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The case-history of a child with von Recklinghausen disease is described: The patient suffered the following tumors: Olfactory nerv meningeoma, optic nerv glioma, acoustic nerv neurinoma, intraventricular meningeomas, intraspinal ependymoma and peripheral neurinomas. The pathogenesis (neurocristopathy) and aetiology are discussed.
BACKGROUND: In patients with sporadic Creutzfeldt-Jakob disease, pathologic disease-associated prion protein (PrPSc) has been identified only in the central nervous system and olfactory-nerve tissue. Understanding the distribution of PrPSc in Creutzfeldt-Jakob disease is important for classification and diagnosis and perhaps even for prevention. METHODS: We used a highly sensitive method of detection--involving the concentration of PrPSc by differential precipitation with sodium phosphotungstic acid, which increased the sensitivity of Western blot analysis by up to three orders of magnitude--to search for PrPSc in extraneural organs of 36 patients with sporadic Creutzfeldt-Jakob disease who died between 1996 and 2002. RESULTS: PrPSc was present in the brain tissue of all patients. In addition, we found PrPSc in 10 of 28 spleen specimens and in 8 of 32 skeletal-muscle samples. Three patients had PrPSc in both spleen and muscle specimens. Patients with extraneural PrPSc had a significantly longer duration of disease and were more likely to have uncommon molecular variants of sporadic Creutzfeldt-Jakob disease than were patients without extraneural PrPSc. CONCLUSIONS: Using sensitive techniques, we identified extraneural deposition of PrPSc in spleen and muscle samples from approximately one third of patients who died with sporadic Creutzfeldt-Jakob disease. Extraneural PrPSc appears to correlate with a long duration of disease.
Manganese (Mn) is an essential mineral that is found at low levels in food, water, and the air. Under certain high-dose exposure conditions, elevations in tissue manganese levels can occur. Excessive manganese accumulation can result in adverse neurological, reproductive, and respiratory effects in both laboratory animals and humans. In humans, manganese-induced neurotoxicity (manganism) is the overriding concern since affected individuals develop a motor dysfunction syndrome that is recognized as a form of parkinsonism. This review primarily focuses on the essentiality and toxicity of manganese and considers contemporary studies evaluating manganese dosimetry and its transport across the blood-brain barrier, and its distribution within the central nervous system (CNS). These studies have dramatically improved our understanding of the health risks posed by manganese by determining exposure conditions that lead to increased concentrations of this metal within the CNS and other target organs. Most individuals are exposed to manganese by the oral and inhalation routes of exposure; however, parenteral injection and other routes of exposure are important. Interactions between manganese and iron and other divalent elements occur and impact the toxicokinetics of manganese, especially following oral exposure. The oxidation state and solubility of manganese also influence the absorption, distribution, metabolism, and elimination of manganese. Manganese disposition is influenced by the route of exposure. Rodent inhalation studies have shown that manganese deposited within the nose can undergo direct transport to the brain along the olfactory nerve. Species differences in manganese toxicokinetics and response are recognized with nonhuman primates replicating CNS effects observed in humans while rodents do not. Potentially susceptible populations, such as fetuses, neonates, individuals with compromised hepatic function, individuals with suboptimal manganese or iron intake, and those with other medical states (e.g., pre-parkinsonian state, aging), may have altered manganese metabolism and could be at greater risk for manganese toxicity.
Research assessed the independent contribution of the trigeminal and olfactory nerves to the detection of airborne chemicals by measuring nasal detection thresholds in subjects clinically diagnosed as lacking a functional sense of smell (anosmics) and in matched normal controls (normosmics). Anosmics can provide only odor-unbiased pungency thresholds. Normosmics provided odor thresholds. Stimuli included homologous alkylbenzenes (from toluene to octylbenzene), chlorobenzene, 1-octene, and 1-octyne. As seen before with homologous alcohols, acetates, and ketones, both types of threshold declined with increasing carbon chain length. Anosmics failed to detect alkylbenzenes above propylbenzene. The strong linear correlation between pungency thresholds and saturated vapor concentration for all tested compounds, as a whole, and the constancy of pungency thresholds expressed as percent of vapor saturation, suggests that nasal pungency from these substances relies heavily on a broadly tuned physicochemical interaction with a susceptible biophase within the cell membrane. Through such a nonspecific mechanism, low, subthreshold levels of a wide variety of volatile organic compounds of low reactivity-as found in many polluted indoor spaces-could add their sensory impact to precipitate noticeable sensory irritation.
mAb-based approaches were used to identify cell surface components involved in the development and function of the frog olfactory system. We describe here a 205-kD cell surface glycoprotein on olfactory receptor neurons that was detected with three mAbs: 9-OE, 5-OE, and 13-OE. mAb 9-OE immunoreactivity, unlike mAbs 5-OE and 13-OE, was restricted to only the axons and terminations of the primary sensory olfactory neurons in the frog nervous system. The 9-OE polypeptide(s) were immunoprecipitated and tested for cross-reactivity with known neural cell surface components including HNK-1, the cell adhesion molecule L1, and the neural cell adhesion molecule (N-CAM). These experiments revealed that 9-OE-reactive molecules were not L1 related but were a subset of the 200-kD isoforms of N-CAM. mAb 9-OE recognized epitopes associated with N-linked carbohydrate residues that were distinct from the polysialic acid chains present on the embryonic form of N-CAM. Moreover, 9-OE N-CAM was a heterogeneous population consisting of subsets both with and without the HNK-1 epitope. Thus, combined immunohistochemical and immunoprecipitation experiments have revealed a new glycosylated form of N-CAM unique to the olfactory system. The restricted spatial expression pattern of this N-CAM glycoform suggests a possible role in the unusual regenerative properties of this sensory system.
The ventral photoreceptors of Limulus polyphemus are unipolar cells with large, ellipsoidal somas located long both "lateral olfactory nerves." As a consequence of their size and location, the cells are easily impaled with microelectrodes. The cells have an average resting potential of -48 mv. The resting potential is a function of the external concentration of K. When the cell is illuminated, it gives rise to the typical "receptor potential" seen in most invertebrate photoreceptors which consists of a transient phase followed by a maintained phase of depolarization. The amplitude of the transient phase depends on both the state of adaptation of the cell and the intensity of the illumination, while the amplitude of the maintained phase depends only on the intensity of the illumination. The over-all size of the receptor potential depends on the external concentration of Na, e.g. in sodium-free seawater the receptor potential is markedly reduced, but not abolished. On the other hand lowering the Ca concentration produces a marked enhancement of both components of the response, but predominantly of the steady-state component. Slow potential fluctuations are seen in the dark-adapted cell when it is illuminated with a low intensity light. A spike-like regenerative process can be evoked by either the receptor potential or a current applied via a microelectrode. No evidence of impulse activity has been found in the axons of these cells. The ventral photoreceptor cell has many properties in common with a variety of retinular cells and therefore should serve as a convenient model of the primary receptor cell in many invertebrate eyes.
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In 20 normal and four anosmic participants, instantaneous inhalation and exhalation flow rates were recorded in response to 15 s stimulations with clean air or propionic acid concentrations (0.16, 1.14, 8.22 and 59.15 p.p.m., v/v) that ranged from peri-threshold for normals to clearly supra-threshold for anosmics. Each odorant/irritant delivery to the face-mask began with an exhalation. This allowed concentration to reach full value before stimulus onset, defined as the point where the participant began to bring the stimulus into the nose by inhalation. Two seconds after this stimulus onset, normals exhibited cumulative inhaled volume (CIV) declines of 39 and 14%, and latencies of 500 and 710 ms, with presentations of 59.15 and 8.22 p.p.m., respectively. With anosmics, 59.15 p.p.m. caused a 19% decline in CIV that began at 730 ms. Examination of the first inhalation after stimulus onset shows that the CIV declines in normals were achieved by a progressive decline in volume (InVol), beginning with a slight drop at 1.14 p.p.m., and a marked decline in duration (InDur) with only the highest concentration. Anosmics exhibited declines in InDur and InVol with only the 59.15 p.p.m. stimulus, and these declines were much more modest than the changes seen in normals. Comparison of these breathing results with perceptual responses from this same experiment demonstrates that: (i) in normals, odor perception rises slightly, but breathing does not change, with the lowest concentration; (ii) the higher breathing sensitivity (declines in InVol) of normals is paralleled by both the higher nasal irritation of these individuals and the presence of odor sensation; (iii) InDur declines in normals only with a stimulus concentration sufficient to cause marked nasal irritation in anosmics; and iv) in anosmics, modest but reliable declines in both InDur and InVol mirror the marked elevation in nasal irritation magnitude seen with only the highest concentration. In view of the failure of prior work to provide evidence that olfactory activation alone can cause any of the breathing changes we observed, we conclude that some breathing parameters are quite useful as rapid and sensitive measures of nasal irritation that arises from activation of nasal trigeminal afferents alone or in combination with the olfactory nerve.
Electro-olfactogram (EOG) oscillations induced by odorant stimulation have been often reported in various vertebrates from fishes to mammals. However, the mechanism of generation of EOG oscillations remains unclear. In the present study, we first characterized the properties of EOG oscillations induced by amino acid odorants in the rainbow trout and then performed a computer simulation based on the main assumption that olfactory receptor neurons (ORNs) have intrinsic oscillatory properties due to two types of voltage-gated ion channels, which have not yet been reported in vertebrate ORNs. EOG oscillations appeared mostly on the peak and decay phases of negative EOG responses, when odorant stimuli at high intensity flowed regularly anterior to posterior olfactory lamellae in the olfactory organ. The appearance of EOG oscillations was dependent on the odorant intensity but not on the flow rate. The maximum amplitude and the maximum power frequency of EOG oscillations were 3.51 +/- 3.35 mV (mean +/- SD, n = 232, range 0.12-16.79 mV) and 10.59 +/- 5.05 Hz (mean +/- SD, n = 232, range 3.51-40.03 Hz), respectively. The simulation represented sufficiently well the characteristics of EOG oscillations; occurrence at high odorant concentration, odorant concentration-dependent amplitude and the maximum power frequency range actually observed. Our results suggest that EOG oscillations are due to the intrinsic oscillatory properties of individual ORNs, which have two novel types of voltage-gated ion channels (resonant and amplifying channels). The simulation program for Macintosh ('oscillation 3.2.4' for MacOS 8.6 or later) is available on the world wide web (http://bio2.sci.hokudai.ac.jp/bio/chinou1/noriyo_home.html).
Following up on recent observations in patients with nasal polyposis (NP), the present study aimed to investigate whether a mechanical obstruction of the anterior olfactory cleft (OC) would produce differential effects on orthonasal and retronasal olfactory functions. To this end, we studied 33 healthy subjects in a randomized trial. Sponges with high content of saline were either placed in the OC or on the respiratory epithelium, such that this was blinded to both subject and observer. The results indicated that orthonasal (P = 0.04) but not retronasal (P = 0.15) olfactory identification ability was lower when the OC was blocked. This confirms the idea that differences between orthonasal and retronasal olfactory functions, as observed in NP patients, are, at least to some degree, due to mechanical obstruction of the anterior portion of the OC. The present data also suggest that mechanical obstruction is a means to induce reversible hyposmia void of side effects which can be performed in a blinded fashion. This might become a valuable model of hyposmia for future investigations.
Cells containing different GnRH peptides currently are thought to have distinct locations and functions in the brain. Lake whitefish is the first salmonid species to have three forms of GnRH peptide in contrast to later-evolving salmonids (salmon and trout) in which only two forms have been identified. Our objective was to isolate the cDNAs that code for these transcripts and to localize the transcripts for the three forms of GnRH in adult lake whitefish brain. Also, we provide phylogenetic analysis of these three whitefish genes based on their preprohormone sequence. From whitefish we isolated cDNAs encoding chicken (c)GnRH-II, salmon (s)GnRH, and the novel whitefish (wf)GnRH. The three cDNAs each encode only one GnRH and are placed in separate groups with phylogenetic analysis. A combination of in situ hybridization and immunocytochemistry with two antisera revealed neurons that expressed protein and/or mRNA for cGnRH-II in the midbrain and hindbrain; sGnRH in the olfactory nerve and bulb, ventral telencephalon, and preoptic area; and wfGnRH in the same latter two brain regions and the hypothalamus. Thus, in the anterior brain, cells containing sGnRH and wfGnRH were in the same brain areas but not at identical locations in the ventral telencephalon and preoptic area. Based on our results, we speculate that both sGnRH and wfGnRH have gonadotropin-releasing roles in the lake whitefish brain.
OBJECTIVES/HYPOTHESIS: In selected unilateral tumors and defects of the anterior skull base, the preservation of contralateral olfaction is achievable through a localized subcranial approach without compromising surgical objectives of resection or repair. STUDY DESIGN: Description of a functional adaptation of anterior skull base surgical techniques through a retrospective patient series. METHODS: Nine patients underwent anterior skull base surgery for unilateral cribriform plate disease including four malignant and two benign tumors, two encephaloceles, and one iatrogenic cribriform injury with cerebrospinal rhinorrhea. All nine patients consented to a localized subcranial approach to the anterior skull base to preserve the contralateral olfactory nerves. In four patients with benign disease a portion of the ipsilateral nerves was additionally conserved. Postoperative olfaction was assessed objectively with a commercially available smell test. Indications, technique, results, and complications are reported and discussed. RESULTS: All patients had eradication of disease with preservation of functional olfaction CONCLUSIONS: Conservation of olfaction is possible in selected cases of anterior skull base surgery when the lesion is unilaterally confined.
The olfactory function could be examined in 101 of 138 patients with anterior communicating artery aneurysms, whom we treated during a recent 6-year period. Among them, 49 patients underwent surgery by the anterior interhemispheric approach and 52 underwent surgery by the basal interhemispheric approach. Fifteen patients (31%) exhibited anosmia after surgery by the anterior interhemispheric approach, whereas only one patient (1.9%) exhibited anosmia after surgery by the basal interhemispheric approach. Unilateral dural incision and unilateral brain retraction without elevation of the frontal lobe from the frontal base are important, because frontal lobe depression and elevation during surgery may injure the olfactory nerve.
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The distribution of pathological lesions present in 20 cases of naturally-occurring Streptococcus suis type 2 meningitis and 20 cases of the disease induced experimentally by intravenous or intracisternal inoculation was examined. It was found that the distribution of lesions was similar; mild lesions were present at the choroid plexuses whilst the most dense cellular accumulations were found at sites of cerebrospinal fluid (CSF) efflux, such as arachnoid villi and olfactory nerve sheaths. The distribution of changes was considered to reflect the dynamics of CSF flow rather than indicate the site of entry of the organisms into the CSF compartment.
Proteolipid protein (PLP) is the major myelin protein of the CNS and is believed to have a structural role in maintaining the intraperiod line of compact myelin. An isoform, DM-20, produced by alternative splicing of exon 3B is expressed earlier than PLP in the CNS and may be involved in glial cell development. DM-20 is also present in myelin-forming and non-myelin-forming Schwann cells, olfactory nerve ensheathing cells, some glial cell lines and cardiac myocytes. Molecular studies suggest the existence of a PLP gene family with sequence similarities between molecules of different species. Such studies also lend credence to the suggestion that PLP and/or DM-20 may function as a membrane pore. Mutations in the PLP gene occur in several animal species and cause severe pleiotropic effects on myelination. In man this presents as Pelizaeus-Merzbacher disease (PMD). The phenotype of such mutants is characterized by dysmyelination with myelin of abnormal periodicity, paucity of mature oligodendrocytes and astrocytosis. Duplication of the PLP gene in transgenic animals or in one form of PMD also results in dysmyelination. X-linked spastic paraplegia (SPG2) is allelic to PMD and is associated with PLP mutations in which the levels of the DM-20 isoform are probably relatively normal. The effects of PLP gene dosage on CNS myelination can be compared in many ways to the variety of phenotypes in the PNS in hereditary neuropathies of the Charcot-Marie-Tooth type in which the peripheral myelin-22 gene is mutated.
A group of nine patients with respiratory symptoms after nonspecific irritating stimuli, but without any IgE-mediated allergy or demonstrable bronchial obstruction, were referred to the asthma/allergy outpatient department for evaluation of suspected asthma. In order to find a provocation model and objectively assess these patients' symptoms in controlled studies, provocation with perfume or placebo was performed. The same patients were also subjected to perfume provocation with or without a carbon filter mask to ascertain whether breathing through a filter with active carbon could prevent the symptoms. The patients breathed through the mouth during the provocations, as they used a nasal clamp to prevent any smell of perfume. We found that the patients' earlier symptoms could be verified by perfume provocation. Breathing through the carbon filter had no protective effect. The conclusion is that symptoms suggesting hyperreactivity of the respiratory tract and asthma can be provoked by perfume without the presence of bronchial obstruction, and that using a carbon filter mask has no preventive effect. The symptoms are not transmitted via the olfactory nerve, since the patients could not smell the perfume, but they may have been induced by a trigeminal reflex via the respiratory tract or by the eyes.
The cDNAs encoding the catfish prepro-gonadotropin-releasing hormone and the chicken prepro-gonadotropin-releasing hormone II of the African catfish (Clarias gariepinus) have been isolated and sequenced. The catfish gonadotropin-releasing-hormone precursor and the chicken gonadotropin-releasing-hormone-II precursor have the same overall architecture as other gonadotropin-releasing-hormone precursors identified so far; each is composed of a signal peptide, gonadotropin-releasing hormone and a gonadotropin-releasing-hormone-associated peptide which is connected to gonadotropin-releasing hormone and chicken gonadotropin-releasing hormone II, in combination with the Gly-Lys-Arg sequence, are highly conserved during evolution when compared with the corresponding regions of mammalian, avian (chicken gonadotropin-releasing hormone I) and other fish gonadotropin-releasing-hormone precursors. However, the gonadotropin-releasing-hormone-associated peptide regions are markedly divergent. Northern-blot analysis revealed the presence of a single catfish gonadotropin-releasing-hormone mRNA species of about 470 bases, and the presence of a single chicken gonadotropin-releasing-hormone-II mRNA species of about 650 bases in the African catfish brain. In situ hybridization revealed catfish gonadotropin-releasing-hormone cell bodies rostro-caudally scattered in the olfactory nerve, along both sides of the midline of the telencephalon, in the preoptic area of the ventral hypothalamus, and in the infundibular stalk close to the pituitary. Chicken gonadotropin-releasing-hormone-II cell bodies, however, were exclusively found in the midbrain tegmentum.