Surgical Treatment for Early Stage Glottic Carcinoma with Involvement of the Anterior Commissure.

Objective Assessment of the value of transoral laser microsurgery (TLM) compared with open surgery (OS) for early stage squamous cell carcinoma of the glottic larynx with special regard to involvement of the anterior commissure (AC). Study Design Case series with chart review. Setting Tertiary care otolaryngology clinic. Subjects and Methods Review of clinicopathological data of all patients with previously untreated T1a, T1b, and T2 glottic squamous cell carcinoma of the larynx who were consecutively enrolled over a 10-year period (January 1, 1992, to December 31, 2002). Results Local recurrence rate was 20.4% (10 of 49) for TLM and 10.7% (3 of 28) for OS. Comparison of the TLM and OS groups regarding local recurrence rates revealed a significant difference only for tumors invading the AC ( P = .046). Within the TLM group, tumors with involvement of the AC showed a significantly higher recurrence rate (38.1%; 8 of 21) compared with tumors without involvement of the AC (7.1%; 2 of 28; P = .008). In the OS group, involvement of the AC revealed no significant difference ( P = .45). The overall survival in both groups was comparable in both groups (TLM, 93.9%; OS, 89.3%; P = .47). Conclusion TLM and OS are equally effective surgical treatments for early stage glottic cancer without involvement of the AC, with selection of treatment based on pretreatment endoscopy. However, TLM is associated with less morbidity. In case of invasion of the AC, OS yields lower recurrence rates.

Validating a Method to Assess Lipreading, Audiovisual Gain, and Integration During Speech Reception With Cochlear-Implanted and Normal-Hearing Subjects Using a Talking Head.

OBJECTIVES: Watching a talker's mouth is beneficial for speech reception (SR) in many communication settings, especially in noise and when hearing is impaired. Measures for audiovisual (AV) SR can be valuable in the framework of diagnosing or treating hearing disorders. This study addresses the lack of standardized methods in many languages for assessing lipreading, AV gain, and integration. A new method is validated that supplements a German speech audiometric test with visualizations of the synthetic articulation of an avatar that was used, for it is feasible to lip-sync auditory speech in a highly standardized way. Three hypotheses were formed according to the literature on AV SR that used live or filmed talkers. It was tested whether respective effects could be reproduced with synthetic articulation: (1) cochlear implant (CI) users have a higher visual-only SR than normal-hearing (NH) individuals, and younger individuals obtain higher lipreading scores than older persons. (2) Both CI and NH gain from presenting AV over unimodal (auditory or visual) sentences in noise. (3) Both CI and NH listeners efficiently integrate complementary auditory and visual speech features. DESIGN: In a controlled, cross-sectional study with 14 experienced CI users (mean age 47.4) and 14 NH individuals (mean age 46.3, similar broad age distribution), lipreading, AV gain, and integration of a German matrix sentence test were assessed. Visual speech stimuli were synthesized by the articulation of the Talking Head system "MASSY" (Modular Audiovisual Speech Synthesizer), which displayed standardized articulation with respect to the visibility of German phones. RESULTS: In line with the hypotheses and previous literature, CI users had a higher mean visual-only SR than NH individuals (CI, 38%; NH, 12%; p < 0.001). Age was correlated with lipreading such that within each group, younger individuals obtained higher visual-only scores than older persons (rCI = -0.54; p = 0.046; rNH = -0.78; p < 0.001). Both CI and NH benefitted by AV over unimodal speech as indexed by calculations of the measures visual enhancement and auditory enhancement (each p < 0.001). Both groups efficiently integrated complementary auditory and visual speech features as indexed by calculations of the measure integration enhancement (each p < 0.005). CONCLUSIONS: Given the good agreement between results from literature and the outcome of supplementing an existing validated auditory test with synthetic visual cues, the introduced method can be considered an interesting candidate for clinical and scientific applications to assess measures important for AV SR in a standardized manner. This could be beneficial for optimizing the diagnosis and treatment of individual listening and communication disorders, such as cochlear implantation.

The Impact of a Cochlear Implant Electrode Array on the Middle Ear Transfer Function.

OBJECTIVES: As a treatment for partial deafness with residual hearing in the lower frequency range, the combined acoustic and electric stimulation of the cochlea has become widespread. Acoustic stimulation is provided by a hearing aid's airborne sound and the electric stimulation by a cochlear implant electrode array, which may be inserted through the round window or a cochleostomy. To take advantage of that concept, it is essential to preserve residual hearing after surgery. Therefore, the intracochlear electrode array should not compromise the middle ear vibration transmission. This study investigates the influence of different electrode types and insertion paths on the middle ear transfer function and the inner ear fluid dynamics. DESIGN: Sound-induced oval and round window net volume velocities were calculated from vibration measurements with laser vibrometers on six nonfixated human temporal bones. After baseline measurements in the "natural" condition, a cochleostomy was drilled and closed with connective tissue. Then, four different electrode arrays were inserted through the cochleostomy. Afterwards, they were inserted through the round window while the cochleostomy was patched again with connective tissue. RESULTS: After having drilled a cochleostomy and electrode insertion, no systematic trends in the changes of oval and round window volume velocities were observed. Nearly all changes of middle ear transfer functions, as well as oval and round window volume velocity ratios, were statistically insignificant. CONCLUSIONS: Intracochlear electrode arrays do not significantly increase cochlear input impedance immediately after insertion. Any changes that may occur seem to be independent of electrode array type and insertion path.

When Hearing Is Tricky: Speech Processing Strategies in Prelingually Deafened Children and Adolescents with Cochlear Implants Having Good and Poor Speech Performance.

Cochlear implants provide individuals who are deaf with access to speech. Although substantial advancements have been made by novel technologies, there still is high variability in language development during childhood, depending on adaptation and neural plasticity. These factors have often been investigated in the auditory domain, with the mismatch negativity as an index for sensory and phonological processing. Several studies have demonstrated that the MMN is an electrophysiological correlate for hearing improvement with cochlear implants. In this study, two groups of cochlear implant users, both with very good basic hearing abilities but with non-overlapping speech performance (very good or very poor speech performance), were matched according to device experience and age at implantation. We tested the perception of phonemes in the context of specific other phonemes from which they were very hard to discriminate (e.g., the vowels in /bu/ vs. /bo/). The most difficult pair was individually determined for each participant. Using behavioral measures, both cochlear implants groups performed worse than matched controls, and the good performers performed better than the poor performers. Cochlear implant groups and controls did not differ during time intervals typically used for the mismatch negativity, but earlier: source analyses revealed increased activity in the region of the right supramarginal gyrus (220-260 ms) in good performers. Poor performers showed increased activity in the left occipital cortex (220-290 ms), which may be an index for cross-modal perception. The time course and the neural generators differ from data from our earlier studies, in which the same phonemes were assessed in an easy-to-discriminate context. The results demonstrate that the groups used different language processing strategies, depending on the success of language development and the particular language context. Overall, our data emphasize the role of neural plasticity and use of adaptive strategies for successful language development with cochlear implants.

Acoustic effects of the reconstructed lateral epitympanic wall in a temporal bone and clinical study.

OBJECTIVE: Acoustic evaluation of reconstruction of the lateral epitympanic wall with bone or cartilage in a temporal bone study, and evaluation of audiometric data of patients who underwent cholesteatoma surgery with reconstruction of the lateral epitympanic wall with horseshoe-shaped cartilage. STUDY DESIGN: Temporal bone study and retrospective chart review. METHODS: Preparation of temporal bones included reconstruction of the epitympanic wall with fixated and loose cartilage and bone. The volume velocities of the stapes footplate were measured from the inner-ear side of the footplate by laser scanning doppler vibrometry following sound stimulation in the outer ear canal. Additionally, the audiometric data of 13 consecutive patients who underwent epitympanic cholesteatoma surgery, with an intact ossicular chain and reconstruction of the scutum with a horseshoe-shaped cartilage in contact with the malleus' neck, were evaluated retrospectively. RESULTS: The experimental results showed similar volume velocities at the stapes footplate for the fixated and unfixated cartilage as well as for the unfixated bone. However, the fixated bone yielded significantly reduced volume velocities. Clinical data confirmed that the cartilaginous horseshoe- technique allowed for a stable reconstruction of the scutum with satisfying audiometric outcome. CONCLUSION: In case of cholesteatoma surgery and the need for the reconstruction of the scutum, no adverse effects on hearing outcome are to be expected by using the malleus' neck as an anchoring point for cartilaginous scutum reconstruction. LEVEL OF EVIDENCE: NA. Laryngoscope, 127:1427-1434, 2017.

Long-term Results of the Cartilage Shoe Technique to Anchor a Titanium Total Ossicular Replacement Prosthesis on the Stapes Footplate After Type III Tympanoplasty.

Importance: Multiple techniques for a more secure and stable anchoring of the foot of a total ossicular replacement prosthesis (TORP) on the footplate have been proposed. To address this issue, a technique was developed that fits a cartilage shoe into the oval niche to guide the base of the prosthesis into a preformed central perforation. Objective: To evaluate the long-term results of the cartilage shoe technique used to anchor a titanium TORP on the stapes footplate in patients after type III tympanoplasty. Design, Setting, and Participants: Medical record review of total ossiculoplasties at a single center. The study included all patients who had undergone a tympanoplasty using a TORP between January 1, 2004, and December 31, 2008, at the Department of Otorhinolaryngology-Head and Neck Surgery, University of Cologne, Cologne, Germany. Main Outcomes and Measures: Hearing thresholds were determined by a 4-frequency (500-4000 Hz) pure-tone average air-bone gap (PTA-ABG). Intraoperative findings from revision surgery and second-look operations are reported. Results: Forty-two ears were eligible for follow-up examination, averaging 6.8 years (range, 4.8-9.1 years) after surgery, that comprised otoscopy and audiometry. The mean age of 22 women and 20 men was 42.8 years (age range, 6-78 years). The overall PTA-ABG decreased from a mean (SD) of 33.0 (8.4) decibels (dB) before surgery to a mean (SD) of 22.0 (10.1) dB after surgery (P ≤ .001, η = 0.402). Before surgery, 64% (27 of 42) of the patients had a PTA-ABG exceeding 30 dB, which was 30 dB or less in 76% (32 of 42) of the patients after surgery. After canal wall down (n = 18) and tympanoplasties with intact canal wall (n = 24), the PTA-ABG was reduced from a mean (SD) of 33.0 (8.9) dB to 24.6 (11.2) dB (P = .01, η = 0.271) and from a mean (SD) of 32.0 (7.3) dB to 19.6 (9.2) dB (P ≤ .001, η = 0.511), respectively. For transmeatal revision ossiculoplasty (n = 33), the PTA-ABG improved from a mean (SD) of 32.0 (8.6) dB to 21.0 (10.2) dB (P ≤ .001, η = 0.389), similar to primary ossiculoplasty (n = 9), with a mean (SD) of 33.0 (5.5) dB PTA-ABG before surgery and a mean (SD) of 21.0 (9.8) dB PTA-ABG after surgery (P = .005, η = 0.478). Intraoperative findings from revision surgery (n = 11) during the study period and second-look procedures (n = 7) showed that the cartilage shoe prevented a lift off the footplate in all but 2 patients, even in the presence of recurrent cholesteatoma. Conclusions and Relevance: The use of the cartilage shoe that anchors a titanium TORP on the stapes footplate can be advocated for good and reliable long-term results after total ossiculoplasty.

Long term results of the titanium clip prosthesis.

The objective of the study is to evaluate the long term results of ossiculoplasty using the clip titanium partial ossicular replacement prosthesis. This study retrospectively reviews the partial ossiculoplasty conducted using clip titanium partial ossicular replacement prosthesis at a tertiary referral center. Audiometric outcomes and intraoperative findings were postoperatively measured from revision surgery of 47 ears (20 women, 27 men, mean age 43 years) averaging 6.5 years. The overall air-bone gap decreased from 25.7 dB preoperatively to 16.8 dB 6.5 years postoperatively (p ≤ 0.001, η p2  = 0.210). An air-bone gap of <20 dB was present in 28 % of ears preoperatively and increased to 72 % postoperatively. In revision (n = 30) and primary tympanoplasties (n = 17), the preoperative air-bone gaps were reduced from 28.9 and 20.1 to 18.7 dB (p ≤ 0.001, η p2  = 0.240) and 13.2 dB (p = 0.033, η p2  = 0.192), respectively. In canal wall down (n = 15) procedures and tympanoplasties with intact canal wall (n = 32), the mean air-bone gaps diminished from 28.9 to 18.1 dB (p = 0.02, η p2  = 0.245) and 24.2 to 16.1 dB (p ≤ 0.001, η p2  = 0.221), respectively. In our own revision tympanoplasties (n = 8) and second look operations (n = 6), we found that the prostheses were safe to remove without any deleterious effects. Two prostheses were dislocated from the stapes' head due to recurrent cholesteatoma. Therefore, it can be concluded that ossiculoplasty using the clip partial ossicular replacement prosthesis allows for good and reliable long term hearing results. Also, the flexible strips reveal no adverse effects on the encompassed stapes' head and do not complicate revision surgery.

Loads and Coupling Modalities Influence the Performance of the Floating Mass Transducer as a Round Window Driver.

HYPOTHESIS: High loads forcing the floating mass transducer (FMT) of a single active middle ear implant toward the round window membrane (RWM) affect the backward stimulation of the cochlea. BACKGROUND: Various factors influence the backward stimulation of the cochlea. We investigated the effects of various loads applied to the FMT together with different coupling techniques at the fully exposed RWM on the vibration transmission. METHODS: Experimental study on temporal bones with the FMT linked to a load cell mounted on a translation stage moving it against the fully exposed RWM with increasing loads up to 200 mN by itself, with interposed perichondrium, cartilage or connected to the round window coupler. Cochlear stimulation is measured by the volume velocities of the stapes footplate using LASER-Doppler-vibrometry. RESULTS: Loads ranging from 5 to 20 mN induce the highest volume velocities of the stapes footplate. Increasing loads decrease the transmission of vibration in the low-frequency range but enhance the transmission of high frequencies. The interposition of perichondrium and cartilage proved to be advantageous. CONCLUSION: The load applied to the FMT distinctly affects the backward stimulation of the cochlea. Although increasing loads have inverse effects on the transmission of low and high frequencies, high loads lead to an overall decrease of cochlear stimulation. Out of the applied coupling techniques interposed perichondrium and cartilage allow for the most efficient stimulation.

Performance of the round window soft coupler for the backward stimulation of the cochlea in a temporal bone model.

The round window vibroplasty is a feasible option for the treatment of conductive, sensorineural and mixed hearing loss. Although clinical data suggest a satisfying clinical outcome with various coupling methods, the most efficient coupling technique of the floating mass transducer to the round window is still a matter of debate. For this, a soft silicone-made coupler has been developed recently that aims to ease and optimize the stimulation of the round window membrane of this middle ear implant. We performed a temporal bone study evaluating the performance of the soft coupler compared to the coupling with individually shaped cartilage, perichondrium and the titanium round window coupler with loads up to 20 mN at the unaltered and fully exposed round window niche. The stimulation of the cochlea was measured by the volume velocities of the stapes footplate detected by a laser Doppler vibrometer. The coupling method was computed as significant factor with cartilage and perichondrium allowing for the highest volume velocities followed by the soft and titanium coupler. Exposure of the round window niche allowed for higher volume velocities while the applied load did not significantly affect the results. The soft coupler allows for a good contact to the round window membrane and an effective backward stimulation of the cochlea. Clinical data are mandatory to evaluate performance of this novel coupling method in vivo.

Effects of Hearing Loss and Cognitive Load on Speech Recognition with Competing Talkers.

Everyday communication frequently comprises situations with more than one talker speaking at a time. These situations are challenging since they pose high attentional and memory demands placing cognitive load on the listener. Hearing impairment additionally exacerbates communication problems under these circumstances. We examined the effects of hearing loss and attention tasks on speech recognition with competing talkers in older adults with and without hearing impairment. We hypothesized that hearing loss would affect word identification, talker separation and word recall and that the difficulties experienced by the hearing impaired listeners would be especially pronounced in a task with high attentional and memory demands. Two listener groups closely matched for their age and neuropsychological profile but differing in hearing acuity were examined regarding their speech recognition with competing talkers in two different tasks. One task required repeating back words from one target talker (1TT) while ignoring the competing talker whereas the other required repeating back words from both talkers (2TT). The competing talkers differed with respect to their voice characteristics. Moreover, sentences either with low or high context were used in order to consider linguistic properties. Compared to their normal hearing peers, listeners with hearing loss revealed limited speech recognition in both tasks. Their difficulties were especially pronounced in the more demanding 2TT task. In order to shed light on the underlying mechanisms, different error sources, namely having misunderstood, confused, or omitted words were investigated. Misunderstanding and omitting words were more frequently observed in the hearing impaired than in the normal hearing listeners. In line with common speech perception models, it is suggested that these effects are related to impaired object formation and taxed working memory capacity (WMC). In a post-hoc analysis, the listeners were further separated with respect to their WMC. It appeared that higher capacity could be used in the sense of a compensatory mechanism with respect to the adverse effects of hearing loss, especially with low context speech.

Song Perception by Professional Singers and Actors: An MEG Study.

The cortical correlates of speech and music perception are essentially overlapping, and the specific effects of different types of training on these networks remain unknown. We compared two groups of vocally trained professionals for music and speech, singers and actors, using recited and sung rhyme sequences from German art songs with semantic and/ or prosodic/melodic violations (i.e. violations of pitch) of the last word, in order to measure the evoked activation in a magnetoencephalographic (MEG) experiment. MEG data confirmed the existence of intertwined networks for the sung and spoken modality in an early time window after word violation. In essence for this early response, higher activity was measured after melodic/prosodic than semantic violations in predominantly right temporal areas. For singers as well as for actors, modality-specific effects were evident in predominantly left-temporal lateralized activity after semantic expectancy violations in the spoken modality, and right-dominant temporal activity in response to melodic violations in the sung modality. As an indication of a special group-dependent audiation process, higher neuronal activity for singers appeared in a late time window in right temporal and left parietal areas, both after the recited and the sung sequences.

Impact of coupling techniques of an active middle ear device to the round window membrane for the backward stimulation of the cochlea.

HYPOTHESIS: Interposed cartilage and the round window coupler (RWC) increase the efficiency of cochlea stimulation with the floating mass transducer (FMT) of a single active middle ear implant (AMEI) placed against the round window membrane. BACKGROUND: Treatment of mixed and conductive hearing loss with an AMEI attached to the round window is effective, yet the best placement technique of its FMT for the most efficient stimulation of the cochlea remains to be determined. METHODS: Experimental study on human temporal bones with the FMT placed against firstly the unaltered round window niche and then subsequently against the fully exposed round window membrane with and without interposed cartilage and the RWC. Cochlea stimulation is measured by the volume velocities of the stapes footplate using LASER vibrometry. RESULTS: At the undrilled round window niche, placement of the FMT by itself and with the RWC resulted in similar volume velocities. The response was significantly raised by interposing cartilage into the undrilled round window niche. Complete exposure of the round window membrane allowed for significantly increased volume velocities. Among these, coupling of the FMT with interposed cartilage yielded responses of similar magnitude compared with the RWC but significantly higher compared with the FMT by itself. CONCLUSION: Good contact to the round window membrane is essential for efficient stimulation of the cochlea. Therefore, interposing cartilage into the undrilled round window niche is a viable option. At the drilled round window membrane, the FMT with interposed cartilage and attached to the RWC are similarly effective.

Neural correlates of speech processing in prelingually deafened children and adolescents with cochlear implants.

Prelingually deafened children with cochlear implants stand a good chance of developing satisfactory speech performance. Nevertheless, their eventual language performance is highly variable and not fully explainable by the duration of deafness and hearing experience. In this study, two groups of cochlear implant users (CI groups) with very good basic hearing abilities but non-overlapping speech performance (very good or very bad speech performance) were matched according to hearing age and age at implantation. We assessed whether these CI groups differed with regard to their phoneme discrimination ability and auditory sensory memory capacity, as suggested by earlier studies. These functions were measured behaviorally and with the Mismatch Negativity (MMN). Phoneme discrimination ability was comparable in the CI group of good performers and matched healthy controls, which were both better than the bad performers. Source analyses revealed larger MMN activity (155-225 ms) in good than in bad performers, which was generated in the frontal cortex and positively correlated with measures of working memory. For the bad performers, this was followed by an increased activation of left temporal regions from 225 to 250 ms with a focus on the auditory cortex. These results indicate that the two CI groups developed different auditory speech processing strategies and stress the role of phonological functions of auditory sensory memory and the prefrontal cortex in positively developing speech perception and production.

Rapid increases of gamma power in the auditory cortex following noise trauma in humans.

Tinnitus is an auditory perception in the absence of any external sound source. It has been suggested that tinnitus is related to enhanced synchronization of neuronal activity in the auditory cortex. Usually a hearing damage can be identified suggesting auditory deprivation to central auditory regions to be fundamental for neurophysiological processes related to tinnitus. Until now, human research has been conducted on patients with chronic tinnitus (>6 months). However, neuronal activity accompanying auditory deprivation and putatively tinnitus may not remain constant over time, making it difficult to directly relate outcomes of current animal studies (acute tinnitus) to chronic tinnitus in humans, and vice versa. We investigated 14 amateur rock musicians who frequently reported a short-term tinnitus immediately after band practice. Magnetoencephalographic resting-state recordings, audiometry and tinnitus testing were performed at two separate occasions: with and without previous exposure to loud music. Analyses revealed that transient tinnitus was accompanied by temporary hearing loss in both ears and increased gamma activity in the right auditory cortex in 13 out of 14 cases. Additionally, tinnitus frequency was strongly correlated to hearing loss. Analogous to animal studies, our results show for the first time in humans that noise trauma leads rapidly to increased neuronal synchrony in the auditory cortex. Importantly, the strongly right-lateralized effect implies that it does not reflect tinnitus percept per se. This could rather have been triggered by greater discontinuities of hearing loss at high frequencies that were particularly pronounced in the left ear.

Remodeling the brain: plastic structural brain changes produced by different motor therapies after stroke.

BACKGROUND AND PURPOSE: Studies on adult stroke patients have demonstrated functional changes in cortical excitability, metabolic rate, or blood flow after motor therapy, measures that can fluctuate rapidly over time. This study evaluated whether evidence could also be found for structural brain changes during an efficacious rehabilitation program. METHODS: Chronic stroke patients were randomly assigned to receive either constraint-induced movement therapy (n=16) or a comparison therapy (n=20). Longitudinal voxel-based morphometry was performed on structural MRI scans obtained immediately before and after patients received therapy. RESULTS: The group receiving constraint-induced movement therapy exhibited far greater improvement in use of the more affected arm in the life situation than the comparison therapy group. Structural brain changes paralleled these improvements in spontaneous use of the more impaired arm for activities of daily living. There were profuse increases in gray matter in sensory and motor areas both contralateral and ipsilateral to the affected arm that were bilaterally symmetrical, as well as bilaterally in the hippocampus. In contrast, the comparison therapy group failed to show gray matter increases. Importantly, the magnitude of the observed gray matter increases was significantly correlated with amount of improvement in real-world arm use. CONCLUSIONS: These findings suggest that a previously overlooked type of brain plasticity, structural remodeling of the human brain, is harnessed by constraint-induced movement therapy for a condition once thought to be refractory to treatment: motor deficit in chronic stroke patients.

Critical role for p47phox in renin-angiotensin system activation and blood pressure regulation.

OBJECTIVE: Renin-angiotensin system (RAS) activation leads to increased production of NAD(P)H oxidase-derived reactive oxygen species (ROS), and both have been implicated in the initiation and progression of arterial hypertension, atherosclerosis, and cardiac hypertrophy. The cytosolic subunit p47phox is critically involved in agonist-induced NAD(P)H oxidase activation. Here, we investigated the role of p47phox in blood pressure control, endothelium-dependent relaxation, cardiac hypertrophy, RAS activation, and renal oxidative stress under resting conditions. METHODS AND RESULTS: Mice deficient in p47phox (on C57BL/6 background) developed significantly higher systolic blood pressure levels compared to C57BL/6 wild-type animals (136.0+/-3.0 mmHg vs. 112.2+/-2.6, P<0.01, n=16) as measured by the tail cuff method from week 6 up to week 12 post partum. The increase in blood pressure in p47phox-/- mice was associated with an impaired endothelium-dependent relaxation (P<0.005 vs. wild-type, n=11). At the age of 12 weeks p47phox-/- mice showed increased plasma renin activity as analyzed by radioimmunoassay (14.5+/-1.8 ng/mL/h vs. 9.6+/-1.7 ng/mL/h, P<0.05, n=10) and enhanced angiotensin converting enzyme (ACE) activity in the kidney and aorta as measured by Hip-His-Leu cleavage (7.6+/-0.8 vs. 4.8+/-0.9 nmol/L His-Leu/mg protein, P<0.05, n=5) compared to wild-type mice. No differences in oxygen radical formation was determined in kidney samples by lucigenin- and luminol-enhanced chemiluminescence or by electron spin resonance spectroscopy. Consistently, treatment with the radical scavenger tempol did not lower blood pressure in p47phox-/- mice, whereas ACE and angiotensin II type I receptor inhibition normalized blood pressure. CONCLUSION: Deficiency of the NAD(P)H oxidase subunit p47phox leads to RAS activation, which subsequently contributes to blood pressure increase in a ROS-independent manner.