The ineffectiveness of applying moisture to the ear on the incidence and severity of otic barotrauma for air passengers.

OBJECTIVE: The application of moisture to the ear is anecdotally claimed to relieve the pain from otic barotrauma that can arise during aircraft descent. This claim was tested in a randomised double-blind study on an aircraft with eight participants heavily predisposed to barotrauma. METHODS: On the outward flight, half the participants wore 'active' devices that applied moisture to the external ear; the remainder wore placebo devices that contained no moisture, but were otherwise identical. On the return flight, the groups were reversed. Participants wore the devices from just before descent until landing, unless they experienced symptoms of barotrauma, in which case they switched to what they knew was an active device. RESULTS: There were no significant differences between conditions regarding the appearance of the tympanic membrane on landing or the discomfort levels immediately before and after any switch. CONCLUSION: Applying moisture is ineffective for passengers heavily predisposed to otic barotrauma.

A phenomenological model of myelinated nerve with a dynamic threshold.

To evaluate coding strategies for cochlear implants a model of the human cochlear nerve is required. Nerve models based on voltage-clamp experiments, such as the Frankenhaeuser-Huxley model of myelinated nerve, can have over forty parameters and are not amenable for fitting to physiological data from a different animal or type of nerve. Phenomenological nerve models, such as leaky integrate-and-fire (LIF) models, have fewer parameters but have not been validated with a wide range of stimuli. In the absence of substantial cochlear nerve data, we have used data from a toad sciatic nerve for validation (50 Hz to 2 kHz with levels up to 20 dB above threshold). We show that the standard LIF model with fixed refractory properties and a single set of parameters cannot adequately predict the toad rate-level functions. Given the deficiency of this standard model, we have abstracted the dynamics of the sodium inactivation variable in the Frankenhaeuser-Huxley model to develop a phenomenological LIF model with a dynamic threshold. This nine-parameter model predicts the physiological rate-level functions much more accurately than the standard LIF model. Because of the low number of parameters, we expect to be able to optimize the model parameters so that the model is more appropriate for cochlear implant simulations.

Stimulus-dependent refractoriness in the Frankenhaeuser-Huxley model.

Phenomenological neural models, such as the leaky integrate-and-fire model, normally have a fixed refractory time-course that is independent of the stimulus. The recovery of threshold following an action potential is typically based on physiological experiments that use a two-pulse paradigm in which the first pulse is suprathreshold and causes excitation and the second pulse is used to determine the threshold at various intervals following the first. In such experiments, the nerve is completely unstimulated between the two pulses. This contrasts the receptor stimuli in normal physiological systems and the electrical stimuli used by cochlear implants and other neural prostheses. A numerical study of the Frankenhaeuser-Huxley conductance-based model of nerve fibre was therefore undertaken to investigate the effect of stimulation on refractoriness. We found that the application of a depolarizing stimulus during the later part of what is classically regarded as the absolute refractory period could effectively prolong the absolute refractory period, while leaving the refractory time-constants and other refractory parameters largely unaffected. Indeed, long depolarizing pulses, which would have been suprathreshold if presented to a resting nerve fibre, appeared to block excitation indefinitely. Stimulation during what is classically regarded as the absolute refractory period can therefore greatly affect the temporal response of a nerve. We conclude that the classical definition of absolute refractory period should be refined to include only the initial period following an action potential when an ongoing stimulus would not affect threshold; this period was found to be about half as long as the classical absolute refractory period. We further conclude that the stimulus-dependent nature of the relative refractory period must be considered when developing a phenomenological nerve model for complex stimuli.

Enhanced information transmission with signal-dependent noise in an array of nonlinear elements.

We have investigated information transmission in an array of threshold units that have signal-dependent noise and a common input signal. We demonstrate a phenomenon similar to stochastic resonance and suprathreshold stochastic resonance with additive noise and show that information transmission can be enhanced by a nonzero level of noise. By comparing system performance to one with additive noise we also demonstrate that the information transmission of weak signals is significantly better with signal-dependent noise. Indeed, information rates are not compromised even for arbitrary small input signals. Furthermore, by an appropriate selection of parameters, we observe that the information can be made to be (almost) independent of the level of the noise, thus providing a robust method of transmitting information in the presence of noise. These result could imply that the ability of hair cells to code and transmit sensory information in biological sensory systems is not limited by the level of signal-dependent noise.

Human herpesvirus 6 limbic encephalitis after stem cell transplantation.

Central nervous system complications are common in stem cell transplant recipients, but selective involvement of the medial temporal area is unusual. The 5 patients reported here presented after stem cell transplantation with increased hippocampal T2 signal on magnetic resonance imaging and increased hippocampal glucose uptake on [F-18]fluorodeoxyglucose-positron emission tomography (FDG-PET) associated with short-term memory loss, insomnia, and temporal lobe electrographic seizure activity. The initial scalp electroencephalograms (EEGs) failed to detect seizure activity in these patients, although the memory dysfunction along with the magnetic resonance imaging and FDG-PET findings suggested subcortical seizure activity. However, extended EEG monitoring revealed repetitive temporal lobe electrographic seizure activity. Follow-up MRIs in 2 patients and postmortem findings on 1 patient suggested that hippocampal sclerosis had developed following the clinical syndrome. Cerebrospinal fluid studies revealed the presence of human herpesvirus 6, variant B, DNA in all of 3 patients who had lumbar punctures. Immunohistochemical staining for the P41 and P101 human herpesvirus 6 protein antigens showed numerous immunoreactive astrocytes and neurons in the hippocampus of 1 of the patients who died from other causes. Because of its subtle clinical presentation, this syndrome may be underrecognized, but can be diagnosed with appropriate magnetic resonance imaging techniques, EEG monitoring, and cerebrospinal fluid viral studies.

Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial.

PURPOSE: Infantile glycogen storage disease type II (GSD-II) is a fatal genetic muscle disorder caused by deficiency of acid alpha-glucosidase (GAA). The purpose of this study was to investigate the safety and efficacy of recombinant human GAA (rhGAA) enzyme therapy for this fatal disorder. METHODS: The study was designed as a phase I/II, open-label, single-dose study of rhGAA infused intravenously twice weekly in three infants with infantile GSD-II. rhGAA used in this study was purified from genetically engineered Chinese hamster ovary (CHO) cells overproducing GAA. Adverse effects and efficacy of rhGAA upon cardiac, pulmonary, neurologic, and motor functions were evaluated during 1 year of the trial period. The primary end point assessed was heart failure-free survival at 1 year of age. This was based on historical control data that virtually all patients died of cardiac failure by 1 year of age. RESULTS: The results of more than 250 infusions showed that rhGAA was generally well tolerated. Steady decreases in heart size and maintenance of normal cardiac function for more than 1 year were observed in all three infants. These infants have well passed the critical age of 1 year (currently 16, 18, and 22 months old) and continue to have normal cardiac function. Improvements of skeletal muscle functions were also noted; one patient showed marked improvement and currently has normal muscle tone and strength as well as normal neurologic and Denver developmental evaluations. Muscle biopsies confirmed that dramatic reductions in glycogen accumulation had occurred after rhGAA treatment in this patient. CONCLUSIONS: This phase I/II first study of recombinant human GAA derived from CHO cells showed that rhGAA is capable of improving cardiac and skeletal muscle functions in infantile GSD-II patients. Further study will be needed to assess the overall potential of this therapy.

Enhanced coding in a cochlear-implant model using additive noise: aperiodic stochastic resonance with tuning.

Analog electrical stimulation of the cochlear nerve (the nerve of hearing) by a cochlear implant is an effective method of providing functional hearing to profoundly deaf people. Recent physiological and computational experiments have shown that analog cochlear implants are unlikely to convey certain speech cues by the temporal pattern of evoked nerve discharges. However, these experiments have also shown that the optimal addition of noise to cochlear implant signals can enhance the temporal representation of speech cues [R. P. Morse and E. F. Evans, Nature Medicine 2, 928 (1996)]. We present a simple model to explain this enhancement of temporal representation. Our model derives from a rate equation for the mean threshold-crossing rate of an infinite set of parallel discriminators (level-crossing detectors); a system that well describes the time coding of information by a set of nerve fibers. Our results show that the optimal transfer of information occurs when the threshold level of each discriminator is equal to the root-mean-square noise level. The optimal transfer of information by a cochlear implant is therefore expected to occur when the internal root-mean-square noise level of each stimulated fiber is approximately equal to the nerve threshold. When interpreted within the framework of aperiodic stochastic resonance, our results indicate therefore that for an infinite array of discriminators, a tuning of the noise is still necessary for optimal performance. This is in contrast to previous results [Collins, Chow, and Imhoff, Nature 376, 236 (1995); Chialvo, Longtin, and Müller-Gerking, Phys. Rev. E 55, 1798 (1997)] on arrays of FitzHugh-Nagumo neurons.

Additive noise can enhance temporal coding in a computational model of analogue cochlear implant stimulation.

Conventional analogue multichannel cochlear implants are unlikely to convey formant information by the fine time structure of evoked discharges. Theoretically, however, the addition of noise to the channel outputs could enhance the representation of formants by time coding. In this study, the potential benefit of noise in analogue coding schemes was investigated using a computer model of cochlear implant stimulation. The cochlear nerve was modelled by the Frankenhauser-Huxley equations. For all five vowels investigated, the optimal addition of noise to the first channel of the simulated implant (200-671 Hz) caused enhancement of the first formant representation (as seen in amplitude spectra of the simulated discharges). For vowels with a low-frequency second formant, clear enhancement of the second formant resulted from the optimal addition of noise to the third channel (1200-2116 Hz). On the basis of the present computational study, additive noise would be expected to enhance the coding of temporal information by the discharges of a single nerve fiber.

Preferential and non-preferential transmission of formant information by an analogue cochlear implant using noise: the role of the nerve threshold.

Previous experiments have shown that, in principle, the addition of noise to any vowel coded by an analogue multichannel cochlear implant can enhance the representation of formant information by the temporal pattern of evoked nerve discharges. The optimal addition of noise to some vowel stimuli caused a largely uniform transmission of all input harmonics, including those related to a formant. But for other vowel stimuli, the optimal addition of noise caused preferential transmission of the harmonic closest to a formant compared with other input harmonics. Such preferential transmission may be useful to a cochlear implantee for formant estimation, but the basis of this transmission is unknown. In the present study, the nature of this preferential transmission was investigated with a set of parallel discriminators (or level-crossing detectors) to determine whether the inherent threshold of a nerve fiber was the main cause of the effect. An explicit threshold was found to account for some but not all of the previously observed preferential transmission. Furthermore, many discriminators were required to obtain preferential transmission. Therefore, preferential transmission of a formant-related harmonic may be best achieved by pre-processing a stimulus and using methods associated with stochastic resonance.

Neurofibromatosis type 1.

Neurofibromatosis (NF) has perhaps been the most notorious of the neurocutaneous disorders. Both Quasimoto of Victor Hugo's The Hunchback of Notre Dame and John Merrick, known as the Elephant Man (who subsequently has been more properly classified as having Proteus syndrome, a quite different disorder), are 2 infamous examples that have shaped many popular misconceptions about this disease. Neurofibromatosis is now understood as a hamartomatous disorder on the basis of molecular genetic studies. Studies on NF have been pivotal to understanding the functions of oncogenes in tumorigenesis.

Enhancement of vowel coding for cochlear implants by addition of noise.

Profoundly deaf people, who gain no benefit from conventional hearing aids, can receive speech cues by direct electrical stimulation of the cochlear nerve. This is achieved by an electronic device, a cochlear implant, which is surgically inserted into the ear. Here we show physiological results from the isolated sciatic nerve of the toad Xenopus laevis, used to predict the response of the human cochlear nerve to vowels coded by a cochlear implant. These results suggest that standard analogue cochlear implants do not evoke the patterns of neural excitation that are normally associated with acoustic stimulation. Adding noise to the stimulus, however, enhanced distinguishing features of the vowel encoded by the fine time structure of neural discharges. On the basis of these results, and those concerning stochastic resonance, we advocate a cochlear implant coding strategy in which noise is deliberately added to cochlear implant signals.

Clonal analysis of human astrocytomas.

Clonal analysis of many human cancers have generally confirmed that they are monoclonal. Although astrocytic neoplasms are the most frequently occurring primary tumors in the central nervous system, their clonal composition has not been systematically studied. In this report, the clonal composition of 22 human astrocytomas of all histological grades (2 well-differentiated astrocytomas, 3 anaplastic astrocytomas and 17 glioblastoma multiforme) was determined by analysis of the pattern of X-chromosome inactivation. Leukocyte and non-tumor brain DNA were used as controls. In addition, specimens from different parts of four glioblastoma multiforme were analyzed to determine whether remote areas of the same tumor had the same clonal composition. Eighteen of nineteen informative astrocytomas had a monoclonal pattern of X-chromosome inactivation; one glioblastoma multiforme had loss of heterozygosity on the X chromosome. Specimens from different areas of the same tumor all had identical patterns of X-chromosome inactivation. Leukocytes and non-tumor brain used as controls uniformly had a polyclonal pattern of X-chromosome inactivation. Furthermore, loss of heterozygosity for chromosomes 10 or 17 p loci was found in 64% (9/14) of informative specimens and identical allelic patterns were observed in specimens from different areas of the same tumor. Our results demonstrate that human astrocytomas from low to high-grade are characterized by monoclonal cell populations. The presence of monoclonality in even low-grade neoplasms suggests that in astrocytic tumors the establishment of monoclonality occurs quite early. Also, the finding of a monoclonal pattern in intermediate- and high-grade astrocytomas further supports the hypothesis that clonal expansion underlies astrocytic tumor progression.

Diagnosis of occult muscular dystrophy: importance of the "chance" finding of elevated serum aminotransferase activities.

We report our experience with four children, including one girl, in whom the eventual diagnosis of muscular dystrophy was made because of persistent, unexplained elevated serum aminotransferase values. Measurement of serum creatine kinase activity and careful physical examination are the most useful and cost-effective means of correctly identifying these patients.

Eastern equine encephalitis presenting with a focal brain lesion.

Eastern equine encephalitis (EEE) virus causes a severe meningoencephalitis with high morbidity and mortality. Despite numerous clinical reports of EEE, there are only 11 patients in whom cranial computed tomographic (CT) findings are described. In 6 patients, CT was normal and in 5 patients diffuse edema was present; none had a focal brain lesion. Based on these reports, it has been suggested that focal findings on CT support the diagnosis of herpes simplex encephalitis rather than EEE. The first patient with serologically-confirmed EEE and a focal lesion demonstrated by cranial CT and magnetic resonance imaging is described; these findings underscore the importance of including EEE in the differential diagnosis of encephalitides that can cause focal brain lesions on neuroimaging.

Diagnosis and management of infantile marfan syndrome.

Marfan syndrome is infrequently diagnosed early in infancy. The experience of the authors with 22 severely affected infants diagnosed as having Marfan syndrome in the first 3 months of life is described and the literature on 32 additional infants with Marfan syndrome is reviewed. It was found that serious cardiac pathology (82% of the patients described in the article, 94% of those described in the literature) may be present at birth, and that congenital contractures (64% of our cases, 47% of literature cases) are often an associated finding. Other useful clinical findings included arachnodactyly, dolichocephaly, a characteristic facies, a high-arched palate, micrognathia, hyperextensible joints, pes planus, anterior chest deformity, iridodenesis, megalocornea, and dislocated lenses. Echocardiography was useful as a noninvasive method for defining the extent of cardiovascular involvement and following its course. Characteristic cardiac findings in early life included mitral valve prolapse, valvular regurgitation, and aortic root dilation. Cardiac function ranged from normal to poor, with a tendency to worsen. Of the 22 cases 3 infants died during the first year of life. Morbidity and mortality may be high when Marfan syndrome is diagnosed during infancy, and prompt recognition of this phenotype can facilitate management and counseling. Most such severe cases appear to be due to a sporadic mutation in a single germ cell of one parent. Many familial cases may have milder manifestations, be more difficult to detect during infancy, and have a better prognosis.

Prenatal diagnosis of a new syndrome: holoprosencephaly with hypokinesia.

Markedly decreased fetal activity (akinesia/hypokinesia) is usually readily apparent to experienced mothers, and frequently this concern leads to attempts at prenatal diagnosis. We report prenatal diagnosis of two fetuses with congenital contractures, markedly decreased fetal movement, and microcephaly due to severe holoprosencephaly. Such familial recurrence to phenotypically normal parents suggests a newly recognized autosomal recessive or X-linked syndrome that is readily detectable by prenatal ultrasonography.

Bilateral renal agenesis in three consecutive siblings.

We report here an unusual recurrence of bilateral renal agenesis (BRA) in three consecutive siblings. Chromosome analysis was normal, as were renal ultrasound studies on both parents and their surviving child. Ultrasound was employed prenatally to diagnose Potter's syndrome in both of the recurrences, and autopsy confirmed BRA in otherwise normal fetuses. Recurrence of BRA points to the usefulness of ultrasound in monitoring subsequent pregnancies in couples who have had one such occurrence. Ultrasound studies should also be performed in non-affected family members to detect the presence of asymptomatic anomalies of the genitourinary system, but a negative family study does not preclude recurrence of BRA.