Egbert H. Huizing

Linkage of Autosomal Dominant Hearing Loss to the Short Arm of Chromosome 1 in Two Families

BACKGROUND At least half of the cases of profound deafness of early onset are caused by genetic factors, but few of the genetic defects have been identified. This is particularly true of the most common hereditary forms of deafness, which occur in the absence of any associated syndrome. METHODS We studied a large Indonesian family in which hearing loss was inherited in an autosomal dominant pattern. The hearing loss first affects the high frequencies during the teens or 20s and becomes profound within 10 years. To locate the responsible gene, we performed genetic-linkage analysis, using microsatellite markers distributed over the entire genome. We then performed linkage analyses in an American family and a Dutch family with similar patterns of hereditary hearing loss. RESULTS In the extended Indonesian family, a gene linked to deafness mapped to chromosome 1p, with a multipoint lod score of more than 7. In the American family, deafness was linked to the same locus on chromosome 1p, with a multipoint lod score of more than 5. In the Dutch family, however, this locus was ruled out. The flanking markers D1S255 and D1S211 defined a region of 6 cM on chromosome 1p that is likely to contain the gene associated with deafness in the first two families. CONCLUSIONS In some families with early-onset autosomal dominant hearing loss, the responsible gene is on chromosome 1p.

Physiologic and hypertonic saline solutions impair ciliary activity in vitro

Objective/Hypothesis: Physiologic saline (NaCl 0.9%) is commonly used in treating acute and chronic rhinosinusitis. Moreover, physiologic saline is used as a control medium, vehicle, or solvent in studies on ciliary beat frequency (CBF). Hypertonic saline (NaCl 7% and 14.4%) has been applied in attempts to enhance mucociliary transport in patients with cystic fibrosis or asthma and in healthy subjects. Therefore the objective of this study is to document in vitro effects of saline solutions in different concentrations on CBF. Study Design: Experimental, in vitro. Methods: The effects on CBF of cryopreserved mucosa of the sphenoidal sinus was measured by a photoelectrical method. Initial frequencies, measured in Locke‐Ringers solution (LR), were compared with CBF after exposure to NaCl in concentrations of 0.9%, 7.0%, and 14.4% (w/v). Results: NaCl 0.9% has a moderately negative effect on CBF. The 7% solution leads to a complete ciliostasis within 5 minutes, although this effect turns out to be reversible after rinsing with LR. A hypertonic solution of 14.4% has an irreversible ciliostatic effect. Conclusion: LR is an isotonic solution that has no effect on CBF. Therefore it is probable that this solution is more appropriate than saline for nasal irrigation and nebulization or antral lavage. Moreover, the results of this study suggest that mucolytic effects induced by hyperosmolarity should be attained preferably with hypertonic saline 7% in patients with cystic fibrosis or asthma. At this concentration, the ciliostatic effect is reversible, whereas irreversible changes are to be expected at higher concentrations.

Cisplatin-induced ototoxicity: morphological evidence of spontaneous outer hair cell recovery in albino guinea pigs?

Cisplatin is frequently used in the treatment of various forms of malignancies. Its therapeutic efficacy, however, is limited by the occurrence of sensorineural hearing loss. Little is known about the course of hearing loss over longer time intervals after cessation of cisplatin administration. Infrequently, recovery of hearing has been described in animals and humans. Stengs et al. (1997) treated guinea pigs with cisplatin at a daily dose of 1.5 mg/kg for 8 consecutive days and subsequently studied cochlear function after survival times varying from 1 day to 16 weeks. Spontaneous improvement of the hair cell-related potentials (cochlear microphonics and summating potentials) was observed starting 2 weeks after cessation of treatment. In the present study we examined light microscopically the cochleas used in the study of Stengs et al. (1997). One day after cessation of cisplatin administration outer hair cell (OHC) loss in the basal cochlear turn averaged 66%. In the 1-week survival group, OHC counts were similar to those of the 1-day survival group. In the 4-week survival group, however, a relatively small loss of OHCs was found in the basal cochlear turn; OHC loss averaged only 15%. A similar loss was found after 8 weeks. In the 16-week survival group, OHC loss in the basal turn increased to 48%, but this was not statistically significant. Our histological observations are in line with the electrophysiological data from the same animals. Our findings suggest that OHCs recover from cisplatin-induced damage 1-4 weeks after treatment. However, the results do not allow a conclusion as to whether the observed recovery is due to the formation of new OHCs or to (self-)repair of damaged OHCs.

Dose-dependent effect of 8-day cisplatin administration upon the morphology of the albino guinea pig cochlea

Numerous studies investigating cisplatin ototoxicity in animals have been performed, but it is difficult to derive a clear dose-effect relation from these studies. The degree of cisplatin-induced ototoxicity depends on a multitude of factors. Many parameters, such as dose, mode of administration, dosage schedule and concomitant administration of protective additives, vary among the published studies. Therefore, we performed a basic dose-effect study on cisplatin ototoxicity in the guinea pig. Albino guinea pigs were treated with cisplatin at daily doses of either 0.7, 1.0, 1.25, 1.5 or 2.0 mg/kg for 8 consecutive days. Electrocochleography was performed on day 10 after which the cochleas were removed and processed for histological examination. The electrophysiological results showed a marked transition from almost no ototoxic effect to a large effect between a daily dose of 1.25 and 1.5 mg/kg (Stengs et al., 1998). Outer hair cell (OHC) counts corresponded well with the electrophysiological results. At daily doses of 0.7, 1.0 and 1.25 mg/kg no statistically significant OHC loss was observed, whereas OHC loss averaged 60% and 65% in the basal turns at daily doses of 1. 5 and 2.0 mg/kg, respectively. Morphological changes in the stria vascularis were present only in cochleas from animals treated with cisplatin doses of 1.0, 1.25 and 1.5 mg/kg/day. Cochleas from animals treated with a daily cisplatin dose of 2.0 mg/kg for 8 consecutive days showed an endolymphatic hydrops. The present study shows that cisplatin, administered at a daily dose of 1.5 mg/kg for 8 consecutive days, provides a degree of OHC loss that is well suited to study the effects of putative protective agents and possible hair cell recovery.

Nasal Mucociliary Transport: New Evidence for a Key Role of Ciliary Beat Frequency †

Objectives/Hypothesis Mucociliary transport is an important defense mechanism of the respiratory tract. Nonetheless, the factors determining mucociliary transport are only partially understood. Ciliary beat frequency is assumed to be one of the main parameters, although the experimental evidence remains inconclusive.

Human Cochlear Pathology in Aminoglycoside Ototoxicity—A Review

The pathological findings due to aminoglycoside ototoxicity in man, as reported in the literature, is reviewed. 21 cases (40 ears) have been studied after serial sectioning, 8 cases (12 ears) have been investigated by the microdissection and surface preparation technique. The combination of both methods provides maximal information. OHCs are primarily affected, followed by IHC loss. Degeneration starts at the basal coil and proceeds towards the apex. The stria vascularis becomes involved in all turns. It is not clear whether stria degeneration is primary or secondary. Supporting cells, nerve fibres and ganglion cells degenerate secondary to hair cell loss. In some cases ingrowth of myelinated nerve fibres in areas with complete destruction of the organ of Corti has been observed. Ototoxic lesions can be asymmetric. Attention is drawn to the audiometric Z-curve in moderate lesions.

A functional anatomic study of the relationship of the nasal cartilages and muscles to the nasal valve area

The functioning of the nasal valve area is largely determined by the stability and the mobility of the lateral nasal wall. To gain insight into the kinematics of the lateral nasal wall, we studied the functional anatomy of the nasal muscles and the intercartilaginous and osseous‐cartilaginous junctions. We performed gross and microscopic nasal dissection and serial sectioning in 15 human cadaveric noses. In addition, two noses were used for three‐dimensional reconstruction of the nasal cartilages. We conclude that the lateral nasal wall can be seen as made up of three parts. At the level of the osseous‐cartilaginous chain of bone, lateral nasal cartilage, and lateral crus, the lateral nasal wall is relatively stable, limited mobility being allowed by translation and rotation in the intercartilaginous joint and a coupled distortion of the cartilages. At the level of the hinge area the lateral nasal wall is supported by one or more accessory cartilages, embedded in soft tissue, and therefore much more compliant. The alar part of the nasalis muscle, which originates from the maxilla and inserts on these cartilages, may dilate the valve area by drawing this hinge area laterally. The third and most compliant part of the lateral nasal wall is the part that is not supported by cartilage, the ala. The dilatator naris muscle largely occupies the ala and is attached to the lateral crus; it opens the vestibule and nostril. The third nasal muscle that influences the lateral nasal wall is the transverse part of the nasalis muscle. It overlies the nose but is not attached to it. This muscle stabilizes the lateral nasal wall, in particular, the lateral nasal cartilage, the intercartilaginous junction, and the hinge area, by moving the nasal skin.

An improved fixation method for guinea pig cochlear tissues

The influence of different fixation methods and of various primary fixatives on the ultrastructural preservation of guinea pig cochlear tissues was investigated. No differences in fixation quality were observed between cochleas fixed by intravascular perfusion and cochleas fixed by intralabyrinthine perfusion. Tri-aldehyde primary fixation resulted, in contrast to other formulae investigated, in an excellent, uniform preservation of all cochlear tissues without obvious fixation artefacts. The influence of OSO4/K4Ru(CN)6- and OSO4/K4Fe(CN)6 postfixation was also tested. Cochlear tissues postfixed with OSO4/K4Ru(CN)6 or OSO4/K4Fe(CN)6 exhibited more cellular detail (e.g., membrane- and glycogen contrast) as compared to tissues postfixed with OSO4 alone. Tri-aldehyde primary fixation followed by OSO4/K4Ru(CN)6- or OSO4/K4Fe(CN)6 postfixation therefore is recommended as a multipurpose procedure for optimal preservation of labyrinthine tissues.

Early Hair Cell Loss in Experimental Hydrops

One, 2, and 4 months after surgical obliteration of the endolymphatic sac, the sequence of degenerative changes in the organ of Corti of the guinea pig was studied. The block surface technique with interference differential (Nomarski) microscopy was used for this investigation to study the morphological changes in the organ of Corti. The hair cell loss was calculated and mapped in cytocochleograms. One month postoperatively a minimal loss of only outer hair cells was observed in the apical cochlear turn. At 2 months a progression of outer hair cell loss was seen, which proceeded in the 4-month group. At 4 months the inner hair cells showed a slight tendency to degenerate, again beginning in the most apical part of the cochlea.

Cisplatin-induced ototoxicity; electrophysiological evidence of spontaneous recovery in the albino guinea pig

For 8 days albino guinea pigs (n = 48) were treated with cisplatin (cis-diamminedichloroplatinum(II), 1.5 mg/kg body weight/day). Compound action potentials (CAP), cochlear microphonics (CM) and summating potentials (SP) were recorded from the apical surface of the cochlea in response to tone bursts ranging in frequency from 0.5 to 16 kHz. The recordings were collected in different groups of animals, 1 day, 1 week, 2, 4, 8 and 16 weeks after cisplatin treatment, respectively. One day after the 8-day treatment we found frequency-dependent loss in the amplitudes of the three cochlear potentials, with the larger losses occurring at the higher frequencies. In terms of threshold shift the losses were larger for the CAP than for the hair cell-related potentials SP and CM. A salient improvement in both CAP and CM amplitude occurred over the next 8 weeks. Also, the SP showed improvement. These results indicate that guinea pig cochlear transduction recovers spontaneously after cisplatin injury. Recovery of the hair cell-related potentials suggests that recovery occurs already at the hair cell level. The question whether this recovery originates with the formation of new hair cells or with repair of damaged hair cells should be answered on the basis of subsequent morphological investigations.