochlear ossification. RESULTS: Auditory outcomes were comparable between the study group and the control group. The control group obtained significantly higher scores than those of the study group when compared using the Categories of Auditory Performance-II test and Speech Intelligibility Rating test batteries. Patients with meningitis produced poorer outcomes within the group comparisons of the study group. None of the patients experienced surgical complications. The extent of ossification was analyzed in terms of its effectiveness on audiological performance. Patients with complete ossification had significantly lower Categories of Auditory Performance-II and Speech Intelligibility Rating test scores. CONCLUSION: Cochlear implantation is a safe and beneficial procedure, even in patients with cochlear ossification. The ossified cochlea may require varied drill techniques beyond traditional implantation surgery for the insertion of the electrode array. It is, however, still difficult to predict audiological outcomes in patients with cochlear ossification.

Quality of Life in Older Adults with Cochlear Implantation: Can It Be Equal to That of Healthy Older Adults?

BACKGROUND AND OBJECTIVES: This study aimed to evaluate the audiologic results after cochlear implantation (CI) in older patients and the degree of improvement in their quality of life (QoL). Subjects and. METHODS: Patients over 65 years old who underwent CI at implant center in Bozyaka Training and Research Hospital were included in this study (n=54; 34 males and 20 females). The control group was patient over 65 years old with normal hearing (n=54; 34 males and 20 females). We administered three questionnaires [World Health Organization Quality of Life-BREF (WHOQOL-BREF), World Health Organization Quality of Life-OLD (WHOQOL-OLD)], and Geriatric Depression Scale (GDS) to evaluate the QoL, CIrelated effects on activities of daily life, and social activities in all the subjects. Moreover, correlations between speech recognition and the QoL scores were evaluated. The duration of implant use and comorbidities were also examined as potential factors affecting QoL. RESULTS: The patients had remarkable improvements (the mean score of postoperative speech perception 75.7%) in speech perception after CI. The scores for the WHOQOL-OLD and WHOQOL-BREF questionnaire responses were similar in both the study and control groups, except those for a two subdomains (social relations and social participation). The patients with longer-term CI had higher scores than those with short-term CI use. In general, the changes in GDS scores were not significant (p<0.05). CONCLUSIONS: The treatment of hearing loss with CI conferred significant improvement in patient's QoL (p<0.01). The evaluation of QoL can provide multidimensional insights into a geriatric patient's progress and, therefore, should be considered by audiologists.

Parents' View on Quality of Life after Cochlear Implantation in Children with Auditory Neuropathy.

OBJECTIVES: The aim of this study is to evaluate the quality of life in pediatric patients with auditory neuropathy according to the perspective of their parents after cochlear implantation. MATERIALS AND METHODS: The pediatric patients, who underwent cochlear implantation with the diagnosis of auditory neuropathy at Izmir Bozyaka Training and Research Hospital ENT Clinic between January 1997 and May 2017, were included to the study. "Parents' Perspective Questionnaire" developed by Nottingham Pediatric Cochlear Implant Programme was used in the study. The questionnaire was composed of 11 subscales and 58 questions in total. RESULTS: The study included 26 pediatric patients (14 female, 12 male) who used cochlear implant for at least 1 year. The mean age of patients was 10.91±3.85 ( 4.3-17.3 years old) and implantation age varied between 14 months and 80 months. (median; 35.65±20.03 months). Patients who attended school had more self-confidence, and also those having implant use over 6 years had a better self confidence and social relationship. CONCLUSION: Cochlear implantation not only improves the ability of hearing but also provides development of speech and language skills and therefore enhancing the patient's quality of life. From the perspective of parents, the use of cochlear implant in the children with auditory neuropathy improves the quality of life in many different ways. The perspective of parents can provide a multidimensional evaluation about the child's progress, therefore, it should be taken into consideration by the staff in implant centers.

Is Pool Water Disinfectant (Hydrogen Peroxide-Silver Composition) Ototoxic in Rats?

OBJECTIVES: The purpose of our study was to evaluate whether hydrogen peroxide and silver composition (H202-Ag) used in pool water disinfectant is ototoxic to individuals with tympanic membrane perforation. MATERIALS AND METHODS: The tympanic membranes of both ears of 14 Wistar-type albino female rats were perforated. Since topical application was performed, the right and left ears were categorized as two subgroups (a: right ear, b: left ear). Baseline auditory brainstem response (ABR) was measured. The groups were classified according to topical applications performed as Ia (30 mg/L H202-Ag), Ib (saline), IIa (70 mg/L H202-Ag), and IIb (saline). The topical applications were performed for 30 min/day for 10 days. The ABR was measured 24 hours after the last application, and the animals were sacrificed. Bilateral temporal bones were examined using light microscopy. RESULTS: An apparent rise in the hearing thresholds of the groups Ia and Ib was not observed. However, there was an apparent rise in the hearing thresholds of the group IIa, which supports ototoxicity. According to histopathology results, there weren't any pathological findings in groups Ia and Ib and did not display special features, but a neurotoxic effect was observed in group II. CONCLUSION: Our study shows that the H202-Ag used in pool water disinfection can have ototoxic and neurotoxic effects, particularly at high concentrations.