Olfactory Response to Altitude Hypoxia: A Pilot Study During a Himalayan Trek.

The adaptation of olfaction to extreme environments is an area of limited understanding. This study aimed to get insights into the factors that constrain olfactory function at high altitudes. To this end, we compared the results of smell tests performed on the same subjects at low (665 m) and high altitude (4,780 m) during the "Kanchenjunga Exploration and Physiology" project in the Himalayas. The most distinct adaptive differences found at high altitude were reductions in the odor intensity, color-odor bimodal association, and memory, and increases in flavor perception. Physiological adaptations of the sense of smell resulting from exposure to hypoxia at altitude may have explanatory validity in unraveling the mechanisms that shape changes in olfactory function in the processes of aging and neurodegenerative diseases.

The companion dog as a unique translational model for aging.

The dog is a unique species due to its wide variation among breeds in terms of size, morphology, behaviour and lifespan, coupled with a genetic structure that facilitates the dissection of the genetic architecture that controls these traits. Dogs and humans co-evolved and share recent evolutionary selection processes, such as adaptation to digest starch-rich diets. Many diseases of the dog have a human counterpart, and notably Alzheimer's disease, which is otherwise difficult to model in other organisms. Unlike laboratory animals, companion dogs share the human environment and lifestyle, are exposed to the same pollutants, and are faced with pathogens and infections. Dogs represented a very useful model to understand the relationship between size, insulin-like growth factor-1 genetic variation and lifespan, and have been used to test the effects of dietary restriction and immunotherapy for Alzheimer's disease. Very recently, rapamycin was tested in companion dogs outside the laboratory, and this approach where citizens are involved in research aimed at the benefit of dog welfare might become a game changer in geroscience.

Swelling of Erectile Nasal Tissue Induced by Human Sexual Pheromone.

Most chemically mediated sexual communication in humans remains uncharacterized. Yet the study of sexual communication is decisive for understanding sexual behavior and evolutive mechanisms in our species. Here we provide the evidence to consider 4,16-androstadien-3-one (AND) as a man's sexual pheromone. Our experiment provides support for the physiological effect of AND on nasal airway resistance (Rna) in women, as assessed by anterior rhinomanometry. We found that AND administration increased the area of turbinate during the ovulatory phase, resulting in an increase of Rna. Thus, we discovered that minute amounts of AND, acting through neuroendocrine brain control, regulate Rna and consequently affect the sexual physiology and behavior. Fascinatingly, this finding provides the evidence of the preservation of chemosexual communication in humans, which it has been largely neglected due to its unconscious perception and concealed nature. Therefore, chemical communication is a plesiomorphic evolutive phenomenon in humans.

Coexpression of Galanin and Nestin in the Chemoreceptor Cells of the Human Carotid Body.

The carotid body is a highly specialized chemoreceptive organ of neural crest origin whose role is to detect changes in arterial oxygen content. The sensory units are the chemoreceptor cells, which are neuronal-like cells, surrounded by sustentacular or glial-like cells. It is suggested that the carotid body contains self-renewing multipotent stem cells, which are putatively represented by glial-like sustentacular cells. The mechanisms of renewal of neuronal-like cells are unclear. Recently, we have demonstrated the expression of galanin, a peptide promoting neurogenesis, in chemoreceptor cells in the human CB. Thus, in the present study we seek to determine whether galanin expression in chemoreceptor cells could be matched with that of nestin, a peptide that is a marker of multipotent neural stem cells, or rather with the glial fibrillary acidic protein (GFAP), a marker for glial cells. The latter would underscore the pluasibly essential role of sustentacular cells in the self-renewal capability of chemorecetors. We found that galanin expression is matched with nestin in chemoreceptor cells of the human carotid body, but not with that of GFAP. Thus, galanin expression in chemoreceptor cells could provide a signal for neurogenesis and chemoreceptor cell differentiation in the carotid body.

Chemoresponsiveness and breath physiology in anosmia.

Anosmia is a model to study the interaction among chemoreception systems. In the head injury, the traumatic irreversible anosmia caused by damage to olfactory nerve fibers and brain regions is of enviable research interest. In this study, psychophysiological tests for a comprehensive assessment of olfactory function were utilized to investigate anosmia, together with a new technique based on the breath real-time monitoring of volatile organic compounds (VOCs). We applied the breath and VOCs analysis to investigate chemoresponsiveness in the long-term irreversible post-traumatic anosmia.

Inhibition of peripheral dopamine metabolism and the ventilatory response to hypoxia in the rat.

Dopamine (DA) is a putative neurotransmitter in the carotid body engaged in the generation of the hypoxic ventilatory response (HVR). However, the action of endogenous DA is unsettled. This study seeks to determine the ventilatory effects of increased availability of endogenous DA caused by inhibition of DA enzymatic breakdown. The peripheral inhibitor of MAO - debrisoquine, or COMT - entacapone, or both combined were injected to conscious rats. Ventilation and its responses to acute 8 % O(2) in N(2) were investigated in a whole body plethysmograph. We found that inhibition of MAO augmented the hyperventilatory response to hypoxia. Inhibition of COMT failed to influence the hypoxic response. However, simultaneous inhibition of both enzymes, the case in which endogenous availability of DA should increase the most, reversed the hypoxic augmentation of ventilation induced by MAO-inhibition. The inference is that when MAO alone is blocked, COMT takes over DA degradation in a compensatory way, which lowers the availability of DA, resulting in a higher intensity of the HVR. We conclude that MAO is the enzyme predominantly engaged in the chemoventilatory effects of DA. Furthermore, the findings imply that endogenous DA is inhibitory, rather than stimulatory, for hypoxic ventilation.

Tissue Dynamics of the Carotid Body Under Chronic Hypoxia: A Computational Study.

The carotid body (CB) increases in volume in response to chronic continuous hypoxia and the mechanisms underlying this adaptive response are not fully elucidated. It has been proposed that chronic hypoxia could lead to the generation of a sub-population of type II cells representing precursors, which, in turn, can give rise to mature type I cells. To test whether this process could explain not only the observed changes in cell number, but also the micro-anatomical pattern of tissue rearrangement, a mathematical modeling approach was devised to simulate the hypothetical sequence of cellular events occurring within the CB during chronic hypoxia. The modeling strategy involved two steps. In a first step a "population level" modeling approach was followed, in order to estimate, by comparing the model results with the available experimental data, "macroscopic" features of the cell system, such as cell population expansion rates and differentiation rates. In the second step, these results represented key parameters to build a "cell-centered" model simulating the self-organization of a system of CB cells under a chronic hypoxic stimulus and including cell adhesion, cytoskeletal rearrangement, cell proliferation, differentiation, and apoptosis. The cell patterns generated by the model showed consistency (from both a qualitative and quantitative point of view) with the observations performed on real tissue samples obtained from rats exposed to 16 days hypoxia, indicating that the hypothesized sequence of cellular events was adequate to explain not only changes in cell number, but also the tissue architecture acquired by CB following a chronic hypoxic stimulus.

Selective Expression of Galanin in Neuronal-Like Cells of the Human Carotid Body.

The carotid body is a neural-crest-derived organ devoted to respiratory homeostasis through sensing changes in blood oxygen levels. The sensory units are the glomeruli composed of clusters of neuronal-like (type I) cells surrounded by glial-like (type II) cells. During chronic hypoxia, the carotid body shows growth, with increasing neuronal-like cell numbers. We are interested in the signals involved in the mechanisms that underlie such response, because they are not well understood and described. Considering that, in literature, galanin is involved in neurotrophic or neuroprotective role in cell proliferation and is expressed in animal carotid body, we investigated its expression in human. Here, we have shown the expression and localisation of galanin in the human carotid body.

Volabolomic Fingerprinting for Post-Mortem Interval Estimation: A Novel Physiological Approach.

Death is a multifaceted process wherein each individual cell and tissue has a metabolic homeostasis and a time of functional cessation defined by the dying process as well as by intrinsic and extrinsic factors. Decomposition is physiologically associated with the release of different types of volatile organic compounds (VOCs), and these form volaboloma mortis. The main purpose of this study was to record the volabolomic fingerprint produced by volatile molecules during the physiological decomposition process of human tissue and muscle cells. The volatile chemical signature has important implications for an open issue in forensics and pathology, namely the estimation of the postmortem interval (PMI), which decreases in accuracy with the passage of time. Volatile metabolites emitted from human tissues and muscle cells at 0, 24, 48, and 72 h were recorded in real time with an electronic nose sensor device. The key findings were the continuous sampling of VOCs emitted from tissues and cells. These showed a common behavior as time progressed; particularly, after 48 h the distributions became dispersed, and after 72 h they became more variable. Volabolomic fingerprinting associated with time progression relevant to the study of PMIs was reconstructed. Additionally, there may be broader applications, such as in dog training procedures for detecting human remains, and perhaps even for studying scavenger and insect attractants.

Real-time breath analysis in type 2 diabetes patients during cognitive effort.

The understanding the functional expression of exhaled volatile organic compounds (VOCs) has gradually expanded from the initial identification of breath pathological markers to direct expression of physiological activity. In the present study we investigated the potential application of breath analysis in real-time monitoring of type 2 diabetes mellitus (T2DM) patients versus control subjects while performing a cognitive task. T2DM is associated with cognitive impairment and neural deficits, because of insulin resistance and high expression of insulin receptors in the hippocampus. We set out to seek the evidence for mutual associations among breath exhale, on the one side, and T2DM and cognitive effort, on the other side. The recording system consisted of a metal oxide semiconductor (MOS) which is able to detect a broad range of volatile organic compounds. The sensor provides a measure of VOCs as ppm CO2 equivalents. The MOS is suitable for a non-invasive real-time monitoring of the breath exhale in humans. The study demonstrates that, apart from the T2DM metabolic derangement, performing a cognitive task, taken as an index of central neural effort, evoked distinct alterations in exhaled breath content. We conclude that exhaled breath content measurement might offer a novel diagnostic and therapeutic non-invasive approach in metabolic and neurodegenerative derangements.

Non-invasive assessment of exhaled breath pattern in patients with multiple chemical sensibility disorder.

Multiple chemical sensitivity (MCS) is a complex disorder initiated by chemical exposure, particularly through the airways. MCS patients report sensitivity or intolerance to low levels of a wide spectrum of chemicals. Symptoms could include asthma-like signs, rhinitis, fatigue, cognitive dysfunction, psycho-physiological alteration, and other specific tissue reactions resembling hypoxic and oxidative stress effects. To recognize physiological signs that would allow the diagnosis of MCS in a non-invasive way we investigated the potential application of a new sensor system. In healthy volunteers, we measured exhaled breath content in the control condition and under exposure to olfactory stressors that mimic hypoxic or pollutant stressors playing a potential role in the generation of the MCS disorder. The recording system used is based on metal oxide semiconductor (MOS) sensor having a sensing range of 450-2,000 ppm CO(2) equivalents, which is able to detect a broad range of compounds playing a potential role in the generation of the MCS disorder, while correlating directly with the CO(2) levels. The results indicate that the recording system employed was suitable for the analysis of exhaled breath content in humans. Interestingly, the system was able to detect and discriminate between the exhaled breath content taken from the control condition and those from conditions under stress that mimicked exposures to pollutant or hypoxia. The results suggest that chronic hypoxia could be involved in the MCS disorder.

Aging and the carotid body: A scoping review.

The carotid body (CB) is a neuroepithelial tissue consisting of O2-sensitive glomus cells that constantly scan the arterial blood for O2 and generate a discharge as an inverse function of O2 content. Aging is a cumulative result of decreased O2 supply paralleled by a decreased O2 tissue demand and oxidative damage to cells derived from aerobic metabolism. Here we studied how CB affects the aging process. This is a study of CB ultrastructural morphometry and immunohistochemical expression of proteins underlying CB responsiveness. The study was based on human CBs obtained from cadavers of people who died due to traumatic events in young and old age. The study was supplemented by investigations of CBs obtained from young and old rats subjected to chronic normoxic and hypoxic conditions. We found changes in the old normoxic CBs akin to the effects of chronic hypoxia such as enhanced extracellular matrix, reduced synaptic contacts between glomus cells, fewer glomus cells, secretory vesicles, and mitochondria. These changes were accompanied by enhanced expressions of hypoxia-inducible factor one-alpha (HIF-1α), vascular endothelial growth factor (VEGF), and nitric oxide synthase (NOS2). We conclude that hypoxia and aging share a common background consisting of deficient O2 tissue supply, mitochondrial dysfunction, and a limited ability to deal with increased cellular oxidative stress. Aging leads to adaptative reductions in CB responsiveness to hypoxia shifting the chemosensory setpoint upward. We submit that the attenuated CB sensitivity at old age may be tantamount to "physiological denervation" leading to a gradual loss of the chemosensing role in the prevention of tissue hypoxia by increasing lung ventilation.

The Evanescent Bouquet of Individual Bear Fingerprint.

The evanescent and invisible communication carried by chemical signals, pheromones, or signature mixtures or, as we prefer, the pheromonal individual fingerprint, between members of the same species is poorly studied in mammals, mainly because of the lack of identification of the molecules. The difference between pheromones and the pheromonal individual fingerprint is that the former generate stereotyped innate responses while the latter requires learning, i.e., different receivers can learn different signature mixtures from the same individual. Furthermore, pheromones are usually produced by a particular gland, while the pheromonal individual fingerprint is the entire bouquet produced by the entire secreting gland of the body. In the present study, we aim to investigate the pheromonal individual fingerprint of brown bears in northern Italy. We collected the entire putative pheromone bouquet from all production sites in free-ranging bears and analyzed the entire crude extract to profile the individual fingerprint according to species-, sex- and subjective-specific characteristics. We were able to putatively characterize the brown bears' pheromonal individual fingerprints and compare them with the partial pheromone identifications published by other studies. This work is a step forward in the study of the complexity of chemical communication, particularly in a solitary endangered species.

Physiological discrimination and correlation between olfactory and gustatory dysfunction in long-term COVID-19.

The spread of the SARS-CoV-2 virus produces a new disease termed COVID-19, the underlying physiological mechanisms of which are still being understood. Characteristic of the infection is the compromising of taste and smell. There is a persistent need to discriminate the dysfunctions and correlation between taste and smell, which are probably epiphenomena of other concealed conditions. Anosmic and ageusic long-term COVID-19 patients were re-evaluated after 1 year using a Volabolomic approach with an e-nose recording system coupled with olfactometric and gustometric tests. Here a range of sensory arrangements was found, from normal taste and smell to complete losses. The following patterns of olfactory threshold (OT)-taste threshold-olfactory uni- and cross-modal perception were found anosmia-severe hypogeusia-anosmia; hyposmia-hypogeusia-severe hyposmia; normosmia-ageusia-hyposmia; severe hyposmia -normogeusia-normosmia. There is a strong correlation between OT and olfactory uni- and cross-modal perception, a moderate correlation between olfactory and taste threshold and no correlation between OT and taste threshold. In conclusion, this study provides evidence for the feasibility of testing the chemical senses to directly objectify function in order to discriminate taste from olfactory impairment. Furthermore, it allows to hypothesize a long-term effect of the virus due to neuroinvasion through, probably, the olfactory system with injury in the related multisensory areas of taste and smell.

Is Skull-Vibration-Induced Nystagmus Modified with Aging?

BACKGROUND: Despite clinical practice utilizing the Dumas test (SVINT), some questions remain unanswered, including the age-related changes in frequency (FN) and slow-phase angular velocity (SPAV). This study aims to retrospectively evaluate their variations in subjects affected by unilateral peripheral vestibular loss (UPVL). METHODS: We evaluated the selected samples based on the results of the SVINT, the results of the vestibular-evoked potentials (C-VEMP and O-VEMP), and the results of the head impulse test (HIT) and we compared the results against the age of the patients. We calculated the timing between the onset of UPVL and clinical evaluation in days. The presence or absence of VEMP indicated the UPVL severity. UPVL and BPPV patients with spontaneous or pseudo-spontaneous nystagmus were compared. RESULTS: Statistical analysis showed changes in the FN and SPAV depending on age and the side of the application of the stimulus. We also observed that, in the UPVL, the severity of the disease modifies the SPAV, but not the frequency. CONCLUSIONS: The SVINT is a simple, reliable, and straightforward test that, if evaluated instrumentally, can show significant differences with aging. Further studies need to be performed to refine the clinical significance of the test and clarify its physiological background.

Unmasking the 'Asymptomatic' COVID-19: A Nose Question.

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has high infectivity, often masked by asymptomatic carriers, which allows it to spread rapidly and become a pandemic. Attempts to slow the pandemic at this stage depend on the ability to unmask asymptomatic carriers. The rapid diagnosis of active coronavirus disease 2019 (COVID-19) infection is one of the cornerstones of pandemic control, as the nasal cavity is the main gateway for SARS-CoV-2 entry and altered sense of smell is a feature of the current virus. In the present study, we therefore tested the olfactory threshold coupled with heart-lung parameters in subjects undergoing traditional molecular testing, resulting in a significantly different score between asymptomatic subjects and healthy controls. In total, 82% of asymptomatic positives showed olfactory impairment; of these, 46% had severe hyposmia and 7% had anosmia, while in the control 9% had severe hyposmia and 0% had anosmia, respectively, which agrees with heart rate, breathing rate, and blood pressure parameter variations. The olfactory test coupled with physiological parameters may help to identify asymptomatic people. In conclusion, our results suggest that most asymptomatic individuals could be unmasked by mass olfactory rapid threshold screening and then referred to traditional slower diagnostic tests.

COVID-19 Smell Impairment and Crosstalk with Hypoxia Physiology.

Since its apomorphic appearance in 2019, severe acute respiratory syndrome Coronavirus type 2 (SARS-CoV-2) nowadays circulates as a plesiomorphic human virus in several synapomorphic variants. The respiratory tract is the most important site of infection, the viral effects in the lungs are well described, and more than half of the patients could develop shortness of breath and dyspnea and require ventilatory support. The physiological sign of this condition is the decrease in the partial pressure of oxygen in the blood, leading to acute hypoxia, which could be a factor in the disease. In severe patients, we recorded several physiological parameters: breath frequency (BF), partial pressure of oxygen in the blood (pO2), partial pressure of carbon dioxide in the blood (pCO2), hemoglobin (Hb), heart rate (HR), and blood pressure in correlation with the olfactory threshold. We found significant correlations between reduced olfactory threshold with pO2 and hemoglobin levels, changes in heart rate, and increased HR and pCO2. These results suggest that COVID-19 causes an impaired sense of smell that decreases in threshold corresponding to the disease severity.

Volatile organic compounds (VOCs) in exhaled breath as a marker of hypoxia in multiple chemical sensitivity.

In the history of diagnostics, breath analysis was one of the first method used until the breakthrough of biochemical testing technology. Today, breath analysis has made a comeback with the development of gas analyzers and e-noses, demonstrating its power in its applicability for diagnosing a wide range of diseases. The physical basis of multiple chemical sensitivity (MCS), an emerging environmental disease, is difficult to understand because it is based on the scenario of chronic hypoxia, with a complex of chemical compounds that trigger the syndrome and result in multiple symptoms. The aim of this study was to investigate MCS by analyzing exhaled volatile organic compounds (VOCs). The volatile, metabolic picture could be a putative gold standard for understanding and diagnosing the disease. The study was based on recording in resting condition using the noninvasive passive e-nose contactless breath test, the Olfactory Real-Time Volatile Organic Compounds (ORT-VOC) test in MCS, and control samples. The VOCs profile distinguished between disease and health. It also distinguished the gender-related volatile profile with significant robustness. The results trace a putative compensatory physiological pathway elicited by increased lactate, leading to acidosis, and hyperventilation, resulting in the production of specific VOCs. We conclude that breath testing is a valuable tool to investigate the hypoxia-related VOC profile, facilitating MCS diagnosis.

Electrophysiological and olfactometric evaluation of long-term COVID-19.

COVID-19 is a public health emergency with cases increasing globally. Its clinical manifestations range from asymptomatic and acute respiratory disease to multiple organ dysfunction syndromes and effects of COVID-19 in the long term. Interestingly, regardless of variant, all COVID-19 share impairment of the sense of smell and taste. We would like to report, as far as we know, the first comprehensive neurophysiological evaluation of the long-term effects of SARS-CoV-2 on the olfactory system with potential-related neurological damage. The case report concerns a military doctor, with a monitored health history, infected in April 2020 by the first wave of the epidemic expansion while on military duty in Codogno (Milan). In this subject, we find the electrophysiological signal in the periphery, while its correlate is absent in the olfactory bulb region than in whole brain recordings. In agreement with this result is the lack of metabolic signs of brain activation under olfactory stimulation. Consequently, quantitative and qualitative diagnoses of anosmia were made by means of olfactometric tests. We strongly suggest a comprehensive series of olfactometric tests from the first sign of COVID-19 and subsequent patient assessments. In conclusion, electrophysiological and metabolic tests of olfactory function have made it possible to study the long-term effects and the establishment of neurological consequences.

Postpartum Uterine Involution in Martina Franca Jennies.

This study investigated the postpartum (PP) uterine involution in nine multiparous Martina Franca jennies with at term, normal, and singleton foaling. Transrectal ultrasonography performed at Days 1, 3, 7, 14, 21, and 28 showed that the uterine tip diameters did not differ between the post-pregnant (PPH) and non-post-pregnant uterine horns (NPPH), whereas the diameter of the middle PPH was larger than the NPPH until Day 7 (p < 0.05). The diameter of the corpora-cornual junction resulted larger in the PPH than NPPH at Day 7 (p < 0.05). At Day 3, the microcaruncolae were not detected. Endometrial glands (GL) number increased, with the highest value on Day 28. Endometrial GL area and perimeter decreased (p < 0.001) from Day 1 to Day 28. Epithelial thickness increased from Days 1-3 to Day 7 (p < 0.001), and concurrently with the foal heat to Day 14 (p < 0.001), with a decrease at Days 21-28. A marked neutrophils reduction on Day 7 and eosinophil increase from the first three days to Days 7-14 was observed. The results suggest that, in Martina Franca jennies with normal foaling, the PP uterine involution can be considered complete on Day 14.