Linkage of otosclerosis to a third locus (OTSC3) on human chromosome 6p21.3-22.3.

Clinical otosclerosis (OMIM 166800/605727) has a prevalence of 0.2-1% among white adults, making it the single most common cause of hearing impairment in this group. It is caused by abnormal bone homeostasis of the otic capsule with the consequent development of sclerotic foci that invade the stapedio-vestibular joint (oval window) interfering with free motion of the stapes. Impaired ossicular chain mobility results in a conductive hearing loss. We identified the first locus for otosclerosis (OTSC1) on chromosome 15 in 1998 and reported a second locus (OTSC2) on chromosome 7 last year. Here we present results of a genome wide linkage study on a large Cypriot family segregating otosclerosis. Results of this study exclude linkage to OTSC1 and OTSC2 and identify a third locus, OTSC3, on chromosome 6p. The defined OTSC3 interval covers the HLA region, consistent with reported associations between HLA-A/HLA-B antigens and otosclerosis.

Otorhinolaryngology through the works of Hippocrates.

This retrospective survey refers to the philosophers and first scientists of the pre-Hippocratic era, which included the foundation of schools in Greece at the time (e.g. Ionia, South Sicily, Kyrinia). During the ensuing Hippocratic era the foundations of medicine as a science were laid. The concepts developed by Hippocrates and his school are set out in the Corpus Hippocraticum. In many sections of this work reference is made to diseases of the ear, nose, larynx, head and neck. It is difficult no to be impressed by the fact that many of the diagnoses and therapies are not very dissimilar to contemporary approaches. The notion that Hippocrates, Father of Medicine, gave meaning to otorhinolaryngology is also discussed here.

The acoustic cortex in frontal dementia.

Frontal dementia is a clinical entity of cognitive impairment, characterized mostly by progressive loss of fluency in speech, eventually resulting in aphasia or anomia, associated frequently with early loss of insight and many forms of inappropriate behavior. Hyperphosphorylation of the isoforms of tau protein, a microtubule-associated protein, which plays an important role in the pathogenetic mechanisms of Alzheimer's disease, is mainly involved in the pathogenesis of frontal dementia. In the present study, the morphological alterations of the acoustic cortex are described in three cases of dementia who fulfilled all the clinical and neuropathological criteria of frontal dementia. Specimens from the acoustic area of the temporal cortex were processed with Golgi silver impregnation techniques, Cajal and Rio Hortega stainings and electron microscopy. A tremendous loss of Cajal-Retzius neurons in layer I of the acoustic cortex was noticed in Golgi staining, associated with dense reactive astrocytosis, visualized clearly in Cajal gold impregnation technique. Loss of dendritic spines was extensively seen in layers III, V, and VI in correlation with normal controls. The electron microscopy revealed numerous Pick bodies, whose tau protein was the main protein constituent. Paired helical filaments were seen in the perikaryon and the axons of the neurons of layers IV, V, and VI. Synaptic alterations were extensively seen in the acoustic cortex consisting mainly of degeneration of the postsynaptic components. The authors think that the impressive morphological alterations of the acoustic cortex in frontal dementia might explain the early onset of deficiency of communication that most of the patients demonstrate in the initial stage of the disease.

Synaptic alterations in the vestibulocerebellar system in Alzheimer's disease--a Golgi and electron microscope study.

Alzheimer's disease is one of the main causes of cognitive impairment in the presenium and senium. Despite increased efforts in investigations of the aetiological background of the disease, most of the pathogenetic mechanisms remain unclear. From the morphological point of view, neurofibrillary degeneration and neuritic plaques, the main hallmarks of Alzheimer's disease, are mostly seen in the hippocampus and the cortex of the cerebral hemispheres. In contrast, the cerebellum and brain stem demonstrate minimal aggregates of neurofibrillary tangles. In addition, the neuronal population is better preserved in the cerebellum in contrast to the cortex of the brain hemispheres. In this study we attempted to detect alterations to the synapses in the vestibulocerebellar system, which is better preserved than the other structures in the central nervous system, even in the advanced stages of Alzheimer's disease. The morphological analysis is based on examination of 10 brains via electron microscopy and silver impregnation in the nodule, flocculus and vestibular nuclei. Morphological analysis revealed a limited number of neuritic plaques and minimal neurofibrillary tangles. However, synaptic alterations of the mossy fibres, granule cell dendrites, parallel fibres and Purkinje cell dendritic spines were extensively seen in Alzheimer's brains, in contrast to normal controls. In the granule layer, granule and Golgi cells were considerably decreased in number. The synapses between the mossy fibres and the granule cell dendrites were also decreased. Some of the synapses contained a limited number of polymorphous synaptic vesicles, numerous atypical mitochondria and dense bodies. Most synaptic alterations were in the mossy fibres' presynaptic terminals. The number of synaptic contacts between the mossy fibre terminals and the dendrites of the granule and Golgi cells was dramatically decreased. In the vestibular nuclei, substantial loss of synapses among the local neuronal circuits was also observed. Morphological alterations of the Golgi apparatus were seen in several neurons of the medial and lateral vestibular nuclei. In conclusion, these observations obviously plead in favour of a synaptic pathology among the primary pathogenetic processes in Alzheimer's.

Synaptic alterations in acoustic cortex in Creutzfeldt-Jacob disease.

The acoustic cortex was studied in electron microscope in 10 cases of Creutzfeldt-Jacob disease. The most prominent finding was the tremendous loss of neurons associated with marked reactive astrocytosis. The so called Cajal-Retzius cell had completely disappeared in the first cortical layer. The neuronal synapses were rare and most of those that were preserved demonstrated marked morphological alterations such as extensive dilatation of the synaptic terminals, synaptic polymorphism, dilatation of the cisternae of the smooth endoplasmic reticulum in the presynaptic terminals and accumulation of fibrillary material in the pre- and postsynaptic terminals. Vacuolization and cavity formation were seen in all the cortical layers resulting in an apparent loss of the lamination pattern of the cortex. Hirano bodies and Pick's bodies were seen in some of the neurons in the acoustic cortex. Amyloid plaques were rare in correlation to the other areas of the temporal isocortex of the same material. Correlating the morphological alterations of the neuronal synapses in acoustic cortex with those seen in other areas of the cortex in case of Creutzfeldt-Jacob disease we believe that acoustic cortex is more seriously affected in Creutzfeldt-Jacob disease than most of the other areas of the temporal isocortex.

Treatment of secretory otitis media with local instillation of hydroxyzine.

The study is a preliminary single-blind, placebo- and prednisolone-controlled investigation of the treatment of 156 children with otitis media with effusion (secretory otitis media, SOM), ranging from 2 to 12 years. The protocol involved tympanotomy and placement of a ventilation tube (grommet), through which control or drug solutions were introduced. Other parameters and coexisting symptoms which could contribute to SOM were also examined. Patients were divided into 3 groups as follows: group A: control (normal saline, 2 ml); group B: prednisolone (25 mg in 2 ml); group C: hydroxyzine pamoate (10(-5) M in 2 ml). The results indicate that in those children treated with hydroxyzine, the rate of relapse was significantly reduced and so was the amount of histamine present in middle ear effusions. The effectiveness of hydroxyzine is discussed in the context of the pathophysiology of SOM, especially with respect to mast cells and their activation by allergic and nonallergic means.

The acoustic cortex in Alzheimer's disease.

The morphology of the acoustic cortex was studied in light and electron microscopy, in 6 post mortem cases of Alzheimer's disease. Silver impregnation techniques and routine stainings were applied for the study of the cytoarchitecture and the cellular morphology of the acoustic cortex. Samples from every part of the acoustic cortex were processed for electron microscopy. The morphological findings were correlated with those of normal controls of relevant age, as well as with the temporal isocortex of the anterior part of the superior temporal gyrus. Silver impregnation techniques revealed a marked loss of dendritic spines in the second, third and fourth cortical layers. An obvious decrease of the axonic collaterals of the large triangular and round neurons was also seen. Neurofibrillary tangles were found in the soma and the initial part of the axon in a large number of neurons, being more prominent in the neurons of the second and third cortical layers. Senile plaques were dispersed all over the acoustic cortex. Electron microscopy revealed numerous paired helical filaments (PHF) located mostly in the soma and the axons of the large neurons as well as numerous Hirano bodies. Synaptic alterations, such as polymorphism of the synaptic vesicles in the presynaptic terminals, dilatation of the synaptic cleft and accumulation of osmiophilic material in the postsynaptic terminals were seen in numerous synaptic profiles in the acoustic cortex. The rare dendritic spines developed synaptic contact practically only with one presynaptic terminal, in contrast to the normal controls which demonstrated numerous dendritic spines developing synapses with more than one presynaptic terminal. The morphological alterations in the acoustic cortex might explain the profound deficit in verbal memory and the language disturbances that are hallmarks in early cases of Alzheimer's disease.

Controlled hypotension during anesthesia for otologic operations. An ultrastructural study of the brain in an experimental animal model.

We have studied the fine structure of the cerebral cortex, the cerebellar cortex, the thalamus, the caudate nucleus, the amygdala, the putamen, the vestibular nuclei, the substantia nigra, the hippocampus and the centrum semiovale in a canine model following 20 min controlled hypotension by the administration of sodium nitroprusside. The neurons and the astrocytes of all structures were intact morphologically. The synapses in the cerebral and cerebellar cortex were all unremarkable. Sensitive areas such as the molecular layer of the cerebellum did not demonstrate any ultrastructural alterations. We believe that carefully controlled sodium-nitroprusside-induced hypotension might be applied in middle ear microsurgery in otherwise healthy patients as an effective and innocuous method without causing any anoxic insult to sensitive areas of the central nervous system.

Perforated synapses in the acoustic area of the human brain.

Morphological studies were made of human acoustic cortex by light and electron microscopy. The synapses of the cortical neurons were described and their morphology was correlated with the morphology of the neurons on each cortical layer. Most of the synapses are triangular, disc-like, ovoid fusiform or mushroom-shaped. Complex-shaped perforated synapses were found in a high proportion in the primary acoustic area of the cortex. These synapses could be of special functional significance since they are mainly located in areas of specific functional importance.

Ultrastructural alterations of the vestibular nuclei in Jacob-Creutzfeld disease.

The morphological alterations of the vestibular nuclei in a case of Jacob-Creutzfeld disease were studied with light and electron microscope. The most prominent histological findings were the neuronal degeneration and neuronal loss resulting in a marked decrease of the total population, the increased reactive astrocytosis which demonstrated an extensive perivascular arrangement, the microgliosis and the interstitial spongiosis. At the ultrastructural level a marked dilatation of the astrocytic processes was seen. Most of them were completely transformed to sizeable cysts which were divided by membranous structures into smaller spaces. A large number of glycogen granules was accumulated into astrocytes and microglial cells. The neurons demonstrated numerous alterations such as (a) large accumulation of lysosomes, (b) fragmentation of the microtubules, (c) dilatation of the cisternae of the smooth endoplasmic reticulum, (d) mitochondrial abnormalities, (e) tremendous loss of the dendritic spines, (f) dilatation of the axonal terminals, (g) decrease of the number of the synaptic vesicles in the presynaptic terminal, (h) dilatation of the synaptic cleft, (j) dilatation and lysosomal accumulation in the postsynaptic component, (k) numerous multivesicular bodies and coated vesicles in pre- and postsynaptic terminals. In the neuropile space there were plenty of degenerated dendritic profiles. The degeneration of the vestibular nuclei of the brain stem was more extensive than the degeneration of the nuclei of the other brain stem cranial nerves.