sábado, 25 de junio de 2011

Audición: Seccion Fisopatologia, estrategias farmacológicas para la prevención del daño coclear

Pharmacological strategies for preventing cochlear damage induced by noise trauma
Barbara Canlon1, Karin Agerman2, Rene Dauman3, Jean-Luc Puel4
1 Department of Physiology and Pharmacolog, Karolinska Institutet, 171 77 Stockholm, Sweden
2 Department of Physiology and Pharmacolog, Karolinska Institutet, 171 77 Stockholm; Department of Molecular Neurobiology, Karolinska Institutet, Stockholm, Sweden
3 Service d´Oto-Rhino-Laryngologie, Unité d´Audiologie, Hospital Pellegrin, C.H.U. de Bordeaux, Bordeau, France
4 INSERM - U. 254, Laboratoire de Neurobiologie de l'Audition, CHU Hôpital St. Charles, Montpellier, France


Hearing loss induced by noise, as well as in combination with other environmental factors, is a significant health problem throughout the world.

Although most structures in the inner ear can be harmed by excessive sound exposure, the sensory cells are the most vulnerable.

Damage to the stereocilia bundle is often the first structural alteration noted.

Once a large number of hair cells are lost, the nerve fibres to that region also degenerate resulting in an irreversible hearing loss.

At present, the underlying mechanism for cochlear damage induced by noise is not fully understood.

The failure of the adult peripheral auditory system to regenerate after injury is a major clinical problem.

However, a number of experimental applications have recently become available and are effective in reducing the damaging effects of noise.

Current experimental designs include strategies for protecting against injury and are primarily based on the fact that the metabolic state of the cochlea can determine the overall degree of hearing loss induced by noise.

The purpose of the present article is to review the current literature dealing with strategies for protecting against noise trauma.

Keywords: auditory, cochlea, noise trauma, protection
How to cite this article:
Canlon B, Agerman K, Dauman R, Puel J. Pharmacological strategies for preventing cochlear damage induced by noise trauma. Noise Health 1998;1:13-23

How to cite this URL:
Canlon B, Agerman K, Dauman R, Puel J. Pharmacological strategies for preventing cochlear damage induced by noise trauma. Noise Health [serial online] 1998 [cited 2011 Jun 25];1:13-23. Available from: http://www.noiseandhealth.org/text.asp?1998/1/1/13/31781

Reducing the damaging effects of noise: The early studies

During the late 70s and early 80s several intriguing experiments demonstrated that the magnitude of hearing loss induced by noise could be modulated.

It was apparent from these early experiments that manipulations of cochlear metabolism directly altered the subsequent damage induced by noise.

Increasing or decreasing body temperature during noise exposure resulted in an increased or decreased cochlear damage (Drescher, 1976; Henry and Chole, 1984).

In addition, increasing the oxygen supply, or removing the thyroid gland was also shown to protect the ear from noise-induced hearing loss (Berndt and Wagner, 1979).

Furthermore, Joachims et al., (1983) studied the effect of magnesium on noise induced hearing thresholds in normotensive rats and spontaneously hypertensive rats and found that magnesium deficiency resulted in a significant increase in the threshold shift in both strains.

All in all, these early experiments demonstrated that the metabolic state of the cochlea could directly determine the overall sensitivity of this organ and provide protection against subsequent noise trauma.

However, this line of experimentation (i.e protecting against injury) was not continued until advances were made in models of brain injury showing protection against neuronal death.

When these demonstrations were successful in the brain similar applications have been made to the cochlea.

Coupling excitotoxicity to noise trauma

Beside the well described changes in stereocilia and hair cells, postsynaptic damage at the synaptic pole of the inner hair cells is also prominent after acoustic trauma.

It entails a disruption of the dendrite ending of the spiral ganglion neurons below the inner hair cells [Figure - 1], leading to synaptic uncoupling (Beagley, 1965; Spoendlin, 1971; Robertson, 1983 ; Pujol, 1990).

Recently, it has been suggested that dendrite damage might be due to excessive release of neurotransmitter from the inner hair cells, which is toxic (excitotoxic) to the structure and function of spiral ganglion neuron (Pujol, 1990).

Consistent with this hypothesis is the high degree of protection against noise trauma that is observed when the glutamate antagonist kynurenate is applied to the cochlea (Puel et al., 1998). Moreover, a synaptic repair mechanism occurring within the first few days post-exposure is partly responsible for the recovery of temporary threshold shifts after an acoustic trauma (Puel et al., 1998).

While the acute synapse disruption primarily depends on alpha­a m i n o - 3 - h y d r o x y - 5 - m e t h y l - 4 - isoxazolepropionic acid (AMPA) and kainate type of receptors (Puel et al., 1994), the repair mechanism involved N-methyl-D-aspartate (NMDA) and metabotropic receptors (Puel et al., 1995; d'Aldin et al., 1997).

This regenerative process does not exclude the possibility that in the case of successive excitotoxic injuries, additive effects could irreversibly damage some neurons, and consequently lower or stop the beneficial effects of re-innervation.

In support of this line of argument, glutamate neurotoxicity has been reported in the developing rat cochlea after systemic administration of glutamate (Janssen et al., 1991).

L-glutamate administered intraperitoneally to developing rats on postnatal days 2 to 9 produced high-frequency threshold elevations.

The major site of peripheral damage was the spiral ganglion neurons in the basal region of the cochlea, where a significant reduction in neurons was noted.

Scanning electron micrographs of surface preparations revealed no significant hair cell death.

Similarly, Juiz et al. (1989) reported that 10 days or more after an intracochlear perfusion of kainate, a subpopulation of spiral ganglion neurons (34%) had degenerated with no apparent damage to cochlear hair cells and supporting cells.

In agreement with the reported selectivity of kainate for glutamaceptive neurons (Coyle, 1983), the neuronal loss induced by kainate was in vitro blocked by the broad spectrum glutamatergic antagonist kynurenate, in a dose­dependent manner (Lefebvre et al., 1991). The pathological consequences of sound-induced excitotoxicity is summarised in [Figure - 1].

Coupling NMDA receptors to NO synthesis for noise trauma

The administration of N-methyl-D-aspartate (NMDA) antagonists have been shown to prevent toxic damage to hair cells in guinea pigs treated with aminoglycoside antibiotics (Basil et al., 1996).

It was suggested that the aminoglycosides bind to the polyamine site on the NMDA receptor and by excitotoxic mechanisms results in the destruction of the hair cells.

Regardless of whether hair cells express NMDA receptors, why are the spiral ganglion neurons spared, which certainly express these receptors?

One explanation that has been proposed is that aminoglycoside activation of NMDA receptors on neurons is not lethal by itself, but causes the release of other toxic substances from neurons which in turn damage the cells in the organ of Corti (Ernfors and Canlon, 1996).

Nitric oxide (NO) is a typical retrograde signal in the brain and the concentration at which it is present determines whether it has protective or toxic effects.

Furthermore, NO has been shown to be one of the underlying molecules involved in the cell death following NMDA-mediated excitotic damage in the CNS.

It is possible that NO is a mediator of hair cell damage in the cochlea because: (i) at high concentrations NO causes the death of any type of cell (thus both hair cells and supporting cells would succumb to it), (ii) it is produced by the spiral ganglion neurons (iii) it is known that excess stimulation of NMDA receptors leads to excess NO release, and (iv) by blocking NO synthesis in the cochlea with the inhibitor NG-methyl-L-arginine prevents chemically induced cytotoxicity.

The overproduction of NO would be expected to damage all cell types in the organ of Corti and the NO hypothesis could explain the loss of both hair cells and supporting cells following severe noise damage.

Any toxic effect from the neurons to the hair cells in the organ of Corti are most likely in balance with protective mechanisms also stemming from the spiral ganglion neurons.

Rapid production of oxygen free radicals in hair cells have been implicated in hearing loss induced by noise (Quirk et al., 1994; Yamane et al., 1995; Seidman et al., 1993).

An upregulation of anti-oxidant enzymes in cochlear tissues have been demonstrated after noise exposure (Jacono et al., 1998).

The upregulation of these enzymes would be expected to attenuate threshold shifts induced by noise exposure.

The susceptibility of the cochlea to noise-induced damage is increased by inhibition of glutathione synthesis (Yamasoba et al., 1998).

These increased thresholds were found after a noise exposure that was repeated for several days. However, when a short term noise exposure was investigated, whole tissue levels of glutathione were not altered suggesting that short duration noise exposure does not alter glutathione homeostasis (Lautermann et al., 1997).

It is not enough to just block the NMDA receptors but rather a combined treatment with for example, NMDA receptor blockers, and anti­oxidant therapy can protect against noise­ induced hearing loss.

Sound conditioning

A number of recent studies have shown that the susceptibility of the inner ear to noise trauma can be reduced by prior exposure to an acoustic stimulus.

At present, two distinct paradigms are employed to reduce the susceptibility of the inner ear to noise trauma.

The first uses a low­level, non-damaging continuous acoustic stimulus before the traumatic exposure [Figure - 2]. This phenomenon has been termed sound "conditioning" and has been demonstrated on a number of species including guinea pigs, gerbils, rabbits, and rats (Canlon et al., 1988; Ryan et al., 1994; Boettcher et al. 1995; Dagli and Canlon, 1994; 1997, Kujawa and Liberman, 1997; Canlon et al., 1992; Pukkila et al., 1997; White et al., 1998).

The second paradigm uses an interrupted schedule at sound levels that produce a temporary threshold shift during the first few days of exposure.

However, as the daily exposure continues the degree of threshold shift is reduced, in some cases to no threshold shift despite an ongoing exposure.

This reduction has been termed "toughening" or resistance to noise­induced hearing loss.

Toughening has been demonstrated in chinchillas, guinea pigs, and gerbils (Clark et al., 1987; Sinex et al., 1987; Campo et al., 1991; Franklin et al., 1991; Boettcher, et al., 1992, 1993; Subramaniam et al 1991, Miyakita et al., 1992; Boettcher, 1993; Henselman et al., 1994; Henderson et al., 1994; McFadden et al., 1997; White et al., 1998).

While the underlying mechanism responsible for protection against noise trauma by sound conditioning is not known, neither the middle ear muscles, nor the efferent system seems to play a significant role.

Studies from three different laboratories, using three different species, have shown that the middle ear muscles do not significantly contribute to the protection from acoustic trauma by sound conditioning (Ryan et al., 1994; Henderson et al., 1994, and Dagli and Canlon, 1995).

The role the efferents play in modulating noise damage after sound conditioning is questioned after a report that compared a sham operated sound conditioned group to a deefferented sound conditioned group and showed similar responses to the traumatic stimulus.

It was suggested that stress factors play a significant role in determining the sensitivity of the ear to trauma.

Noise and other types of stress, for example, restraint, have been shown to increase glucocorticoid levels (Rarey et al., 1995; Curtis and Rarey 1995).

An interesting study by Jacono et al. (1998) has shown that a sound conditioning paradigm caused an increase in antioxidant systems.

The finding that low­ level acoustic stimulation increases endogenous levels of antioxidant systems in the cochlea opens many new avenues for future studies on protecting against noise trauma.

Could the sound-induced increase in endogenous antioxidant systems provide protection against other environmental toxins? Future experiments are needed to address this question.

Pharmacological Studies

Reactive oxygen species are implicated in a variety of hearing disorders.

The ultimate fate of free radicals is the induction of membrane lipid peroxidation which leads to alteration in ion homeostasis and energy metabolism and eventual destruction of the plasma membrane.

The subcellular source of oxyradicals is the mitochondria where oxygen radicals are generated during the electron-transport process.

Two oxyradicals that play predominant roles as initiators of membrane lipid peroxidation are the hydroxyl radical and peroxynitrite.

The hydroxyl radical can also interact with nitric oxide to form peroxynitrite. These processes occur in many different acute and chronic degenerative conditions and can lead to a cascade of events that culminate in apoptotic cell death.

The inhibition of free radical generation (anti­oxidative processes) can protect the membrane from damage and can maintain ion homeostasis and cellular energy metabolism.

Noise and ototoxic drugs affect inner ear function, possibly through free radicals, and are therefore expected to affect cellular defence mechanisms.

Glutathione, an endogenous antioxidant substance, that has been localised primarily to the stria vascularis, has been shown to protect against noise trauma.

The antioxidant system is sensitive towards environmental influences and show differences in cochlear glutathione and glutathione-related enzymes in different species. (Lautermann et al., 1997).

Gentamicin ototoxicity has been shown to depend on dietary factors and to correlate with tissue glutathione levels (Lautermann e al., 1995).

Thus, compounds that could potentially protect against gentamicin ototoxicity may be more correctly assessed in animal models of deficient nutritional states in which endogenous detoxifying mechanisms are compromised.

The inhibition of the generation of reactive oxygen species has been a successful means of protecting against noise-induced hearing loss (Seidman et al., 1993; Quirk et al., 1994; Yamane et al., 1995; Jacono et al., 1998; Yamasoba et al., 1998).

Reduced cochlear blood flow by vasoconstriction has been implicated in noise­induced hearing loss (Hawkins, 1971).

Ohlsen et al has shown the effectiveness of topical application of vasodilating agents in increasing cochlear blood flow (Ohlsen et al., 1992).

Others have shown that oxygen (i.e. cochlear­oxygenation) is a more important factor than CO2 (i.e., as a vasodilator) in protection of the cochlea from noise induced damage (Hatch et al., 1991).

Experiments where all calcium channels were blocked caused a reduction in noise-induced microvascular permeability which in turn can reduce temporary threshold shifts (Goldwyn et al., 1997).

Exposure of noise to the cochlea may result in local vasoconstriction of cochlear vessels, which leads to a decrease in cochlear blood.

This may lead to hypoxia and subsequently formation of free oxygen radicals. Seidman et al have shown that both superoxide dismutase and allopurinol can prevent noise-induced damage, indicating that this damage may be related to free oxygen radicals (Seidman et al., 1993).

Other experiments show that free oxygen radical induced lipid peroxidation is an important mechanism in noise-induced hearing loss (Quirk et al., 1994).

Acoustic trauma and tinnitus

Worthy of note is the frequent occurrence of tinnitus (i.e. auditory perception in absence of sound stimulation) and the overexpression of NMDA receptors after an acoustic trauma (Axelsson and Barrenas, 1991, Puel et al., 1996).

In contrast to AMPA/kainate receptors that simply mediate fast depolarising responses, activation of NMDA receptors can result in long­lasting changes in synaptic efficacy, responsible for the induction of long-term potentiation (LTP). Briefly, LTP is a sustained increase in synaptic efficacy following tetanic stimulation of some excitatory pathways, and has attracted wide interest as a potential mechanism for information storage in the brain (i.e. learning and memory).

Although the precise mechanisms underlying this form of plasticity are unknown, NMDA receptor antagonists have been shown to prevent its induction in hippocampal pathways, even though these substances have little effect on excitatory postsynaptic potentials (EPSPs) (see Collingridge et al., 1988).

Subsequent investigations have also demonstrated that NMDA receptor antagonists can suppress epileptiform activity (paroxysmal depolarisations, burst firing) induced in vitro by convulsant drugs, and by kindling-like electrical stimulation, and can block convulsions in many animals models of epilepsy (Dingledine et al., 1990 ; Chapman, 1991).

Thus, one speculation is that, if altered, or excessively stimulated (e.g. resulting from ischaemia/acoustic trauma), NMDA receptors in the cochlea also could give rise to an increased spontaneous and repetitive or "epileptic-like" firing, which could be interpreted as tinnitus by the brain auditory centres.

At first glance, treatment with glutamate antagonists that alter neurotransmission does not seem appropriate to treat hearing loss and tinnitus.

Interestingly, NMDA and metabotropic receptors that appear to be an important component in pathological conditions (i.e, neosynaptogenesis, tinnitus, neuronal death), are those involved to a lesser degree in excitatory synaptic function, making them an attractive therapeutic target.

Another neuropharmacologi­cal approach for pathologies linked to glutamate excitotoxicity might also take into account the pharmacology of some lateral efferent agonists.

Numerous neuroactive substances have been found in these synapses: ACh, GABA, dopamine, encephalins, dynorphins, and CGRP (see Eybalin, 1993).

Once again, these molecules, which have limited effects on the normal functioning of the cochlea, are released under pathological conditions such as noise (Drescher et al., 1983 ; Eybalin et al., 1987b, Gil Loyzaga et al., 1993), and could be involved in synaptic plasticity such as the guidance of newly formed dendrites and/or the stabilisation of the IHC synapses (Puel et al., 1995).

Clinical Considerations

What is clear at this point is that there is much work to be done before the above pharmacological speculations can be put into clinical practice.

Future research that relies on molecular information, such as antisense oligonucleotide experiments, knockout strategies, and gene transfer protocols, is still necessary to better understand both physiological and pathological mechanisms underlying synaptic plasticity, control of neuronal excitability, and neuronal death.

Indeed, it is reasonable to assume that subtle molecular mechanisms involved in cochlear function and disease will be more clearly understood in the near future, there are certain restrictions that have to be taken into account for their possible clinical application.

Since the hair cells of the mammalian cochlea do not have the ability to regenerate, we are only left with the hope of finding effective intervention therapies.

A possible concern here is whether, in the therapeutic dose range, these products will cause side effect on the central functions.

Addressing these questions will require the development of a local application of drugs directly into the cochlea.

However, before intervention therapies can be implemented several issues concerning the choice of patients, the route of administration, and the choice of drugs to be applied needs to be determined.

It would be best to reserve in situ cochlear pharmacology for those patients with a normal contralateral ear or with an ear that can easily be fitted with a hearing device.

Decision for the best route of administration will be partially governed by the techniques routinely used in the clinic, and partially by economic soundness.

Two possibilities include an extra-cochlear approach (round or oval window), or, to a direct, intra­cochlear administration.

The extra-cochlear approach has several disadvantages compared to the intra-cochlear administration. It is most conceivable that the extra-cochlear approach, an invasive operation, will be a one-time procedure.

Taking into the consideration the rapid turnover of perilymph, the therapy drug will be quickly diluted and removed from the perilymph.

As a result of the rapid perilymph turnover, this route of administration may not offer any substantial benefit.

Repeated application would therefore be necessary, but would be unpractical.

It is most likely that cochlear implant patients will have a major role to play in the development of in situ cochlear pharmacology.

The simultaneous implantation of both the cochlear implant electrodes together with a mini-osmotic pump would be possible and the mini-osmotic pump could allow for continuous infusion for weeks.

Even if longer infusion times are required a simple procedure to refill the osmotic pump is all that would be required.

Continued animal experiments are necessary for determining the drug of choice or a combination of drugs as well as their appropriate concentrations. At present, little is known about the long-term effects of drug therapy.

Most animal experiments have ended after either two or four weeks and it is therefore important to gain more information about longer survival times (years) for the morphology and physiology of the hair cells and spiral ganglion neurons.


Our understanding of cochlear protective mechanisms has made significant advances in recent years.

These results have led to new concepts for the homeostasis of the cochlea.

These new concepts consider that the balance of retrograde and anterograde trophic signalling factors determines the overall susceptibility of organ of Corti and spiral ganglion neurons to damage, as schematically shown in [Figure - 3] (Ernfors and Canlon, 1996).

Compromising the organ of Corti will deplete spiral ganglion neurons of neurotrophic support and will eventually result in the death of these cells and disrupting the neurons should deprive hair cells of trophic support causing cell death.

Regardless of the mechanisms of action and whether the effects are direct or not, the fact of the matter is that a giant leap has been made for preventing neuronal and organ of Corti damage and now there are candidate drugs with protective properties for spiral ganglion neurons as well as for cochlear hair cells.

It is conceivable that clinical trials can be performed in the near future and new strategies for preventing hearing loss established.


This study was supported by grants from the Swedish Council for Work Life Research (79-0800), Medical Research Council (09476), Stiftelsen Tysta Skolan, and the Karolinska Institute. A joint publication of PAN partners (European Commission BIOMED 2 concerted action - Contract BMH 4-CT96-0110).[66]


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50. Puel J.L., Safieddine S. , Gervais d'Aldin C., Eybalin M. and Pujol R. (1995) Synaptic regeneration and functional recovery after excitotoxic injury in the cochlea. C.R. Acad. Sci., Serie III, 318, 67-75. Back to cited text no. 50
51. Puel, J.-L, D'Aldin C., Safieddine S., Eybalin M. et Pujol R (1996). Excitotoxicity and plasticity of the IHC-auditory nerve synapse contribute to both TTS and PTS. In: Scientific Basis of Noise Induced Hearing Loss, A. Axelsson, R.P. Hamernik et R.J. Salvi (eds), Thieme Medical Publishers, INC., New York, , pp.36-42. Back to cited text no. 51
52. Puel J-L., Puel J., d'Aldin C. and Pujol R. (1998) Excitotoxicity and repair of cochlear synapses after noise­trauma induced hearing loss. NeuroReport 9, in press Back to cited text no. 52
53. Puel, J-L., Ladrech, S., Chabert, R., Pujol, R., and Eybalin, M. (1991) Electrophysiological evidence for the presence of NMDA receptors in the guinea pig cochlea. Hear Res 51, 255-264. Back to cited text no. 53
54. Pujol R., Puel J-L., Gervais d'Aldin C., Eybalin M. (1993) Pathophysiology of the glutamatergic synapses in the cochlea. Acta Otolaryngol 113, 330-334. Back to cited text no. 54
55. Pujol R., Rebillard G., Puel J.-L., Lenoir M., Eybalin M. et Recasens M. (1990) Glutamate neurotoxicity in the cochlea : a possible consequence of ischaemic or anoxic conditions occurring in aging. Acta Otolaryngol. (Stockh.), suppl. 476, 32-36. Back to cited text no. 55
56. Pukkila, M., Zhai, S., Virkkala, J., Pirovola, U., and Ylikoski, J. (1997) The "toughening" phenomenon in rat´s auditory organ. Acta Otolaryngol. 529:59-62. Back to cited text no. 56
57. Quirk W.S., Shivapuja B.G., Schwimmer C.L., Seidman M..D. (1994) Lipid peroxidation inhibitor attenuates noise-induced temporary threshold shifts. Hear Res 74, 217-220. Back to cited text no. 57
58. Rarey, K.E., Gerhardt, K.J., Curtis, L.M., and ten Cate, W.­J-F. (1995) Effect of stress on cochlear glucocorticoid protein: acoustic stress. Hear. Res. 82: 135-138. Back to cited text no. 58
59. Robertson, D. (1983) Functional significance of dendritic swelling after loud sounds in the guinea pig cochlea. Hear. Res. 9, 263-278. Back to cited text no. 59
60. Ryan, A.F., Bennett, T.M., Woolf, N.K., and Axelsson, A. (1994). Protection from noise-induced hearing loss by prior exposure to a nontraumatic stimulus: Role of the middle ear muscles, Hear. Res. 72, 23-28. Back to cited text no. 60
61. Seidman, M.D., Shivapuja, B.G., and Quirk, W.S. (1993) The protective effects of allopurinol and superoxide dismutase on noise-induced cochlear damage. Otolaryngol. Head Neck Surg. 109, 1052-1056. Back to cited text no. 61
62. Sinex, D.G., Clark, W.W., and Bohne, B.A. (1987). Effect of periodic rest on physiological measures of auditory sensitivity following exposure to noise, J. Acoust. Soc. Am. 82, 1265-1273. Back to cited text no. 62
63. Spoendlin, H. (1971) Primary structural changes in the organ of Corti after acoustic overstimulation. Acta Otolaryngol (Stockh). 71, 166-176. Subramaniam, M., Campo, P., and Henderson, D. (1991) The effect of exposure level on the development of progressive resistance to noise. Hear. Res. 52, 181-188. Back to cited text no. 63
64. White DR, Boettcher FA, Miles LR, Gratton MA (1998) Effectiveness of intermittent and continuous acoustic stimulation in preventing noise-induced hearing and hair cell loss. J. Acoust Soc Am 103(3):1566-1572. Back to cited text no. 64
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Fuente: http://www.noiseandhealth.org/article.asp?issn=1463-1741;year=1998;volume=1;issue=1;spage=13;epage=23;aulast=Canlon

Audición: seccción fisiopatología, el rol protector de los glucocorticoides

Protección del sistema auditivo con glucocorticoides

Bárbara Canlon
un Eulers von vag 8
Stockholm Suecia
Barbara Canlon, Audiophysiology, Karolinska instituet.


Los glucocorticoides son hormonas que se liberan después de episodios relacionados con estrés y su función es la de mantener la homeostasis.

Los receptores de glucocorticoides, se localizan entre otras partes en las células ciliadas, ligamento espiral y las neuronas del ganglio espiral.

La protección del receptor de glucocorticoides contra daño inducido por trauma acústico se encuentra en: I) antes del tratamiento con agonistas de glucocorticoides, ll) la retención de la tensión aguda, y ll) en el acondicionamiento sonoro.

Por el contrario, los antagonistas del receptor de glucocorticoides exacerban la pérdida de audición.

Estos hallazgos tienen relevancia clínica importante, ya que los glucocorticoides sintéticos se utilizan comúnmente para tratar la pérdida de la audición.

Sin embargo, este tratamiento tiene un éxito limitado, ya que si bien mejoran la audición a menudo no mantienen esta mejoría una vez finalizado el tratamiento, lo que reduce el atractivo general para este tratamiento.

Debe tenerse en cuenta que a pesar del uso extendido de estos fármacos para tratar trastornos de la audición, los mecanismos moleculares que subyacen a este tratamiento no están bien caracterizados.

En esta revisión se dan una idea de algunos de los mecanismos fisiológicos y bioquímicos subyacentes a tratamiento con glucocorticoides para prevenir la pérdida de la audición

Palabras clave: Trauma acústico, la audición, pérdida de la audición, la cóclea, el eje HPA, la corticosterona, la protección

fuente: ScienceDirect.com

domingo, 19 de junio de 2011

Hipoacusia: Genes involucrados en la perdida de la audición: DFNA40

DFNA40 - deafness, autosomal dominant 40
Homo sapiens
fuente de la imagen: prensalibreonline.com.ar
Birkenhäger, R. et al., Schönberger, J. et al., Bespalova, I.N. et al., Yueh, B. et al., Dodge, P.R. et al., et al.
Kelsell, Dunlop, Stevens, Lench, Liang, Parry, Mueller, Leigh, Gopal, Yueh, Shapiro, MacLean, Shekelle, Chiang, Roden, Copeland, Pillsbury,

Disease relevance of DFNA40
• Transient conductive hearing impairment was found in 16 per cent of the sample, but in no case was there apparent improvement in a sensorineural deficit over time [1].
• Thiamine-responsive megaloblastic anaemia syndrome (TRMA; MIM 249270) is an autosomal recessive disorder with features that include megaloblastic anaemia, mild thrombocytopenia and leucopenia, sensorineural deafness and diabetes mellitus [2].
• Thus, our results suggest that mutations in MYH9 result in three megakaryocyte/platelet/leukocyte syndromes and are important in the pathogenesis of sensorineural deafness, cataracts and nephritis [3].
• Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)1 [4].
• Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure [5].

Psychiatry related information on DFNA40
• Only 14 children (14 percent) had persisting neurologic sequelae: sensorineural hearing loss in 11 (unilateral in 6 and bilateral in 5), seizure disorder in 2, and hemiplegia and mental retardation in 1 [6].
• MELAS is a mitochondrial encephalomyopathy characterized clinically by recurrent stroke-like episodes, seizures, sensorineural deafness, dementia, hypertrophic cardiomyopathy, and short stature [7].
• Progressive optic atrophy and sensorineural hearing loss due to chronic glue sniffing [8].
• Mercury is known to cause sensorineural hearing loss and impaired speech perception [9].
• Auditory stimulus intensity and reaction time in listeners with longstanding sensorineural hearing loss [10].

High impact information on DFNA40
• Unlike previously described sensorineural deafness genes, all of which underlie cochlear cell pathologies, DFNB59 is the first human gene implicated in nonsyndromic deafness due to a neuronal defect [11].
• Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss [12].
• We find that the affected individuals of two families also presented with progressive sensorineural high-frequency hearing loss (gene DFNA39) [13].
• Additional aspects of the phenotype include sensorineural deafness, reduced lifespan and decreased reproductive fitness [14].
• We have identified two frameshift mutations and a large deletion in the copy containing 29 coding exons in two families affected by autosomal recessive non-syndromal sensorineural deafness linked to the DFNB16 locus [15].

Chemical compound and disease context of DFNA40
• Thiamine-responsive megaloblastic anaemia (TRMA), also known as Rogers syndrome, is an early onset, autosomal recessive disorder defined by the occurrence of megaloblastic anaemia, diabetes mellitus and sensorineural deafness, responding in varying degrees to thiamine treatment (MIM 249270) [16].
• Patients with a nonsense mutation in CD151 display end-stage kidney failure associated with regional skin blistering and sensorineural deafness, and mice lacking the integrin alpha3 subunit die neonatally because of severe abnormalities in the lung and kidney epithelia [17].
• The objective of this study was to determine whether a mitochondrial DNA mutation and defective oxidative phosphorylation are present in a pedigree with maternally inherited sensorineural deafness, levodopa-responsive parkinsonism, and neuropathy [18].
• Pendred's syndrome is an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification [19].
• The affected subject was a 22-yr-old man with a history of myoclonic epilepsy and mild sensorineural hearing loss, a 1-yr duration of diabetes mellitus, and a low level C peptide response to oral glucose [20].

Biological context of DFNA40
• Using positional information from a patient with a 21-kb deletion in chromosome Xq22 and sensorineural deafness along with dystonia, we characterized a novel transcript lying within the deletion as a candidate for this complex syndrome [21].
• Usher syndrome type IIa (OMIM 276901), an autosomal recessive disorder characterized by moderate to severe sensorineural hearing loss and progressive retinitis pigmentosa, maps to the long arm of human chromosome 1q41 between markers AFM268ZD1 and AFM144XF2 [22].
• DFNB3, a locus for nonsyndromic sensorineural recessive deafness, maps to a 3-centimorgan interval on human chromosome 17p11.2, a region that shows conserved synteny with mouse shaker-2 [23].
• Blood viscosity as a factor in sensorineural hearing impairment [24].
• Ablation or missense mutations of the pump cause deafness, as described for the G283S mutation in the deafwaddler (dfw) mouse [25].

Anatomical context of DFNA40
• Our findings revealed a unique ultrastructural malformation of inner-ear architecture associated with non-syndromic hearing loss, and suggest that tectorial membrane abnormalities may be one aetiology of sensorineural hearing loss primarily affecting the mid-frequencies [26].
• Patients with ATP6B1 mutations also have sensorineural hearing loss; consistent with this finding, we demonstrate expression of ATP6B1 in cochlea and endolymphatic sac [27].
• Pendred syndrome is an autosomal recessive disorder associated with developmental abnormalities of the cochlea, sensorineural hearing loss and diffuse thyroid enlargement (goitre) [28].
• To our knowledge, this is the first non-syndromic sensorineural autosomal deafness susceptibility gene to be identified, which implicates Cx26 as an important component of the human cochlea [29].
• Screening is endorsed by most professional organizations, including the US Preventive Services Task Force. While most hearing loss in older adults is sensorineural and due to presbycusis, cerumen impaction and chronic otitis media may be present in up to 30% of elderly patients with hearing loss and can be treated by the primary care clinician [30].

Associations of DFNA40 with chemical compounds
• As compared with those who received placebo, the patients who received dexamethasone became afebrile earlier (1.6 vs. 5.0 days; P less than 0.001) and were less likely to acquire moderate or more severe bilateral sensorineural hearing loss (15.5 vs. 3.3 percent; P less than 0.01) [31].
• Pharmacological doses of thiamine correct the anaemia, and in some cases improve the diabetes, although progressive sensorineural deafness is irreversible [32].
• Stickler and Marshall syndromes are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural-hearing deficit [33].
• Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss [34].
• Steroid-responsive postinfectious sensorineural hearing loss [35].

Physical interactions of DFNA40
• Otosclerosis is a disease of complex unknown etiology causing progressive conductive and/or sensorineural hearing loss (HL) [36].

Other interactions of DFNA40

• We report here a dominant mutation in the GJB3 gene (D66del) in a family affected with peripheral neuropathy and sensorineural hearing impairment [37].
• Mutations in SOX10, a transcription modulator crucial in the development of the enteric nervous system (ENS), melanocytes and glial cells, are found in Shah-Waardenburg syndrome (WS4), a neurocristopathy that associates intestinal aganglionosis, pigmentation defects and sensorineural deafness [38].
• The much rarer Jervell-Lange-Nielsen syndrome (with marked QT prolongation and sensorineural deafness) arises when a child inherits mutant KVLQT1 or minK alleles from both parents [39].
• A gene for an autosomal dominant form of progressive sensorineural hearing loss (DFNA5) was previously assigned by us to a 15-cM region on chromosome 7p15 [40].
• Defects in the human gene encoding DSPP cause inherited dentin defects, and these defects can be associated with bilateral progressive high-frequency sensorineural hearing loss [41].

Analytical, diagnostic and therapeutic context of DFNA40
• The hearing loss was characterized by a high-frequency sensorineural deficit, which necessitated hearing aids in six patients [42].
• The number of days of illness (symptoms) before hospitalization and institution of antibacterial treatment was not correlated with the development of sensorineural deafness [1].
• Correlation between antibodies to type II collagen and treatment outcome in bilateral progressive sensorineural hearing loss [43].
• On pure-tone audiometry, 19 patients were shown to have sensorineural hearing loss, 3 of whom had evidence of an added conductive element [44].
• Cochlear implants have dramatically changed the treatment and prognosis for patients with profound sensorineural hearing loss [45].

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38. Human Connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10. Bondurand, N., Girard, M., Pingault, V., Lemort, N., Dubourg, O., Goossens, M. Hum. Mol. Genet. (2001)
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40. Refined mapping of a gene for autosomal dominant progressive sensorineural hearing loss (DFNA5) to a 2-cM region, and exclusion of a candidate gene that is expressed in the cochlea. Van Laer, L., Van Camp, G., van Zuijlen, D., Green, E.D., Verstreken, M., Schatteman, I., Van de Heyning, P., Balemans, W., Coucke, P., Greinwald, J.H., Smith, R.J., Huizing, E., Willems, P. Eur. J. Hum. Genet. (1997)
41. A novel splice acceptor mutation in the DSPP gene causing dentinogenesis imperfecta type II. Kim, J.W., Nam, S.H., Jang, K.T., Lee, S.H., Kim, C.C., Hahn, S.H., Hu, J.C., Simmer, J.P. Hum. Genet. (2004)
42. Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. Olivieri, N.F., Buncic, J.R., Chew, E., Gallant, T., Harrison, R.V., Keenan, N., Logan, W., Mitchell, D., Ricci, G., Skarf, B. N. Engl. J. Med. (1986)
43. Correlation between antibodies to type II collagen and treatment outcome in bilateral progressive sensorineural hearing loss. Helfgott, S.M., Mosciscki, R.A., San Martin, J., Lorenzo, C., Kieval, R., McKenna, M., Nadol, J., Trentham, D.E. Lancet (1991)
44. Impaired hearing in X-linked hypophosphataemic (vitamin-D-resistant) osteomalacia. Davies, M., Kane, R., Valentine, J. Ann. Intern. Med. (1984)
45. Cochlear implantation for the treatment of deafness. Copeland, B.J., Pillsbury, H.C. Annu. Rev. Med. (2004)

fuente: http://www.wikigenes.org/e/gene/e/63945.html

Acúfenos: Sección tratamiento, La acción antidepresiva de la natación

Aspectos moleculares involucrados en el entrenamiento con ejercicios de natación para reducir la anhedonia en un modelo de ratas con depresión.

Andre Roberto Sigwalt1, 2, Henning Budde3, 7, Ingo Helmich4, Viviane Glaser1, Karina Ghisoni1, Silvia Lanza1, Eduardo Lusa Cadore5, Francisco Luiz Rodrigues Lhullier5, Andreza Fabro de Bem1, Alexandre Hohl6, Filipe José de Matos1, Paulo Alexandre de Oliveira8, Rui Daniel Schröder Prediger8, Luiz Guilherme Antonacci Guglielmo2 and Alexandra Latini1, Corresponding Author Contact Information, E-mail The Corresponding Author

1 Laboratório de Bioenergética e Estresse Oxidativo, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil

2 Laboratório de Esforço Físico, Centro de Desportos, Universidade Federal de Santa Catarina, Florianópolis, Brazil

3 Department of Training and Movement Sciences, Institute of Sport Science, Humboldt Universität zu Berlin, Berlin, Germany

4 Department for Neurology, Psychosomatic and Psychiatry, Institute of health promotion and clinical movement science, German Sport University Cologne, Germany

5 Exercise Research Laboratory, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

6 Departamento de Clínica Médica, Serviço de Endocrinologia e Metabologia, Hospital Universitário da Universidade Federal de Santa Catarina, Florianópolis, Brazil

7 Department of physical education, University of Suwon, Seoul, South Korea

8 Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil

Los pacientes que sufren de depresión con frecuencia muestran una hiperactividad del eje hipotálamo-hipofisario-adrenal (HPA) que resulta en niveles elevados del cortisol.

Uno de los síntomas principales de esta condición es la anhedonia. Existe evidencia de que el ejercicio puede ser utilizado como una intervención de rehabilitación en el tratamiento de los trastornos depresivos. En este escenario, el objetivo del presente estudio fue evaluar el efecto de un protocolo de ejercicio aeróbico en el comportamiento de tipo depresivo, anhedonia, inducida por la administración de dexametasona en dosis repetidas.

Anhedonia/fuente de la imagen: shockmd.com

El estudio se llevó a cabo en ratas Wistar machos adultos divididos al azar en cuatro grupos:
El "grupo de control" (C),
"grupo de ejercicio" (E),
"grupo de dexametasona" (D)
Y el "grupo de dexametasona más ejercicio" (DE).

El entrenamiento consistió en practicar natación (1 h / día, 5 días / semana) durante tres semanas, con una sobrecarga del 5% del peso corporal de la rata. Cada día las ratas fueron inyectadas con dexametasona (D / DE) o solución salina (C / E).

Se utilizaron en paralelo controles apropiadamente positivos usando fluoxetina,

. los animales tratados con dexametasona mostraban: Disminución de los niveles sanguíneos de corticosterona, reducción de la síntesis del colesterol y del peso suprarrenal adrenal (HPA interrupción), preferencia por reducir el consumo de sacarosa y mayor tiempo de inmovilidad (comportamiento símil depresivo), oxidación aumentada del ADN del hipocampo, el aumento de IL-10 y del total de factor neurotrófico derivado del cerebro (BDNF, Pro-hacia las formas maduras) y una grave pérdida de masa corporal.

fuente de la imagen: stockphotos.mx

Además de un aumento de las concentraciones de testosterona en sangre, el entrenamiento de natación protegía a las ratas depresivas del estado anhedónico, siguiendo el mismo perfil que la fluoxetina, y también de la neuroquímica alterada inducida por dexametasona. Los datos indican que el ejercicio físico puede ser una herramienta útil en la prevención y el tratamiento de los trastornos depresivos.
Fuente: http://www.sciencedirect.com/science/article/pii/S0306452211006725

Nota: (de acuerdo al articulo de http://es.wikipedia.org/wiki/Anhedonia ,La anhedonia es la incapacidad para experimentar placer, la pérdida de interés o satisfacción en casi todas las actividades. Se considera una falta de reactividad a los estímulos habitualmente placenteros. Constituye uno de los síntomas o indicadores más claros de depresión, aunque puede estar presente en otros trastornos, como por ejemplo, en algunos casos de demencias (Alzheimer).

La cultura tiene una gran influencia: una conducta puede ser aceptada por un grupo cultural y no ser bien vista por otro. Los factores biológicos son la causa principal donde se encuentran las influencias perinatales y la salud física. Es el médico psiquiatra el que determinará si es normal o anormal.

Los criterios generales para diagnosticarla como un trastorno son ver el grado de insatisfacción con las capacidades y logros del paciente, evaluar sus relaciones interpersonales y la forma en que afronta los acontecimientos de su vida. Lo importante es que el paciente aprenda a aceptar los hechos como se presentan; si su comportamiento le causa un daño a él y/o a los demás, entonces se transforma en una patología que debe ser tratada.

sábado, 18 de junio de 2011

Audición: Sección fisopatologia: Efectos del agotamiento brusco de Tiroxina sobre la audición humana

Effects of acute thyroxin depletion on hearing in humans†

1. Zan Mra MD1,
2. Mark K. Wax MD2,*

Author Information

1. 1

Department of Otolaryngology—Head and Neck Surgery, Oregon Health Sciences Center, Portland, Oregon
2. 2

State University of New York at Buffalo, Buffalo, New York, and the Department of Otolaryngology—Head and Neck Surgery, Oregon Health Sciences Center, Portland, Oregon

*Correspondence: Mark K. Wax MD, Department of Otolaryngology—Head and Neck Surgery, Oregon Health Sciences University, 3181 Sam Jackson Park Road, Portland, Oregon 97201–3011, U.S.A.

1. †

Presented at the Meeting of the Southern Section of the American Laryngological, Rhinological and Otological Society, Inc., New Orleans, Louisiana, January 16, 1999.

Fuente de la imagen: http://www.umm.edu/graphics/images/es/14058.jpg


Objective: To study the physiologic effect of acute thyroid hormone depletion on hearing and the function of outer hair cells.

Design: Audiologic and otoacoustic emission testing of subjects undergoing total thyroidectomy before surgery and up to 6 weeks after surgery. Magnitude of thyroxin depletion monitored by serum thyroid-stimulating hormone levels.

Setting: Hearing research laboratory at a state university. Subjects: Ten patients undergoing total thyroidectomy.

Main Outcome Measures: Detection of hearing loss on audiogram and decrease or disappearance of otoacoustic emissions as a result of acute thyroxin depletion.

Results: No significant changes in the audiogram and otoacoustic emission configurations were detected, although thyroid-stimulating hormone levels became elevated after total thyroidectomy.

Conclusion: Although thyroid hormone is thought to play a role in the physiology of hearing in humans, no deleterious effects on hearing can be identified up to 6 weeks after thyroxin depletion

Fuente: The Laryngoscope, Volume 109, Issue 3, pages 343–350, March 1999
Mra, Z. and Wax, M. K. (1999), Effects of acute thyroxin depletion on hearing in humans. The Laryngoscope, 109: 343–350. doi: 10.1097/00005537-199903000-00001

Sindrome de Meniere: Etiopatologia: relacion con disfunción tiroidea

Prevalencia de la disfunción tiroidea en pacientes con enfermedad de Meniere

Autores: Michael Brenner, MD, Dick Hoistad L., MD, Timothy C. Hain, MD

Departamento de Otorrinolaringología de la Universidad de Washington, St. Louis, Mo (Dr. Brenner), y los Departamentos de Otorrinolaringología (Dres. Hoistad y Hain), Neurología (Dr. Hain), y Terapia Física y Ciencias del Movimiento Humano (Dr. Hain), la Universidad de Northwestern, Chicago, Illinois,

los autores no tienen ningún interés económico correspondiente en este artículo.


Objetivo: Determinar la prevalencia de hipotiroidismo en una población de pacientes con la enfermedad de Meniere (MD).

Diseño: Estudio retrospectivo de casos y controles, estudio que comparó el uso de suplementos de hormona tiroidea entre los pacientes con DM y los controles.
Marco: Clínica de consultas externas de neurología especializada en el manejo de pacientes que sufren mareos.
Pacientes: Cincuenta pacientes que cumplían los criterios 1995 de la Academia Americana de Otorrinolaringología para los controles de MD y 50 de la misma edad y el sexo que experimentan mareos.

Resultados: Los 50 pacientes que cumplían los criterios de MD fueron identificados a partir de una base de datos de más de 2000 pacientes con mareo visto a lo largo de un período de 5 años.

De estos, 16 (32%) tomaban suplementos de la hormona tiroidea en contraste con los 2 (4%) de los 50 controles (P 0.001).

La media de edad de los pacientes con DM fue de 60 años, y cinco (19%) de los 26 pacientes menores de 60 años tomaban suplementos de hormona tiroidea, en comparación con 11 (46%) de 24 pacientes mayores de 60 años (P 0,05).

No hubo diferencias estadísticamente significativas en la severidad de la pérdida de la audición, el patrón de pérdida de audición, o la prevalencia de pérdida auditiva bilateral entre los pacientes con MD que tomaban suplementos de hormona tiroidea y los pacientes con DM que no.

Conclusión: La enfermedad de Meniere se asocia con hipotiroidismo corregido.

La enfermedad de Ménière (MD), fue descripta por primera vez por Ménière, en 1861, es un trastorno caracterizado por episodios de vértigo, pérdida auditiva, tinnitus, y plenitud auditiva.

la asociación de MD con hidrops endolinfático es bien conocida, pero la etiología precisa de la MD se desconoce y puede ser multifactorial.

Estudios previos que intentaron determinar la prevalencia de hipotiroidismo en pacientes con MD antes que las pruebas de sensibilidad de la función tiroidea estuvieran disponibles mostraban un resultado de las estimaciones de prevalencia que varía del 3% al 17%.

Nosotros tratamos de determinar si los pacientes con DM eran más propensos a padecer de hipotiroidismo tratado, que un grupo de control de los pacientes con mareos solamente (sin MD)


Para este estudio retrospectivo (de casos y controles), se realizaron búsquedas en una base de datos informatizada de texto que consta de todas las historias de la clínica de más de 2000 pacientes atendidos durante un período de cinco años por el mismo médico (TCH) e identificó a varios cientos de registros con la mención de MD.

Los pacientes con enfermedades potencialmente confusas fueron excluidos.

Los criterios de exclusión fueron :
antecedentes de accidente cerebrovascular,
esclerosis múltiple,
la malformación de Arnold-Chiari,
trastornos psiquiátricos importantes,
convulsiones, o
alguna otra enfermedad otológica como tumor glómico, pérdida de la audición congénita, otitis media, colesteatoma, otosclerosis, fístula perilinfática, neuritis vestibular, laberintitis, vértigo postraumático, otosifilis, o cirugía de oídos anterior por una razón que no sea MD.

De este grupo de pacientes, 50 cumplían los criterios establecidos en el 1995 por la Academia Americana de ORL para MD.

De la misma base de datos de 2000-pacientes, tomamos un grupo control generado al azar, de la misma edad y sexo, de 50 pacientes con vértigo, pero sin antecedentes de pérdida de audición, tinnitus, o sensación de plenitud aural.

Todos los pacientes diagnosticados con DM fueron clasificados con:
afectación unilateral o bilateral sobre la base de los criterios diagnósticos descritos por Kitahara, , con la excepción de que, de acuerdo con la Academia Americana de 1995 los criterios de Otorrinolaringología de MD unilateral, una pérdida de audición documentada por el audiograma, no es necesario que fluctúe para ser considerada significativa.

Los pacientes con MD que habían recibido suplementos de hormona tiroidea entre sus medicamentos fueron contactados por teléfono, Se les preguntó:
sobre la causa de su enfermedad de la tiroides,
la posibilidad de una asociación de esta enfermedad con síntomas MD,
y si tenían antecedentes de enfermedades autoinmunes sistémicas.

De los 50 pacientes con mareo y pérdida significativa de la audición documentada, 16 (32%) habían tomado suplementos de tiroides en comparación con 2 (4%) en el grupo control.

La comparación de dos de las pruebas del uso de suplementos de tiroides por los pacientes con DM y un grupo control de pacientes con vértigo sin MD fue muy significativa (p 0,001).

Hubo una interacción significativa entre el uso de la tiroides y la edad entre los 50 pacientes del estudio.

Su edad media era de 60 años, y cinco (19%) de los 26 pacientes menores de 60 años tomaban suplementos de hormona tiroidea, en comparación con 11 (46%) de los 24 pacientes mayores de 60 años (P 0,05).

No hubo diferencias estadísticamente significativas en la severidad de la pérdida de la audición o la prevalencia de pérdida auditiva bilateral en los pacientes con MD que tomaban suplementos de hormona tiroidea en comparación con aquellos que no lo hacían.

Todos los 16 pacientes que tomaban suplementos de tiroides fueron contactados.
Se señaló que no hay relación temporal consistente entre la aparición de la enfermedad de la tiroides y el inicio de la MD.

Tres de los pacientes creen que los niveles elevados o deprimidos de la hormona tiroidea circulante han influido en sus síntomas MD.

Ninguno de los pacientes que toman suplementos de hormona tiroidea informó de un historial de cáncer de tiroides o una cirugía.

Además de tener hipotiroidismo corregido, 4 pacientes tenían también una de las siguientes enfermedades autoinmunes sistémicas:

1. artritis reumatoide,
2. síndrome CREST (calcinosis cutánea, fenómeno de Reynaud, dismotilidad esofágica, esclerodactilia y telangiectasias),
3. síndrome de Sjögren
4. lupus eritematoso sistémico.


1. Se encontró una tasa significativamente más alta de uso de suplementos de hormona tiroidea en los pacientes con DM (32%) que entre los controles igualados por edad y sexo (4%).
2- Más del 50% de los pacientes con MD mayores de 60 años tomaban suplementos de hormona tiroidea, lo que supera con creces la tasa de los suplementos de la hormona tiroidea en la población general.

3-No se han realizado estudios recientes de la prevalencia de la enfermedad de la tiroides en pacientes con MD. En la literatura más antigua, Pulec y House informó que el 3% de 120 pacientes con DM tenía antecedentes de hipotiroidismo y Powers encontró hipotiroidismo en el 17% de sus pacientes con MD.
Por lo tanto, nuestra encuesta más reciente muestra una mayor incidencia de hipotiroidismo.

Este hallazgo puede ser causado por la reciente disponibilidad pruebas hormonales para el hipotiroidismo de alta sensibilidad, lo que ha hecho posible que las personas con disfunción de la tiroides menos grave sean diagnosticadas y se traten.

4-Es poco probable que la asociación de la disfunción de la tiroides con la edad sea sólo un reflejo de la mayor prevalencia general de disfunción tiroidea en la población de edad avanzada, dado que la prevalencia de la enfermedad de la tiroides en las personas mayores de 55 años es inferior al 10% 0,8-11 Por lo tanto , nuestros datos apoyan la posibilidad de una prevalencia mucho mayor del uso de medicación de la tiroides en pacientes con DM en general, y una prevalencia especialmente elevada en los pacientes mayores.

5-La enfermedad tiroidea autoinmune es la enfermedad autoinmune más común en la población de los Estados Unidos, y los suplementos de tiroides tienen una alta correlación con la enfermedad.
En un estudio reciente realizado por Diez de 13655 pacientes con
• El hipotiroidismo por enfermedad de Hashimoto representaron el 47% de los casos,
• seguido de hipotiroidismo postoperatorio (26,7%),
• de causa desconocida (13,1%),
• y la terapia para un hipertiroidismo anterior (9,6%).

6- Ninguno de los pacientes que tomaban suplementos de hormona tiroidea en nuestro estudio tenía antecedentes de cirugía de la tiroides o ablación de tiroides.
Por lo tanto, la tiroiditis autoinmune es el diagnóstico más probable en nuestros pacientes que los suplementos.

Hay varias explicaciones posibles para nuestros hallazgos:

• Históricamente, un número de investigadores sugirió inicialmente que los cambios metabólicos que ocurren en el hipotiroidismo eran capaces de producir los síntomas observados en MD. sin embargo otros, más tarde rechazaron esta explicación.

• Otra posibilidad sería que la enfermedad tiroidea autoinmune directamente puede causar algunos casos de MD, sin embargo, esto también parece poco probable dado que una clara asociación entre la MD y la enfermedad autoinmune de tiroides clínicamente significativa (es decir, que requiera tratamiento) ha sido reportada en sólo un puñado de pacientes.

• Una conexión menos directa podría ser un factor de susceptibilidad compartida entre la enfermedad tiroidea autoinmune y MD.

• La Autoinmunidad sigue siendo un mecanismo potencial para algunos casos de MD. Esta idea es apoyada por nuestra observación de que cuatro de los pacientes que tomaban suplementos de hormona tiroidea había co morbilidad enfermedades autoinmunes sistémicas.

• Tanto la enfermedad tiroidea autoinmune y MD autoinmunes podrían derivar de una susceptibilidad subyacente común a las alteraciones autoinmunes.

7- Nuestros resultados demuestran una asociación entre la MD y una hipofunción tiroidea activa.

8- Los médicos deberían considerar la posibilidad de detección de la disfunción tiroidea en pacientes con DM que no están tomando suplementos.

9- La probabilidad de encontrar el hipotiroidismo es mayor en los pacientes MD mayores de 60 años.

Fuente: ARCH Otolaryngol of head and neck Surg / Vol 130, feb 2004 WWW.ARCHOTO.COM 226

Audición: Sección fisiopatologia: BERA y Trastornos tiroideos

Respuestas auditivas del tronco cerebral en enfermedades de la tiroides antes y después del tratamiento.

Autores: Di Lorenzo L, L Foggia, N Panza, MR Calabrese, G Motta, G Tranchino, Orio F Jr, G. Lombardi
Department of Medical-Surgical Endocrinology, University Federico II School of Medicine, Naples, Italy


El objetivo de este estudio fue evaluar a través de las respuestas auditivas evocadas del tronco cerebral (BERA) los eventos eléctricos generados a lo largo de la vía auditiva en 56 pacientes adultos afectados con hiper e hipotiroidismo.

Veinticuatro pacientes con audición normal e hipertiroidismo afectados con la enfermedad de Graves y 32 pacientes hipotiroideos con audición normal (9 con hipotiroidismo subclínico y 23 con hipotiroidismo clínico) fueron sometidos a BERA estándar (con clics en 21 pps) y sensibilizados sonidos de banda ancha (enmascaramiento).

Además, se realizaron a todos los pacientes una Gamma grafía tiroidea y una ecografía, mediciones de T3 y T4 libre, T3 y T4, TSH totales, anticuerpos antimicrosomales y antitiroglobulina, audiometría y pruebas de impedancia.

Este estudio fue repetido a los 6-12 meses de tratamiento en condiciones de eutiroidismo.

Los resultados mostraron cambios de BERA, tanto en el procedimiento estándar, así como en la prueba sensibilizada: en 6 casos de hipertiroidismo subclínico (25%) y en 8 pacientes con hipotiroidismo (25%).

Todos los pacientes con BERA anormal tenían hipotiroidismo manifiesto (8 / 23; 34,7%).

El BERA se normalizó en 5 de los 6 pacientes de Graves después de 6-12 meses de tratamiento con metimazol.

El BERA se mantuvo anormal en todos los pacientes con hipotiroidismo a pesar de haber estado en tratamiento con L-tiroxina de 6-12 meses y estaban eutiroideos por lo menos 5 meses antes de que se repitiera el estudio.

Estos hallazgos sugieren que las anormalidades BERA son sólo indicativas de una lesión no específica en los centros bulbo-ponto-mesen cefálicos.

Las Alteraciones del BERA en enfermedades de la tiroides no son específicas en relación con hiper o hipotiroidismo.

Por último, existe una relación entre las anormalidades BERA y el grado de hipotiroidismo, aunque las alteraciones del BERA no siempre son reversibles tras la terapia a largo plazo.

Fuente: Horm Res.. 1995; 43 (5) :200-5.

Audición: Sección fisiopatologia: el rol de la hornona tiroidea en la audicion postnatal

Expresión postnatal de los receptores alfa tiroideos en la cóclea de la rata.

Autores: Jürgen Lautermann y Wouter-Jan F ten Catea
Department of Oto-Rhino-Laryngology, University of Essen, Hufelandstraße 55, 45122 Essen, Germany

Los Receptores de la hormona tiroidea pertenecen a la superfamilia de receptores nucleares que se expresa en muchos tejidos.

Los niveles reducidos de las hormonas tiroideas en el hipotiroidismo adquirido o congénito pueden causar pérdidas de audición que pueden ser irreversibles.

En este estudio se investigó la distribución inmuno histoquímica postnatal de los receptores de la triiodotironina α en la cóclea de la rata.
Las regiones celulares de alta sensibilidad hacia las hormonas tiroideas deberían tener supuestamente una alta densidad de receptores de hormonas tiroideas.

Se observó una intensa inmuno reactividad para el receptor de la hormona tiroidea-α en las células del ganglio espiral, así como en las células ciliadas internas y externas de la cóclea.

Pudo ser detectada una tinción en todas las etapas investigadas desde el primer día después del parto hasta el día 30 y todas tenían un patrón en el núcleo celular.

Estas observaciones sugieren que las células del ganglio espiral y las células ciliadas son las regiones de destino de las hormonas tiroideas en el adulto y también durante el desarrollo de la cóclea.

Las hormonas tiroideas por lo tanto podrían jugar un papel importante en la maduración del oído interno.

fuente: http://www.sciencedirect.com/science/article/pii/S0378595597000142

Audición: Sección fisiopatologia, Resistencia a la Hornona Tiroidea y Audición

Prevalencia y mecanismos de pérdida de la audición en pacientes con resistencia a la hormona tiroidea.

1. F Brucker-Davis,
2. M C Skarulis,
3. A Pikus,
4. D Ishizawar,
5. M Un Mastroianni,
6. M Koby y
7. B D Weintraub

Lugar de trabajo del autor: 1- Molecular and Cellular Endocrinology Branch, National Institute of Diabetes, Digestive, and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892-1758, USA


La aparición de hipoacusia fue informada de forma anecdótica en la Resistencia a Hormonas Tiroideas (RTH), enfermedad causada por mutaciones en el gen receptor de la hormona beta-tiroidea (TR beta).

Debido a su distribución ontogénica en la cóclea, el TR beta puede tener un papel fundamental en el desarrollo de la función auditiva.

Para evaluar la prevalencia y los mecanismos de pérdida de audición en el RTH, 82 pacientes RTH-positivos (RTH +)y 55 familiares no afectados (RTH -) se sometieron a un examen audiológico sistemático, incluyendo audiometría tonal y logo audiometría, pruebas de estudio del oído medio (timpanometría y reflejos acústicos), pruebas de integridad coclear (otoemisiones acústicas), y retrococlear (potenciales auditivos evocados del tallo cerebral).

Se encontró una pérdida auditiva significativa en el 21% de los pacientes RTH + vs. ninguna en los pacientes RTH (-).

Los pacientes RTH + tenían timpanometrías anormales (34% vs. 12%) y reflejos anormales (39% vs. 19%).

Se encontraron casos de hipoacusia conductiva aislada en 7 de 17 pacientes RTH + con pérdida auditiva, se encontró hipoacusia neurosensorial aislada en 7 casos, e hipoacusia mixta en 3 casos.

Hubo disfunción coclear en el 50% de los pacientes RTH +, con o sin pérdida de la audición.

La función retrococlear fue normal.

No se observaron anormalidades morfológicas cocleares en la tomografía computada del hueso temporal.

En conclusión, la pérdida de audición es un problema significativo en la RHT, con una frecuencia igual de hipoacusia conductiva (probablemente relacionada con las infecciones frecuentes del oído) y déficit neurosensorial.

Las emisiones otacústicas anormales sugieren que el mutante TR beta tiene una repercusión negativa sobre la función coclear.

Neurociencia cognitiva: Las neuronas para sonidos novedosos (excéntricos)
Félix Cheung


Las neuronas en el sector auditivo del núcleo reticular del tálamo muestran un aumento de las respuestas a estímulos sonoros novedosos

Cita del artículo original
Yu, XJ, Xu, XX, Él, y Él S., J. Detección de cambio de las neuronas talámicas reticular. Naturaleza Neurosci. doi: 10.1038/nn.2373 (2009).

© (2009) istockphoto.com / Ivan Bliznetsov

Nosotros, los humanos tendemos a prestar atención a todo aquello que esté fuera de lo normal, porque nuestros cerebros tienen una marcada preferencia por los estímulos novedosos (desviación preferencial). Se cree que el núcleo reticular del tálamo (TRN) - una lámina delgada de neuronas situadas entre el tálamo y la corteza -.tiene un sector auditivo que responde a estímulos sonoros

Utilizando un procedimiento oddball ( de estímulos novedosos o excentricos), Shigang Él, de la Academia de Ciencias de China en Beijing y Jufang He, de la Hong Kong Polytechnic University y co-trabajadores1 han demostrado que el sector de la audición del TRN tiene una desviación preferencial.

Los investigadores expusieron repetidamente a ratas a una melodía de dos tonos, que se oía la mayor parte del tiempo a una frecuencia estándar y de vez en cuando a una frecuencia anormal. Ellos encontraron que la frecuencia de desviación suscitó respuestas mucho más fuertes en las neuronas TRN que la frecuencia estándar.

Algunas neuronas del cuerpo geniculado medial (MGB, una parte del tálamo auditivo) también respondió a la frecuencia anormal. Sin embargo, las respuestas fueron sustancialmente más fuertes en las neuronas del TRN que en las neuronas del MGB.

Se sabe que una inyección de lidocaína en el TRN inactiva las neuronas TRN.

Los investigadores encontraron que las neuronas MGB aumentaban sus respuestas a estímulos sonoros cuando las neuronas TRN fueron inactivadas. El hallazgo confirma el efecto modulador de la TRN en el tálamo auditivo.

Los investigadores sugieren que la desviación preferencial hace que las neuronas TRN desactiven las neuronas circundantes al TRN en respuesta a estímulos sonoros novedosos, alterando así la respuesta auditiva tálamo e induciendo un aumento de la atención (sobre el estimulo sonoro novedoso)

Los autores de este trabajo pertencen al:
CAS-Hong Kong Joint Research Laboratory for Visuo-Auditory Integration, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Laboratory of Applied Neuroscience, Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hong Kong, China.

Yu, X. J., Xu, X. X., He, S. & He, J. Change detection by thalamic reticular neurons. Nature Neurosci. doi:10.1038/nn.2373 (2009). |
fuente: http://www.nature.com/nchina/2009/090826/full/nchina.2009.170.html

Nota del Dr.Dario Roitman, Centro de Acufenos Buenos Aires.
Este mecanismo descripto en el artículo precedente puede explicar el lugar donde ocurren tanto la atencion sobre los acufenos al inicio de los mismos (como estimulo novedoso), como su inhibicion luego de un tratamiento de reentrenamiento auditivo TRT (tinnitus retraining therapy)

audición: Sección fisiología auditiva

Detección de la desviación auditiva (ante estimulos sonoros novedosos), Reexaminado: Nueva evidencia de un sistema jerárquico

fuente de la imagen: lookfordiagnosis.com
Autores: Sabine Grimmlow(a) y Carles Esceraa,(b)

a-Instituto del Cerebro, la Cognición y la Conducta (IR3C) de la Universidad de Barcelona, Cataluña-España
b Grupo de Investigación Neurociencia Cognitiva del Departamento de Psiquiatría y Psicobiología Clínica de la Universidad de Barcelona, Cataluña-España

Junio 2011

La rápida detección de los estímulos novedosos o desviados es una propiedad notable del procesamiento auditivo central que refleja los principios básicos de la organización del sistema auditivo y al mismo tiempo es de gran importancia práctica.

En la electrofisiología humana, la detección de la desviación se ha relacionado con la aparición una negatividad de desajuste (MMN) - un componente de los potenciales relacionados con eventos (ERP) que aparece desde 100 hasta 250 ms. después de la aparición de un sonido irregular o novedoso.

Recientemente, se ha demostrado en estudios con animales que una parte considerable de las neuronas de la vía auditiva exhibe una propiedad llamada “estímulo específico de adaptación” (o detección preferencial de estímulos sonoros novedosos) que les permite codificar las relaciones entre sonido su descarga, a tasas más altas en los cambios novedosos en la estimulación acústica.

Estas respuestas neuronales se han relacionado con el potencial evocado anormal medido en el cuero cabelludo, pero tales respuestas se producen en los niveles anatómicamente inferiores (por ejemplo, la corteza auditiva primaria, y el colículo inferior) y se obtienen tempranamente (20-30 ms. después del sonido de inicio) en comparación con la MMN.

Además, no son lo suficientemente importantes en tamaño para ser interpretados como una correlación neural directa de la MMN.

Aquí revisamos una serie de hallazgos recientes que suponen un primer paso para llenar el vacío entre lo registrado en los animales y las grabaciones en humanos, demostrando que comparativamente las modulaciones tempranas, debida a la desviación ante un sonido novedoso, se pueden observar en los seres humanos, particularmente en la parte media de latencia de los ERP en los primeros 50 ms. después de la aparición del sonido.

La existencia de índices de detección temprana de la desviación anterior al componente MMN apoya firmemente la idea de que la codificación de las regularidades y la detección de fenómenos auditivos novedosos son un principio básico del procesamiento de la audición humana que actúa en varios niveles.

Esto sostiene la idea de un sistema de detección de desviaciones en el sistema auditivo humano novedoso y jerárquicamente organizado.

Contactar al Autor en: Departamento de Psiquiatría y Psicobiología Clínica de la Facultad de Psicología de la Universidad de Barcelona, P. Vall d'Hebron 171, 08035 Barcelona Cataluña-España. Tel.: + 34 933 125 854, fax: + 34 934 021 584.

fuente: http://www.sciencedirect.com/science/article/pii/S0167876011001747