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An analysis of nasal irritation thresholds using a new solvation equation.

In the present paper we have developed a quantitative structure-activity relationship (QSAR) equation for nasal pungency caused by nonreactive volatile organic compounds (VOCs). Our QSAR was developed upon previously published nasal pungency thresholds in anosmics, i.e., patients lacking a sense of smell and thus responding only to sensory irritation evoked by trigeminal nerve stimulation. The reported solvation equation, which fits the data with considerable precision, describes sensory potency in terms of interaction via electron pairs, dipolarity/polarizability, hydrogen bond acidity and basicity, and hydrophobicity. It correspondingly suggests relevant physicochemical properties of the biophase where the sensory response is brought about. The equation implies that in the range of molecular size where nonreactive VOCs can produce any pungency, transport from the air to the biophase strictly determines potency. In this respect, the potency of nasal pungency shares characteristics with the ability of VOCs to cause narcosis and anesthesia.

Adult↗

Design and evaluation of an olfactometer for the assessment of 3-methylindole-induced hyposmia.

Few studies objectively evaluate olfactory function in animals following exposure to chemicals that induce nasal toxicity. An olfactometer capable of generating a reproducible olfactory stimulus and measuring an odorant-cued behavioral response was developed for rats from a commercially available two-way shuttle box. The box was modified to deliver the test odorant, acetaldehyde, to either of two chambers separated by a physical barrier consisting of a downward-directed airwall sandwiched between two exhaust panels. Male Fisher 344 rats were trained with either a coupled odorant- or tone-cued active avoidance paradigm in order to compare auditory-cued versus olfactory-cued learning and memory. Odorant-cued animals had faster acquisition and longer retention of the avoidance behavior than tone-cued animals. Animals given the model olfactory toxicant 3-methylindole (3-MI, 400 mg/kg, ip) had reduced odorant-cued avoidance, while no effect on tone-cued behavior was observed. In a follow-up study, additional odorant-trained rats were dosed with 0, 100, 200, or 300 mg/kg of 3-MI ip and olfactory function reassessed 6 days later. Histopathologic evidence of moderate to severe olfactory epithelial damage was observed in all rats 7 days after 3-MI administration. Only the highest 3-MI dose (300 mg/kg) was associated with a significant reduction in odor-cued avoidance behavior as compared to that seen in control. These results indicate that use of this olfactometer can provide a functional assessment of chemically induced olfactory toxicity and complements more routine nasal pathology.

Animals↗

The significance of olfaction and social cues in milt availability, sexual hormone status, and spawning behavior of male rainbow trout (Oncorhynchus mykiss).

Male rainbow trout orientate to a "releaser" pheromone emitted by an ovulated female. This chemical signal is not necessary for the completion of spawning behavior: anosmic males spawned as readily as intact males when paired with ovulated females. The amount of "strippable" milt and plasma concentrations of testosterone (T) and 17 alpha,20 beta-dihydroxy-4-pregnen-3-one (17,20 beta-P) were greater in males paired for 3 hr with ovulated females than in isolated males, or males placed with nonvitellogenic adult females or in all male groups. Milt and plasma T, 17,20 beta-P, and 11-ketotestosterone (11-KT) were reduced in anosmic males paired with ovulated females, indicating the existence of a priming pheromone. Milt, T, 11-KT, and 17,20 beta-P increased in intact males within 4 hr after injection of salmon gonadotrophin-releasing hormone analogue, lyophilized salmon pituitary extract, or homogenized fresh rainbow trout pituitary material. The results indicate that the priming pheromone acts through the hypothalamus-pituitary-gonad axis.

Animals↗

Hippocampal formation lesions impair performance in an odor-odor association task independently of spatial context.

The rodent hippocampal system is known to play an important role in memory. Evidence that this role is not limited to spatial memory has come from studies using a variety of non-spatial memory tasks. One example is the social transmission of food preference paradigm, a task in which rats learn an odor-odor association with no explicit spatial memory component. However, because training and testing in this task typically take place in the same environment, it is possible that memory for the spatial context in which odors are experienced during training is critical to subsequent retention performance. If this is the case, it might be expected that lesions of the hippocampal system would impair memory performance by disrupting the establishment of a representation of the training environment. We addressed this issue by training rats in one spatial context and then testing them either in the same or a different spatial context. Normal control rats performed equally well when tested in an environment that was the same or different from that used during training, and the retention impairment exhibited by rats with hippocampus plus subiculum lesions was equivalent in the two test environments. These results support the view that the hippocampal system is necessary for the flexible expression of nonspatial memories even when the spatial context in which the memory is acquired is not critical to retrieval.

Animals↗

Olfactory disturbances caused by the anti-cancer drug tegafur.

Olfactory disturbances induced by the anti-cancer drug tegafur were studied in separate clinical and experimental investigations. Five patients with olfactory dysfunction after tegafur were studied and were found to have normal endoscopic findings of the olfactory cleft mucosa. The average period for drug administration was 22 months. Recovery from the olfactory disturbance was poor and biopsy of the olfactory mucosa revealed severely degenerated epithelium. In experimental studies in a guinea pig animal model, effects of oral tegafur on mitotic cells in the olfactory epithelium were examined using bromodeoxyuridine (BrdU) uptake as index. At the conclusion of 3 weeks' treatment, no pronounced morphological changes were seen, but the number of BrdU-incorporating cells decreased in proportion to the dose of tegafur used. Following long-term administration of tegafur 18 months, mitotic cells reacting to BrdU or proliferating cell nuclear antigen had virtually disappeared, indicating persistent inhibition of mitotic cell activity. Morphological changes present included decreased olfactory cell numbers, loss of cells in areas just above basal cells and degeneration of the mucous layer.

Adult↗

Kallmann's syndrome and chemosensory evoked potentials.

Kallmann's syndrome is generally assessed by history and subjective tests of olfactory function. In this study three patients suffering from Kallmann's syndrome were investigated with more objective techniques, including the recording of chemosensory evoked potentials (CSEPs). After testing olfactory function by means of a simple odor identification test, anosmia was confirmed in only one patient, since the other two patients were able to distinguish between several odorants. However, investigations in which CSEPs were employed indicated that all three patients had complete loss of their olfaction as well as hypersensitivity of the trigeminal nerve. These findings prove the usefulness of CSEPs in clinical investigations of the sense of smell.

Adolescent↗

Immunocytochemical and ultrastructural correlates of the pineal inhibition of prolactin cell activity in blind-anosmic female rats.

The effects of the pineal gland on the light microscopic-immunocytochemical and ultrastructural appearance of pituitary mammotrophs were studied in female rats eight weeks after prepubertal blinding and olfactory bulbectomy. Blinding and anosmia resulted in a marked decrease in the size of the pars distalis concomitant with a reduction in the apparent number and size of PRL cells as compared with intact animals. Ultrastructurally, these cells appeared much less active than those of intact rats. The small and angular-shaped mammotrophs of blind-anosmic rats characteristically exhibited scant arrays of rough endoplasmic reticulum, small Golgi complexes with few immature secretory granules, few mature secretory granules and rare exocytosis patterns. Pinealectomy tended to reverse the effects of blinding and anosmia on pars distalis size and PRL cell size, apparent number and ultrastructure. In fact, the mammotrophs of blind-anosmic-pinealectomized rats were quite similar in ultrastructural appearance to those of intact rats. From these data we conclude that the pineal causes mammotroph hypotrophy and hypoplasia in blind-anosmic female rats.

Animals↗

Deletions of the steroid sulphatase gene in "classical" X-linked ichthyosis and in X-linked ichthyosis associated with Kallmann syndrome.

We have studied 16 men, from 10 unrelated Italian families, affected by steroid suphatase (STS) deficiency, which is the basic defect of X-linked ichthyosis (XLI). The patients' clinical diagnoses were of either isolated ichthyosis or ichthyosis associated with Kallmann syndrome (KS) (hypogonadotropic hypogonadism and anosmia). DNA from patients and their relatives was analysed by Southern blotting followed by hydridization with an STS cDNA probe. None of the patients affected by either XLI or XLI/KS showed any hybridization signal, thus revealing a deletion in the STS gene. We suggest that a gene deletion may be the most common molecular defect involved in XLI and that the syndrome XLI/KS may be due to a deletion of both the STS and the KS loci.

Chromosome Deletion↗

X-linked ichthyosis, due to steroid sulphatase deficiency, associated with Kallmann syndrome (hypogonadotropic hypogonadism and anosmia): linkage relationships with Xg and cloned DNA sequences from the distal short arm of the X chromosome.

We report a large Italian pedigree in which five out of six males are affected by a syndrome, following an X-linked inheritance pattern, characterized by ichthyosis, hypogonadotropic hypogonadism, and anosmia. The concurrence of features of X-linked ichthyosis (XLI) with those of Kallmann syndrome, another disease often inherited as an X-linked trait, prompted us to perform biochemical, cytogenetic, and molecular studies in relation to the short arm of the X chromosome (Xp). Steroid sulphatase (STS) activity was found to be completely deficient in all affected members of the family. Prometaphase chromosome analyses of two obligate heterozygous women and one affected male showed normal karyotypes. Xg blood group antigen analysis and molecular studies employing cloned DNA sequences from the distal segment of the Xp (probes RC8, 782, dic56, and M1A), did not provide evidence for deletions or rearrangements of the X chromosome. The linkage analysis showed no crossovers between the disease, Xg, and DXS143, the locus defined by probe dic56, thus suggesting the possibility of a linkage between these two markers of the distal segment of Xp and the X-linked ichthyosis, hypogonadism, and anosmia syndrome.

Adolescent↗

Familial cerebellar ataxia with hypogonadism.

A brother and sister with congenital cerebellar ataxia, anosmia, oligophrenia, hypogonadism and anomalies of amino acid distribution are reported. Ties between the different symptoms are difficult to establish. It seems to be a new syndrome rather than a new disease. Once more these associations emphasize the need for metabolic and biochemical research in heredodegenerative diseases. The evolution of the disease in these cases might make it possible to classify and locate it more accurately.

Adult↗

Occupational exposure to hydrogen sulfide in the sour gas industry: some unresolved issues.

Occupational exposure to hydrogen sulfide (H2S) and the medical management of H2S-associated toxicity remains a problem in the sour gas industry and some other industrial settings. The acute effects of exposure to H2S are well recognized, but accurate exposure-response data are limited to acutely lethal effects, even in animal studies. Odor followed by olfactory paralysis and keratoconjunctivitis are the characteristics effects of H2S at lower concentrations. H2S-induced acute central toxicity leading to reversible unconsciousness is a "knockdown"; it is controversial whether repeated or prolonged knockdowns are associated with chronic neurologic sequelae but the evidence is suggestive. Knockdowns can be acutely fatal as a consequence of respiratory paralysis and cellular anoxia. Pulmonary edema is also a well-recognized acute effect of H2S toxicity. Human studies of sublethal exposure with satisfactory exposure assessment are almost nonexistent. There are indications, poorly documented at present, of other chronic health problems associated with H2S exposure, including neurotoxicity, cardiac arrhythmia, and chronic eye irritation but apparently not cancer. Rigorous and comprehensive studies in the sour gas industry are difficult, in part because of confounding exposures and uncertain end points.

Air Pollutants, Occupational↗

Microscopic studies of human olfactory epithelia following traumatic anosmia.

We devised our own instrument for obtaining biopsy specimens of human olfactory epithelium. We obtained specimens from two patients with anosmia caused by head trauma. The morphological changes in the olfactory epithelia were studied by light microscopy and transmission electron microscopy. With little damage or early stage of changes, the characteristic finding involved degeneration of the olfactory vesicles, especially with the disappearance of cilia. In the case of great damage and the final stage of injury, no olfactory vesicles were found at the epithelial surface and the olfactory epithelia presented a disorganized cellular arrangement of cells with an atrophic appearance. Our findings indicate that the epithelial degeneration occurring in traumatic olfactory dysfunction varies according to the degree of damage incurred and the time lapse present from injury.

Adult↗

Examination and classification of human olfactory mucosa in patients with clinical olfactory disturbances.

To determine objectively the degree of olfactory disturbance, we biopsied the olfactory mucosa from patients who complained of anosmia. The olfactory disturbances in this study were caused by choanal atresia, chronic sinusitis, viral inflammation, and head trauma, as well as by congenital and idiopathic anosmia. The biopsy specimens were examined by light microscopy and the degree of mucosal degeneration present was classified according to five grades. The clinical courses of the patients studied paralleled the changes found in the olfactory mucosa.

Adolescent↗

Specific anosmia in the laboratory mouse.

As an approach to a general theory of olfaction, different specific anosmia phenotypes characterized by different profiles of odorant sensitivities have been proposed for humans. In the present experiments, male inbred mice were tested for relative odorant sensitivity using a conditioned aversion technique and odors classified as primary or complex for humans. C57BL/6J and C57BL/10J mice appeared to be less sensitive to the primary odorant isovaleric acid than were males of seven other inbred strains (A/J, AKR/J, BALB/cJ,C3HeB/FeJ, DBA/2J, SJL/J, and SWR/J). In comparisons of C57BL/6J and AKR/J strains, the relative insensitivity of C57 to isovaleric acid did not generalize to the musklike primary odor of pentadecalactone or to the complex odor of amyl acetate. The C57BL/6J genotype may provide an animal model of a specific anosmia as characterized among humans.

Animals↗