Voice Reactivity as a Response to Acute Hypobaric Hypoxia at High Altitude.

BACKGROUND: Although the understanding of hypobaric hypoxia is increasing, it remains a hazard in aviation medicine. This study examined the feasibility of detecting voice markers sensitive to acute hypobaric hypoxia in an early presymptomatic (PRE-SYMP) stage.METHOD: Eight subjects qualified with hypobaric training completed a series of standardized speech tests in a hypobaric chamber at 20,000 ft and 25,000 ft (6096 and 7620 m) of altitude. Voice response patterns were analyzed in terms of fundamental frequency (F0), F0 range, and voice onset time (VOT). We hypothesized a PRE-SYMP compensatory stage in voice reactivity.RESULTS: There was a different dose-response reactivity course at 20,000 ft vs. 25,000 ft, nonlinear to altitude. At 20,000 ft, our hypothesis was confirmed. In comparison to sea level, a PRE-SYMP compensatory stage could be distinguished, characterized by a decreased F0 range, decreased VOT, and increased F0. During a transitional (TRANS) stage, in comparison with sea level, the F0-range reset, VOT decreased, and F0 increased. During a symptomatic (SYMP) stage, F0 increased, F0 range increased, and VOT decreased. At 25,000 ft, in comparison to sea level, voice reactivity showed increased F0 and F0 range and decreased VOT in a PRE-SYMP stage and increased F0 and F0 range in the SYMP stage.DISCUSSION: The compensatory PRE-SYMP stage is suggested to be the expression of ongoing bottom-up and top-down regulatory mechanisms, whereas the 25,000-ft results are interpreted as a combination of tonic and phasic voice reactivity. This tonic component needs to be foreseen in sea level baseline measures.Van Puyvelde M, Neyt X, Vanderlinden W, Van den Bossche M, Bucovaz T, De Winne T, Pattyn N. Voice reactivity as a response to acute hypobaric hypoxia at high altitude. Aerosp Med Hum Perform. 2020; 91(6):471-478.

Classification Algorithm for Nocturnal Hypoxemia Using Nocturnal Pulse Oximetry.

This paper describes an automatic classification algorithm for nocturnal hypoxemia in patients receiving home oxygen therapy (HOT). Nocturnal hypoxemia is a well-known complication in patients with chronic respiratory disease, and the number of patients receiving HOT has increased in recent years. Many studies have reported that 40% of patients receiving HOT have sleep-related oxygen desaturation. To deal with this situation, a nocturnal pulse oximetry is used to measure oxygen saturation (SpO2) and control the flow rate of highly concentrated oxygen. However, in some cases, the flow rate is not controlled properly and the same flow rate is adopted both during the day and night. There are several types of nocturnal hypoxemia, and it is difficult to classify these types only according to a subjective assessment of a medical doctor. Furthermore, it is difficult to continuously monitor the measurement results of pulse oximetry, although a flexible treatment depending on the state of hypoxemia is desired. To overcome these difficulties, an automatic classification method for SpO2 measured by the nocturnal pulse oximetry is proposed in this paper. The proposed method uses the time domain waveform and the frequency characteristics of SpO2. The classification performance of the method is evaluated by using 48 measured SpO2 values from patients receiving the HOT. The classification results are validated with decisions of ten chest physicians.

Transcription factor ΔFosB acts within the nucleus of the solitary tract to increase mean arterial pressure during exposures to intermittent hypoxia.

ΔFosB is a member of the activator protein-1 family of transcription factors. ΔFosB has low constitutive expression in the central nervous system and is induced after exposure of rodents to intermittent hypoxia (IH), a model of the arterial hypoxemia that accompanies sleep apnea. We hypothesized ΔFosB in the nucleus of the solitary tract (NTS) contributes to increased mean arterial pressure (MAP) during IH. The NTS of 11 male Sprague-Dawley rats was injected (3 sites, 100 nl/site) with a dominant negative construct against ΔFosB (ΔJunD) in an adeno-associated viral vector (AAV)-green fluorescent protein (GFP) reporter. The NTS of 10 rats was injected with AAV-GFP as sham controls. Two weeks after NTS injections, rats were exposed to IH for 8 h/day for 7 days, and MAP was recorded using telemetry. In the sham group, 7 days of IH increased MAP from 99.8 ± 1.1 to 107.3 ± 0.5 mmHg in the day and from 104.4 ± 1.1 to 109.8 ± 0.6 mmHg in the night. In the group that received ΔJunD, IH increased MAP during the day from 95.9 ± 1.7 to 101.3 ± 0.4 mmHg and from 100.9 ± 1.7 to 102.8 ± 0.5 mmHg during the night (both IH-induced changes in MAP were significantly lower than sham, P < 0.05). After injection of the dominant negative construct in the NTS, IH-induced ΔFosB immunoreactivity was decreased in the paraventricular nucleus ( P < 0.05); however, no change was observed in the rostral ventrolateral medulla. These data indicate that ΔFosB within the NTS contributes to the increase in MAP induced by IH exposure. NEW & NOTEWORTHY The results of this study provides new insights into the molecular mechanisms that mediate neuronal adaptations during exposures to intermittent hypoxia, a model of the hypoxemias that occur during sleep apnea. These adaptations are noteworthy as they contribute to the persistent increase in blood pressure induced by exposures to intermittent hypoxia.

Temperature affects the hypoxia tolerance of neotropical Cichlid Geophagus brasiliensis

Oxygen and temperature are the most limiting factors in aquatic environments. Several species are exposed to variations of these factors in water because of physical, chemical and biological processes. The objective of this study was to evaluate the metabolic profile and the tolerance to the hypoxia of Geophagus brasiliensis exposed to changes in temperature and oxygen availability. The fish were exposed to 20 and 90% of oxygen saturation combined with different temperatures (20°, 24° and 28° C) for 8 h. Hepatic and muscular glycogen, as well as the activities of lactate dehydrogenase (LDH), malate dehydrogenase (MDH), citrate synthase (CS) and their ratios were evaluated. Both glycogen and MDH activity showed a significant difference in the liver. While CS showed increased activity only in the heart. The increase in LDH activity in the white muscle shows the importance of the anaerobic pathway as energy source in this tissue. The MDH / LDH ratio increased in all tissues, while CS / LDH increased in the liver and decreased in the heart. Based on the results of the present study it may be concluded that this species used the anaerobic metabolism as the main strategy for hypoxia tolerance.(AU)

O oxigênio e a temperatura são os fatores mais limitantes em ambientes aquáticos. Várias espécies são expostas a variações destes fatores na água como resultado de processos físicos, químicos e biológicos. O estudo objetivou avaliar o perfil metabólico e a tolerância à hipóxia de Geophagus brasiliensis expostos a alterações na temperatura e disponibilidade de oxigênio. Os peixes foram expostos a 20% e 90% de saturação de oxigênio combinadas com diferentes temperaturas (20 ° C, 24 ° C e 28 ° C) durante 8h. Foram avaliados o glicogénio hepático e muscular, assim como as atividades das enzimas lactato desidrogenase (LDH), malato desidrogenase (MDH), citrato sintase (CS) e suas razões. Tanto o glicogênio quanto a atividade da MDH apresentaram diferença significativa no fígado. Enquanto a CS apresentou aumento de sua atividade apenas no coração. O aumento da atividade LDH no músculo branco mostra a importância da via anaeróbia como fonte de energia neste tecido. A razão MDH/LDH aumentou em todos os tecidos, enquanto CS/LDH apresentou aumento no fígado e diminuição no coração. Os resultados obtidos permitem concluir que esta espécie utilizou o metabolismo anaeróbio como principal estratégia de tolerância à hipóxia.(AU)

Novos reguladores de resposta envolvidos na virulência de Pseudomonas aeruginosa / New response regulators involved in Pseudomonas aeruginosa virulence

Os sistemas de sinalização de dois componentes são sistemas prevalentes em bactérias, permitindo a adaptação a diferentes condições ambientais. O sistema de dois componentes classicamente possui uma proteína histidina quinase, o primeiro componente, capaz de reconhecer o estímulo ambiental e fosforilar o regulador de resposta, o segundo componente. Pseudomonas aeruginosa é uma proteobactéria ubíqua, capaz de infectar hospedeiros filogeneticamente distintos. Esse patógeno oportunista apresenta um dos maiores conjuntos de sistemas de dois componentes em bactérias, que permite que ela sobreviva numa grande gama de ambientes, incluindo humanos. P. aeruginosa UCBPP-PA14 apresenta pelo menos 64 histidina quinases e 76 reguladores de resposta codificados em seu genoma. Diversos sistemas de dois componentes já foram correlacionados com a virulência, sendo o sistema GacSA o exemplo melhor caracterizado. Há poucos estudos sistemáticos sobre o envolvimendo dos reguladores de resposta na virulência de P. aeruginosa e os sinais que induzem a ativação dos reguladores de resposta precisam ser encontrados. Para identificar novos reguladores de resposta envolvidos na patogenicidade, infecções in vitro em macrófagos e in vivo em Drosophila melanogaster foram realizadas neste trabalho. Os macrófagos foram infectados com cada mutante dos reguladores de resposta ou com a linhagem selvagem, e a produção da citocina pró-inflamatória TNF-α e o clearance bacteriano foram determinados. Alternativamente, as moscas foram infectadas utilizando-se a estratégia de feeding e a sobrevivência foi verificada. Utilizando-se essas abordagens, a identificação de diversos reguladores de resposta com papel na virulência foi alcançada, além de se corfirmar o papel de reguladores de resposta já estudados. Um dos novos genes envolvidos em virulência, PA14_26570 (nomeado neste trabalho de atvR), codifica um regulador de resposta atípico com substituição no aspartato fosforilável para glutamato, o que usualmente induz um estado sempre ativo. Um mutante não polar em atvR foi construído e macrófagos infectados com a linhagem ΔatvR confirmaram um maior clearance bacteriano e maior produção de TNF-α em comparação aos macrófagos infectados com a linhagem selvagem. Para comprovar a participação de AtvR durante a patogênese, um modelo de pneumonia aguda em camundongos foi utilizado. Camundongos infectados com a linhagem ΔatvR apresentaram uma maior sobrevivência em comparação aos camundongos infectados com a linhagem selvagem. Além disso, os camundongos infectados com ΔatvR apresentaram menor carga bacteriana, aumento no recrutamento de neutrófilos ativados e aumento na produção de citocinas pró-inflamatórias (TNF-α e IFN-γ). Utilizando-se uma abordagem transcritômica (RNA-Seq), foi determindo diversos genes são regulados positivamente na linhagem superexpressando AtvR em relação à linhagem controle. Dentre esses, os clusters de respiração anaeróbia nar, nir, nor e nos estão incluídos. Esse resultado foi confirmado por qRT-PCR e análises fenotípicas, em que a linhagem ΔatvR apresentou menor crescimento e expressão da nitrato redutase durante condições de hipóxia em comparação à linhagem selvagem. Em suma, neste trabalho foi demonstrado que diversos reguladores de resposta são importantes para a virulência de P. aeruginosa em macrófagos in vitro e in vivo em Drosophila, além de caracterizar o regulador de resposta atípico AtvR, que regula a respiração anaeróbica por desnitrificação, permitindo que P. aeruginosa possa infectar e colonizar o hospedeiro com maior eficiência

Two-component systems are widespread in bacteria, allowing the adaptation to environmental changes. A two-component system is classically composed by a sensor kinase that phosphorylates a cognate response regulator. Pseudomonas aeruginosa is a ubiquitous proteobacterium able to cause disease in several hosts. This opportunistic pathogen presents one of the largest sets of two-component systems known in bacteria, which certainly contributes to its ability to thrive in a wide range of environmental settings, including humans. P. aeruginosa UCBPP-PA14 genome codes for at least 64 sensor kinases and 76 response regulators. Some response regulators are already known to be related to virulence, with the GacSA system as the best characterized. There are no systematic studies about the involvement of P. aeruginosa response regulators in virulence. Moreover, the input signal that triggers the response regulator activation is yet to be uncovered for most systems. To find new response regulators involved in virulence, in vitro infections werecarried out using macrophages. Briefly, the macrophages were infected with each response regulator mutant or the wild-type strain, the pro-inflammatory cytokine production (TNF-α) and the bacterial clearance were evaluated. Using this approach, we identified several response regulators involved in virulence, and we also confirmed the involvement of known response regulators in this process. One of the novel virulence-related response regulators, PA14_26570 (named here as AtvR), is an atypical response regulator with a substitution in the phosphorylable aspartate to glutamate, that usually leads to an always-on state. A non-polar mutant was constructed, and macrophage infection with ΔatvR confirmed an increased bacterial clearance as well as a higher TNF-α production as compared to the wild-type strain. To ascertain the role of AtvR during the pathogenic process, an acute pneumonia model was used. Mice infected with ΔatvR showed an increased survival as compared to mice infected with the wildtype strain. In addition, ΔatvR infected mice showed reduced bacterial burden, increased neutrophil recruitment and activation, as well as increased pro-inflammatory cytokine production (TNF-α and IFN-γ). Also, using a transcriptomic approach (RNASeq), we showed that several genes were upregulated in the strain overexpressing AtvR. These genes include the anaerobic respiration clusters nar, nir, nor and nos. This result was confirmed by qRT-PCR and phenotypic analysis, in which ΔatvR showed reduced growth and nitrate reductase expression during hypoxic conditions as compared to the wild-type strain. In conclusion, we have demonstrated that several response regulators are important for P. aeruginosa virulence in vitro. In addition, we further characterized the atypical response regulator AtvR, which regulates anaerobic respiration via denitrification, allowing this bacterium to infect and colonize the host more efficiently

Pulmonary hypertensive vasculopathy in parenchymal lung diseases and/or hypoxia: Number 1 in the Series "Pathology for the clinician" Edited by Peter Dorfmüller and Alberto Cavazza.

Pulmonary hypertension (PH) with complicating chronic lung diseases and/or hypoxia falls into group 3 of the updated classification of PH. Patients with chronic obstructive lung disease (COPD), diffuse lung disease (such as idiopathic pulmonary fibrosis (IPF)) and with sleep disordered breathing are particularly exposed to the risk of developing PH. Although PH in such a context is usually mild, a minority of patients exhibit severe haemodynamic impairment, defined by a mean pulmonary arterial pressure (mPAP) of ≥35 mmHg or mPAP values ranging between 25 mmHg and 35 mmHg with a low cardiac index (<2 L·min-1·m-2). The overlap between lung parenchymal disease and PH heavily affects life expectancy in such a patient population and complicates their therapeutic management. In this review we illustrate the pathological features and the underlying pathophysiological mechanisms of pulmonary circulation in chronic lung diseases, with an emphasis on COPD, IPF and obstructive sleep apnoea syndrome.

[Mechanisms of sympathetic activity in rats exposed to different patterns of hypoxia and the correlation with blood pressure].

OBJECTIVE: To observe the effects of two different hypoxia patterns on blood pressure and the underlying mechanisms. METHODS: Eighteen male SD rats were randomly divided into three groups: the intermittent hypoxia group (IH group), the continuous hypoxia group (CH group) and the normal control group (NC group). The rats of the IH and CH group were subjected to intermittent hypoxia (7 h/d) and continuous hypoxia (7 h/d) for 42 days respectively. The NC group rats were untreated. The levels of arteria caudilis systolic pressure (ACSP) were measured with noninvasive rats arteria caudilis gauge before the experiment, at the end of 3rd, 6th week of the experiment. The concentrations of norepinephrine (NE) in serum and neuropeptide Y (NPY) in plasma were respectively measured by enzyme-linked-immunosorbent assay (ELISA) and radioimmunoassay. The contents of malondialdehyde (MDA) and the ability of inhibiting hydroxyl free radical in serum were analyzed by thiobarbituric acid colorimetric analysis (TBAR) at the end of 6th week. RESULTS: At the end of 3rd week, the levels of ACSP were considerably higher than those before the treatment (P<0.05). The concentrations of ACSP, NE, MDA, NPY in the IH group were significantly higher than those in the other two groups at the end of 6th week (all P<0.01). The ability of inhibiting hydroxyl free radical were decreased by the intermittent hypoxia treatment (all P<0.01). However, there was no significant difference in ACSP, NE, MDA, NPY between CH and NC group (all P>0.05). The levels of NE, NPY and MDA were positively related with ACSP (r=0.873, P<0.01; r=0.671, P<0.01; r=0.582, P<0.05). The correlation between the ability of inhibiting hydroxyl free radical and ACSP was negative (r=-0.790, P<0.01). the concentrations of MDA were positively related with NE and NPY respectively (r=0.843, 0.777, P<0.01) and the ability of inhibiting hydroxyl free radical was negatively related with NE and NPY respectively (r=-0.864, -0.717, P<0.01). CONCLUSION: Intermittent hypoxia can induce high blood pressure, which may be related to the sympathetic over-activity and the oxidative stress.

Mallampati class is not useful in the clinical assessment of sleep clinic patients.

STUDY OBJECTIVES: To assess the utility of Mallampati class, a simple grade of oropharyngeal appearance used to assess difficulty of intubation, to predict severe obstructive sleep apnea and absence of OSA (rule in severe OSA and rule out OSA). METHOD: Retrospective review of consecutive patients undergoing diagnostic polysomnography in a tertiary referral sleep disorders center. Modified Mallampati class and other simple patient characteristics (age, gender, body mass index) were compared to apnea-hypopnea index (AHI). The sensitivity, specificity, and the positive and negative likelihood ratios (LR+ and LR-) were calculated for Mallampati class IV to detect an AHI > 30 (rule in severe OSA) and Mallampati class I to detect an AHI < 5 (rule out OSA). RESULTS: A total of 953 consecutive patients (619 male) undergoing diagnostic polysomnography were included. The age of the cohort was 50.0 ± 6.4 years, with a BMI of 33.8 ± 8.6 kg/m² and AHI of 26.1 ± 25.1 /h (95% CI 1.4-78.8). Mallampati class was significantly associated with AHI (r = 0.13, p < 0.001), but there were no differences in AHI between Mallampati classes. A Mallampati class IV had a sensitivity of 40%, specificity of 67%, LR+ of 1.21, and LR- of 0.90 for an AHI > 30. A Mallampati class I was only 13% sensitive but 92% specific for an AHI < 5, with LR+ of 1.63 and LR- 0.90. CONCLUSIONS: Mallampati class is associated with AHI but does not significantly modify likelihood of severe OSA or absence of OSA. As such, it is of limited use to "rule in" severe OSA or "rule out OSA" in the sleep clinic population.

Respiratory responses to acute intermittent hypoxia and hypercapnia in awake rats.

This article deals with the recognition of early changes in the breathing pattern, in response to acute intermittent stimuli in awake rats. Two different types of stimuli were given: 9% hypoxia in N(2) and 10% hypercapnia in O(2). Animals were exposed to 3 consecutive cycles consisting of 3-min stimulus period separated by 8-min normoxic recovery intervals. Features of the breathing pattern, such as respiratory frequency, tidal volume, minute ventilation, inspiration and expiration times, peak inspiratory and expiratory flows, were measured by whole body plethysmography. The data were analyzed with the use of pattern recognition methods. We conclude that the overall respiratory changes were rather slight. However, computerized analysis using a k-nearest neighbor decision rule (k-NN) allowed for a good recognition of the respiratory responses to the stimuli. The misclassification rate (E(r)) varied from 5 to 10%. After feature selection, E(r) decreased below 1%. The k-NN classifier differentiated correctly also the type of intermittent stimulus. Our experimental results demonstrate usefulness of pattern recognition algorithms in studying respiratory effects in biological models.

Effects of low and high levels of moderate hypoxia on anaerobic energy release during supramaximal cycle exercise.

The purpose of this study was to investigate whether hypoxia can alter anaerobic energy release during supramaximal exercise. Seven male subjects performed 12 submaximal cycling tests to establish the relationship between workload and O2 demand. The subjects also performed 40 s Wingate tests (WT) under normoxia (room air), two levels of moderate hypoxia of 16.4% O2 and 12.7% O2. We measured the power output and oxygen uptake (VO2) during each test and estimated the O2 demand, O2 deficit and percentage of anaerobic energy release (%AnAER). These data were analyzed for each 20 s interval. At all intervals, there were no differences in Pmean per body mass (BM)(-1), O2 demand per BM(-1) or O2 deficit per BM(-1) among the three O2 conditions. However, under hypoxia of 12.7%, VO2 per BM(-1) was significantly decreased and %AnAER was significantly increased in the late phase (20-40 s) of the WT, compared to normoxia (P<0.05). There were no such significant differences between normoxia and hypoxia of 16.4%. Thus, the present results show that the degree of hypoxia affects the magnitude of the hypoxia-induced increase in anaerobic energy release in the late phase of the WT and suggest that certain degrees of hypoxia induce significant increases in the amount of anaerobic energy released, compared to normoxia.

Significance of hypoxemia screening in candidates for liver transplantation: our experience.

Hepatopulmonary syndrome (HPS) is recognized as one of the causes of hypoxemia in patients with chronic liver disease. This complication is responsible for increased mortality and increased perioperative risk in liver transplantation candidates. Recent data from the literature suggest extending the screening for HPS to all candidates for liver transplantation. The aim of this retrospective study was to evaluate the incidence of hypoxemia among a population of patients awaiting liver transplantation. Using pulse oximetry as a screening tool for hypoxemia, 39 of 198 patients (20%) were hypoxemic. The results of this study confirmed the importance of screening for hypoxemia among patients awaiting liver transplantation. In these patients, a more accurate evaluation of respiratory function should be performed to confirm or exclude the diagnosis of HPS.

Exercise training improves lung gas exchange and attenuates acute hypoxic pulmonary hypertension but does not prevent pulmonary hypertension of prolonged hypoxia.

Our laboratory has previously shown an attenuation of hypoxic pulmonary hypertension by exercise training (ET) (Henderson KK, Clancy RL, and Gonzalez NC. J Appl Physiol 90: 2057-2062, 2001), although the mechanism was not determined. The present study examined the effect of ET on the pulmonary arterial pressure (Pap) response of rats to short- and long-term hypoxia. After 3 wk of treadmill training, male rats were divided into two groups: one (HT) was placed in hypobaric hypoxia (380 Torr); the second remained in normoxia (NT). Both groups continued to train in normoxia for 10 days, after which they were studied at rest and during hypoxic and normoxic exercise. Sedentary normoxic (NS) and hypoxic (HS) littermates were exposed to the same environments as their trained counterparts. Resting and exercise hypoxic arterial P(O2) were higher in NT and HT than in NS and HS, respectively, although alveolar ventilation of trained rats was not higher. Lower alveolar-arterial P(O2) difference and higher effective lung diffusing capacity for O2 in NT vs. NS and in HT vs. HS suggest ET improved efficacy of gas exchange. Pap and Pap/cardiac output were lower in NT than NS in hypoxia, indicating that ET attenuates the initial vasoconstriction of hypoxia. However, ET had no effect on chronic hypoxic pulmonary hypertension: Pap and Pap/cardiac output in hypoxia were similar in HS vs HT. However, right ventricular weight was lower in HT than in HS, although Pap was not different. Because ET attenuates the initial pulmonary vasoconstriction of hypoxia, development of pulmonary hypertension may be delayed in HT rats, and the time during which right ventricular afterload is elevated may be shorter in this group. ET effects may improve the response to acute hypoxia by increasing efficacy of gas exchange and lowering right ventricular work.

Nocturnal hypoxia is associated with silent cerebrovascular disease in a high-risk Japanese community-dwelling population.

BACKGROUND: Sleep-disordered breathing (SDB) is recognized as a risk factor for cerebrovascular disease. The objective of this study was to investigate the relationship between nocturnal hypoxia and silent cerebral infarct (SCI) in the general population. METHODS: In the 2001 annual health check in Nishiarita, Japan, 170 individuals at high risk were screened who met more than three of the following criteria: high blood pressure, hypercholesterolemia, left ventricular hypertrophy by electrocardiography, hemoglobinA(1)c >6.5%, proteinuria, central obesity, heavy smoking habit, heavy drinking, and family history of stroke. Overnight pulse oximetry, brain magnetic resonance imaging, and carotid/cardiac ultrasonography were performed in 146 (mean age 67.4 +/- 9.0 years) of the 170 individuals in whom pulse oximetry was successfully performed. RESULTS: Subjects were classified into a nocturnal hypoxia group (n = 36) and a nonhypoxia group (n = 110) based on a 3% oxygen desaturation index (ODI) 5.6 times per hour during sleep (highest quartile) by pulse oximetry. The presence of silent cerebral infarct (SCI) (57% v 35%, P = .03) was significantly higher in the hypoxia group than in the nonhypoxia group. The number of SCI was positively correlated with age (r = 0.23, P < .01), systolic blood pressure (r = 0.196, P < .05), and 3% ODI (r = 0.318, P < .001). Even after adjustment for confounding factors using logistic regression analysis, nocturnal hypoxia (odds ratio = 2.2, 95% confidence interval = 1.10 to 5.30, P = .026) as well as systolic blood pressure and age (10-year increase: odds ratio = 1.22, 95% confidence interval 1.00 to 1.48, P = .048) were independently associated with SCI in the study subjects. CONCLUSIONS: Based on the study results, SDB assessed by overnight pulse oximetry was associated with silent cerebral disease in a high-risk, community-dwelling Japanese population.

Markers of endothelial dysfunction and severity of hypoxaemia in the Eisenmenger syndrome.

Endothelial dysfunction has been reported in hypoxaemic patients with the Eisenmenger syndrome, but a direct correlation between levels of endothelial markers and the severity of hypoxaemia has not been explored. With this in mind, we compared the levels in the plasma of tissue-type plasminogen activator, thrombomodulin, and von Willebrand factor in 25 patients with the Eisenmenger syndrome. They had a median age of 31 years, and were divided into 2 groups according to their recent clinical history. Thus, 18 patients were stable, being in functional class II or III, seen as outpatients, and having peripheral saturations of oxygen of 89 plus or minus 5 percent. In contrast, 7 patients were unstable, showing episodes of symptoms placing them in functional class IV, requiring care in hospital, and manifesting saturations of oxygen of 77 plus or minus 5 percent. We were able to follow 12 patients, 8 who were stable and 4 unstable, for 24 months. At baseline, levels of von Willebrand factor were higher in the unstable patients when compared to those who were stable, at 142 plus or minus 29 and 110 plus or minus 25 units per decilitre, respectively (p equal to 0.013). This correlated positively with oxygen desaturation (p less than 0.020). The structural abnormalities also correlated positively with the magnitude of hypoxaemia (p less than 0.020). Levels remained higher in the unstable patients throughout the period of follow-up (p equal to 0.006). Tissue-type plasminogen activator was also increased, at 14.3 plus or minus 8.4 versus 6.5 plus or minus 2.7 nanograms per millilitre in controls (p less than 0.001), whereas thrombomodulin was decreased, with values of 14.4 versus 34.6 nanograms per millilitre in controls (p for median values of less than 0.001). There was no correlation with saturations of oxygen. We conclude that measurement of von Willebrand factor, as compared with tissue-type plasminogen activator and thrombomodulin, will prove a better marker of endothelial response to hypoxaemia in patients with the Eisenmenger syndrome.

Tyrosine hydroxylase expression and activity in the rat brain: differential regulation after long-term intermittent or sustained hypoxia.

Tyrosine hydroxylase, a hypoxia-regulated gene, may be involved in tissue adaptation to hypoxia. Intermittent hypoxia, a characteristic feature of sleep apnea, leads to significant memory deficits, as well as to cortex and hippocampal apoptosis that are absent after sustained hypoxia. To examine the hypothesis that sustained and intermittent hypoxia induce different catecholaminergic responses, changes in tyrosine hydroxylase mRNA, protein expression, and activity were compared in various brain regions of male rats exposed for 6 h, 1 day, 3 days, and 7 days to sustained hypoxia (10% O(2)), intermittent hypoxia (alternating room air and 10% O(2)), or normoxia. Tyrosine hydroxylase activity, measured at 7 days, increased in the cortex as follows: sustained > intermittent > normoxia. Furthermore, activity decreased in the brain stem and was unchanged in other brain regions of sustained hypoxia-exposed rats, as well as in all regions from animals exposed to intermittent hypoxia, suggesting stimulus-specific and heterotopic catecholamine regulation. In the cortex, tyrosine hydroxylase mRNA expression was increased, whereas protein expression remained unchanged. In addition, significant differences in the time course of cortical Ser(40) tyrosine hydroxylase phosphorylation were present in the cortex, suggesting that intermittent and sustained hypoxia-induced enzymatic activity differences are related to different phosphorylation patterns. We conclude that long-term hypoxia induces site-specific changes in tyrosine hydroxylase activity and that intermittent hypoxia elicits reduced tyrosine hydroxylase recruitment and phosphorylation compared with sustained hypoxia. Such changes may not only account for differences in enzyme activity but also suggest that, with differential regional brain susceptibility to hypoxia, recruitment of different mechanisms in response to hypoxia will elicit region-specific modulation of catecholamine response.

Fructose feeding and intermittent hypoxia affect ventilatory responsiveness to hypoxia and hypercapnia in rats.

We hypothesized that, in male rats, 10% fructose in drinking water would depress ventilatory responsiveness to acute hypoxia (10% O2 in N2) and hypercapnia (5% CO2 in O2) that would be depressed further by exposure to intermittent hypoxia. Minute ventilation (Ve) in air and in response to acute hypoxia and hypercapnia was evaluated in 10 rats before fructose feeding (FF), during 6 wk of FF, and after FF was removed for 2 wk. During FF, five rats were exposed to intermittent air and five to intermittent hypoxia for 13 days. Six rats given tap water acted as control and were exposed to intermittent air and subsequently intermittent hypoxia. In FF rats, plasma insulin levels increased threefold in the rats exposed to intermittent hypoxia and during washout returned to levels observed in rats exposed to intermittent air. During FF, ventilatory responsiveness to acute hypoxia was depressed because of decreased tidal volume (Vt) responsiveness. During washout, Ve decreased as a result of decreased Vt and frequency of breathing, and the ventilatory responsiveness to hypoxia in intermittent hypoxia rats did not recover. In all rats, the ventilatory responses to hypercapnia were decreased during FF and recovered after washout because of an increased Vt responsiveness. In the control group, hypoxic responsiveness was not depressed after intermittent hypoxia and was augmented after washout. Thus FF attenuated the ventilatory responsiveness of conscious rats to hypoxia and hypercapnia. Intermittent hypoxia interacted with FF to increase insulin levels and depress ventilatory responses to acute hypoxia that remained depressed during washout.