Melanoma of the middle ear: initial presentation, Fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography imaging and follow up.

BACKGROUND: We present a rare case of primary mucosal melanoma of the middle ear imaged with 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT). METHOD: Clinical, radiological, intra-operative and histological findings are discussed. RESULTS: An 88-year-old woman presented with intermittent otorrhoea of the left ear for several months. Otoscopy revealed a livid protrusion of the tympanic membrane. Melanoma was not suspected initially, but was established on transmembranous biopsy. Pre-operative 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography revealed a mass lesion in the left tympanic cavity with high fluoro-deoxyglucose uptake, as well as an ipsilateral intraparotid lymph node metastasis. The patient underwent surgical treatment. The diagnosis of melanoma was confirmed histologically. CONCLUSION: In this rare case, clinical, radiological and surgical findings led to the diagnosis of a primary mucosal melanoma of the middle ear.

Importance of beta(2)adrenergic receptor genotype, gender and race on albuterol-evoked bronchodilation in asthmatics.

To determine whether race and gender affect beta(2)receptor-stimulated bronchodilation, we quantified FEV(1)and plasma concentrations of albuterol at various times following the oral administration of a single 8-mg dose of albuterol in 15 black and 15 white male and female asthmatics. No important racial or gender differences in albuterol-evoked FEV(1)or percent-predicted FEV(1)were evident, although females tended to be more sensitive compared to males. Pharmacodynamic (PD) models were fitted to data in 19 patients (63%); FEV(1)was too erratic to fit in three, and a clockwise hysteresis in the FEV(1)vs. albuterol concentration relationship was observed in eight asthmatics. Mean +/- SD baseline (E(0)), maximal FEV(1)(E(max)) and C(50)were: 3.18 + 1.03 l, 4.00 +/- 1.12 l, 7.84 +/- 10.2 microg/l, respectively. beta(2)receptor genotype was determined in 16 patients. All Arg 16 homozygotes exhibited proportional FEV(1)response vs. plasma albuterol concentration relationships, and thus were fitted by PD models. All those having a poor FEV(1)vs. albuterol concentration relationship carried the Gly 16 allele. We conclude that receptor genotype, but not race or gender, is an important determinant of albuterol pharmacodynamics.

Impact of genetic polymorphisms of the beta2-adrenergic receptor on albuterol bronchodilator pharmacodynamics.

OBJECTIVE: To determine whether genetic polymorphisms of the beta2-adrenergic receptor gene affect the relationship between albuterol (INN, salbutamol) plasma concentrations and the forced expiratory volume in 1 second (FEV1) in subjects with moderate asthma. METHODS: Sixteen clinically stable patients with moderate asthma who participated in a pharmacokinetic-pharmacodynamic study of albuterol volunteered to provide a blood sample for determination of beta2-adrenergic receptor genotype. FEV1 and plasma concentrations of albuterol were determined at various times after administration of an oral solution that contained 8 mg albuterol. Patients withheld inhaled beta2-agonist and corticosteroid therapy 12 and 24 hours, respectively, before the study. beta2-Adrenergic receptor genotype was determined by polymerase chain reaction with allele-specific oligonucleotide hybridization. RESULTS: Albuterol-evoked FEV1 was higher and the response was more rapid in Arg16 homozygotes compared with the cohort of carriers of the Gly16 variant: Maximal percentage increase in FEV1 (%deltaFEV1), 18% versus 4.9% (P < .03); area under FEV1 albuterol concentration curve, 194%.mL/ng versus 30%.mL/ng (P < .05); initial slope (dE/dC), 1.43%.mL/ng versus 0.55%.mL/ng (P < .003). CONCLUSIONS: The beta2-adrenergic receptor gene polymorphism is a major determinant of bronchodilator response to albuterol. Future pharmacodynamic studies of beta2-agonists should include determination of 02-adrenergic receptor genotype.

Effects of gender and race on albuterol pharmacokinetics.

We evaluated the effects of race and gender on albuterol pharmacokinetics in 30 patients with moderate asthma (15 blacks, 15 whites, 16 men, 14 women). Subjects received a single dose of albuterol 8 mg oral solution and had blood samples collected at various times for 12 hours after the dose. Albuterol plasma concentrations were determined by HPLC with fluorescence detection, and pharmacokinetics were determined by compartmental analysis. The apparent volume of distribution of albuterol was significantly higher in men than in women (631+/-171 and 510+/-109 L, respectively, p<0.05). Consequently, the maximum concentration was lower in men than women (10.3+/-2.1 and 12.0+/-1.9 ng/ml, respectively, p<0.05). Elimination rates were 0.136+/-0.008 and 0.160+0.012 hour(-1), respectively (p<0.10). When corrected for ideal body weight, apparent volume of distribution was not different by gender. No differences between blacks and whites other than lag time were noted in albuterol kinetics. The greater apparent volume of distribution in men is likely explained by differences in ideal body weight or lean body mass.

Influence of pulse sequence, polarity and amplitude on magnetic stimulation of human and porcine peripheral nerve.

1. Mammalian phrenic nerve, in a trough filled with saline, was excited by magnetic coil (MC)-induced stimuli at defined stimulation sites, including the negative-going first spatial derivative of the induced electric field along a straight nerve, at a bend in the nerve, and at a cut nerve ending. At all such sites, the largest amplitude response for a given stimulator output setting was elicited by an induced damped polyphasic pulse consisting of an initial quarter-cycle hyperpolarization followed by a half-cycle depolarization compared with a predominantly 'monophasic' quarter-cycle depolarization. 2. Simulation studies demonstrated that the increased efficacy of the induced quarter-cycle hyperpolarizing-half-cycle depolarizing polyphasic pulse was mainly attributed to the greater duration of the outward membrane current phase, resulting in a greater outward charge transfer afforded by the half-cycle (i.e. quarter-cycles 2 and 3). The advantage of a fast rising initial quarter-cycle depolarization was more than offset by the slower rising, but longer duration depolarizing half-cycle. 3. Simulation further revealed that the quarter-cycle hyperpolarization-half-cycle depolarization showed only a 2.6 % lowering of peak outward current and a 3.5 % lowering of outward charge transfer at threshold, compared with a half-cycle depolarization alone. Presumably, this slight increase in efficacy reflects modest reversal of Na+ inactivation by the very brief initial hyperpolarization. 4. In vitro, at low bath temperature, the nerve response to an initial quarter-cycle depolarization declined in amplitude as the second hyperpolarizing phase progressively increased in amplitude and duration. This 'pull-down' phenomenon nearly disappeared as the bath temperature approached 37 C. Possibly, at the reduced temperature, delay in generation of the action potential permitted the hyperpolarization phase to reduce excitation. 5. Pull-down was not observed in the thenar muscle responses to median nerve stimulation in a normal human at normal temperature. However, pull-down emerged when the median nerve was cooled by placing ice over the forearm. 6. In a nerve at subnormal temperature straddled with non-conducting inhomogeneities, polyphasic pulses of either polarity elicited the largest responses. This was also seen when stimulating distal median nerve at normal temperature. These results imply excitation by hyperpolarizing-depolarizing pulse sequences at two separate sites. Similarly, polyphasic pulses elicited the largest responses from nerve roots and motor cortex. 7. The pull-down phenomenon has a possible clinical application in detecting pathologically slowed activation of Na+ channels. The current direction of the polyphasic waveform may become a significant factor with the increasing use of repetitive magnetic stimulators which, for technical reasons, induce a cosine-shaped half-cycle, preceded and followed by quarter-cycles of opposite polarity.

Transcranial magnetic stimulation in study of the visual pathway.

The authors critically reviewed experiments in which transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) of the higher visual pathway were used. Topics include basic mechanisms of neural excitation by TMS and their relevance to the visual pathway (excitatory and inhibitory effects), TMS and rTMS of calcarine cortex (suppression, unmasking, and phosphenes), TMS of V5 (suppression), TMS and rTMS of higher level temporoparietooccipital areas (perceptual errors, unmasking, and inattention), the role of frontal lobe output in visual perception, and vocalization of perceived visual stimuli (role of consciousness of linguistic symbols).

Preliminary evidence for the evolution in complexity of heart rate dynamics during autonomic maturation in neonatal swine.

Previous studies suggest that the autonomic nervous system plays an important role in the generation of complex heart rate dynamics. Therefore, we hypothesized that the complexity (irregularity) of cardiac interbeat intervals would evolve with the maturation of autonomic innervation to the heart. Twelve healthy newborn piglets were implanted with ECG transmitters and studied at one or more different ages up to 33 days of age, the period during which pigs develop functional sympathetic innervation of the heart from the stellate ganglia. Three animals underwent right stellate ganglionectomy, two a left stellate ganglionectomy, two a right cardiac vagotomy and five a sham procedure. The statistic, approximate entropy (ApEn), was used to quantify the regularity of interbeat interval fluctuations. Sham-operated animals showed an increase in the standard deviation (SD) and irregularity (ApEn) of cardiac interval fluctuations with increasing age. Right stellate ganglionectomized piglets had lower interbeat interval ApEn values, but similar SD's by 26-27 days of age compared to sham-operated animals. Left stellate ganglionectomy, which affects cardiac inotropy rather than chronotropy, had no effect on cardiac interval irregularity, while vagotomy had an indeterminant effect. The increasing irregularity of interbeat interval dynamics during autonomic maturation and the apparent attenuation of heartbeat irregularity when right stellate ganglion innervation is interrupted, provides empirical support for the notion that complex heartbeat dynamics in the mature animal are the result of a network of autonomic neural pathways that enables an organism to adapt to stress.

A new method using neuromagnetic stimulation to measure conduction time within the cauda equina.

Using principles derived from electric field measurements and studies of phrenic nerve in vitro, neuromagnetic stimuli in humans were predicted to excite selective low threshold sites in proximal and distal cauda equina. Physical models, in which induced electric fields were recorded in a segment of human lumbosacral spine immersed in a saline filled tank, supported this prediction. Conclusions from the model were tested and confirmed in normal human subjects. Ipsilateral motor evoked potentials were elicited in lower limb muscles and striated sphincters by magnetic coil (MC) stimulation of both proximal and distal cauda equina. Over proximal cauda equina a vertically oriented MC junction and cranially directed induced current elicited a newly identified compound muscle action potential (CMAP). The F response latency and lack of attenuation when the target muscle was vibrated suggest that the proximal response is a directly elicited M response arising near or at the rootlet exit zone of the conus medullaris. Over distal cauda equina, lumbar roots were optimally excited by a horizontally oriented MC junction, and sacral roots by an approximately vertically oriented MC junction, eliciting CMAPs with similar appearance but shorter latency consistent with the known intrathecal lengths of the lower lumbar and sacral nerve roots. The induced current was usually most effective when directed towards the spinal fluid filled thecal sac. Normal subjects showed stable CMAP onset latencies elicited at proximal and distal cauda equina despite wide variation in amplitude. Thus, cauda equina conduction time can be directly calculated. This new method may improve the detection and classification of peripheral neuropathies affecting lower limbs and striated sphincters.

[Clinical experiences with local capsaicin treatment of chronic rhinopathy]. / Klinische Erfahrungen mit lokaler Capsaicinbehandlung bei chronischer Rhinopathie.

Eighty-four patients with clinical findings of hyperactive rhinopathy and no significant septal deviations were treated for 4 weeks with topical applications of capsaicin, which is the pungent substance in hot peppers. A neutral solution of low-dose capsaicin allowed patients to administer self-therapy without the need for local anesthesia. The majority of the patients showed a marked reduction in symptoms without significant side effects. Patients with (additional) allergic or medication-related rhinopathy seemed to show fewer therapeutic effects when compared to patients with only hyperactive rhinopathy.

The polarity of the induced electric field influences magnetic coil inhibition of human visual cortex: implications for the site of excitation.

Human perception of 3 briefly flashed letters in a horizontal array that subtends a visual angle of 3 degrees or less is reduced by a magnetic coil (MC) pulse given, e.g., 90 msec later. Either a round or a double square MC is effective when the lower windings or central junction region, respectively, are tangential to the skull overlying calcarine cortex and symmetrical across the midline. The modeled, induced electric field has peak amplitude at the midline, but the peak spatial derivatives lie many centimeters laterally. Thus, the foveal representation near the midline is closer to the peak electric field than to its peak spatial derivatives, i.e., excitation of calcarine cortex differs from excitation of a straight nerve. With an MC pulse that induces an electric field which is substantially monophasic in amplitude, the lateral-most letter (usually the right-hand letter) in the trigram is preferentially suppressed when the electric field in the contralateral occipital lobe is directed towards the midline. Inferences from using peripheral nerve models imply that medially located bends in geniculo-calcarine or corticofugal fibers are the relevant sites of excitation in visual suppression; end excitation of fiber arborizations or apical dendrites is considered less likely. This conclusion is supported by the fact that the induced electric field polarity in paracentral lobule for optimally eliciting foot movements is opposite to that for visual suppression, the major bends occurring at different portions of the fiber trajectories in the two systems.

In vitro evaluation of a 4-leaf coil design for magnetic stimulation of peripheral nerve.

The performance of a 4-leaf magnetic coil was evaluated during magnetic stimulation of a peripheral nerve in vitro. The site of stimulation was below the coil center, and a 90 degrees rotation of the coil was equivalent to a change in current polarity. A hyperpolarizing magnetic stimulus failed to slow or block a propagating action potential.

Recognition potential: sensitivity to visual field stimulated.

The recognition potential (RP) was distinguished from P3 and eye blink responses by its sensitivity to visual area stimulated. Images were flashed in upper and lower hemifields. Current source density profiles were computed, using 16 midline scalp electrodes. For P3 and eye blink profiles, the hemifield stimulated was not a significant factor. For the recognition potential, upper and lower field stimulation produced radically different profiles. An improved recognition potential signal was obtained by a new mathematical procedure. It used the difference in sensitivity to visual area stimulated to reject P3 and eye blink responses.

Measurement of information processing delays in human visual cortex with repetitive magnetic coil stimulation.

Previous work disclosed that single magnetic coil (MC) pulses applied over human calcarine cortex could suppress perception of letters briefly presented, e.g. 80-100 ms earlier. Although individual MC stimuli presented 0-60 ms, or more than 140 ms after the visual stimulus were apparently ineffective, combinations of 2 or 3 MC pulses at such intervals temporarily depressed visual perception. Thus, progressing of such language information could be slowed, without being abolished. By contrast, when the first MC pulse was delivered 120 ms or later, a second MC pulse 40 ms later had no detectable effect, implying that calcarine cortex had already transmitted the information. Perceptual recovery of 5-character words initially occurred no earlier than that of random letters, nor or random letters vs. arbitrary linear patterns, implying that the processing delays in calcarine cortex were similar.

Unmasking human visual perception with the magnetic coil and its relationship to hemispheric asymmetry.

Visual suppression by a magnetic coil (MC) pulse delivered over human calcarine cortex after a transient visual stimulus 80-100 ms earlier has been used to suppress the representation of a 'masking' visual stimulus and thus to unmask a 'target' visual stimulus given, e.g., 100 ms before the mask. The resulting target unmasking as a function of the interval between mask and MC pulse is approximately the inverse of the visual suppression curve. Arbitrary visual linear patterns can similarly be unmasked. At the long target-mask interval used, the site of masking is deduced to lie beyond calcarine cortex. In several right-handed subjects tested, powerful MC stimulation of the left (but not right) temporo-parieto-occipital cortex also led to (weaker) unmasking.

Magnetic coil stimulation of straight and bent amphibian and mammalian peripheral nerve in vitro: locus of excitation.

1. According to classical cable theory, a magnetic coil (MC) should excite a linear nerve fibre in a homogeneous medium at the negative-going first spatial derivative of the induced electric field. This prediction was tested by MC stimulation of mammalian phrenic and amphibian sciatic nerve and branches in vitro, immersed in Ringer solution within a trough, and identifying the sites of excitation by recording responses of similar latency to local electrical stimulation. Subsequently, the identified sites of excitation were compared with measurements of the induced electric field and its calculated first spatial derivative. A special hardware device was used to selectively reverse MC current direction and to generate predominantly monophasic- or polyphasic-induced pulse profiles whose initial phases were identical in polarity, shape and amplitude. When using the amphibian nerve preparation, a complication was excitation at low threshold points related to cut branches. 2. Reversal of monophasic current resulted in latency shifts corresponding approximately to the distance between induced cathode and anode. The location of each site of excitation was at, or very near, the negative-going first spatial derivative peaks of the induced electric field measured parallel to the straight nerve. Significantly, excitation of the nerve did not occur at the peak of the induced electric field above the centre of the 'figure of eight' MC junction. 3. A polyphasic pulse excited the nerve at both sites, by the negative-going first phase at one location, and approximately 150 microseconds later, by the reversed negative-going second phase at the other location. Polyphasic and monophasic pulses elicited responses with similar latency when the induced current flowed towards the recording electrode. 4. Straddling a nerve with non-coding solid lucite cylinders created a localized spatial narrowing and increase in the induced electric field, resulting in a lowered threshold of excitation. The corresponding closer spacing between first spatial derivative peaks was exhibited by a significant reduction in latency shift when MC current direction was reversed. 5. When a nerve is bent and the induced current is directed along the nerve towards the bend, the threshold of excitation is reduced there. Increasing the angle of the bend from 0 deg to more than 90 deg graded the decrease in threshold. 6. In a straight nerve the threshold was lowest when current was directed towards the cut end.(ABSTRACT TRUNCATED AT 400 WORDS)

Modelling magnetic coil excitation of human cerebral cortex with a peripheral nerve immersed in a brain-shaped volume conductor: the significance of fiber bending in excitation.

To help elucidate some basic principles of magnetic coil (MC) excitation of cerebral cortex, a model system was devised in which mammalian phrenic nerve, or amphibian sciatic nerve with its branches was suspended in appropriate Ringer's solution in a human brain-shaped volume conductor, an inverted plastic skull. The nerve was recorded monophasically out of the volume conductor. The site of nerve excitation by the MC was identified by finding where along the nerve a bipolar electrical stimulus yielded a similar action potential latency. MC excitation of hand-related corticospinal (CT) neurons was modelled by giving the distal end of nerve attached to the lateral skull an initial radial (perpendicular) trajectory, with subsequent bends towards the base and posterior part of the skull; this nerve was optimally excited by a laterally placed figure 8 or round MC when the induced electric field led to outward membrane current at the initial bend. By contrast, nerve given a trajectory modelling CT neurons related to the foot was optimally excited when the coil windings were across the midline, but again when membrane current flowed outward at the first bend. Corticocortical fibers were modelled by placing the nerve in the anteroposterior axis lateral to the midline; with the round MC vertex-tangentially orientated, optimal excitation occurred at the bend nearest the interaural line, i.e., near the peak electric field. The findings emphasize the importance of orientation and direction of current in the MC and fiber bends in determining nerve excitation. The findings in the peripheral nerve-skull model help explain (1) why lateral and vertex-tangentially orientated MCs preferentially excite arm-related CT neurons directly and indirectly (through corticocortical fibers), respectively, and (2) why the MC orientations for optimally exciting directly arm and leg-related CT neurons differ.

Respiratory modulation of sympathetic activity in neonatal swine.

Spontaneous efferent sympathetic activity (cervical sympathetic and splanchnic nerves) was recorded simultaneously with efferent phrenic discharge, with aortic pressure, and with the electrocardiogram in less than 1- to 51-day-old neonatal swine anesthetized with Saffan (alfaxalone). Power spectral analyses of sympathetic discharge revealed a frequency range of 4-36 Hz, with peaks distributed in four regions of the spectrum (4-6 Hz, 8-15 Hz, 16-22 Hz, and 28-36 Hz). Inspiratory modulation was readily apparent since sympathetic power spectral energy was greatest during the time of phrenic activity. Alterations in pulmonary afferent inputs (e.g., lung inflation tests and/or vagotomy) altered both phrenic and sympathetic activity. Use of the respiratory-cardiac modulation ratio indicated that respiratory modulation of sympathetic activity was greater than cardiac modulation. Complex afferent inputs, i.e., fictive Valsalva maneuver, indicated an immaturity of integration within the cardiovascular regulatory system. The adult patterns of blood pressure changes and heart rate responses were delayed until approximately 1 mo of age. Calculations of Valsalva ratios (ratio of maximal R-R interval to minimal R-R interval) indicated delayed onset of heart rate responses, reflecting the maturation of cardiovascular reflexes during the neonatal period.

Power spectral analysis of the baroreflex in neonatal swine.

The baroreflex was observed in neonatal swine as young as 4 h of age. Bolus injections of Na nitroprusside (NP) and phenylephrine (PE), induced changes in blood pressure and elicited changes in both heart rate and in cervical sympathetic and splanchnic discharge; changes in sympathetic discharge were reflected in altered power spectral magnitude. Measures of heart rate showed that the magnitude of the PE-induced decreases was positively correlated with increasing postnatal age. The results indicate that the baroreflex, as indicated by changes in sympathetic discharge and heart rate, is present in early neonatal swine.

Measurement of the electric field induced into inhomogeneous volume conductors by magnetic coils: application to human spinal neurogeometry.

We measured the electric fields induced by round and figure "8" magnetic coils (MCs) in homogeneous and inhomogeneous volume conductors. In homogeneous media, the round MC held tangential (i.e., flat) to the volume conductor induced an annular electric field. When the round MC was held on-edge (i.e., orthogonal) to the volume conductor, the induced electric field consisted of two loops mainly parallel to the surface of the volume conductor and which approximated each other directly under the contacting edge of the MC. The tangentially oriented figure "8" MC similarly induced two electric field loops which approximated one another maximally under the region of the junction in its long axis. In a complex inhomogeneous volume conductor, such as a segment of human cervical-thoracic vertebral spine located eccentrically within a large cylindrical tank and submerged in isotonic saline, the direction of electric fields within the spinal canal and across the intervertebral neuroforamina was similar to that observed in the homogeneous volume conductor. However, in and near a single neuroforamen, the electric field and especially its first spatial derivative were markedly elevated compared to that recorded within the long central axis of the vertebral canal. Motor unit and compound muscle action potentials elicited in limb muscles by MC stimulation of human cervical spine confirmed predictions derived from the physical model. The predictions included: (1) absence of spinal cord stimulation compared to relative ease of nerve root stimulation by current that is most likely concentrated at the neuroforamina. When stimulating current is directed towards the periphery, the most likely low threshold site of stimulation is inferred to be just distal to the neuroforamina. It is emphasized that with supramaximal stimulation, more distal sites of excitation may occur; (2) invariant latency shifts at threshold intensities when moving the MC along the rostrocaudal axis of the cervical vertebral column; (3) significant effect (on motor unit activation thresholds) of the direction of induced current flow across the neuroforamina; (4) reduced stimulation when the targeted nerve roots are close to the null point of the electric field, i.e., between locations of high electric field intensity, of opposite polarity; and (5) relatively focal nerve root stimulation by the junction of a transversely orientated figure "8" MC, i.e., parallel to the nerve roots.