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Molecular genetic analysis of the mechanism of tumorigenesis in acoustic neuroma.

OBJECTIVE: Acoustic neuroma, both familial and sporadic, is clinically and biologically a heterogeneous condition with a wide variation in age of presentation, length of history, and tumor growth rate. In an attempt to correlate this clinical diversity with the underlying molecular pathology, we have analyzed 43 paired blood-tumor DNA samples from patients with acoustic neuromas. DESIGN: Molecular genetic analysis. SETTING: Molecular genetic research laboratory. PATIENTS: Paired blood-tumor DNA samples were obtained from 43 patients (41 sporadic and two patients with neurofibromatosis type 2). MAIN OUTCOME MEASURES: Loss of constitutional heterozygosity was looked for in the region of tumor suppressor genes on chromosomes 3p, 5q, 11p, 17p, 17q, and 22. RESULTS: We found loss of heterozygosity exclusively for markers on chromosome 22. Thirty-nine percent of tumors showed allele loss, and in each case the loss of heterozygosity included the region of the neurofibromatosis type 2 (NF2) gene. No loss of heterozygosity was detected in the region of known or putative suppressor genes in chromosomes 3p, 5q, 11p, 17p, and 17q. CONCLUSIONS: This study has demonstrated that (1) chromosome 22 allele loss is a frequent event in sporadic acoustic neuroma; (2) the minimal region of loss of heterozygosity in acoustic neuroma includes the NF2 gene; (3) the known tumor suppressor genes investigated (VHL, adenomatous polyposis coli, WT2, p53, and NF1) do not appear to be important in the pathogenesis of acoustic neuroma; and (4) patients with extensive chromosome 22 loss tended to be younger and with a slightly shorter clinical history than those with no detectable allele loss.

Adult↗

Cystic acoustic neuromas. Results of translabyrinthine surgery.

OBJECTIVE: This study was designed to investigate the surgical outcome of translabyrinthine surgery of cystic acoustic neuromas. DESIGN: Prospective registration of audiovestibular, otoneurologic, and neuroradiologic data of all patients operated on for cystic neuromas in the period 1976 to 1992. The diagnosis was proposed by neuroradiologic investigation, confirmed at surgery, and verified histologically. Clinical follow-up was performed 1 year after surgery. SETTING: The study included all patients with cystic acoustic neuromas from the entire country, referred to the centralized otoneurosurgical team in the Department of Otorhinolaryngology-Head and Neck Surgery, Gentofte University Hospital, and Department of Neurosurgery, Rigshospitalet, University of Copenhagen, Denmark. PATIENTS: The study included 23 patients (11 female and 12 male). Ages ranged between 23 and 77 years with a median of 51.2 years. MAIN OUTCOME: Our hypothesis suggested that surgical outcome of cystic acoustic neuromas was poorer compared with noncystic acoustic neuromas of matching size. The results of this study seem to confirm the hypothesis. RESULTS: The results are rather poor compared with results achieved in surgery of noncystic tumors of matching size, particularly the poor postoperative facial nerve function. CONCLUSIONS: Even though the operation for a cystic acoustic neuroma may appear to be easier and faster than the operation for a solid tumor, there is a high risk for accidental lesion of the facial nerve, in spite of using facial nerve monitoring. Rapid symptomatic worsening may occur due to sudden expansion of cystic elements and, therefore, a wait-and-see policy should not be applied to patients with cystic tumors.

Adult↗

Fetal acoustic stimulation in early labor and pathological fetal acidemia: a preliminary report.

OBJECTIVE: To determine if a nonreactive response to fetal acoustic stimulation in early labor can predict a significantly higher risk of umbilical arterial pH <7.10 or <7.00. METHODS: Fetal acoustic stimulation was applied to the fetuses of term parturients (gestational age > or =37 weeks) with cervical dilation of < or =5 cm. The responses to stimulation were correlated with cesarean delivery for fetal distress and umbilical arterial pH. Student's t-test, Chi-square, and Fisher exact test were used; P < 0.05 was considered significant. Relative risks (RR) and 95% confidence intervals (CI) were calculated. RESULTS: The study population contained 271 subjects, of which 90% (244) had a reactive response following acoustic stimulation and 10% (27) a nonreactive response. The maternal demographics, time interval from stimulation to delivery (8.3 +/- 8.7 vs. 8.3 +/- 8.4 h; P = 1.00) were similar in the two groups. Compared to those with a reactive response, patients with a nonreactive response had a significantly greater risk for: 1) cesarean delivery for fetal distress (2.0% vs. 11.1%; P = 0.03, RR 4.1, 95% Cl 1.5, 60.5), 2) umbilical arterial pH <7.10 (2.0% vs. 14.8%; P = 0.007, RR 5.0, 95% CI 2.2, 11.6), and 3) umbilical arterial pH <7.00 (0.8% vs. 7%; P = 0.05, RR 5.0, 95% CI 1.8, 15.2). CONCLUSION: A nonreactive response to fetal acoustic stimulation in early labor is associated with a significantly increased risk for cesarean delivery for fetal distress and neonatal acidosis. This finding extends the potential value of acoustic stimulation as an intrapartum admission screening test.

Acidosis↗

Squirrel monkey chuck call: vocal response to playback chucks based on acoustic structure and affiliative relationship with the caller.

Adult female squirrel monkeys (genus Saimiri) that are socially familiar often exchange the chuck vocalization, which differs acoustically across individuals. We used behavioral observations, vocalization playback experiments, and analysis of the acoustic properties of vocalizations to investigate the effect of caller identity and acoustic structure on vocal response to playback chucks in two all-female social groups (n=10 females). Females were most likely to respond with a chuck to the playback chucks of their closely affiliated partners compared to those of nonaffiliated group members. This shows for the first time that the chuck stimulus alone is sufficient to elicit a chuck response from a female's affiliated partner. Additionally, females responded with a chuck mostly to familiar playback chucks from their own group and least to playbacks of silent controls. Unfamiliar playback chucks from the same species and a different squirrel monkey species elicited chuck responses intermediate between familiar chucks and silent controls. Post-hoc discriminant function analyses provide preliminary evidence that females are most likely to respond to unfamiliar chucks when those chucks are close in acoustic structure to familiar chucks from their own social group. These results provide a provisional explanation for error in the squirrel monkey signal processing system, in which unfamiliar chucks never heard before nevertheless elicit a chuck response if they are similar in acoustic structure to familiar group chucks.

Acoustics↗

Scale-up and optimization of an acoustic filter for 200 L/day perfusion of a CHO cell culture.

Acoustic cell retention devices have provided a practical alternative for up to 50 L/day perfusion cultures but further scale-up has been limited. A novel temperature-controlled and larger-scale acoustic separator was evaluated at up to 400 L/day for a 10(7) CHO cell/mL perfusion culture using a 100-L bioreactor that produced up to 34 g/day recombinant protein. The increased active volume of this scaled-up separator was divided into four parallel compartments for improved fluid dynamics. Operational settings of the acoustic separator were optimized and the limits of robust operations explored. The performance was not influenced over wide ranges of duty cycle stop and run times. The maximum performance of 96% separation efficiency at 200 L/day was obtained by setting the separator temperature to 35.1 degrees C, the recirculation rate to three times the harvest rate, and the power to 90 W. While there was no detectable effect on culture viability, viable cells were selectively retained, especially at 50 L/day, where there was a 5-fold higher nonviable washout efficiency. Overall, the new temperature-controlled and scaled-up separator design performed reliably in a way similar to smaller-scale acoustic separators. These results provide strong support for the feasibility of much greater scale-up of acoustic separations.

Acoustics↗

Giant neurons in the caudal pontine reticular formation receive short latency acoustic input: an intracellular recording and HRP-study in the rat.

The reticular formation is composed of heterogeneous cell populations with multiple functions. Among these multiple functions is the processing of sensory information in the context of behavior. The purpose of the present study was to identify and characterize neurons in the reticular formation of the rat that receive auditory input. In order to do so, we combined intracellular electrophysiology in vivo with intracellular injection of horseradish peroxidase, enabling us to correlate electrophysiology unequivocally with anatomy at the single cell level. We found that many neurons in the caudal pontine reticular nucleus (PnC), which we analyzed intracellularly, responded to acoustic stimuli and were excited at short latency (mean EPSP latency: 2.6 ms; mean spike latency: 5.2 ms). This short latency suggests a direct input from the cochlear nucleus, the first central nucleus of the auditory pathway. The morphology revealed that the acoustically driven PnC neurons have very large somata (mean diameter: 44.0 microns). They can therefore be referred to as "giant PnC neurons." Complex dendritic arbors extended from these neurons into the reticular formation and thus formed a large membrane surface for the integration of multimodal inputs. Most of the giant PnC neurons sent their axons caudally into the medial longitudinal fasciculus and can therefore be regarded as reticulospinal neurons. The results demonstrate that the giant reticulospinal PnC neurons are in a position to transmit acoustic information very quickly to spinal cord neurons and to receive converging input from other parts of the brain. They are thus good candidates for participation in the mediation and modulation of acoustically elicited behaviors, such as the short latency acoustic startle response.

Acoustic Stimulation↗

Medical history, cigarette smoking and risk of acoustic neuroma: an international case-control study.

Acoustic neuroma (vestibular schwannoma) is a benign tumor of the vestibulocochlear nerve. Its recorded incidence is increasing but risk factors for this tumor have scarcely been investigated. We conducted a population-based case-control study of risk factors for acoustic neuroma in the UK and Nordic countries, including 563 cases and 2,703 controls. Tumor risk was analyzed in relation to medical history and cigarette smoking. Risk of acoustic neuroma was significantly raised in parous compared with nulliparous women (OR = 1.7, 95% CI: 1.1-2.6), but was not related to age at first birth or number of children. Risk was not associated with a history of allergic disease, past head injury, past diagnosis of a neoplasm or birth characteristics, but was significantly raised for past diagnosis of epilepsy (OR = 2.5, 95% CI: 1.3-4.9). Tumor risk was significantly reduced in subjects who had ever regularly smoked cigarettes (OR = 0.7, 95% CI: 0.6-0.9), but the reduction applied only to current smokers (OR = 0.5, 95% CI: 0.4-0.6), not ex-smokers (OR = 1.0, 95% CI: 0.8-1.3). The reduced risk of acoustic neuroma in smokers and raised risk in parous women might relate to sex hormone levels, or smoking might suppress tumor growth, but effects of parity and smoking on timing of diagnosis of the tumor are also a potential explanation. The raised risk in relation to past diagnosis of epilepsy might be a surveillance artefact or imply that epilepsy and/or antiepileptic medication use predispose to acoustic neuroma. These findings need replication by other studies and possible mechanisms need to be clarified.

Adolescent↗

Investigation of elasto-mechanical properties of alginate microcapsules by scanning acoustic microscopy.

High-frequency scanning acoustic microscopy (SAM) was used for investigation of acoustic impedance and 3D-surface topography of full alginate microspheres that act as model of artificial biological cells. Elasto-mechanical properties of the investigated specimens have been characterized by acoustic impedance. Mean surface impedance of microspheres (diameter: 300 microm) was measured with SAM at 900 MHz with a spatial resolution of 1.5 microm. The sensitivity and reproducibility of SAM had to be increased considerable to receive and quantify signals in the very low impedance region. The multilayer analysis method was used to get quantitative data of acoustic impedance with SAM at a microscopic level. 3D images show details of structure and surface topography. As a reference, bulk measurements were performed on full alginate cylinders. The acoustical impedance and the mechanical stiffness c(11) were obtained from mass density and longitudinal ultrasound velocity at 6 MHz. The impedances received with both methods are in close agreement. The results demonstrate the SAM as a powerful tool for characterizing mechano-elastical parameters as well as surface structure and topography of microspheres with high spatial resolution.

Acoustics↗

Using fetal acoustic stimulation to shorten the biophysical profile.

PURPOSE: To determine whether fetal acoustic stimulation can decrease the time required to achieve a reassuring biophysical profile. METHODS: Patients scheduled for a biophysical profile were prospectively assigned to study and control groups. The study group received 3 seconds of acoustic stimulation if fetal breathing, tone, or movement were not present during the first 5 minutes of the study. The biophysical profile was completed in the standard fashion, for both groups. RESULTS: A total of 870 patients were enrolled (458 control, 412 with stimulation). The fetal acoustic stimulation group had decreased testing time (3 minutes) and fewer non-reassuring tests (5%). The fetal acoustic stimulation group had fewer studies without breathing, potentially reducing the need for further testing or intervention. CONCLUSIONS: Fetal acoustic stimulation can be used to decrease the biophysical profile testing time and to reduce the number of non-reassuring tests.

Acoustic Stimulation↗

Acoustic noise characteristics of a 4 Telsa MRI scanner.

PURPOSE: To quantify the acoustic noise characteristics of a 4 Tesla MRI scanner, and determine the effects of structural acoustics and gradient pulse excitations on the sound field so that feasible noise control measures can be developed. MATERIALS AND METHODS: Acoustic noise emissions were measured in the ear and mouth locations of a typical adult. The sound pressure measurements were acquired simultaneously with the electrical current signals of the gradient pulses. Two forms of gradient waveforms (impulsive and operating pulses) were studied. RESULTS: The sound pressure levels (SPLs) emitted by the MRI scanner operating in echo-planar imaging (EPI) mode were in the range of 120-130 decibels. Three types of sound pressure responses were observed in the EPI sequences: 1) harmonic, 2) nonharmonic, and 3) broadband. The frequency-encoding gradient pulses were the most dominant and produced generally odd-number harmonics and nonharmonics. The phase-encoding gradient pulses generated mostly even-number harmonics, and the slice-selection gradient pulses produced primarily a broadband spectrum. CONCLUSION: The operating condition acoustic spectrum can be predicted from the magnet-structural acoustic transfer functions, which are independent of imaging sequences. This finding is encouraging because it shows that it is possible to treat such noises with an active noise control application.

Acoustics↗

NF-kappaB mediated glucocorticoid response in the inner ear after acoustic trauma.

The inner ear of humans and experimental animals demonstrate an abundance of glucocorticoid receptors (GR). Glucocorticoids (GC) are widely used to treat different hearing disorders; yet the mechanisms of GC action on the inner ear are unknown. We demonstrate how GR can directly modulate hearing sensitivity in response to a moderate acoustic trauma that results in a hearing loss (10-30 dB). The GC agonist (dexamethasone) and the drugs (metyrapone + RU 486) showed opposing effects on hearing threshold shifts. GC agonist (dexamethasone) decreased the hearing threshold whereas pre-treatment with a GC synthesis inhibitor (metyrapone) in combination with a GR antagonist (RU 486) exacerbated auditory threshold shifts (25-60 dB) after acoustic trauma with statistically significant increase in GR mRNA and GR protein compared with the vehicle and acoustic trauma group. Acoustic trauma caused a significant increase in the nuclear transport of NF-kappaB, whereas pre-treatment with the drugs (metyrapone and RU 486) blocked NF-kappaB nuclear transport into spiral ganglion nuclei. An NF-kappaB inhibitor, pyrrolidine dithiocarbamate ammonium blocked the trauma-induced translocation of NF-kappaB and resulted in a hearing loss (45-60) dB. These results indicate that several factors define the responsiveness of the inner ear to GC, including the availability of ligand or receptor, and the nuclear translocation of GR and NF-kappaB. These findings will further our understanding of individual GC responsiveness to steroid treatment, and will help improve the development of pharmaceuticals to selectively target GR in the inner ear for individuals with increased sensitivity to acoustic trauma.

Acoustic Stimulation↗

Angiographic diagnosis of acoustic neurinomas and meningiomas in the cerebellopontine angle--a reappraisal.

Forty-two acoustic neurinomas and seven meningiomas in the cerebellopontine angle were reviewed, and the radiological differential diagnosis of these tumors is discussed. Though enlarged internal auditory meati and characteristic CT findings were reasonably reliable indicators for the diagnosis of acoustic neurinomas, it was angiography which substantiated their correct diagnosis. An arcuate vein was frequently demonstrated with acoustic neurinomas, but never with meningiomas. Visualization of tangled veins seems to favor a diagnosis of acoustic neurinomas. Contrary to earlier reports, tumor stains were most frequently visualized using selective external carotid arteriography. The degree of tumor stains did not aid in differentiating acoustic neurinomas from meningiomas. The importance of using angiotomography, especially in the anteroposterior projection, and external carotid angiography during prolonged injections of large amounts of contrast media, is emphasized.

Basilar Artery↗

The long-term growth rate of residual acoustic neurinomas.

The growth rate of 19 residual acoustic neurinomas was examined in a long-term follow-up study (median, 10 years; range, 5 to 17 years) following intracapsular removal. Of these, 10 (53%) had regrowth, three (16%) showed regression, and six (32%) were unchanged. The 10 acoustic neurinomas showing regrowth were divided into two categories, either solid or cystic, according to computed tomographic findings. Five acoustic neurinomas with cyst formation showed rapid regrowth, with the tumour doubling time ranging from 0.15 to 5.0 years (median, 4.5 years), and required re-operation. Five solid tumours showed slow regrowth, with the tumour doubling time ranging from 9 to 34 years (median, 15 years). Although cyst formation is a major factor in rapid regrowth, residual acoustic neurinomas without cyst formation have a slower growth potential. In this study, 74% of the residual acoustic neurinomas have never required re-operation. It is advisable to choose intracapsular removal if there is major risk of neurological deficits.

Adult↗

Pneumothorax detection using pulmonary acoustic transmission measurements.

Pneumothorax is a common clinical condition that can be life threatening. The current standard of diagnosis includes radiographic procedures that can be costly and may not always be readily available or reliable. The objective of this study was to investigate the hypothesis that pneumothorax causes detectable pathognomonic changes in pulmonary acoustic transmission. An animal model was developed whereby 15 mongrel dogs were anaesthetised, intubated and mechanically ventilated. A thoracoscopic trocar was placed into the pleural space for the introduction of air and confirmation of a approximately 30% pneumothorax by direct visualisation. Broadband acoustic signals were introduced into the endotracheal tube, while transmitted waves were measured at the chest surface. Pneumothorax was found consistently to lower the pulmonary acoustic transmission in the 200-1200 Hz frequency band, whereas smaller transmission changes occurred at lower frequencies (p< 0.0001, sign test). The ratio of acoustic energy between low-(< 220 Hz) and high-(550-770 Hz) frequency bands was significantly different in the control and pneumothorax states (p < 0.0001, sign test). This implies that pneumothoraces can be reliably detected using pulmonary acoustic transmission measurements in the current animal model. Further studies are needed to investigate the feasibility of using this technique in humans.

Acoustics↗

Measurement of upper airway movement by acoustic reflection.

The acoustic reflection method provides a noninvasive way to determine the airway geometry. Based on a discrete upper airway model, an inverse scheme is developed to infer the upper airway area as a function of distance. We incorporate this scheme into a system that can generate multiple acoustic pulses to sample the upper airway geometry at a maximum frequency of 30 Hz, making possible determination of the airway area-distance relation as a function of time. Therefore, we can monitor the dynamic behavior of the upper airway during breathing. To validate the approach, we visualized vocal cord movements in three normal subjects via laryngoscopy; simultaneously acoustic measurements were made at 10 Hz. Video images of vocal cord movement were recorded and digitized. We compared the laryngeal area from analysis of the video images with the acoustic assessment at the level of the glottis. Linear regression analysis shows that the correlation coefficients are between 0.85 and 0.9 for all three subjects. We conclude that the acoustic reflection method is a useful tool for measuring vocal cord movement without the use of laryngoscopy, and the approach promises to be a useful one to measure the movement of the whole upper airway. This paper also discusses the limitations inherent in the algorithm and some useful procedures to ensure accurate and reliable area computation during implementation.

Acoustics↗

Placement of esophageal stethoscope by acoustic criteria does not consistently yield an optimal location for the monitoring of core temperature.

The esophageal stethoscope has evolved into a device for both acoustic and core temperature monitoring. To test whether routine placement according to acoustic criteria results in placement of the core temperature sensor in the region of contiguity between the esophagus and the heart, we determined the depth of placement electrocardiographically. All patients were undergoing nonthoracic elective operations requiring general anesthesia and tracheal intubation. First, we established that different observers selected the same esophageal depth within +/- 1 cm electrocardiographically, using the criterion of a symmetric biphasic P wave of maximal amplitude (7 patients). Then, in 30 more patients, we compared routine acoustic placements with the depths of the maximal-amplitude biphasic P wave. Stethoscopes placed according to acoustic criteria were within +/- 3 cm of P-wave depths in 15 of 30 patients. In the remaining patients, measured discrepancies ranged up to 13.5 cm. We conclude that the prevailing stethoscope design, with a thermistor at the tip, below the acoustic window, does not ensure placement of the thermistor within the optimal region for monitoring of core temperature. A modification in design that would take advantage of the reliability of electrocardiographic positioning is suggested.

Acoustics↗

Lasting effect of repeated cocaine administration on acoustic and fear-potentiated startle in rats.

RATIONALE: Following cocaine withdrawal, humans may experience an abstinence syndrome with high levels of anxiety. Studying anxious behavior in animals following repeated cocaine administration may help elucidate important variables that contribute to a withdrawal syndrome. OBJECTIVES: This study investigated whether repeated cocaine pre-exposure produced lasting increases in conditioned fear as measured by fear-potentiated startle responses in rats. METHODS: Startle was measured in response to 50 ms acoustic stimuli of 95, 105 and 115 dB. Cocaine (20 mg/kg, IP) or saline was administered for 7 days and after each injection rats were either placed in startle chambers for 30 min or returned to the home cage. After a 1-week cocaine-free period, most rats were given ten light-footshock pairings in the startle chamber. Fear-potentiated startle was tested by presenting acoustic startle-eliciting stimuli of 95, 105 and 115 dB in the presence or absence of the light. Rats that were not fear conditioned received acoustic stimuli one week after 7 days of 20 mg/kg cocaine. RESULTS: Startle responses, both in the presence and absence of the light CS, were greater in fear-conditioned rats that received cocaine pre-exposure in the startle chamber than in saline pre-exposed rats. Startle responses in the presence of the light CS were further augmented at 115 dB. In contrast, home-cage exposure to cocaine did not enhance startle responses. In rats that were not fear conditioned, cocaine pre-exposure reduced acoustic startle. CONCLUSIONS: Repeated cocaine pre-exposure can increase, decrease or not change acoustic startle depending on whether fear conditioning occurred and whether cocaine was given in the testing chamber. The data suggest that cocaine pre-exposure may act as a contextually conditioned occasion setting stimulus that can facilitate anxious behavior similar to the postulated human cocaine abstinence syndrome.

Acoustic Stimulation↗

Caffeine and prepulse inhibition of the acoustic startle reflex.

RATIONALE: A stimulus presented immediately prior to a startle reflex-eliciting stimulus inhibits the startle reflex. This is termed prepulse inhibition (PPI) and is postulated to index automatic and controlled attentional processing of the prepulse. OBJECTIVE: Two experiments investigated the effect of 0, 2, and 4 mg/kg oral caffeine on PPI of the acoustic startle eyeblink reflex across stimulus onset asynchronies (SOAs) ranging from 30 to 420 ms. In experiment 1, acoustic prepulses were used and automatic attention was investigated, whereas in experiment 2, acoustic and tactile prepulses were used and automatic and controlled attention was investigated. Controlled attention was investigated by instructing the subjects to attend to one stimulus (attended stimulus) and not to another stimulus (non-attended stimulus). METHODS: Caffeine was administrated to human subjects in within-subjects designs (n = 24 and n = 18). Startle reflexes to 100 dB noise were recorded by electromyography. A mood scale and readings of blood pressure indexed arousal. RESULTS: Caffeine increased the indexes of arousal. There were, however, no significant main effects of caffeine on startle, nor did caffeine significantly interact with any other variable. Attended acoustic prepulses increased PPI at the 120 ms and longer SOAs. Caffeine 4 mg/kg abolished this difference between attended and non-attended stimuli. Attended tactile prepulses facilitated startle at short SOAs, and caffeine reduced facilitation of startle by tactile prepulses. CONCLUSIONS: Caffeine did not facilitate automatic attention. Caffeine 4 mg/kg abolished the effect of controlled attention on PPI. Facilitation of startle by attended acoustic prepulses is best explained by facilitation of motoneurons in the facial nucleus.

Acoustic Stimulation↗