Physicians as healthcare surrogate for terminally ill children.

The parents of some terminally ill children have reported that being asked to authorise removal of life-sustaining measures is akin to being requested to sign a "death warrant". This dilemma leaves families not only enduring the grief of losing a loved one, but also with feelings of ambivalence, anxiety and guilt. A straightforward method by which the parents of terminally ill children can entrust the role of healthcare surrogate to the treating physician is presented. The cornerstone of this paradigm is parental awareness that the physician will act in the child's best interest, even if that means discontinuing life-sustaining measures. The goal is to mitigate parental guilt and fear of misperception, by self and others, of having given up on their child. From a moral standpoint this concept is an appealing option as it conforms to the four basic principles of medical ethics. While laws in the USA and several European nations prevent members of the medical team from taking on the responsibilities of healthcare surrogate for terminally ill patients, formal and informal precedence for this option already exists in France, The Netherlands, Norway, Sweden, Switzerland, and the Canadian province of Manitoba.

Dizziness and headache: a common association in children and adolescents.

Vertigo has long been recognized by the clinician as a frequent accompanying symptom of the adult migraine syndrome. This association has not been so readily identified in the pediatric population, and, as a consequence, children undergo unnecessary evaluations. We reviewed the charts of all children and adolescents referred for vestibular function testing to the Balance Center at the Barrow Neurological Institute between July 1994 and July 2000 (N = 31). Items analyzed included age, gender, symptoms that prompted the referral, test outcomes, family medical history, and final diagnosis. The most common justification for vestibular testing referral was the combination of dizziness and headache. Other less common reasons were "passing out" episodes, poor balance, and blurred vision. Normal test results were obtained from 70% of patients (n = 22). The most common abnormal test outcome was unilateral vestibular dysfunction (n = 5). Bilateral peripheral vestibular dysfunction was present in three patients. One patient had central vestibular dysfunction. The final diagnoses were vestibular migraine (n = 11), benign paroxysmal vertigo of childhood (n = 6), anxiety attacks (n = 3), Meniere's disease (n = 2), idiopathic sudden-onset sensorineural hearing loss (n = 1), vertigo not otherwise specified (n = 1), familial vertigo/ataxia syndrome (n = 1), and malingering (n = 1); in five patients, no definitive diagnosis was established. The stereotypical patient with vestibular migraine was a teenage female with repeated episodes of headache and dizziness, a past history of carsickness, a family history of migraine, and a normal neurologic examination. Patients who fit this profile are likely to have migrainous vertigo. Consequently, a trial of prophylactic migraine medication should be considered for both diagnostic and therapeutic purposes. Brain imaging and other tests are appropriate for patients whose symptoms deviate from this profile.

Sensory cells determine afferent terminal morphology in cross-innervated electroreceptor organs: implications for hair cells.

Type I and type II hair cells of the vestibular system are innervated by afferents that form calyceal and bouton terminals, respectively. These cannot be experimentally cross-innervated in the inner ear to determine how they influence each other. However, analogous organs are accessible for transplantation and cross-innervation in the brown ghost electric fish. These fish possess three types of electroreceptor organs. Of these, the sensory receptors of the type I tuberous organ are S-100- and parvalbumin-positive with a calbindin-positive afferent that forms a large calyx around the organ. Neither the sensory receptors nor the afferents of the ampullary organs label with these antibodies, and the afferent branches form a single large bouton beneath each receptor cell. In controls, when cut ampullary afferents reinnervate transplanted ampullary organs, they have characteristic calbindin-negative terminals with large boutons. When type I tuberous afferents reinnervate ampullary organs, receptor cells remain S-100- and parvalbumin-negative, and the tuberous afferents still express calbindin. The nerve terminals, however, make large ampullary-like boutons on the receptor cells. These results suggest that (1) afferent terminal morphology is dictated by the receptor organ; (2) expression of calbindin by the afferent is not suppressed by innervation of the incorrect end organ; (3) ampullary organs generate ampullary receptor cells although innervated by tuberous afferents; and (4) ampullary receptor cells can be trophically supported by tuberous afferents.

Anatomical basis of a congenital hearing impairment: basilar papilla dysplasia in the Belgian Waterslager canary.

Recent investigations into the anatomy of the inner ear of Belgian Waterslager canaries (BWC) have demonstrated myriad malformations associated with dysgenesis of the pars inferior of the otocyst. In those studies, the surface anatomy of BWC's basilar papilla and sacculus was examined utilizing scanning electron microscopy. In the present investigation, we utilized both light microscopy and transmission electron microscopy to describe the cross sectional anatomical pathology of the BWC's basilar papilla. Examination of the BWC's organ of Corti revealed numerous dysmorphologies: 1) hair cells from the tall hair cell region appeared broad and stunted, with deformed cuticular plates, abnormal stereocilia, and recognizable microvilli; 2) quantitative analysis of these hair cells revealed disproportionately large nuclei and abnormally short stereocilia; 3) hair cells from the short hair cell region of the papilla were absent, replaced by a population of large cells with electron-lucent cytoplasm; and 4) the tectorial membrane in the BWC papilla was narrow, covering only the area where the deformed tall hair cells were found. The malformations appeared to be more severe at the apex and midsection of the basilar papilla than at the base. These observations allow us to suggest a hypothesis to account for the distinct anatomofunctional hearing deficit observed in these birds. In addition, they further support our hypothesis that the inner ear of BWC is afflicted by a disorder similar to Scheibe's dysplasia, the most common inner ear defect associated with congenital hearing loss in humans.

Tuberous electroreceptor organs form in denervated regenerating skin of a weakly electric fish.

Weakly electric fish use tuberous electroreceptor organs to detect their own electric fields. We investigated the role of innervation upon regeneration and differentiation of tuberous electroreceptor organs. The left, infraorbital, anterior lateral line nerve of brown ghosts (Apteronotus leptorhynchus) was sectioned, and the proximal stump was dipped in ricin to prevent regrowth. Immediately after denervation, a piece of cheek skin (approximately 0.5 cm2) was removed bilaterally to induce skin regeneration. After survival periods of 3, 4, or 5 weeks, regenerated skin from the left (denervated) and the right (reinnervated) sides was removed and processed for immunocytochemistry or electron microscopy. Tuberous electroreceptor organs were present in regenerated reinnervated, as well as regenerated denervated skin patches at all survival times. With increased time after skin removal, the number of fully differentiated organs increased in the reinnervated regenerated skin while the number of organs with degenerating receptor cells or entirely devoid of receptor cells increased in the denervated regenerated skin. These results suggest that innervation is not essential for tuberous electroreceptor organ development, but that it is necessary for complete sensory cell differentiation and long-term survival.

Hair cell replacement in avian vestibular epithelium: supporting cell to type I hair cell.

Previous investigations have demonstrated that the sensory epithelium of the avian vestibular system possesses the capacity to replace hair cells both on an ongoing basis and following severe damage. Supporting cells, within the sensory epithelium, are believed to be the progenitors of the regenerated hair cells. In the present study we describe the series of events leading to the formation of a regenerated vestibular hair cell in post-hatched birds. Young chickens received injections of streptomycin sulfate in order to damage the sensory epithelium of the vestibular system. These injections were followed by injections of the cell proliferation marker tritiated-thymidine. At predetermined intervals, the animals were killed, and the vestibular organs were processed for tissue autoradiography. Our results confirm that hair cells originate from supporting cells. The data also indicate that postmitotic cells migrate towards the lumen of the epithelium where they differentiate into Type II hair cells. At a later time, some of the new Type II hair cells further differentiate into Type I hair cells. These results suggest that both types of avian vestibular hair cells have a common ancestor. The data also provide evidence in support of the hypothesis that calyx enclosed Type I hair cells, only present in birds and mammals, are a more differentiated stage of Type II hair cells.

Belgian Waterslager canaries are afflicted by Scheibe's-like dysplasia.

Behavioral investigations of Belgian Waterslager canaries (BWCs) have demonstrated a congenital hearing impairment that primarily affects high frequencies. Research into the surface anatomy of the basilar papilla of these birds has pointed to the hair cells as the site of the lesion. Given that the basilar papilla and the vestibular organs both develop from the otocyst, we were interested in ascertaining whether the vestibular sensory epithelia also displayed abnormal hair cells. The inner ear of adult BWCs was examined by scanning electron microscopy. As expected, hair cells in the basilar papilla of BWCs were abnormal. As for the vestibular parenchyma, abnormal hair cells were detected in only one structure: the sacculus. Morphological abnormalities of the cochlea and sacculus are pathognomonic signs of Scheibe's dysplasia, the most common inner ear defect associated with congenital hearing loss. Our results suggest that BWCs are afflicted by this genetic disorder.

Effects of denervation upon receptor cell survival and basal cell proliferation in tuberous electroreceptor organs of a weakly electric fish.

Weakly electric fish generate electric fields for the purposes of electrolocation and communication. These fields are detected by specialized receptor organs: the tuberous organs. In the present study we investigated the effects of denervation upon receptor cell survival and progenitor (basal) cell proliferation rate. The left, infraorbital, anterior lateral line nerve of brown ghosts (Apteronotus leptorhynchus) was sectioned, and the proximal stump was dipped in ricin to prevent regrowth. In groups of four, the animals were given two daily injections of the cell proliferation marker bromodeoxyuridine (BrdU) for 2 days at 1, 2, 3, or 4 weeks following denervation. At the completion of the BrdU injection schedule, a piece of cheek skin, rostroventral to the eye, was removed from the left (denervated) and the right (intact) sides and processed for light microscopy or immunocytochemistry. Our results show: (1) there is progressive receptor cell death and tuberous organ degeneration following denervation; (2) basal cell proliferation increases steadily with time after denervation and tuberous organ degeneration; and (3) despite denervation, some proliferating basal cells differentiate into receptor cells, but these new receptor cells eventually die. These results suggest that innervation is essential for tuberous electroreceptor cell survival and that the rate at which basal cells proliferate is regulated by receptor cell health, locally released factors, or both.

Identification of hair cell progenitors and intermitotic migration of their nuclei in the normal and regenerating avian inner ear.

Postembryonic production of sensory hair cells occurs in both normal and aminoglycoside-damaged avian inner ears. The cellular source and mechanism that results in new differentiated hair cells were investigated in the avian vestibular epithelia using three distinct cell-cycle-specific labeling methods to identify proliferating sensory epithelial cells. First, immunocytochemical detection of the proliferating cell nuclear antigen, an auxiliary protein of DNA polymerase, allowed labeling of cells in late G1, S, and early G2 phases of the cell cycle. Second, a pulse-fix tritiated thymidine autoradiographic protocol was used to identify cells in S phase of the cell cycle. Finally, Hoechst 33342, a fluorescent DNA stain, was used to identify epithelial cells in mitosis. The distribution of cells active in the cell cycle within the normal and ototoxin-damaged vestibular epithelium suggests that supporting cells within the sensory epithelia are the cellular precursors to the regenerated hair cells. Differences between the proliferation marker densities in control and damaged end organs indicate that the upregulation of mitotic activity observed after streptomycin treatment is due primarily to an increase in the number of dividing progenitor cells. The differences between the extent of ototoxic damage and the level of reparative proliferative response suggest a generalized stimulus, such as a soluble chemical factor, plays a role in initiating regeneration. Finally, after DNA replication is initiated, progenitor cell nuclei migrate from their original location close to the basement membrane to the lumenal surface, where cell division occurs. This pattern of intermitotic nuclear migration is analogous to that observed in the developing inner ear and neural epithelium.

Hair cell regeneration after streptomycin toxicity in the avian vestibular epithelium.

Recent reports documented the ability of the posthatch avian vestibular epithelia to produce hair cells continually at a low rate. This project was designed to investigate whether, in addition, the chicken vestibular system is capable of regenerating its sensory epithelium in response to a lesion. Aminoglycoside injections were given to young birds in order to damage the vestibular epithelium. Tritiated thymidine injections were used to label cells produced in response to the lesion. Treatment and age-matched control animals were killed at 1 day, 20 days, or 60 days after aminoglycoside injections, and vestibular organs were processed for autoradiography. Our results show that the chicken vestibular sensory epithelium is capable of regenerating hair cells after severe damage. Moreover, the epithelium is capable of complete anatomical recovery. Finally, drug damage increases the pace at which hair cells are replaced, compared to the rate of hair cell turnover in untreated tissue.

Hair cell regeneration in the avian vestibular epithelium.

Research conducted in the past 4 years has shown that the avian vestibular system retains the capacity to generate hair cells postnatally. In the present paper we review information on postnatal proliferation and differentiation of hair cells in the avian vestibular system. In addition, we present preliminary accounts of recent experiments regarding regeneration of vestibular hair cells following aminoglycoside toxicity. The overall consensus is that the avian vestibular system is able to regenerate hair cells, both on an ongoing basis and after damage.

Ongoing production of sensory cells in the vestibular epithelium of the chick.

Recent studies have shown that the vestibular and auditory systems of some species of birds have the capacity to generate sensory hair cells postnatally. We used a traditional technique, 3H-thymidine autoradiography, and a newer method, bromodeoxyuridine immunocytochemistry, to determine whether ongoing proliferation of hair cells occurs in the intact chick vestibular epithelium. A ten-day course of 3H-thymidine, bromodeoxyuridine, or both was administered to twelve-day-old chicks. Both autoradiographic and immunocytochemical labeling demonstrated ongoing production of supporting cells and Type II hair cells in all chick vestibular organs. No evidence for production of Type I hair cells was seen in this investigation. New sensory cells were distributed throughout the epithelium; there was no peripheral growth zone analogous to that found in other vertebrates. Labeled Type II hair cells were frequently seen immediately above labeled supporting cells. This observation suggests that supporting cells are precursors for new hair cells. The ongoing, postnatal regeneration of vestibular epithelial cells also suggests that this epithelium may retain the potential for repair after trauma or ototoxic damage.

Hair cell regeneration in the avian inner ear.

The postembryonic production of hair cells in fish and reptiles has been known for several decades. Until recently it was assumed that this capacity was absent in the more highly specialized inner ears of birds and mammals. Recent research has shown, however, that birds have the capacity to rebuild a damaged inner ear. Summarized here are studies conducted in our laboratory which address the following questions: (1) Which are the precursors of the regenerated hair cells? (2) Are the new hair cells functional? (3) What are the ultrastructural properties of regenerated hair cells? and (4) Can the level of proliferation be regulated? Both the auditory and the vestibular systems of the avian inner ear were studied. Our results provide some answers to these questions. The implications of the results are discussed.

Peripheral generators of the vestibular evoked potentials (VsEPs) in the chick.

Electrophysiological activity in response to linear acceleration stimuli was recorded from young chickens by means of subcutaneous electrodes. This investigation had 2 purposes: (1) to establish the vestibular origin of the potentials; and (2) to investigate the contribution of each vestibular labyrinth to the response. The stimuli consisted of pulses of linear acceleration delivered by a mechanical vibrator (shaker). In the first set of experiments vestibular evoked potentials (VsEPs) were recorded prior to and 24 h after bilateral cochlea removal. In the second set of experiments responses were recorded before and after unilateral or bilateral intralabyrinthine injections of tetrodotoxin (TTX). Different groups of subjects were used for each experimental condition. The general morphology of the VsEPs was maintained after bilateral cochlea removal. Absolute latency of wave P2, the most prominent component of the response, was not significantly affected by the manipulation. Unilateral intralabyrinthine TTX injections consistently prolonged the latency and reduced the amplitude of wave P2. Following binaural TTX injections we were unable to elicit responses at the acceleration levels used in this study. The results from these experiments suggest that: (1) the activity recorded in response to linear acceleration stimuli is vestibular in origin; (2) when recorded from intact animals the evoked response is composed of activity from both vestibular systems; and (3) TTX consistently blocks the activity of the vestibular portion of the VIIIth cranial nerve.

Reversible blockade of vestibular evoked activity in the chick.

Vestibular evoked potentials (VsEP) were recorded from young chickens following bilateral intralabyrinthine injections of Tetrodotoxin (TTX). The purpose of this study was to document the long term effects of TTX on the electrophysiological activity of the vestibular system. VsEP components were eliminated within 30 min of TTX injections. Twelve hours post-treatment the early waves of the response began to emerge from the background noise. Recordings completed 24 h after the manipulation were not different from baseline responses. Our results indicate that TTX is a useful substance for reversibly blocking vestibular afferent pathways without permanently damaging the labyrinth or neural components. In addition, VsEP is an appropriate tool to objectively evaluate vestibular system function. Their combination can be applied to study the significance of afferent influences on the development and function of vestibular nuclei.

Evaluation of four Spanish word-recognition-ability lists.

Tests of word recognition ability (formerly Speech Discrimination) should be suitable for the linguistic background of the person being tested. Few efforts have been made to develop a standardized test in the Spanish language. Current literature reports on six studies that have several drawbacks. The purpose of the present study was to evaluate a commercially available Spanish language test. The material consists of four lists of 50 bisyllabic tetraphonemic Spanish words. The words were recorded at a professional laboratory (Auditec of St. Louis) by a native Spanish speaker. In the present study, the lists were evaluated in terms of interlist equivalence, word difficulty, intelligibility of the talker, and slope of the performance/intensity (PI) function. Taped lists were presented to 16 normal-hearing native Spanish speaking adults at four presentation levels. Mean intelligibility scores were poorest for list three. Statistical analysis indicated that the intelligibility of list three is significantly different than the other lists at the 0.05 level. On the average, at low presentation levels, the nine subjects of Mexican origin obtained better scores than the seven subjects of other nationalities. The slope of the PI-PB function (4.3%) was comparable to that obtained by other investigators of English lists. The words most frequently missed contain the /s/ sound and are words that retain their meaning even after deletion of the final /s/. The talker's speech intelligibility was judged to be very clear.

[Vestibular evoked potentials in "Gallus Domesticus"]. / Potenciales evocados vestibulares en "Gallus Domesticus".

Electrophysiological activity in response to linear acceleration stimuli was recorded from Gallus Domesticus by means of subcutaneous electrodes. This investigation had two purposes: 1) to obtain normative data for our laboratory, and 2) to rule out auditory and somatosensory contributions to the Vestibular Evoked Potentials (VsEP). The stimulus consisted of a sigmoid-shaped voltage function generated by a digital-to-analog converter. This signal was amplified, attenuated, and directed to a shaker (selenoid-based, linear mechanical vibrator). The animal's head was firmly attached to a small platform which in turn was coupled to the transducer. The recorded electrophysiological activity was filtered, amplified, and averaged over 256 stimulus presentations. The VsEP are composed of a positive wave, a prominent negativity, and three to five additional positive waves which occur within the first 10 milliseconds following the stimulus. The first three elements are the most robust components of the response. Latency/acceleration and amplitude/acceleration functions were constructed for each of these three waves. Clear and replicable responses were obtained at an acceleration of 2.00 g. At this level the amplitude of the components ranged between 3 and 5 microvolts. On the average, threshold responses were recorded at 0.0935 g. VsEP were not affected by high intensity white noise. However, bilateral intralabyrinthine injection of tetrodotoxin (TTX), a voltage-gated sodium channel blocker, abolished the responses. These results suggest that the activity recorded in response to linear acceleration stimuli is of vestibular origin.