Blood metal ion levels are not a useful test for adverse reactions to metal debris: A systematic review and meta-analysis.

OBJECTIVES: Alarm over the reported high failure rates for metal-on-metal (MoM) hip implants as well as their potential for locally aggressive Adverse Reactions to Metal Debris (ARMDs) has prompted government agencies, internationally, to recommend the monitoring of patients with MoM hip implants. Some have advised that a blood ion level >7 µg/L indicates potential for ARMDs. We report a systematic review and meta-analysis of the performance of metal ion testing for ARMDs. METHODS: We searched MEDLINE and EMBASE to identify articles from which it was possible to reconstruct a 2 × 2 table. Two readers independently reviewed all articles and extracted data using explicit criteria. We computed a summary receiver operating curve using a Bayesian random-effects hierarchical model. RESULTS: Our literature search returned 575 unique articles; only six met inclusion criteria defined a priori. The discriminative capacity of ion tests was homogeneous across studies but that there was substantial cut-point heterogeneity. Our best estimate of the "true" area under curve (AUC) for metal ion testing is 0.615, with a 95% credible interval of 0.480 to 0.735, thus we can state that the probability that metal ion testing is actually clinically useful with an AUC ≥ 0.75 is 1.7%. CONCLUSION: Metal ion levels are not useful as a screening test for identifying high risk patients because ion testing will either lead to a large burden of false positive patients, or otherwise marginally modify the pre-test probability. With the availability of more accurate non-invasive tests, we did not find any evidence for using blood ion levels to diagnose symptomatic patients.Cite this article: M. Pahuta, J. M. Smolders, J. L. van Susante, J. Peck, P. R. Kim, P. E. Beaule. Blood metal ion levels are not a useful test for adverse reactions to metal debris: a systematic review and meta-analysis. Bone Joint Res 2016;5:379-386. DOI: 10.1302/2046-3758.59.BJR-2016-0027.R1.

The multiple sclerosis susceptibility genes TAGAP and IL2RA are regulated by vitamin D in CD4+ T cells.

Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals. The majority of the MS-associated gene variants are located in genetic regions with importance for T-cell differentiation. Vitamin D is a potent immunomodulator, and vitamin D deficiency has been suggested to be associated with increased MS disease susceptibility and activity. In CD4+ T cells, we have analyzed in vitro vitamin D responsiveness of genes that contain an MS-associated single-nucleotide polymorphism (SNP) and with one or more vitamin D response elements in their regulatory regions. We identify IL2RA and TAGAP as novel vitamin D target genes. The vitamin D response is observed in samples from both MS patients and controls, and is not dependent on the genotype of MS-associated SNPs in the respective genes.

GM-CSF production by CD4+ T cells in MS patients: regulation by regulatory T cells and vitamin D.

BACKGROUND/OBJECTIVE: Data from animal models of MS suggest that GM-CSF(+)CD4(+)T cells are pathogenic cells. Therefore, GM-CSF production by CD4(+)T cells of MS patients and their susceptibility to regulatory mechanisms were investigated. METHODS: Intracellular flowcytometry was performed to determine the GM-CSF(+)CD4(+)T cell fraction in PBMC and CSF of MS patients and controls. The effect of regulatory T cells (Tregs) on GM-CSF production by CD4(+)T cells was studied in MS patients using a proliferation-suppression assay. Finally, GM-CSF(+)CD4(+)T cell fraction and GM-CSF protein levels in supernatant were assessed in anti-CD3-stimulated CD4(+)T cell cultures derived from healthy controls and MS patients, in the presence or absence of the active vitamin D metabolite calcitriol. RESULTS: The GM-CSF(+)CD4(+)T cell fraction in the peripheral blood did not differ between controls and MS patients. This T cell population could also be detected in the CSF of both subjects with MS as well as subjects with another diagnosis. In the CSF, it comprised a significant fraction of the T cell population. Upon in vitro stimulation of PBMC with anti-CD3 antibody, no differences were observed in GM-CSF(+)CD4(+)T cell frequencies. GM-CSF secretion was susceptible to regulation by Treg and vitamin D. Suppression of GM-CSF secretion by vitamin D was reduced in MS patients. CONCLUSIONS: Our study showed no elevation in GM-CSF(+)CD4(+)T cell fractions in MS patients compared to controls. Furthermore, GM-CSF secretion was prone to regulation by Treg and vitamin D, the latter being less effective in MS patients.

Increased inflammasome related gene expression profile in PBMC may facilitate T helper 17 cell induction in multiple sclerosis.

The NLRP3 inflammasome is a macromolecular complex importantly involved in IL-1ß processing. A role for this has been described in multiple sclerosis (MS). One mechanism by which IL-1ß might be involved in MS is by inducing pathogenic Th17 cells, i.e. GM-CSF+ Th17 cells. In the present study, we show that expression of the inflammasome related genes, NLRP3, caspase-1, IL-1ß and the IL-1ß/IL-1Ra ratio, was increased in PBMC from MS patients compared to healthy controls (HC). However, in an in vitro inflammasome activity assay with PBMC, IL-1ß protein secretion and the IL-1ß/IL-1Ra protein ratio were similar in MS patients and HC. Th cells cultured in the presence of supernatant derived from LPS/ATP inflammasome activated PBMC showed increased Th17 and GM-CSF+ Th17 cell frequencies in HC and MS patients and decreased anti-inflammatory IL-10+Th cell frequency in HC compared to Th cells cultured in the presence of control supernatant. Moreover, addition of the immune modulator calcitriol to the former condition resulted in reduced frequencies of Th17 and GM-CSF+Th17 cells, and also of IL-10+ Th cells. Evidently, our data indicate that inflammasome activity can skew the Th cell population toward a more pro-inflammatory composition, an effect that might be inhibited by vitamin D, and that might be importantly involved in inflammation within the central nervous system.

Water permeability of the mammalian cochlea: functional features of an aquaporin-facilitated water shunt at the perilymph-endolymph barrier.

The cochlear duct epithelium (CDE) constitutes a tight barrier that effectively separates the inner ear fluids, endolymph and perilymph, thereby maintaining distinct ionic and osmotic gradients that are essential for auditory function. However, in vivo experiments have demonstrated that the CDE allows for rapid water exchange between fluid compartments. The molecular mechanism governing water permeation across the CDE remains elusive. We computationally determined the diffusional (PD) and osmotic (Pf) water permeability coefficients for the mammalian CDE based on in silico simulations of cochlear water dynamics integrating previously derived in vivo experimental data on fluid flow with expression sites of molecular water channels (aquaporins, AQPs). The PD of the entire CDE (PD = 8.18 × 10(-5) cm s(-1)) and its individual partitions including Reissner's membrane (PD = 12.06 × 10(-5) cm s(-1)) and the organ of Corti (PD = 10.2 × 10(-5) cm s(-1)) were similar to other epithelia with AQP-facilitated water permeation. The Pf of the CDE (Pf = 6.15 × 10(-4) cm s(-1)) was also in the range of other epithelia while an exceptionally high Pf was determined for an epithelial subdomain of outer sulcus cells in the cochlear apex co-expressing AQP4 and AQP5 (OSCs; Pf = 156.90 × 10(-3) cm s(-1)). The Pf/PD ratios of the CDE (Pf/PD = 7.52) and OSCs (Pf/PD = 242.02) indicate an aqueous pore-facilitated water exchange and reveal a high-transfer region or "water shunt" in the cochlear apex. This "water shunt" explains experimentally determined phenomena of endolymphatic longitudinal flow towards the cochlear apex. The water permeability coefficients of the CDE emphasise the physiological and pathophysiological relevance of water dynamics in the cochlea in particular for endolymphatic hydrops and Ménière's disease.

Fraction of IL-10+ and IL-17+ CD8 T cells is increased in MS patients in remission and during a relapse, but is not influenced by immune modulators.

In the present study, circulating proportions of CD8(+) T (Tc) cell subsets, including IL-17 (Tc17) and IL-10 (Tc10) producing cells, were assessed in relapsing-remitting MS (RRMS) patients and a possible effect of beta interferon (IFN-ß), glatiramer acetate (GA), and vitamin D (VitD) on these cell subsets was investigated. We show that both Tc17 and Tc10 cell fractions are elevated in the circulation of RRMS patients in remission compared to healthy subjects and that these Tc subsets remain unaffected by current immune modulating regimens.

Fluctuations of MS births and UV-light exposure.

BACKGROUND: Patients with multiple sclerosis (MS) are more frequently born in spring when compared to autumn. Fluctuation of UV-light has been hypothesized to drive this phenomenon. AIM: To assess the correlation between fluctuation of sunlight and birth season in persons with MS. METHODS: For this record-linkage study, we collected from the international MSBase and the Italian MS iMed-web databases the dates of birth of 11,415 patients with MS from 36 centres from 15 countries worldwide and compared these to dates of live-births from national registries. From all participating sites, we collected data on UV-light fluctuation and assessed its correlation with seasonal fluctuation in MS births. RESULTS: Compared with the reference cohort, an increased proportion of persons with MS were born in spring and a decreased proportion in autumn (odds ratio (OR) to be born in spring versus autumn = 1.158, χ² = 36.347, P < 0.001). There was no significantly increased fluctuation of MS births with increased quartile of ambient UV-light fluctuation (Ptrend = 0.086). CONCLUSION: Seasonal fluctuation of MS births as found in this worldwide cohort of patients with MS did not correlate with variation in seasonal fluctuation of UV-light. Most likely, it results from a complex interplay between fluctuation of sunlight, behavioural factors, other environmental factors and (epi)genetic factors.

Fatigue and heat sensitivity in patients with multiple sclerosis.

OBJECTIVES: Fatigue is one of the most common and troubling symptoms of multiple sclerosis (MS), and heat is often reported as a trigger. Although it is assumed that this heat sensitivity is specific for MS, the evidence for disease specificity is limited. We studied the relationship between fatigue, heat sensitivity, and environmental temperature, and its specificity for MS. MATERIALS AND METHODS: We compared 88 MS patients with 76 patients with ulcerative colitis (UC), another chronic auto-immune disease. As most important outcome measures, heat sensitivity, physical fatigue, mental fatigue, environmental temperature, and ambient UV-light levels were determined. RESULTS: More patients with MS reported heat sensitivity for fatigue, compared to patients with UC (53.4% vs 35.5%, respectively, P = 0.016). However, heat-sensitive patients were equally fatigued as heat-insensitive patients. Climatological data, including day temperature and amount of ambient UV light, were not related to fatigue in both heat-sensitive and heat-insensitive patients with MS. CONCLUSIONS: Our findings support the assumption that heat sensitivity regarding fatigue has an MS-specific component. Although patients with MS experience a relationship between environmental temperature and fatigue, objective assessment by climatological data could not confirm this.

Vitamin D status in patients with MS is negatively correlated with depression, but not with fatigue.

BACKGROUND: Depressive symptoms and fatigue are frequent and disabling symptoms of multiple sclerosis (MS). Depression and fatigue have been associated with a poor vitamin D status, and a poor vitamin D status is often found in MS. AIM: Assess whether vitamin D status contributes to depressive symptoms and fatigue in MS. METHODS: Patients with MS that participated in previous studies in which depression and fatigue were assessed and of whom serum 25-hydroxyvitamin D (25(OH)D) levels were available within a timeframe of less than one half-life of 25(OH)D were included. Depression and fatigue were assessed with the Hospital Anxiety and Depression Scale and the Multidimensional Fatigue Inventory. RESULTS: Fifty-nine patients were included. Mean scores of fatigue and depression were 14.6 (SD 4.2) and 6.2 (SD 4.4), respectively. The mean vitamin D status was 62.3 nm (SD 27.8). Vitamin D status correlated negatively with depression (r=-0.326, P=0.006). No significant correlation was found between vitamin D status and fatigue. In a multiple regression model, vitamin D status was not a significant contributor to depression, after controlling for age Expanded Disability Status Scale score and fatigue (P=0.078). Alternatively, depression and fatigue did not contribute to vitamin D status. DISCUSSION: This study shows a negative correlation between vitamin D status and depressive symptoms in patients with MS. Although multiple confounders exist, we observed an indication that vitamin D status might contribute to the presence of depressive symptoms in MS. Therefore, further studies on vitamin D in MS should include depressive symptoms as outcome measures to confirm these findings.

Changes in bone mineral density in the proximal femur after hip resurfacing and uncemented total hip replacement: A prospective randomised controlled study.

We undertook a randomised prospective follow-up study of changes in peri-prosthetic bone mineral density (BMD) after hip resurfacing and compared them with the results after total hip replacement. A total of 59 patients were allocated to receive a hip resurfacing (n = 29) or an uncemented distally fixed total hip replacement (n = 30). The BMD was prospectively determined in four separate regions of interest of the femoral neck and in the calcar region corresponding to Gruen zone 7 for the hip resurfacing group and compared only to the calcar region in the total hip replacement group. Standardised measurements were performed pre-operatively and after three, six and 12 months. The groups were well matched in terms of gender distribution and mean age. The mean BMD in the calcar region increased after one year to 105.2% of baseline levels in the resurfaced group compared with a significant decrease to 82.1% in the total hip replacement group (p < 0.001) by 12 months. For the resurfaced group, there was a decrease in bone density in all four regions of the femoral neck at three months which did not reach statistical significance and was followed by recovery to baseline levels after 12 months. Hip resurfacing did indeed preserve BMD in the inferior femoral neck. In contrast, a decrease in the mean BMD in Gruen zone 7 followed uncemented distally fixed total hip replacement. Long term follow-up studies are necessary to see whether this benefit in preservation of BMD will be clinically relevant at future revision surgery.

Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis.

BACKGROUND: Multiple Sclerosis is associated with low serum levels of 25-hydroxyvitamin D (25(OH)D). We investigated the association between serum levels of 25(OH)D and 1,25-dihydroxyvitamin D (1,25(OH)2D), the biologically active metabolite, and clinical MS severity as expressed by EDSS-score and relapse rate. STUDY-DESIGN: Cross-sectional study. PATIENTS AND METHODS: Serum samples from 267 MS patients were collected for 25(OH)D and 1,25(OH)2D measurement. Clinical MS parameters at the date of serum sampling were determined. RESULTS: Both metabolite levels were significantly lower in the progressive forms compared to the relapsing remitting (RR)MS phenotype. In RRMS patients (disease course < or = 5 years), high 25(OH)D levels were associated with a high chance of remaining relapse-free. Low 25(OH)D levels were associated with high EDSS-scores. 1,25(OH)2D was not directly associated with relapse rate or EDSS-score, and was dependent of age and 25(OH)D level. CONCLUSION: Serum levels of 25(OH)D were associated with both relapse rate and disability in MS patients. These results are suggestive for a disease modulating effect of the serum concentrations of 25(OH)D on MS. The low circulating 1,25(OH)2D levels in progressive MS are due to older age and lower 25(OH)D levels. The potential consequences for vitamin D supplementation in MS will be discussed.

Brain-derived neurotrophic factor treatment does not improve functional recovery after hair cell regeneration in the pigeon.

CONCLUSIONS: Brain-derived neurotrophic factor (BDNF) supply to the inner ear does not improve the time course or the extent of functional recovery after hair cell regeneration. Specifically it does not improve the residual threshold elevation observed after the completion of spontaneous recovery. OBJECTIVE: The avian inner ear is capable of hair cell regeneration and substantial functional recovery, but residual hearing deficits remain. We investigated whether functional recovery can be improved by intracochlear application of BDNF, which plays an important role in auditory ontogenesis and maintenance during adult life. METHODS: Hair cells in adult pigeons were destroyed by local application of gentamicin. After 3 days either BDNF or control solution was administered to the scala tympani by implanted osmotic minipumps for 8 weeks. Auditory brain stem responses (ABR) to tone pips were used to assess recovery of hearing thresholds in both groups. RESULTS: The application of gentamicin caused a frequency-dependent hearing loss that ranged from 24.8 dB SPL at low frequencies to 66.2 dB SPL at high frequencies. After day 10 substantial recovery was observed, but a significant threshold shift remained. The time course of recovery in the control and BDNF-treated groups was similar, without significant residual threshold differences in any frequency range.

[Balance disorder and subacute hydrocephalus due to haemorrhage in a cerebral cavernous malformation]. / Evenwichtsstoornis en subacute hydrocefalus door bloeding in een cerebrale caverneuze malformatie.

A 58-year-old man presented with a balance disorder, followed by progressive memory disturbance, urinary incontinence and vomiting. MRI of the brain revealed multiple cavernous malformations, with recent haemorrhage from one of them, in the brainstem, causing a hydrocephalus. After treatment for the hydrocephalus, the symptoms resolved quickly. Cerebral cavernomas may cause epileptic seizures, haemorrhaging and progressive neurological deficits. Diagnosis is on the basis of the typical MRI pattern of a hyperintense core, surrounded by a hypointense rim of old blood. Treatment consists of surgery if the lesion is easily accessible and can be completely removed. Other options are gamma-knife surgery, stereotactic radiotherapy and conservative treatment.

Functional recovery of hearing following ampa-induced reversible disruption of hair cell afferent synapses in the avian inner ear.

Hair cells in the avian inner ear can regenerate after acoustic trauma or ototoxic insult, and significant functional recovery from hearing loss occurs. However, small residual deficits remain, possibly as a result of incomplete reestablishment of the hair cell neural synaptic contacts. The aim of the present study was to determine if intracochlear application of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), an excitotoxic glutamate agonist, causes reversible disruption of hair cell neural contacts in the bird, and to what extent functional recovery occurs if synaptic contacts are reestablished. Compound action potential (CAP) responses to tone bursts were recorded to determine hearing thresholds during a recovery period of up to 4 months. Subsequently, the response properties of single auditory nerve fibers were analyzed in the same animals. Instillation of AMPA into the perilymph of the scala tympani led to immediate abolition of CAP thresholds. Partial recovery occurred over a period of 2-3 weeks, without further improvement of thresholds thereafter. High-frequency thresholds did not reach control values even after 3-4 months of recovery. Single-ganglion cell response properties, obtained 3-4 months after AMPA treatment, showed elevated thresholds at the fiber's characteristic frequency (CF) for units with CF above 0.3 kHz. Sharpness of tuning (Q(10 dB)) was reduced in units with CF above 0.4 kHz. The spontaneous firing rate was higher in units with CF above 0.18 kHz. The maximum sound-evoked discharge rate was also increased. Transmission electron micrographs of the basilar papilla showed that, following AMPA treatment, the nerve endings went through a sequence of swelling, degeneration and recovery over a period of 3-7 days. The process of neosynaptogenesis was completed 14 days after exposure. The present findings are strong evidence for a role of glutamate or a related excitatory amino acid as the afferent transmitter in the avian inner ear. In addition they show that functional recovery after disruption and regeneration of hair cell neural synapses, without apparent damage to the hair cells, is incomplete.

Functional recovery in the avian ear after hair cell regeneration.

Trauma to the inner ear in birds, due to acoustic overstimulation or ototoxic aminoglycosides, can lead to hair cell loss which is followed by regeneration of new hair cells. These processes are paralleled by hearing loss followed by significant functional recovery. After acoustic trauma, functional recovery is rapid and nearly complete. The early and major part of functional recovery after sound trauma occurs before regenerated hair cells become functional. Even very intense sound trauma causes loss of only a proportion of the hair cell population, mainly so-called short hair cells residing on the abneural mobile part of the avian basilar membrane. Uncoupling of the tectorial membrane from the hair cells during sound overexposure may serve as a protection mechanism. The rapid functional recovery after sound trauma appears not to be associated with regeneration of the lost hair cells, but with repair processes involving the surviving hair cells. Small residual functional deficits after recovery are most likely associated with the missing upper fibrous layer of the tectorial membrane which fails to regenerate after sound trauma. After aminoglycoside trauma, functional recovery is slower and parallels the structural regeneration more closely. Aminoglycosides cause damage to both types of hair cells, starting at the basal (high frequency) part of the basilar papilla. However, functional hearing loss and recovery also occur at lower frequencies, associated with areas of the papilla where hair cells survive. Functional recovery in these low frequency areas is complete, whereas functional recovery in high frequency areas with complete hair cell loss is incomplete, despite regeneration of the hair cells. Permanent residual functional deficits remain. This indicates that in low frequency regions functional recovery after aminoglycosides involves repair of nonlethal injury to hair cells and/or hair cell-neural synapses. In the high frequency regions functional recovery involves regenerated hair cells. The permanent functional deficits after the regeneration process in these areas are most likely associated with functional deficits in the regenerated hair cells or shortcomings in the synaptic reconnections of nerve fibers with the regenerated hair cells. In conclusion, the avian inner ear appears to be much more resistant to trauma than the mammalian ear and possesses a considerable capacity for functional recovery based on repair processes along with its capacity to regenerate hair cells. The functional recovery in areas with regenerated hair cells is considerable but incomplete.

AMPA-type glutamate receptor subunits are expressed in the avian cochlear hair cells and ganglion cells.

The cellular localization of AMPA-type glutamate receptor subunits was examined in the pigeon inner ear using subunit specific polyclonal antibodies (GluR1-4). In the auditory ganglion cell bodies immunoreactivity for the subunits GluR2/3 and GluR4, but not for GluR1 was detected. The hair cells showed diffuse immunoreactivity for GluR4. Additionally, immunostaining for the subunits GluR2/3 and GluR4 was present below the hair cells. These results indicate that the AMPA type glutamate receptors play a role in neurotransmission at the hair cell afferent synapse in the avian auditory system.

Responses of auditory nerve fibers innervating regenerated hair cells after local application of gentamicin at the round window of the cochlea in the pigeon.

Hair cells in the basilar papilla of birds have the capacity to regenerate after injury. There is also functional recovery of hearing after regeneration of the hair cells. The present study was undertaken to determine the effect of local aminoglycoside application on the physiology of auditory nerve fibers innervating regenerated hair cells. Collagen sponges loaded with gentamicin were placed at the round window of the cochlea in adult pigeons. The local application of gentamicin-loaded collagen sponges resulted in total hair cell loss over at least the basal 62% of the basilar papilla. According to the pigeon cochlear place-frequency map (Smolders, Ding-Pfennigdorff and Klinke, Hear. Res. 92 (1995) 151-169), frequencies above 0.3 kHz are represented in this area. Physiological data on single auditory nerve fibers were obtained 14 weeks after gentamicin treatment. The response properties showed the following characteristics when compared to control data: CF thresholds (CF = characteristic frequency) were elevated in units with CF above 0.15 kHz, sharpness of tuning (Q10dB) was reduced in units with CF above 0.38 kHz, low-frequency slopes of the tuning curves were reduced in units with CF above 0.25 kHz, high frequency slopes of the tuning curves were reduced in units with CF above 0.4 kHz, spontaneous firing rate was reduced in units with CF above 0.38 kHz, dynamic range of rate-intensity functions at CF was reduced in units with CF above 0.4 kHz and the slopes of these rate-intensity functions were elevated in units with CF above 0.4 kHz. Maximum discharge rate was the only parameter that remained unchanged in regenerated ears. The results show that the response properties of auditory nerve fibers which innervate areas of the papilla that were previously devoid of hair cells are poorer than the controls, but that action potential generation in the afferent fibers is unaffected. This suggests that despite structural regeneration of the basilar papilla, functional recovery of the auditory periphery is incomplete at the level of the hair cell or the hair cell-afferent synapse.

Hair cell regeneration after local application of gentamicin at the round window of the cochlea in the pigeon.

Hair cells in the basilar papilla of birds have the capacity to regenerate after injury. Methods commonly used to induce cochlear damage are systemic application of ototoxic substances such as aminoglycoside antibiotics or loud sound. Both methods have disadvantages. The systemic application of antibiotics results in damage restricted to the basal 50% of the papilla and has severe side effects on the kidneys. Loud sound damages only small parts of the papilla and is restricted to the short hair cells. The present study was undertaken to determine the effect of local aminoglycoside application on the physiology and morphology of the avian basilar papilla. Collagen sponges loaded with gentamicin were placed at the round window of the cochlea in adult pigeons. The time course of hearing thresholds was determined from auditory brain stem responses elicited with pure tone bursts within a frequency range of 0.35-5.565 kHz. The condition of the basilar papilla was determined from scanning electron micrographs. Five days after application of the collagen sponges loaded with gentamicin severe hearing loss, except for the lowest frequency tested, was observed. Only at the apical 20% of the basilar papilla hair cells were left intact, all other hair cells were missing or damaged. At all frequencies there was little functional recovery until day 13 after implantation. At frequencies above 1 kHz functional recovery occurred at a rate of up to 4 dB/day until day 21, beyond that day recovery continued at a rate below 1 dB/day until day 48 at the 5.6 kHz. Below 1 kHz recovery occurred up to day 22, the recovery rate was below 2 dB/day. A residual hearing loss of about 15-25 dB remained at all frequencies, except for the lowest frequency tested. At day 20 new hair cells were seen on the basilar papilla. At day 48 the hair cells appeared to have recovered fully, except for the orientation of the hair cell bundles. The advantage of the local application of the aminoglycoside drug over systemic application is that it damages almost all hair cells in the basilar papilla and it has no toxic side effects. The damage is more extensive than with systemic application.

Hair cell loss and regeneration after severe acoustic overstimulation in the adult pigeon.

The extent of hair cell regeneration following acoustic overstimulation severe enough to destroy tall hair cells, was determined in adult pigeons. BrdU (5-bromo-2'-deoxyuridine) was used as a proliferation marker. Recovery of hearing thresholds in each individual animal was measured over a period of up to 16 weeks after trauma. In ears with loss of both short and tall hair cells, little or no functional recovery occurred. In ears with less damage, where significant functional recovery did occur, there were always a few rows of surviving hair cells left at the neural edge of the basilar papilla. In the region of hair cell loss, numerous BrdU labeled cells were found. However, only a small minority of these cells were regenerated hair cells, the majority being monolayer cells. Irrespective of the extent of the region of hair cell loss, regenerated hair cells were observed predominantly in a narrow strip at the transition from the abneural area of total hair cell loss and the neural area of hair cell survival. With increasing damage this strip moved progressively towards the neural edge of the papilla. No regeneration of hair cells was observed in the abneural region of total hair cell loss, even up to 16 weeks after trauma. The results indicate that there is a gradient in the destructive effect of loud sound across the width of the basilar papilla, from most detrimental at the abneural edge to least detrimental at the neural edge. Both tall and short hair cells can regenerate after sound trauma. Whether they do regenerate or not depends on the degree of damage to the area of the papilla where they normally reside. Regeneration of new hair cells occurs only in a narrow longitudinal band, which moves from abneural into the neural direction with increasing damage. In the area neural to this band, hair cells survive the overstimulation. In the area abneural to this band, sound damage is so severe, that no regeneration of hair cells occurs. As a consequence morphological and functional deficits persist.