A comparison of the effects of isoflurane and ketamine anesthesia on auditory brainstem response (ABR) thresholds in rats.

The auditory brainstem response (ABR) is an acoustically evoked potential commonly used to determine hearing sensitivity in laboratory animals. Both isoflurane and ketamine/xylazine anesthesia are commonly used to immobilize animals during ABR procedures. Hearing threshold determination is often the primary interest. Although a number of studies have examined the effect of different anesthetics on evoked potential waveforms and growth functions, none have directly compared their effect on ABR hearing threshold estimates. The present study used a within-subject comparison and typical threshold criteria, to examine the effect of isoflurane and ketamine/xylazine on ABR thresholds for clicks and pure-tone stimuli extending from 8 to 32 kHz. At comparable physiological doses, hearing thresholds obtained with isoflurane (1.7% in O(2)) were on average elevated across a broad frequency range by greater than 27 dB compared to ketamine/xylazine (ketamine HCl, 50mg/kg; xylazine, 9 mg/kg). This highly significant threshold effect (F(1,6) = 158.3403, p = 3.51 × 10(-22)) demonstrates a substantial difference between general anesthetics on auditory brainstem sensitivity. Potential mechanisms and implications for ABR threshold determination under anesthesia are discussed.

Luminescent metal-organic frameworks.

Metal-organic frameworks (MOFs) display a wide range of luminescent behaviors resulting from the multifaceted nature of their structure. In this critical review we discuss the origins of MOF luminosity, which include the linker, the coordinated metal ions, antenna effects, excimer and exciplex formation, and guest molecules. The literature describing these effects is comprehensively surveyed, including a categorization of each report according to the type of luminescence observed. Finally, we discuss potential applications of luminescent MOFs. This review will be of interest to researchers and synthetic chemists attempting to design luminescent MOFs, and those engaged in the extension of MOFs to applications such as chemical, biological, and radiation detection, medical imaging, and electro-optical devices (141 references).

In situ tensile testing of human aortas by time-resolved small-angle X-ray scattering.

The collagen diffraction patterns of human aortas under uniaxial tensile test conditions have been investigated by synchrotron small-angle X-ray scattering. Using a recently designed tensile testing device the orientation and d-spacing of the collagen fibers in the adventitial layer have been measured in situ with the macroscopic force and sample stretching under physiological conditions. The results show a direct relation between the orientation and extension of the collagen fibers on the nanoscopic level and the macroscopic stress and strain. This is attributed first to a straightening, second to a reorientation of the collagen fibers, and third to an uptake of the increasing loads by the collagen fibers.

Single lamellar mechanics of the human lumbar anulus fibrosus.

The mechanical behavior of the entire anulus fibrosus is determined essentially by the tensile properties of its lamellae, their fiber orientations, and the regional variation of these quantities. Corresponding data are rare in the literature. The paper deals with an in vitro study of single lamellar anulus lamellae and aims to determine (i) their tensile response and regional variation, and (ii) the orientation of lamellar collagen fibers and their regional variation. Fresh human body-disc-body units (L1-L2, n=11) from cadavers were cut midsagittally producing two hemidisc units. One hemidisc was used for the preparation of single lamellar anulus specimens for tensile testing, while the other one was used for the investigation of the lamellar fiber orientation. Single lamellar anulus specimens with adjacent bone fragments were isolated from four anatomical regions: superficial and deep lamellae (3.9+/-0.21 mm, mean +/- SD, apart from the outer boundary surface of the anulus fibrosus) at ventro-lateral and dorsal positions. The specimens underwent cyclic uniaxial tensile tests at three different strain rates in 0.15 mol/l NaCl solution at 37 degrees C, whereby the lamellar fiber direction was aligned with the load axis. For the characterization of the tensile behavior three moduli were calculated: E(low) (0-0.1 MPa), E(medium) (0.1-0.5 MPa) and E(high) (0.5-1 MPa). Additionally, specimens were tested with the load axis transverse to the fiber direction. From the second hemidisc fiber angles with respect to the horizontal plane were determined photogrammetrically from images taken at six circumferential positions from ventral to dorsal and at three depth levels. Tensile moduli along the fiber direction were in the range of 28-78 MPa (regional mean values). Superficial lamellae have larger E(medium) (p=0.017) and E(high) (p=0.012) than internal lamellae, and the mean value of superficial lamellae is about three times higher than that of deep lamellae. Tensile moduli of ventro-lateral lamellae do not differ significantly from the tensile moduli of dorsal lamellae, and E(low) is generally indifferent with respect to the anatomical region. Tensile moduli transverse to the fiber direction were about two orders of magnitude smaller (0.22+/-0.2 MPa, mean +/- SD, n=5). Tensile properties are not correlated significantly with donor age. Only small viscoelastic effects were observed. The regional variation of lamellar fiber angle phi is described appropriately by a regression line |phi|=23.2 + 0.130 x alpha (r(2)=0.55, p<0.001), where alpha is the polar angle associated with the circumferential position. The single anulus lamella may be seen as the elementary structural unit of the anulus fibrosus, and exhibits marked anisotropy and distinct regional variation of tensile properties and fiber angles. These features must be considered for appropriate physical and numerical modeling of the anulus fibrosus.

Determination of constitutive equations for human arteries from clinical data.

Stress-strain analyses of vessel walls require appropriate constitutive equations. Determination of constitutive equations is based on experimental data of (i) diameter and length of a vessel segment subject to internal pressure and external axial force, and (ii) the load-free reference geometry. Typical clinical data, however, provide only pressure-diameter relations in the diastolic-systolic pressure range. In order to overcome this problem, an approach is proposed allowing the determination of constitutive equations from clinical data by means of reasonable assumptions regarding in situ configurations and stress states of arterial walls. The approach is based on a two-dimensional Fung-type stored-energy function capturing the characteristic nonlinear and anisotropic responses of arteries. Examples concerning human aortas from a normotensive and a hypertensive subject illustrate the potential of the approach.

Elevated fusiform cell activity in the dorsal cochlear nucleus of chinchillas with psychophysical evidence of tinnitus.

Chinchillas with psychophysical evidence of chronic tinnitus were shown to have significantly elevated spontaneous activity and stimulus-evoked responses in putative fusiform cells of the dorsal cochlear nuclei (DCN). Chinchillas were psychophysically trained and tested before and after exposure to a traumatic unilateral 80 dB (sound pressure level) 4 kHz tone. Before exposure, two groups were matched in terms of auditory discrimination performance (noise, and 1, 4, 6, and 10 kHz tones). After exposure, a single psychophysical difference emerged between groups. The exposed group displayed enhanced discrimination of 1 kHz tones (p = 0.00027). Postexposure discrimination of other stimuli was unaffected. It was hypothesized that exposed animals experienced a chronic subjective tone (i.e., tinnitus), resulting from their trauma, and that features of this subjective tone were similar enough to 1 kHz to affect discrimination of 1 kHz objective signals. After psychophysical testing, single-unit recordings were obtained from each animal's DCN fusiform cell layer. Putative fusiform cells of exposed animals showed significantly (p = 0.0136) elevated spontaneous activity, compared with cells of unexposed animals. Putative fusiform cells of exposed animals showed a greater stimulus-evoked response to tones at 1 kHz (p = 0.0000006) and at characteristic-frequency (p = 0.0000009). This increased activity was more pronounced on the exposed side. No increase in stimulus-evoked responses was observed to other frequencies or noise. These parallel psychophysical and electrophysiological results are consistent with the hypothesis that chronic tonal tinnitus is associated with, and may result from, trauma-induced elevation of activity of DCN fusiform cells.

Assessing tinnitus and prospective tinnitus therapeutics using a psychophysical animal model.

Subjective tinnitus is a common and often debilitating disorder that is difficult to study because it is a perceptual state without an objective stimulus correlate. Studying tinnitus in humans is further complicated by the heterogeneity of tinnitus quality, severity, and associated hearing loss. As a consequence, the pathophysiology of tinnitus is poorly understood and treatments are often unsuccessful. In the present study, an animal psychophysical model was developed to reflect several features of tinnitus observed in humans. Chronic tinnitus was induced in rats by a single intense unilateral exposure to noise. The tinnitus was measured using a psychophysical procedure, which required the animals to discriminate between auditory test stimuli consisting of tones, noise, and 0 dB. Tinnitus was indicated by a frequency-specific shift in discrimination functions with respect to control subjects not exposed to noise. The psychophysical consequences of the noise exposure were best explained by a tinnitus hypothesis and could not be explained easily by other consequences of noise exposure such as hearing loss. The qualitative features of the tinnitus were determined and related to the duration of noise exposure and the associated cochlear trauma. The tinnitus was found to persist and intensify over 17 months of testing. Finally, the tinnitus was reversibly attenuated by treatment with gabapentin, a GABA agonist. It was concluded that this model reflected several features of human tinnitus, such as its tonality and persistence, and could be useful as a screen for potential therapeutics as well as a tool to help unravel the pathophysiology of the disorder of phantom auditory perception.

Effects of chronic salicylate on GABAergic activity in rat inferior colliculus.

It is well accepted that salicylate ototoxicity results in reversible tinnitus in humans. Salicylate-induced tinnitus may be an example of plasticity of the central auditory system and could potentially serve as a model to further understand mechanisms of tinnitus generation. This study examined levels of glutamic acid decarboxylase (GAD) and the binding characteristics of the GABA(A) receptor in auditory brainstem structures of Long-Evans rats chronically treated with salicylate. Western blotting revealed a significant 63% (P<0.008) elevation of GAD levels in the inferior colliculus (IC) of salicylate-treated subjects. This occurred in subjects demonstrating behavioral evidence of tinnitus. Muscimol saturation analysis was indicative of a salicylate-related increase in receptor affinity. Linear regression of [(3)H]muscimol saturation analysis data revealed a significant (P<0.05) reduction in K(d) values in whole IC (-48%), as well as in the central nucleus of IC (CIC, -58%) and combined external and dorsal cortex of IC (E/DCIC, -46%). The number of GABA(A) binding sites (B(max)) were also significantly (P<0.05) decreased. These changes were observed only in central auditory structures. This suggests that GAD expression and GABA(A) receptor binding characteristics may be altered with chronic exposure to sodium salicylate and these changes may represent aberrant plasticity clinically experienced as tinnitus.

Asthma quality of life during 1 year of treatment with budesonide with or without formoterol.

The Formoterol and Corticosteroids Establishing Therapy (FACET) study has provided the first opportunity to examine the long-term effects of inhaled steroids and long-acting beta2-agonists on asthma-specific quality of life. The objectives of the present study were to: evaluate the effects of long-term (1 yr) formoterol and increasing doses of budesonide on asthma quality of life; 2) to determine whether initial improvements in quality of life are sustained when improvements in clinical indices persist; and 3) to evaluate the long-term relationship between changes in clinical indices and changes in quality of life. Of the 852 asthmatic adults enrolled, 470 from five countries participated in this quality of life evaluation. After a 4-week run-in on 1,600 microg budesonide, patients were randomized to either 200 microg (Bud200) or 800 microg budesonide (Bud800) in combination with either 24 microg formoterol (F) or placebo daily for 1 yr. The Asthma Quality of Life Questionnaire (AQLQ) was completed and conventional clinical indices measured at enrolment and randomization and on seven occasions during the following 12 months. During the run-in, there was an improvement in AQLQ score (changes (delta) in overall score approximately 0.50; p<0.0001). After randomization, there was a further improvement in the Bud800+F group (delta=0.21; p=0.028). One month post-randomization, improvements in all groups stabilized and were sustained throughout the 12 months in a pattern very similar to that observed for the conventional clinical indices. The correlation of individual patient changes in clinical indices and changes in AQLQ score during the 12-month randomized period were weak to moderate (maximum r=0.51). Improvements in quality of life, which were greatest in the 800 microg budesonide plus 24 microg formoterol group, were sustained throughout the 12 months in a similar manner to the clinical indices. Long-term changes in conventional clinical indices cannot be used to predict the effect of treatment on individual patient experience.

Behavioral model of chronic tinnitus in rats.

An animal model of tinnitus was developed to study chronic salicylate-induced tinnitus in rats. Novel features of the model included oral dosing of salicylate, test stimuli that included a range of pure tones and silence, and assessment of tinnitus for several months. Experimental subjects were given sodium salicylate in their drinking water while control subjects received normal tap water. Subjects were conditioned to press a lever for food in the presence of continuous white noise. At random intervals, offset of the noise was paired with a noxious stimulus, resulting in cessation of lever pressing during the silent test periods. At other randomly scheduled intervals, a test tone was substituted for the white noise, unpaired with noxious stimuli. When the test stimuli were pure tones, the salicylate-treated subjects suppressed less than the control subjects. One explanation for this result is that the experimental subjects' sensations of tones were noisier than those of the controls because experimental subjects were experiencing tinnitus.

Detection of glutamate decarboxylase isoforms in rat inferior colliculus following acoustic exposure.

The inferior colliculus is a central auditory structure which serves as a site for the integration of ascending and descending auditory information. Changes in central auditory structures may occur with acoustic exposure, which cannot be explained by alterations in cochlear function alone. Rats were exposed to a 10-kHz tone at 100 dB SPL for 9 h. Auditory brainstem response measures showed an initial 25-30-dB threshold shift across all tested frequencies. By 30 days post-exposure, thresholds for clicks and most frequencies returned to near control levels; however, thresholds remained elevated at 10 and 20 kHz. Inner hair cell loss was confined to apical and basal ends of the cochlea, and did not exceed 20%. Inferior colliculus levels of the two isoforms of the GABA synthetic enzyme glutamate decarboxylase (65,000 and 67,000 mol. wt forms) were measured immediately post-exposure (0 h) and at two and 30 days post-exposure using quantitative immunocytochemical and western blotting techniques. Zero-hour measures revealed a significant increase in the level of glutamate decarboxylase (mol. wt 67,000) protein (118%), as well as in the optical density (35%) of immunolabeled cells. By 30 days post-exposure, inferior colliculus protein levels of both glutamate decarboxylase isoforms were significantly below unexposed controls (39% and 21% for the 65,000 and 67,000 mol. wt forms, respectively). These studies describe increased markers for GABA immediately following acoustic exposure, followed by a decline to below control levels from two to 30 days post-exposure. It remains to be determined whether noise trauma-induced changes in glutamate decarboxylase levels in the inferior colliculus reflect protective up-regulation in response to intense stimulation, followed by the establishment of new neurotransmitter equilibrium levels.

Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group.

The identification, prevention, and prompt treatment of exacerbations are major objectives of asthma management. We looked at change in PEF, symptoms, and use of rescue beta-agonists during the 425 severe exacerbations that occurred during a 12-mo parallel group study (FACET) in which low and high doses of budesonide with and without formoterol were compared in patients with asthma. Oral corticosteroids were prescribed for severe exacerbations, the main study end point, defined as the need for a course of oral corticosteroids (n = 311) or a reduction in morning PEF of > 30% on two consecutive days. PEF, symptoms, and bronchodilator use over the 14 d before and after the exacerbation were obtained from diary cards. Exacerbations were characterized by a gradual fall in PEF over several days, followed by more rapid changes over 2 to 3 d; an increase in symptoms and rescue beta-agonist use occurred in parallel, and both the severity and time course of the changes were similar in all treatment groups. Exacerbations identified by the need for oral corticosteroids were associated with more symptoms and smaller changes in PEF than those identified on the basis of PEF criteria. Female sex was the main patient characteristic associated with an increased risk of having a severe exacerbation. Exacerbations may be characterized predominantly by change in symptoms or change in PEF, but the pattern was not affected by the dose of inhaled corticosteroid or by whether the patient was taking formoterol.

Reverse transcription polymerase chain reaction analysis of pituitary hormone, Pit-1 and steroidogenic factor-1 messenger RNA expression in pituitary tumors.

Pit-1 is a transcription factor that appears early in embryonic pituitary gland formation and is necessary for the development of somatotropes, lactotropes and thyrotropes. Steroidogenic factor-1 (SF-1) is another early appearing transcription factor that is involved in the development of gonadotropes. In this study we have compared RT-PCR analysis of hormone mRNA with traditional IHC for classification of 27 pituitary tumors and have evaluated the correlation of Pit-1 and SF-1 mRNA with hormone mRNA. RT-PCR detected concordant hormone mRNA in 100% of GH IHC positive, 100% of PRL IHC positive, 33% of TSH IHC positive, and 93% of gonadotropin IHC positive tumors. IHC, however, was concordant in only 71% of GH mRNA positive, 78% of PRL mRNA positive, 17% of TSH beta mRNA positive, and 76% of FSH beta mRNA positive tumors. Pit-1 mRNA was positive in 87% of tumors in which mRNA for GH, PRL or TSH beta was detected and in only 17% of GH, PRL and TSH beta mRNA negative tumors. SF-1 mRNA was positive in 94% of tumors in which mRNA for FSH beta was present and in no FSH beta mRNA negative tumors. We conclude that RT-PCR analysis of hormone mRNA may be more sensitive than traditional hormone IHC for classification of pituitary tumors. Furthermore, tumor Pit-1 mRNA positively correlates with GH, PRL and TSH beta mRNA while tumor SF-1 mRNA correlates well with FSH beta mRNA. Combined analysis of hormone and transcription factor mRNA in pituitary tumor tissue may therefore be a more meaningful approach to pituitary tumor characterization.

Targeting of the myosin-I myr 3 to intercellular adherens type junctions induced by dominant active Cdc42 in HeLa cells.

Myr 3, a member of the myosin-I family from rat, is shown in this study to be localized at adherens-type intercellular junctions in epithelial and nonepithelial tissues. Formation of intercellular junctions and the accompanying recruitment of myr 3 to these junctions involves signaling by the Rho subfamily of small GTP-binding proteins. This conclusion is based on studies with HtTA-1 HeLa cells that were induced by overexpression of constitutively active Cdc42Hs to form typical adherens-type intercellular junctions enriched in cadherins (N-cadherin), beta-catenin, filamentous actin and myr 3. Recruitement of myr 3 to Cdc42-induced adherens junctions in HeLa cells was dependent on a short region of the tail domain and a functional myosin motor domain, but was independent of its myosin-I tail homology and SH3 regions. Overexpression of constitutively active Rac1 induced a distinct type of adherens junction in HeLa cells that was characterized by elaborate intercellular interdigitations enriched in N-cadherin, beta-catenin and F-actin. Myr 3 was often present, but not specifically enriched in the intercellular junctions induced by constitutively active Rac1.

Bambuterol raises high-density lipoprotein levels in patients with hyperlipidaemia.

OBJECTIVE: The objective of this study was to investigate the effects of bambuterol (a prodrug of the beta 2-agonist terbutaline) on lipid and lipoprotein levels in patients with hyperlipidaemia. Both these drugs are extensively used in the treatment of patients with bronchial asthma. Earlier studies in healthy volunteers and in patients with noninsulin dependent diabetes mellitus have shown that terbutaline and bambuterol increase HDL cholesterol levels, and therefore bambuterol might have beneficial effects on HDL levels in patients with hyperlipidaemia. DESIGN: The present study was a randomized, double-blind, crossover study, comparing 20 mg of bambuterol with placebo, each one given for 6-8 weeks with a 3-4 week washout period in between. SETTING: The study was performed in an out-patient lipid clinic at Malmö University Hospital. SUBJECTS: Thirty-one patients with hyperlipidaemia (S-cholesterol > 6.5 mmol L-1 and S-triglycerides > 2.0 mmol L-1) were included. MAIN OUTCOME MEASUREMENTS AND RESULTS: The results showed that bambuterol increased S-HDL cholesterol levels by 7% (P = 0.012). Increases were 23% for P-HDL2 and 7% for P-HDL3 fractions, but no effect was apparent on S-apolipoprotein A-1 levels. CONCLUSION: This study suggests that the beta 2-agonist bambuterol might be used as an alternative or as a complement in the treatment of dyslipidemic patients, when an increase in HDL cholesterol is desired.

Dimensions of the sinus tympani and its surgical access via a retrofacial approach.

The sinus tympani (ST) is a critical anatomic region of the temporal bone. It lies medial to the facial nerve, between the ponticulus and the subiculum, and therefore is not easily visualized by routine surgical approaches to the middle ear and mastoid. This limited access makes the ST a site that is notorious for residual cholesteatoma. An extensive evaluation of the anatomic dimensions of the ST was made from human temporal bones. Three hundred twenty-seven bones were examined at four standardized levels to describe the dimensions and anatomic relationships of the ST with other structures of the temporal bone. The region of the stapedial tendon was found to be the most limited anatomic substructure in the vicinity of the ST. This study demonstrates the feasibility of a retrofacial approach to the ST as an aid in eradication of otherwise hidden disease.

Update on facial nerve disorders.

Many issues involving the diagnosis and treatment of facial nerve disorders continue to engender controversy and debate. This article examines the theory that Bell's palsy is a herpes simplex neuritis and proposes facial nerve decompression for recurrent palsies. The contemporary management of herpes zoster oticus, temporal bone fractures, otogenic facial paralysis, and hemifacial spasm is reviewed.

Long-term result of vocal cord augmentation with autogenous fat.

The use of autogenous fat for augmentation of the paralyzed vocal fold is a promising substitute for alternate injectable material such as Teflon (polytef paste, polytetrafluoroethylene; Ethicon) and Gelfoam (absorbable gelatin sponge; Upjohn). Long-term histologic evaluation of fat grafts to the larynx has not previously been reported in the literature. We present a case report of autogenous fat augmentation of a paralyzed vocal fold with documentation of persistent fat graft present 5 months after transplant.

Diatrizoate and dextran treatment of sudden sensorineural hearing loss.

Many treatments have been proposed to manage sudden sensorineural hearing loss. The University of Iowa has used a protocol of intravenous radiopaque contrast and volume expander for the last 10 years in the treatment of sudden sensorineural hearing loss. A retrospective analysis of these cases was performed to review the efficacy of this treatment with respect to the natural history of the disease, as reported in previous studies. Sixty-four percent of 39 cases showed audiometric improvement in their pure-tone averages, speech reception thresholds, and speech discriminations while receiving treatment. Forty-eight percent of these showed improvement after their first treatment doses. Eighty percent of patients who presented more than 7 days after the onset of their hearing loss showed audiometric improvement with treatment, whereas 71 percent of patients presenting before 7 days showed audiometric improvement. However, the patients who presented earlier showed more marked improvement. Speech discrimination with the W-22 word list was a predictor of early recovery. Patients with measurable speech discrimination scores on presentation uniformly improved with treatment, even if their pure-tone average was profound. Our findings were suggestive of a pathophysiologic mechanism for some cases of sensorineural hearing loss for which intravenous contrast is efficacious. Although our findings were far from conclusive in this uncontrolled study, these initial results support the use of these agents in a rigorous clinical trial.