Publications by authors named "Saku T Sinkkonen"

33 Publications

Tubomanometry Measurement Success Rate in Clinical Practice.

Otol Neurotol 2020 12 31. Epub 2020 Dec 31.

Department of Otorhinolaryngology - Head and Neck Surgery, Head and Neck Center, Helsinki University Hospital and University of Helsinki, Helsinki Department of Otorhinolaryngology - Head and Neck Surgery, Turku University Hospital and University of Turku, Turku, Finland.

Objectives: Tubomanometry (TMM) is an objective method for investigating Eustachian tube (ET) function, but difficulties in technique and interpretation may reduce its usability. The objective of our study was to investigate common difficulties with TMM in different ET dysfunction (ETD) patient groups and at different pressures (30, 40, and 50 mbars) when first introducing TMM to otologic practice. Furthermore, we wanted to investigate whether it would be possible to perform TMM at only one pressure and obtain a representative result.

Methods: A retrospective chart review of a 2-year cohort of 114 patients with a history of ETD treated at a tertiary referral center. Primary outcome was the success rate of TMM, secondary the reasons for unsuccessful measurements. Tertiary outcome was the correlation of TMM results at adjacent pressures.

Results: TMM success rate was 91%, varying 81 to 94% in different ETD patient groups and 87 to 94% at different pressures. Unsuccessful measurements resulted from air-leaks from the external ear canal, abnormal ear canal pressure curves (R < 0) and at 50 mbar, difficulties in reaching sufficient nasopharyngeal pressure. TMM results were similar in 88% of cases at 30 and 40 mbars and in 86% of cases at 40 and 50 mbars.

Conclusions: TMM success rate seems sufficiently high for clinical diagnostics, and most difficulties may be overcome with proper interpretation during the TMM measurement session, and thus repeating the measurements when necessary. Considering the diagnostic information that would be lost if using only a single, predefined pressure, we suggest using all three pressures.
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http://dx.doi.org/10.1097/MAO.0000000000003018DOI Listing
December 2020

Stress and Tinnitus; Transcutaneous Auricular Vagal Nerve Stimulation Attenuates Tinnitus-Triggered Stress Reaction.

Front Psychol 2020 17;11:570196. Epub 2020 Sep 17.

Department of Otolaryngology-Head & Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Introduction: Tinnitus can become a strong stressor for some individuals, leading to imbalance of the autonomous nervous system with reduction of parasympathetic activity. It can manifest itself as sleep disturbances, anxiety and even depression. This condition can be reversed by bioelectrical vagal nerve stimulation (VNS). Conventional invasive VNS is an approved treatment for epilepsy and depression. Transcutaneous VNS (taVNS) stimulating the auricular branch of the vagus nerve has been shown to activate the vagal pathways similarly as an implanted VNS. Therefore, taVNS might also be a therapeutic alternative in health conditions such as tinnitus-related mental stress (TRMS). This retrospective study in 171 TRMS patients reports the clinical features, psychophysiological characteristics, and results of the heart rate variability (HRV) tests before and after test-taVNS. This study also reports the therapy outcomes of 113 TRMS patients treated with taVNS, in combination with standard tinnitus therapy.

Methods: Diagnostic tinnitus and hearing profiles were defined. To detect possible cardiac adverse effects, test-taVNS with heart rate monitoring as well as pre- and post-stimulation HRV tests were performed. Daily taVNS home therapy was prescribed thereafter. To assess therapeutic usefulness of taVNS, 1-year follow-up outcome was studied. Results of HRV tests were retrospectively analyzed and correlated to diagnostic data.

Results: The large majority of patients with TRMS suffer from associated symptoms such as sleep disturbances and anxiety. Baseline HRV data showed that more than three quarters of the 171 patients had increased sympathetic activity before test-taVNS. Test-taVNS shifted mean values of different HRV parameters toward increased parasympathetic activity in about 80% of patients. Test-taVNS did not cause any cardiac or other side effects. No significant adverse effects were reported in follow-up questionnaires.

Conclusion: TRMS is an example of a stress condition in which patients may benefit from taVNS. As revealed by HRV, test-taVNS improved parasympathetic function, most efficiently in patients with a low starting HRV level. Our tinnitus treatment program, including taVNS, effectively alleviated tinnitus stress and handicap. For wider clinical use, there is a great need for more knowledge about the optimal methodology and parameters of taVNS.
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http://dx.doi.org/10.3389/fpsyg.2020.570196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527536PMC
September 2020

The status of Eustachian tube balloon dilations in Nordic countries.

World J Otorhinolaryngol Head Neck Surg 2019 Sep 19;5(3):148-151. Epub 2019 Oct 19.

Region Hospital West Jutland, ENT Department, Holstebro Denmark.

There is no unanimous consensus for indications of eustachian tube balloon dilation (ETBD). Nordic countries have relatively similar hospital organizations and treatment guidelines. Therefore, it was logical to organize a consensus meeting of ETBD. The symposium: Nordic Experiences on Eustachian Tube Balloon Dilation, in Copenhagen, 30-31 March, 2017. The panellists from Denmark, Finland, Norway and Sweden and the attendees of the meeting agreed a consensus on the following issues: Candidates, Definition of Eustachian Tube Dysfunction, Diagnostic Work up, Differential Diagnosis, Contraindications, ETBD Procedure, Complications, Follow-up, and Outcomes. The article also presents the status for ETBD in each of these countries. Thereafter the consensus statement has been discussed in the national societies and meetings for ear surgeons in each of these countries. It can be assumed that surgeons in the hospitals of these Nordic countries generally follow the recommendations from the consensus meeting.
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http://dx.doi.org/10.1016/j.wjorl.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849347PMC
September 2019

A Comparison of Four Digital Otoscopes in a Teleconsultation Setting.

Laryngoscope 2020 06 31;130(6):1572-1576. Epub 2019 Oct 31.

Department of Otorhinolaryngology and Head & Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Objectives/hypothesis: This study compares image quality and appropriateness for teleconsultations for three different otological conditions.

Study Design: Web-based survey.

Methods: We compared four digital otoscopes via a Web-based questionnaire distributed to all Finnish ear, nose, and throat (ENT) specialists and residents. The survey consisted of three fictional patient cases, each of which was presented with images taken using the otoscopes studied. Respondents assessed the image quality on a visual analog scale (VAS), assessing its appropriateness for teleconsultations and comparing images taken using different otoscopes to one another.

Results: In total, 98 individuals responded, consisting of 81 ENT specialists and 17 ENT residents. The CellScope Oto and Digital MacroView received higher VAS scores for image quality and appropriateness for teleconsultations than the FireFly and Delfino otoscopes (P < .001 for all comparisons). Respondents considered the CellScope Oto more appropriate for teleconsultations for exostoses than the three other otoscopes. The CellScope Oto and Digital MacroView were equally appropriate in the two other cases (normal ear and perforated tympanic membrane).

Conclusions: Both digital otoscopes and the underlying otological conditions affect the appropriateness of teleconsultations. Moreover, both factors should be considered when evaluating the suitability of otologic teleconsultations. Among the otoscopes evaluated, images taken using the CellScope Oto received the best overall assessments.

Level Of Evidence: NA Laryngoscope, 130:1572-1576, 2020.
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http://dx.doi.org/10.1002/lary.28340DOI Listing
June 2020

Otitis Media-associated Bacterial Meningitis in Children in a Low-income Country.

Pediatr Infect Dis J 2019 08;38(8):791-797

Department of Otorhinolaryngology and Head and Neck Surgery, University of Turku, Turku, Finland.

Background: Otitis media (OM) is a common childhood infection that may result in bacterial meningitis (BM). However, OM-associated BM remains poorly characterized. We aimed to study the occurrence, clinical presentation and outcome of this type of childhood BM in Luanda, Angola.

Methods: Five hundred twelve children from our previous clinical BM trial, with the ear meticulously examined, were analyzed whether they had or not OM, and according to their age, ≤12 month old and >12 month old. Prospectively collected clinical data, laboratory test results and outcome for these groups were assessed.

Results: Sixty-two children (12%) had OM-associated BM, of whom 39 had otorrhea. Ear discharge was more common in older children (median age 45 months old vs. 12 months old; P < 0.001). Children with OM often showed an additional infectious focus (n = 20, 32% vs. n = 82, 18%; P = 0.016), were dehydrated (n = 16, 26% vs. n = 66, 15%; P = 0.04), and showed higher odds of complicated clinical course or death (odds ratios 2.27, 95% CI: 1.004-5.15, P = 0.049) compared with children without OM. The >12-month-old children with OM often arrived in poor clinical condition with coma and/or ptosis. Otorrhea was associated with HIV positivity. Infants with otorrhea frequently lived under poor socioeconomic conditions.

Conclusions: Children with OM-associated BM were prone to many problems, such as being especially ill at presentation, undergoing a difficult clinical course and showing a higher risk of complicated or fatal outcome. HIV infection and malnutrition were common in children with otorrhea, which was also associated with low socioeconomic status.
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http://dx.doi.org/10.1097/INF.0000000000002335DOI Listing
August 2019

Multiple actions of fenamates and other nonsteroidal anti-inflammatory drugs on GABA receptors.

Eur J Pharmacol 2019 Jun 28;853:247-255. Epub 2019 Mar 28.

Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

The nonsteroidal anti-inflammatory drug (NSAID) niflumic acid, a fenamate in structure, has many molecular targets, one of them being specific subtypes of the main inhibitory ligand-gated anion channel, the GABA receptor. Here, we report on the effects of other fenamates and other classes of NSAIDs on brain picrotoxinin-sensitive GABA receptors, using an autoradiographic assay with [S]TBPS as a ligand on mouse brain sections. We found that the other fenamates studied (flufenamic acid, meclofenamic acid, mefenamic acid and tolfenamic acid) affected the autoradiographic signal at low micromolar concentrations in a facilitatory-like allosteric fashion, i.e., without having affinity to the [S]TBPS binding site. Unlike niflumic acid that shows clear preference for inhibiting cerebellar granule cell layer GABA receptors, the other fenamates showed little brain regional selectivity, indicating that their actions are not receptor-subtype selective. Of the non-fenamate NSAIDs studied at 100 μM concentration, diclofenac induced the greatest inhibition of the binding, which is not surprising as it has close structural similarity with the potent fenamate meclofenamic acid. Using two-electrode voltage-clamp assays on Xenopus oocytes, the effect of niflumic acid was found to be dependent on the β subunit variant and the presence of γ2 subunit in rat recombinant α1β and α1βγ2 GABA receptors, with the β1 allowing the niflumic acid inhibition and β3 the stimulation of the receptor-mediated currents. In summary, the fenamate NSAIDs constitute an interesting class of compounds that could be used for development of potent GABA receptor allosteric agonists with other targets to moderate inflammation, pain and associated anxiety/depression.
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http://dx.doi.org/10.1016/j.ejphar.2019.03.039DOI Listing
June 2019

Management of jugular bulb injury during drilling of the internal auditory canal (ICA) for vestibular schwannoma surgery.

Am J Otolaryngol 2019 Mar - Apr;40(2):341. Epub 2019 Jan 24.

Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

The retrosigmoid approach for vestibular schwannoma surgery has remained the standard approach by most neurosurgeons. Drilling the posterior wall of the internal auditory meatus (IAM) is an essential step in removing the intrameatal tumor. During IAM drilling, three anatomical structures can be encountered, including the posterior semicircular canal, vestibular aqueduct, and jugular bulb. Any of these can be injured during drilling, especially if the jugular bulb lies above the inferior edge of the IAM. Although IAM drilling is performed in most vestibular schwannoma surgeries, information on how to manage complications such as jugular bulb injury is lacking. Here we use an intraoperative video to demonstrate how to manage the inadvertent injury to the jugular bulb in order to avoid massive blood loss. We present a case of a 39-year-old woman with hearing loss, diagnosed with a cerebellopontine angle mass extending into the IAM. Surgery was required due to tumor progression. We used the retrosigmoid approach to access the tumor. During IAM drilling, the jugular bulb was injured. A thin layer of bone wax was applied under continuous suction. The margins of the wax were then gently compressed with a dissector; great care was taken to avoid pushing the wax into the jugular bulb. Excess bone wax was removed (video 1). A small diamond drill (2 mm) was used for further drilling. Our instructional video shows the surgical approach, microsurgical anatomy, and technical aspects of managing massive bleeding from jugular bulb injury. It should therefore be helpful for young neurosurgeons.
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http://dx.doi.org/10.1016/j.amjoto.2019.01.004DOI Listing
June 2019

Balloon Eustachian tuboplasty under monitored anaesthesia care with different balloon dilation devices: A pilot feasibility study with 18 patients.

Clin Otolaryngol 2019 01 4;44(1):87-90. Epub 2018 Nov 4.

Department of Otorhinolaryngology - Head and Neck Surgery, Head and Neck Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.1111/coa.13236DOI Listing
January 2019

Cochlear Implantation With a Novel Long Straight Electrode: the Insertion Results Evaluated by Imaging and Histology in Human Temporal Bones.

Otol Neurotol 2018 10;39(9):e784-e793

Department of Otorhinolaryngology, Kuopio University Hospital, Kuopio.

Hypothesis: To evaluate the insertion results of a novel straight array (EVO) by detailed imaging and subsequent histology in human temporal bones (TB).

Background: The main focuses of modern cochlear implant surgery are to prevent damage to the intracochlear structures and to preserve residual hearing. This is often achievable with new atraumatic electrode arrays in combination with meticulous surgical techniques.

Methods: Twenty fresh-frozen TBs were implanted with the EVO. Pre- and postoperative cone beam computed tomography scans were reconstructed and fused for an artifact-free representation of the electrode. The array's vertical position was quantified in relation to the basilar membrane on basis of which trauma was classified (Grades 0-4). The basilar membrane location was modeled from previous histologic data. The TBs underwent subsequent histologic examination.

Results: The EVOs were successfully inserted in all TBs. Atraumatic insertion (Grades 0-1) were accomplished in 14 of 20 TBs (70%). There were three apical translocations, and two basal translocations due to electrode bulging. One TB had multiple translocations. The sensitivity and specificity of imaging for detecting insertion trauma (Grades 2-4) was 87.5% and 97.3.0%, respectively.

Conclusion: Comparable insertion results as reported for other arrays were also found for the EVO. Insertion trauma can be mostly avoided with meticulous insertion techniques to prevent bulging and by limiting the insertion depth angle to 360 degrees. The image fusion technique is a reliable tool for evaluating electrode placement and is feasible for trauma grading.
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http://dx.doi.org/10.1097/MAO.0000000000001953DOI Listing
October 2018

Multiple cranial nerve injuries and neck abscesses caused by a transorally penetrating organic stick.

BMJ Case Rep 2018 Jul 24;2018. Epub 2018 Jul 24.

Head and Neck Center, Otorhinolaryngology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Foreign bodies cause a remarkable number of otolaryngological emergency visits and occasionally result in life-threatening conditions and later-emerging complications. Patient recovery depends on the detection and proper extraction of all foreign materials. Despite various obtainable diagnostic tools, adequate anamnesis forms the basis of clinical reasoning and should direct later examinations and radiological imaging. This case report describes a challenging patient with a unique trauma mechanism: many pieces of a fragmented organic foreign body emerged within 1 year of the initial injury, leading to repeated operations, a long period in an intensive care unit and a long-term swallowing and speech dysfunction.
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http://dx.doi.org/10.1136/bcr-2017-224021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059225PMC
July 2018

Balloon Eustachian Tuboplasty: Systematic Review of Long-term Outcomes and Proposed Indications.

J Int Adv Otol 2018 Apr;14(1):112-126

Department of Otorhinolaryngology - Head and Neck Surgery, Head and Neck Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Balloon Eustachian tuboplasty (BET) aims to improve the function of the Eustachian tube (ET). The objective of this study was to review the long-term outcome of BET and present the process and results of outlining indications for BET by the Finnish Otosurgical Society. The literature review is based on a database search performed in May 2017. The search resulted in 100 individual articles, which were screened for relevance. Five articles fulfilled the inclusion criteria (follow-up ≥12 months). Five additional articles (follow-up, 6-11 months) were analyzed to obtain supportive information. The proposed BET indications were constituted in the 2016 annual meeting of the Finnish Otosurgical Society. The workshop included a review of the Eustachian tube physiology, middle ear aeration mechanisms, and BET outcome studies. Thereafter, the members of the Society first voted and then discussed 14 cases in order to conclude whether BET was indicated in each case, and subsequently, a consensus statement on the indications for BET was outlined. The long-term follow-up studies were heterogeneous regarding the Eustachian tube dysfunction (ETD) definition, patient selection, follow-up duration, additional treatments, and outcome measures. The current, but limited, evidence suggests that BET is effective in the long-term. However, more long-term studies with uniform criteria and outcome measures as well as placebo-controlled studies are needed. The proposed indications for BET by the Finnish Otosurgical Society include chronic bothersome symptoms referring to ETD, ETD-related symptoms when pressure changes rapidly, or recurring serous otitis media. With the current evidence, we suggest treating only adults with BET.
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http://dx.doi.org/10.5152/iao.2018.4769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354503PMC
April 2018

Patient satisfaction in the long-term effects of Eustachian tube balloon dilation is encouraging.

Acta Otolaryngol 2018 Feb 10;138(2):122-127. Epub 2017 Oct 10.

a Department of Otorhinolaryngology, Head and Neck Center , Helsinki University Hospital, University of Helsinki , Helsinki , Finland.

Object: To investigate the long-term effects of balloon Eustachian tuboplasty (BET) from patient's perspective and to discover which symptoms of Eustachian tube dysfunction (ETD) benefit the most from BET.

Method: We designed a retrospective postal questionnaire based on the seven-item ETD questionnaire (ETDQ-7). Our questionnaire covered the severity of present ETD symptoms in comparison with the preoperative situation, the severity of current overall ear symptoms, and possible surgical interventions after BET. Forty-six patients treated in our institution between 2011 and 2013 fulfilled the inclusion criteria and 74% (34 patients; total 52 ears treated with BET) returned the questionnaire with a mean follow-up time of 3.1 years (range 1.8-4.6 years).

Results: Pain in the ears, feeling of pressure in the ears, and feeling that ears are clogged had reduced in 75% of the ears that suffered from these symptoms preoperatively. Seventy-seven percent of all the responders felt that their overall ear symptoms were reduced. Altogether, 82% of all the patients stated that they would undergo BET again if their ear symptoms returned to the preoperative level.

Conclusion: Patient satisfaction in the long-term effects of BET is encouraging. These results may help clinicians in preoperative patient selection and counselling.
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http://dx.doi.org/10.1080/00016489.2017.1384568DOI Listing
February 2018

Balloon Eustachian tuboplasty under local anesthesia: Is it feasible?

Laryngoscope 2017 May 3;127(5):1021-1025. Epub 2017 Feb 3.

Department of Otorhinolaryngology-Head and Neck Surgery, Head and Neck Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Objective: To study whether balloon Eustachian tuboplasty (BET) is a feasible and safe procedure under local anesthesia.

Study Design: Prospective multicenter case-control study.

Methods: Patients undergoing either BET (n = 13) or endoscopic sinus surgery (ESS) (n = 12) under local anesthesia, with the possibility of sedation and analgesia, were monitored during the procedure and recovery period for possible adverse effects. After the procedure, the patients responded to a questionnaire assessing their experience.

Results: No adverse effects were detected in the BET group. Patients in the BET group reported similar Visual Analog Scale scores for pain during the operation as the ESS group (5.0 ± 0.7 vs. 3.2 ± 0.7, mean ± standard error of the mean). However, patients in the BET group experienced more discomfort (4.2 ± 0.6 vs. 2.5 ± 0.3, respectively, P = 0.049). Seventy-seven and 92% of the patients in the BET and ESS groups, respectively, considered the anesthesia and pain relief to be sufficient. Patients from both the BET and ESS groups were almost devoid of pain 1 to 2 hours postoperatively (0.8 ± 0.2 and 1.4 ± 0.3, respectively). In total, 12 of 13 patients in the BET group, and all 12 patients in the ESS group, would choose local anesthesia with sedation and analgesia if they needed to undergo the same procedure again.

Conclusion: BET is a safe and feasible procedure under monitored anesthesia care, including local anesthesia along with sedation and analgesia. There is need for further methodological improvement to reduce pain and discomfort during the operation.

Level Of Evidence: 4. Laryngoscope, 127:1021-1025, 2017.
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http://dx.doi.org/10.1002/lary.26488DOI Listing
May 2017

Jugulotympanic paragangliomas in southern Finland: a 40-year experience suggests individualized surgical management.

Eur Arch Otorhinolaryngol 2017 Jan 5;274(1):389-397. Epub 2016 Jul 5.

Head and Neck Centre, Otorhinolaryngology, Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4, 00029, Helsinki, HUS, Finland.

Treatment of jugulotympanic paragangliomas (JTPGLs) remains challenging with no clear guidelines for management or follow-up. The aim of this retrospective case-note study was to assess long-term results of operatively and conservatively managed JTPGLs between years 1974-2013. A total of 36 patients with JTPGLs were identified. Clinical characteristics and management outcomes of patients were reviewed. Data were extracted on demographics, symptoms, timing of diagnosis, tumor location and size, embolization, and management, including pre- and post-operative imaging, analysis of operative techniques, and follow-up. Pulsatile tinnitus and hearing loss were the most common presenting symptoms. Thirty-four (94 %) patients were treated with primary surgical therapy and two (6 %) with radiotherapy. The surgical approaches included endaural approach for Fisch Class A tumors and a variety of approaches for Fisch Class B-D tumors with an increasing predilection for function-preserving surgery. Eight (24 %) patients received subtotal resection. Five (15 %) patients had a local recurrence within 10 years after primary surgery. Two (6 %) patients suffered a permanent cranial nerve (CN) deficit after primary surgery. We advocate radical surgery when tumor resection is possible without compromising CNs. Function-preserving surgery with at least a 10-year follow-up for Fisch Class B-D tumors should be considered if CNs are in danger.
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http://dx.doi.org/10.1007/s00405-016-4184-1DOI Listing
January 2017

[Tympanic membrane perforation ].

Duodecim 2014 ;130(8):810-8

Tympanic membrane perforation may be caused by, e.g., trauma or acute or chronic middle ear infection. Perforation causes conductive hearing loss. Since it predisposes to infections, it is important to keep the ear dry. In most cases traumatic perforations heal spontaneously. Perforations caused by acute middle ear infections are treated with antibiotics. Chronic perforation due to chronic middle ear infection or cholesteatoma will usually not heal without surgery. Most perforation cases can be taken care of in primary care. ENT consultation is needed when alarming signs, such as continuous pain, vertigo or facial paralysis exist, or if the perforation persists.
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June 2014

[Acute mastoiditis in children].

Duodecim 2014 ;130(3):251-7

Acute mastoiditis in children develops when acute otitis media (AOM) spreads into the mastoid air cells inside the temporal bone. The diagnosis is based on clinical findings of AOM with simultaneous signs of infection in the mastoid area. The most common pathogen causing acute mastoiditis in children is Streptococcus pneumoniae. Intravenous antimicrobial medication, tympanostomy and microbial sample are the cornerstones of the treatment. If a complication of mastoiditis is suspected, imaging studies are needed, preferably with magnetic resonance imaging. The most common complication of acute mastoiditis is a subperiosteal abscess.
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April 2014

Evaluation of Temporal Difference Limen in Preoperative Non-Invasive Ear Canal Audiometry as a Predictive Factor for Speech Perception after Cochlear Implantation.

Audiol Res 2014 Mar 27;4(1):91. Epub 2014 Feb 27.

Department of Otorhinolaryngology, Head & Neck Surgery, Helsinki University Central Hospital , Finland.

The temporal difference limen (TDL) can be measured with noninvasive electrical ear canal stimulation. The objective of the study wa to determine the role of preoperative TDL measurements in predicting patients' speech perception after cochlear implantation. We carried out a retrospective chart analysis of fifty-four cochlear implant (CI) patients with preoperative TDL and postoperative bisyllabic word recognition measurements in Helsinki University Central Hospital between March 1994 and March 2011. Our results show that there is no correlation between TDL and postoperative speech perception. However, patient's advancing age correlates with longer TDL but not-directly with poorer speech perception. The results are in line with previous results concerning the lack of predictive value of preoperativ TDL measurements in CI patients.
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http://dx.doi.org/10.4081/audiores.2014.91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627137PMC
March 2014

Experience of head and neck extracranial schwannomas in a whole population-based single-center patient series.

Eur Arch Otorhinolaryngol 2014 Nov 3;271(11):3027-34. Epub 2014 Jan 3.

Department of Otorhinolaryngology, Head and Neck Surgery, Helsinki University Central Hospital and University of Helsinki, P.O.B 220, 00029, HUCH, Finland,

Due to their rarity most of the literature concerning head and neck extracranial schwannomas consists of case reports and small patient series. The aim of the study was to describe population-based incidence, presenting signs and symptoms, management and outcome of head and neck extracranial schwannomas in a larger patient group. All the head and neck extracranial schwannoma patients managed during 1987-2008 at the Helsinki University Central Hospital with a referral area of 1.5 million inhabitants were searched. Altogether 47 patients were identified and subjected to retrospective chart review. Population-based incidence of head and neck extracranial schwannomas was 0.14/100,000/year. Eighty-eight percent of the patients had symptoms, which had lasted on average for 11.5 months prior to diagnosis. Presenting signs and symptoms were diverse depending on the affected nerve. Ninety-four percent of the patients were treated surgically. Sixty-four percent of the operations were macroscopically radical. The tumor capsule was intentionally left in place in 9 %. Surgery-related complications were detected in only 7 % of the patients, but 1 month postoperatively 52 % of them had symptoms, majority relating to different nerve deficits. Treatment of extracranial head and neck schwannomas remains challenging. The tumor is benign, and it grows slowly in a vast majority of cases, but its symptoms are highly variable. Correct timing of surgery is essential, as also patients who are preoperatively asymptomatic may suffer severe postoperative morbidity. Preoperative patient counseling needs to address the risks of neurological sequelae.
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http://dx.doi.org/10.1007/s00405-013-2871-8DOI Listing
November 2014

Transient, afferent input-dependent, postnatal niche for neural progenitor cells in the cochlear nucleus.

Proc Natl Acad Sci U S A 2013 Aug 12;110(35):14456-61. Epub 2013 Aug 12.

Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.

In the cochlear nucleus (CN), the first central relay of the auditory pathway, the survival of neurons during the first weeks after birth depends on afferent innervation from the cochlea. Although input-dependent neuron survival has been extensively studied in the CN, neurogenesis has not been evaluated as a possible mechanism of postnatal plasticity. Here we show that new neurons are born in the CN during the critical period of postnatal plasticity. Coincidently, we found a population of neural progenitor cells that are controlled by a complex interplay of Wnt, Notch, and TGFβ/BMP signaling, in which low levels of TGFβ/BMP signaling are permissive for progenitor proliferation that is promoted by Wnt and Notch activation. We further show that cells with activated Wnt signaling reside in the CN and that these cells have high propensity for neurosphere formation. Cochlear ablation resulted in diminishment of progenitors and Wnt/β-catenin-active cells, suggesting that the neonatal CN maintains an afferent innervation-dependent population of progenitor cells that display active canonical Wnt signaling.
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http://dx.doi.org/10.1073/pnas.1307376110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761577PMC
August 2013

Intrinsic regenerative potential of murine cochlear supporting cells.

Sci Rep 2011 29;1:26. Epub 2011 Jun 29.

Department of Otolaryngology - Head & Neck Surgery, Stanford University School of Medicine, Stanford CA 94305, USA.

The lack of cochlear regenerative potential is the main cause for the permanence of hearing loss. Albeit quiescent in vivo, dissociated non-sensory cells from the neonatal cochlea proliferate and show ability to generate hair cell-like cells in vitro. Only a few non-sensory cell-derived colonies, however, give rise to hair cell-like cells, suggesting that sensory progenitor cells are a subpopulation of proliferating non-sensory cells. Here we purify from the neonatal mouse cochlea four different non-sensory cell populations by fluorescence-activated cell sorting (FACS). All four populations displayed proliferative potential, but only lesser epithelial ridge and supporting cells robustly gave rise to hair cell marker-positive cells. These results suggest that cochlear supporting cells and cells of the lesser epithelial ridge show robust potential to de-differentiate into prosensory cells that proliferate and undergo differentiation in similar fashion to native prosensory cells of the developing inner ear.
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http://dx.doi.org/10.1038/srep00026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3216513PMC
August 2013

Serial analysis of gene expression in the chicken otocyst.

J Assoc Res Otolaryngol 2011 Dec 19;12(6):697-710. Epub 2011 Aug 19.

Departments of Otolaryngology-Head & Neck Surgery and Molecular & Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5739, USA.

The inner ear arises from multipotent placodal precursors that are gradually committed to the otic fate and further differentiate into all inner ear cell types, with the exception of a few immigrating neural crest-derived cells. The otocyst plays a pivotal role during inner ear development: otic progenitor cells sub-compartmentalize into non-sensory and prosensory domains, giving rise to individual vestibular and auditory organs and their associated ganglia. The genes and pathways underlying this progressive subdivision and differentiation process are not entirely known. The goal of this study was to identify a comprehensive set of genes expressed in the chicken otocyst using the serial analysis of gene expression (SAGE) method. Our analysis revealed several hundred transcriptional regulators, potential signaling proteins, and receptors. We identified a substantial collection of genes that were previously known in the context of inner ear development, but we also found many new candidate genes, such as SOX4, SOX5, SOX7, SOX8, SOX11, and SOX18, which previously were not known to be expressed in the developing inner ear. Despite its limitation of not being all-inclusive, the generated otocyst SAGE library is a practical bioinformatics tool to study otocyst gene expression and to identify candidate genes for developmental studies.
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http://dx.doi.org/10.1007/s10162-011-0286-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214236PMC
December 2011

Human locus coeruleus neurons express the GABA(A) receptor gamma2 subunit gene and produce benzodiazepine binding.

Neurosci Lett 2010 Jun 22;477(2):77-81. Epub 2010 Apr 22.

Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, POB 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland.

Noradrenergic neurons of the locus coeruleus project throughout the cerebral cortex and multiple subcortical structures. Alterations in the locus coeruleus firing are associated with vigilance states and with fear and anxiety disorders. Brain ionotropic type A receptors for gamma-aminobutyric acid (GABA) serve as targets for anxiolytic and sedative drugs, and play an essential regulatory role in the locus coeruleus. GABA(A) receptors are composed of a variable array of subunits forming heteropentameric chloride channels with different pharmacological properties. The gamma2 subunit is essential for the formation of the binding site for benzodiazepines, allosteric modulators of GABA(A) receptors that are clinically often used as sedatives/hypnotics and anxiolytics. There are contradictory reports in regard to the gamma2 subunit's expression and participation in the functional GABA(A) receptors in the mammalian locus coeruleus. We report here that the gamma2 subunit is transcribed and participates in the assembly of functional GABA(A) receptors in the tyrosine hydroxylase-positive neuromelanin-containing neurons within postmortem human locus coeruleus as demonstrated by in situ hybridization with specific gamma2 subunit oligonucleotides and autoradiographic assay for flumazenil-sensitive [(3)H]Ro 15-4513 binding to benzodiazepine sites. These sites were also sensitive to the alpha1 subunit-preferring agonist zolpidem. Our data suggest a species difference in the expression profiles of the alpha1 and gamma2 subunits in the locus coeruleus, with the sedation-related benzodiazepine sites being more important in man than rodents. This may explain the repeated failures in the transition of novel drugs with a promising neuropharmacological profile in rodents to human clinical usage, due to intolerable sedative effects.
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http://dx.doi.org/10.1016/j.neulet.2010.04.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282555PMC
June 2010

Complication rates of radiofrequency surgery in the upper airways: a single institution experience.

Acta Otolaryngol 2009 Dec;129(12):1469-73

Department of Otorhinolaryngology, Head & Neck Surgery, Helsinki University Central Hospital, Helsinki, Finland.

Conclusion: Radiofrequency (RF) surgery of the upper airways appears to be a safe procedure with an acceptable incidence of minor and moderate complications.

Objectives: RF surgery is increasingly used in the treatment of patients with sleep disordered breathing and inferior turbinate hypertrophy. Our aim was to investigate the incidence and the severity of the complications of RF surgery in the upper airways.

Patients And Methods: This was a retrospective, observational study at a tertiary care centre, academic teaching hospital during 1 year. Data from medical records were collected on 753 consecutive patients treated with RF surgery of the inferior turbinate, soft palate and base of the tongue. Patients with synchronous surgical treatment were excluded.

Results: In all, 413 patients (66.3% males) with a mean age of 44.7 years (range 8-83 years) were treated with 2926 RF surgery ablations in 524 treatment sessions. There were no severe complications. The overall incidence of minor and moderate complications was low, i.e. 2.7% (11/524) and 0.6% (3/524) of the treatment sessions, and 0.5% (11/2926) and 0.1% (3/2926) of the ablations, respectively.
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http://dx.doi.org/10.3109/00016480802706719DOI Listing
December 2009

Brain regional distribution of GABA(A) receptors exhibiting atypical GABA agonism: roles of receptor subunits.

Neurochem Int 2009 Nov 4;55(6):389-96. Epub 2009 May 4.

Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, University of Helsinki, FI-00014 Helsinki, Finland.

The major inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA), has only partial efficacy at certain subtypes of GABA(A) receptors. To characterize these minor receptor populations in rat and mouse brains, we used autoradiographic imaging of t-butylbicyclophosphoro[(35)S]thionate ([(35)S]TBPS) binding to GABA(A) receptors in brain sections and compared the displacing capacities of 10mM GABA and 1mM 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a competitive GABA-site agonist. Brains from GABA(A) receptor alpha1, alpha4, delta, and alpha4+delta subunit knockout (KO) mouse lines were used to understand the contribution of these particular receptor subunits to "GABA-insensitive" (GIS) [(35)S]TBPS binding. THIP displaced more [(35)S]TBPS binding than GABA in several brain regions, indicating that THIP also inhibited GIS-binding. In these regions, GABA prevented the effect of THIP on GIS-binding. GIS-binding was increased in the cerebellar granule cell layer of delta KO and alpha4+delta KO mice, being only slightly diminished in that of alpha1 KO mice. In the thalamus and some other forebrain regions of wild-type mice, a significant amount of GIS-binding was detected. This GIS-binding was higher in alpha4 KO mice. However, it was fully abolished in alpha1 KO mice, indicating that the alpha1 subunit was obligatory for the GIS-binding in the forebrain. Our results suggest that native GABA(A) receptors in brain sections showing reduced displacing capacity of [(35)S]TBPS binding by GABA (partial agonism) minimally require the assembly of alpha1 and beta subunits in the forebrain and of alpha6 and beta subunits in the cerebellar granule cell layer. These receptors may function as extrasynaptic GABA(A) receptors.
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http://dx.doi.org/10.1016/j.neuint.2009.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760098PMC
November 2009

Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over-expressing hippocampal extrasynaptic alpha6beta GABA(A) receptors.

J Neurochem 2008 Apr 16;105(2):338-50. Epub 2007 Nov 16.

Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.

The behavioral and functional significance of the extrasynaptic inhibitory GABA(A) receptors in the brain is still poorly known. We used a transgenic mouse line expressing the GABA(A) receptor alpha6 subunit gene in the forebrain under the Thy-1.2 promoter (Thy1alpha6) mice ectopically expressing alpha6 subunits especially in the hippocampus to study how extrasynaptically enriched alphabeta(gamma2)-type receptors alter animal behavior and receptor responses. In these mice extrasynaptic alpha6beta receptors make up about 10% of the hippocampal GABA(A) receptors resulting in imbalance between synaptic and extrasynaptic inhibition. The synthetic GABA-site competitive agonist gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; 3 mg/kg) induced remarkable anxiolytic-like response in the light : dark exploration and elevated plus-maze tests in Thy1alpha6 mice, while being almost inactive in wild-type mice. The transgenic mice also lost quicker and for longer time their righting reflex after 25 mg/kg gaboxadol than wild-type mice. In hippocampal sections of Thy1alpha6 mice, the alpha6beta receptors could be visualized autoradiographically by interactions between gaboxadol and GABA via [(35)S]TBPS binding to the GABA(A) receptor ionophore. Gaboxadol inhibition of the binding could be partially prevented by GABA. Electrophysiology of recombinant GABA(A) receptors revealed that GABA was a partial agonist at alpha6beta3 and alpha6beta3delta receptors, but a full agonist at alpha6beta3gamma2 receptors when compared with gaboxadol. The results suggest strong behavioral effects via selective pharmacological activation of enriched extrasynaptic alphabeta GABA(A) receptors, and the mouse model represents an example of the functional consequences of altered balance between extrasynaptic and synaptic inhibition.
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http://dx.doi.org/10.1111/j.1471-4159.2007.05136.xDOI Listing
April 2008

Compensation by reduced L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor responses in a mouse model with reduced gamma-aminobutyric acid type A receptor-mediated synaptic inhibition.

J Neurosci Res 2007 Feb;85(3):668-72

Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.

L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists increase the threshold for electroshock-induced convulsions. Here, we show that a transgenic mouse line overexpressing cerebellum-restricted gamma-aminobutyric acid type A (GABA(A)) receptor alpha6 subunit in the hippocampal CA1 pyramidal cells (Thy1alpha6 mouse line) exhibits about a 20% increase in the electroshock current intensity inducing tonic hindlimb extension convulsion in 50% of the mice compared with that of their wild-type controls. AMPA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in patch clamp recordings of CA1 pyramidal neurons in hippocampal slices had decreased amplitudes (8.4 +/- 2.2 pA) in the transgenics compared with the wild types (10.3 +/- 2.5 pA) but showed no change in current decay or frequency. Our results suggest that decreased AMPA-mediated neurotransmission might explain the increased threshold for electroconvulsions and warrant further studies on the regulation between various components of inhibition and excitation in neurons.
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http://dx.doi.org/10.1002/jnr.21138DOI Listing
February 2007

Impact of epsilon and theta subunits on pharmacological properties of alpha3beta1 GABAA receptors expressed in Xenopus oocytes.

BMC Pharmacol 2006 Jan 13;6. Epub 2006 Jan 13.

Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, University of Helsinki, POB 63 (Haartmaninkatu 8), FI-00014, Finland.

Background: Gamma-aminobutyric acid type A (GABAA) receptors provide the main inhibitory control in the brain. Their heterogeneity may make it possible to precisely target drug effects to selected neuronal populations. In situ hybridization using rat brain sections has revealed a unique expression of GABAA receptor epsilon and theta subunit transcripts in the locus coeruleus, where they are accompanied at least by alpha3, alpha2, beta1 and beta3 subunits. Here, we studied the pharmacology of the human alpha3beta1, alpha3beta1epsilon, alpha3beta1theta and alpha3beta1epsilontheta receptor subtypes expressed in Xenopus oocytes and compared them with the gamma2 subunit-containing receptors.

Results: The GABA sensitivites and effects of several positive modulators of GABAA receptors were studied in the absence and the presence of EC25 GABA using the two-electrode voltage-clamp method. We found 100-fold differences in GABA sensitivity between the receptors, alpha3beta1epsilon subtype being the most sensitive and alpha3beta1gamma2 the least sensitive. Also gaboxadol dose-response curves followed the same sensitivity rank order, with EC50 values being 72 and 411 microM for alpha3beta1epsilon and alpha3beta1gamma2 subtypes, respectively. In the presence of EC25 GABA, introduction of the epsilon subunit to the receptor complex resulted in diminished modulatory effects by etomidate, propofol, pregnanolone and flurazepam, but not by pentobarbital. Furthermore, the alpha3beta1epsilon subtype displayed picrotoxin-sensitive spontaneous activity. The theta subunit-containing receptors were efficiently potentiated by the anesthetic etomidate, suggesting that theta subunit could bring the properties of beta2 or beta3 subunits to the receptor complex.

Conclusion: The epsilon and theta subunits bring additional features to alpha3beta1 GABAA receptors. These receptor subtypes may constitute as novel drug targets in selected brain regions, e.g., in the brainstem locus coeruleus nuclei.
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http://dx.doi.org/10.1186/1471-2210-6-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1363348PMC
January 2006

Evidence for a reduction of coupling between GABAA receptor agonist and ionophore binding sites by inorganic phosphate.

Neurochem Res 2005 Dec;30(12):1471-82

Institute of Biomedicine, Pharmacology, University of Helsinki, P.O.Box 63, Helsinki, FI-00014, Finland.

[35S]TBPS binding to the GABAA receptor ionophore binding site is anion dependent. Using autoradiography on rat brain sections, we show that permeabilities of anions through the receptor channel correlate with their efficiencies to promote basal [35S]TBPS binding. Phosphate made an exception as it induced more binding than expected from its permeability. Well-permeable anions (chloride, nitrate, formate) allowed [35S]TBPS binding to be effectively displaced by 1 mM GABA, whereas low-permeable anions (acetate, phosphate, propionate) markedly prevented this GABA effect, especially in the thalamus, the transition from the high to the low GABA effect being between formate and acetate. In the presence of phosphate, GABA enhanced [3H]flunitrazepam binding to benzodiazepine site of recombinant alpha1beta2gamma2 receptors with the same efficacy but lower potency as compared to the presence of chloride, whereas [35S]TBPS binding was abnormally modulated by GABA. These results suggest that inorganic phosphate affects coupling between agonist and ionophore sites in GABAA receptors.
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http://dx.doi.org/10.1007/s11064-005-8824-xDOI Listing
December 2005

GABA(A) receptor subtypes as targets for neuropsychiatric drug development.

Pharmacol Ther 2006 Jan 5;109(1-2):12-32. Epub 2005 Jul 5.

Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, P.O. Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland.

The main inhibitory neurotransmitter system in the brain, the gamma-aminobutyric acid (GABA) system, is the target for many clinically used drugs to treat, for example, anxiety disorders and epilepsy and to induce sedation and anesthesia. These drugs facilitate the function of pentameric A-type GABA (GABA(A)) receptors that are extremely widespread in the brain and composed from the repertoire of 19 subunit variants. Modern genetic studies have found associations of various subunit gene polymorphisms with neuropsychiatric disorders, including alcoholism, schizophrenia, anxiety, and bipolar affective disorder, but these studies are still at their early phase because they still have failed to lead to validated drug development targets. Recent neurobiological studies on new animal models and receptor subunit mutations have revealed novel aspects of the GABA(A) receptors, which might allow selective targeting of the drug action in receptor subtype-selective fashion, either on the synaptic or extrasynaptic receptor populations. More precisely, the greatest advances have occurred in the clarification of the molecular and behavioral mechanisms of action of the GABA(A) receptor agonists already in the clinical use, such as benzodiazepines and anesthetics, rather than in the introduction of novel compounds to clinical practice. It is likely that these new developments will help to overcome the present problems of the chronic treatment with nonselective GABA(A) agonists, that is, the development of tolerance and dependence, and to focus the drug action on the neurobiologically and neuropathologically relevant substrates.
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http://dx.doi.org/10.1016/j.pharmthera.2005.05.009DOI Listing
January 2006

Behavioural correlates of an altered balance between synaptic and extrasynaptic GABAAergic inhibition in a mouse model.

Eur J Neurosci 2004 Oct;20(8):2168-78

Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, PO Box 63, FI-00014 University of Helsinki, Helsinki, Finland.

GABAA receptors mediate fast phasic inhibitory postsynaptic potentials and participate in slower tonic extrasynaptic inhibition. Thy1alpha6 mice with ectopic forebrain expression of GABAA receptor alpha6 subunits exhibit increased extrasynaptic GABAA receptor-mediated background conductance and reduced synaptic GABAA receptor currents in hippocampal CA1 neurons [W. Wisden et al. (2002) Neuropharmacology 43, 530-549]. Here we demonstrate that isolated CA1 neurons of these mice showed furosemide-sensitivity of GABA-evoked currents, confirming the functional expression of alpha6 subunit. In addition, receptor autoradiography of the CA1 region of Thy1alpha6 brain sections revealed pharmacological features that are unique for alpha6betagamma2 and alpha6beta receptors. The existence of atypical alpha6beta receptors was confirmed after completely eliminating GABAA receptors containing gamma1, gamma2, gamma3 or delta subunits using serial immunoaffinity chromatography on subunit-specific GABAA receptor antibodies. Behaviourally, the Thy1alpha6 mice showed normal features with slightly enhanced startle reflex and struggle-escape behaviours. However, they were more sensitive to GABAA antagonists DMCM (shorter latency to writhing clonus) and picrotoxinin (shorter latency to generalized convulsions). Tiagabine, an antiepileptic GABA-uptake inhibitor that increases brain GABA levels, delayed picrotoxinin-induced convulsions at a low dose of 3.2 mg/kg in Thy1alpha6 mice, but not in control mice; however, the overall effect of higher tiagabine doses on the convulsion latency remained smaller in the Thy1alpha6 mice. Altered balance between extrasynaptic and synaptic receptors thus affects seizure sensitivity to GABAergic convulsants. Importantly, the increased extrasynaptic inhibition, even when facilitated in the presence of tiagabine, was not able fully to counteract enhanced seizure induction by GABAA antagonists.
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http://dx.doi.org/10.1111/j.1460-9568.2004.03684.xDOI Listing
October 2004