Ventilatory function and oxygen delivery at high altitude in the Himalayas.

This study aimed to evaluate changes in lung function assessed by spirometry and blood gas content in healthy high-altitude sojourners during a trek in the Himalayas. A group of 19 Italian adults (11 males and 8 females, mean age 43 ± 15 years, and BMI 24.2 ± 3.7 kg/m2) were evaluated as part of a Mount Everest expedition in Nepal. Spirometry and arterial blood gas content were evaluated at baseline in Kathmandu (≈1400 m), at the Pyramid Laboratory - Observatory (peak altitude of ≈5000 m), and on return to Kathmandu 2-3 days after arrival at each site. All participants took 250 mg of acetazolamide per os once daily during the ascent. We found that arterial hemoglobin saturation, O2 and CO2 partial pressures, and the bicarbonate level all decreased (in all cases, p < 0.001 with R2 =0.70-0.90), while pHa was maintained stable at the peak altitude. Forced vital capacity (FVC) remained stable, while forced expiratory volume in 1 s (FEV1) decreased (p = 0.010, n2p =0.228), resulting in a lower FEV1/FVC ratio (p < 0.001, n2p =0.380). The best predictor for acute mountain sickness was the O2 partial pressure at the peak altitude (p = 0.004, R2 =0.39). Finger pulse oximetry overestimated peripheral saturation relative to arterial saturation. We conclude that high-altitude hypoxia alters the respiratory function and the oxygen saturation of the arterial blood hemoglobin. Additionally, air rarefaction and temperature reduction, favoring hypoxic bronchoconstriction, could affect respiration. Pulse oximetry seems not enough to assist medical decisions at high altitudes.

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.

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.

Fertility Impairment after Trekking at High Altitude: A Proof of Mechanisms on Redox and Metabolic Seminal Changes.

Many authors described negative but reversible effects of high-altitude hypoxic exposure on animal and human fertility in terms of sperm concentration, function, and biochemical alterations. The aim of this study was to evaluate the acute and chronic effects of high-altitude exposure on classical sperm parameters, redox status, and membrane composition in a group of travellers. Five healthy Italian males, all lowlanders not accustomed to the altitude, were evaluated after 19 days-trekking through low, moderate, and high altitudes in the Himalayas. Sperm samples were collected before (Pre), 10 days after (Post), and 70 days after the end of the expedition (Follow-up). Sperm concentration, cholesterol and oxysterol membrane content, and redox status were measured. Hypoxic trek led to a significant reduction in sperm concentration (p < 0.001, η2p = 0.91), with a reduction from Pre to Post (71.33 ± 38.81 to 60.65 ± 34.63 × 106/mL) and a further reduction at Follow-up (to 37.13 ± 39.17 × 106/mL). The seminal volume was significantly affected by the hypoxic trek (p = 0.001, η2p = 0.75) with a significant reduction from Pre to Post (2.86 ± 0.75 to 1.68 ± 0.49 mL) and with partial recovery at Follow-up (to 2.46 ± 0.45 mL). Moreover, subjects had an increase in ROS production (+86%), and a decrease in antioxidant capacity (−37%) in the Post period with partial recovery at Follow-up. These results integrated the hormonal response on thyroid function, hypothalamus−pituitary−gonadal axis, and the prolactin/cortisol pathways previously reported. An uncontrolled ROS production, rather than a compromised antioxidant activity, was likely the cause of impaired sperm quality. The reduction in fertility status observed in this study may lie in an evolutionary Darwinian explanation, i.e., limiting reproduction due to the "adaptive disadvantage" offered by the combined stressors of high-altitude hypoxia and daily physical exercise.

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.

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.

The effects of exercise training on lipid profile in patients with sarcoidosis.

This study aimed to determine the use of lipid profiling to assess the effects of moderate intensity exercise training (ET) on patients with sarcoidosis. Fourteen patients with sarcoidosis (mean age, 46.0 ± 9.6 years) were examined before and after 3-week of ET programme in hospital settings. Symptoms (fatigue: FAS, dyspnoea: MRC), lung function tests and physical function tests (6 MWT, muscle force) were measured before and after ET. Proton nuclear magnetic resonance (NMR) spectroscopy combined with orthogonal partial least squares-discriminant analysis (OPLS-DA) was used to determine lipid profile before and after ET. Twenty-five NMR signals from lipid compounds were selected for further analysis as well as serum lipid and inflammatory markers. Three weeks of ET results in improvement of symptoms (FAS: 27.5 vs. 21.0; p < 0.001, MRC: 0.86 vs. 0.14; p = 0.002) and physical function (6MWT: 508.43 vs. 547.29; p = 0.039). OPLS-DA analysis of the lipid profiles of patients with sarcoidosis revealed differences among the samples before and after ET, including decreases in fatty acids (p < 0.017), triglycerides (p < 0.022) and total cholesterol (p < 0.020). Other changes included shifts in fatty acids oxidation products and triacylglycerol esters. A short-time, in-hospital exercise training benefits patients with sarcoidosis by enhancing their physical function. Additionally, positive effect on lipid profile was observed also in this study. It is suggested that lipid profiling could become a new prognostic method to assess effects of pulmonary rehabilitation in patients with sarcoidosis.

Role of IP3 Receptors in Shaping the Carotid Chemoreceptor Response to Hypoxia But Not to Hypercapnia in the Rat Carotid Body: An Evidence Review.

This article addresses the disparity in the transduction pathways for hypoxic and hypercapnic stimuli in carotid body glomus cells. We investigated and reviewed the experimental evidence showing that the response to hypoxia, but not to hypercapnia, is mediated by 1,4,5-inositol triphosphate receptors (IP3R/s) regulating the intracellular calcium content [Ca2+]c in glomus cells. The rationale was based on the past observations that inhibition of oxidative phosphorylation leads to the explicit inhibition of the hypoxic chemoreflex. [Ca2+]c changes were measured using cellular Ca2+-sensitive fluorescent probes, and carotid sinus nerve (CSN) sensory discharge was recorded with bipolar electrodes in in vitro perfused-superfused rat carotid body preparations. The cell-permeant, 2-amino-ethoxy-diphenyl-borate (2-APB; 100 µM) and curcumin (50 µM) were used as the inhibitors of IP3R/s. These agents suppressed the [Ca2+]c, and CSN discharge increases in hypoxia but not in hypercapnia, leading to the conclusion that only the hypoxic effects were mediated via modulation of IP3R/s. The ATP-induced Ca2+ release from intracellular stores in a Ca2+-free medium was blocked with 2-APB, supporting this conclusion.

Smell and Taste in Severe CoViD-19: Self-Reported vs. Testing.

One of the most striking reported symptoms in CoViD-19 is loss of smell and taste. The frequency of these impairments and their specificity as a potential central nervous system function biomarker are of great interest as a diagnostic clue for CoViD-19 infection as opposed to other similar symptomatologic diseases and because of their implication in viral pathogenesis. Here severe CoViD-19 was investigated by comparing self-report vs. testing of smell and taste, thus the objective severity of olfactory impairment and their possible correlation with other symptoms. Because a significant discrepancy between smell and taste testing vs. self-report results (p < 0.001) emerges in our result, we performed a statistical analysis highlighting disagreement among normosmia (p < 0.05), hyposmia, severe hyposmia, and anosmia (p < 0.001) and, in hypogeusia and severe hypogeusia, while no differences are observed in normogeusia and ageusia. Therefore, we analyzed the olfactory threshold by an objective test revealing the distribution of hyposmic (34%), severe hyposmic (48%), and anosmic (13%) patients in severe CoViD-19. In severe CoViD-19 patients, taste is lost in 4.3% of normosmic individuals, 31.9% of hyposmic individuals, 46.8% of severe hyposmic individuals, and 17% of anosmic individuals. Moreover, 95% of 100 CoViD-19 patients objectively tested were affected by smell dysfunction, while 47% were affected by taste dysfunction. Furthermore, analysis by objective testing also highlighted that the severity of smell dysfunction in CoViD-19 subjects did not correlate with age and sex. In conclusion, we report by objective testing that the majority of CoViD-19 patients report severe anosmia, that most of the subjects have olfactory impairment rather than taste impairment, and, finally, that the olfactory impairment correlate with symptom onset and hospitalization (p < 0.05). Patients who exhibit severe olfactory impairment had been hospitalized for about a week from symptom onset; double time has taken place in subjects with normosmia. Our results may be limited by the relatively small number of study participants, but these suggest by objective testing that hyposmia, severe hyposmia, and anosmia may relate directly to infection severity and neurological damage. The smell test assessment could be a potential screening symptom that might contribute to the decision to test suspected cases or guide quarantine instructions, further therapeutic approach, and evaluation of neurological damage.

Comparison of the Effectiveness of High-Intensity Interval Training in Hypoxia and Normoxia in Healthy Male Volunteers: A Pilot Study.

AIMS: The study investigated the effect of high-intensity interval training in hypoxia and normoxia on serum concentrations of proangiogenic factors, nitric oxide, and inflammatory responses in healthy male volunteers. METHODS: Twelve physically active male subjects completed a high-intensity interval training (HIIT) in normoxia (NorTr) and in normobaric hypoxia (HypTr) (FiO2 = 15.2%). The effects of HIIT in hypoxia and normoxia on maximal oxygen uptake, hypoxia-inducible factor-1-alpha, vascular endothelial growth factor, nitric oxide, and cytokines were analyzed. RESULTS: HIIT in hypoxia significantly increases maximal oxygen uptake (p=0.01) levels compared to pretraining levels. Serum hypoxia-inducible factor-1 (p=0.01) and nitric oxide levels (p=0.05), vascular endothelial growth factor (p=0.04), and transforming growth factor-ß (p=0.01) levels were increased in response to exercise test after hypoxic training. There was no effect of training conditions for serum baseline angiogenic factors and cytokines (p > 0.05) with higher HIF-1α and NO levels after hypoxic training compared to normoxic training (F = 9.1; p < 0.01 and F = 5.7; p < 0.05, respectively). CONCLUSIONS: High-intensity interval training in hypoxia seems to induce beneficial adaptations to exercise mediated via a significant increase in the serum concentrations of proangiogenic factors and serum nitric oxide levels compared to the same training regimen in normoxia.

Effects of Manual Somatic Stimulation on the Autonomic Nervous System and Posture.

Low back pain frequently involves a multifactorial etiology and requires medical attention. The aim of the study was to assess the associations among pain, posture, and autonomic nervous system function in patients with low back pain, using neuromuscular manual therapy versus a generic peripheral manual stimulation (back massage therapy). Twenty young patients with low back pain were enrolled into the study. The patients were randomly divided into two groups: treated with neuromuscular manual therapy performed after a specific structural evaluation and treated with back massage therapy. Both groups performed eight sessions of 30 min each, once a week for two months. There were three main time points of the assessment: during the first, the fourth, and the last eighth session. In each of these three sessions, data were collected before onset of session (baseline), 5 min from onset, at end of session, and 5 min after the end. All patients were subjected to stabilometric evaluation and were assessed on a visual analogue scale to quantify postural and pain changes. Tabletop capnography and pulse oximetry were used to monitor autonomic changes. The findings were that the improvement in posture and pain reduction were appreciably better in patients subjected to neuromuscular manual therapy than in those subjected to back massage therapy, with a comparable autonomic response in both groups. In conclusion, the study demonstrates that posture modification was significantly more advantageous in patient treated with neuromuscular manual therapy.

Ageing of the carotid body.

The ageing process is characterized by a decline in several physiological functions resulting in a reduced capability to maintain homeostasis. The lowered homeostatic capacity seems to involve the carotid body (CB), whose role is to modulate ventilation and tissue oxygen supply. It thus plays a prime role in all ageing processes. Ageing causes marked changes in CB morphology. In older animals, it is enlarged and shows a concomitant decrease in the percentage of chemoreceptor tissue, as well as a proliferation of type II cells. The carotid glomitis is present with aggregates of lymphocytes and fibrosis of the lobules. Type I cells are dehydrated, with a profound vacuolization, a shrinking nucleus, and lipofuscin accumulation. With increased age, human CB shows a reduction in the number and volume of mitochondria, fewer synaptic junctions between glomi, along with a reduction in CB content of neurotransmitters, leading to a sort of 'physiological denervation'. Ageing could be interpreted as a cumulative result of oxidative damage to cells, which derives from aerobic metabolism. Moreover, metabolic rate is tightly correlated with life duration; thus a loss in mitochondrial function is one of the prime factors affecting CB ageing processes. The age-related reduction in synaptic junctions might be a self-protective mechanism through which cells buffer themselves against an accumulation of reactive oxygen species. The correlation between hypoxia and the life duration of CB cells remains an open question until how and why cells sense oxygen is understood.

Physiological effects of high-altitude trekking on gonadal, thyroid hormones and macrophage migration inhibitory factor (MIF) responses in young lowlander women.

Altitude hypoxia is often associated with impairment of human reproduction. In this study, hormones and macrophage migration inhibitory factor (MIF, a proinflammatory cytokine with key roles in human reproduction) were determined in seven regularly menstruating, lowlander native women living at sea level participating in 14 days of trekking at moderate and high altitude. Blood and saliva samples were collected from each subject at high altitude (5050 m a.s.l. [above sea level]), and at sea level before and after the expedition. Testosterone level was lowered by high altitude and was restored after the end of the expedition, while progesterone decreased significantly in all participants at the end of the expedition, although most of the participants were in the luteal phase. The salivary concentration of MIF decreased greatly at altitude, but its levels were completely restored after the return to sea level. Our findings showed high sensitivity and rapid changes in the determined parameters in response to the high-altitude hypoxic environment, particularly MIF.

Functional and neurochemical interactions within the amygdala-medial prefrontal cortex circuit and their relevance to emotional processing.

The amygdala-medial prefrontal cortex (mPFC) circuit plays a key role in emotional processing. GABA-ergic inhibition within the mPFC has been suggested to play a role in the shaping of amygdala activity. However, the functional and neurochemical interactions within the amygdala-mPFC circuits and their relevance to emotional processing remain unclear. To investigate this circuit, we obtained resting-state functional magnetic resonance imaging (rs-fMRI) and proton MR spectroscopy in 21 healthy subjects to assess the potential relationship between GABA levels within mPFC and the amygdala-mPFC functional connectivity. Trait anxiety was assessed using the State-Trait Anxiety Inventory (STAI-Y2). Partial correlations were used to measure the relationships among the functional connectivity outcomes, mPFC GABA levels and STAI-Y2 scores. Age, educational level and amount of the gray and white matters within 1H-MRS volume of interest were included as nuisance variables. The rs-fMRI signals of the amygdala and the vmPFC were significantly anti-correlated. This negative functional coupling between the two regions was inversely correlated with the GABA+/tCr level within the mPFC and the STAI-Y2 scores. We suggest a close relationship between mPFC GABA levels and functional interactions within the amygdala-vmPFC circuit, providing new insights in the physiology of emotion.

The influence of altitude hypoxia on uroflowmetry parameters in women.

There is scientific evidence to suggest a correlation between hypoxia and the physiology of micturition. During a Himalayan Scientific and Mountaineering Expedition, we performed tests to investigate the functional interactions between altitude hypoxia and uroflowmetry parameters in women. The tests were carried out in seven women (36.3 ± 7.1 yr) from normoxic [1,340 meters above sea level (m a.s.l.)] to hypoxic conditions (up to 5,050 m a.s.l.) and during the return descent. The following measures were determined: uroflowmetry parameters and saturation of peripheral oxygen (SpO2 ). As expected, SpO2 decreased from 97.7 to 77.8% with increasing altitude. Micturition flow time, flow volume, and voiding time increased with altitude (P < 0.04 for all), indicating a negative correlation with SpO2 In conclusion, in young adult women, micturition physiological parameters were affected during adaptation to hypoxia; the correlation with SpO2 strongly suggests a role of hypoxia in these changes. These data could help to support the design of new strategies for both prevention and medical treatment. An example of the latter might be hyperbaric oxygen therapy, which in some studies has proved able to reduce the symptoms in patients with hypoxic bladder.

Olfactory phenotypic expression unveils human aging.

The mechanism of the natural aging of olfaction and its declinein the absence of any overt disease conditions remains unclear. Here, we investigated this mechanism through measurement of one of the parameters of olfactory function, the absolute threshold, in a healthy population from childhood to old age. The absolute olfactory threshold data were collected from an Italian observational study with 622 participants aged 5-105 years. A subjective testing procedure of constant stimuli was used, which was also compared to the 'staircase' method, with the calculation of the reliability. The n-butanol stimulus was used as an ascending series of nine molar concentrations that were monitored using an electronic nose. The data were analyzed using nonparametric statistics because of the multimodal distribution. We show that the age-related variations in the absolute olfactory threshold are not continuous; instead, there are multiple olfactory phenotypes. Three distinct age-related phenotypes were defined, termed as 'juvenile', 'mature' and 'elder'. The frequency of these three phenotypes depends on age. Our data suggest that the sense of smell does not decrease linearly with aging. Our findings provide the basis for further understanding of olfactory loss as an anticipatory sign of aging and neurodegenerative processes.

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.

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.