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Background: Food insecurity is a major public health concern in the United States, particularly for pregnant and postpartum individuals. In 2020, ∼13.8 million (10.5%) U.S. households experienced food insecurity. However, the association between food security and pregnancy outcomes in the United States is poorly understood., Purpose: The purpose of this review was to critically appraise the state of the evidence related to food insecurity as a determinant of health within the context of pregnancy in the United States. We also explored the relationship between food insecurity and pregnancy outcomes., Methods: PubMed, CINAHL, Web of Science, and Food and Nutrition Science databases were used. The inclusion criteria were peer-reviewed studies about food (in)security, position articles from professional organizations, and policy articles about pregnancy outcomes and breastfeeding practices. Studies conducted outside of the United States and those without an adequate definition of food (in)security were excluded. Neonatal health outcomes were also excluded. Included articles were critically appraised with the STROBE and Critical Appraisal Skills Program checklists., Results: Nineteen studies met the inclusion criteria. Inconsistencies exist in defining and measuring household food (in)security. Pregnant and postpartum people experienced several adverse physiological and psychological outcomes that impact pregnancy compared with those who do not. Intersections between neighborhood conditions and other economic hardships were identified. Findings regarding the impact of food insecurity on breastfeeding behaviors were mixed, but generally food insecurity was not associated with poor breastfeeding outcomes in adjusted models., Conclusion: Inconsistencies in definitions and measures of food security limit definitive conclusions. There is a need for standardizing definitions and measures of food insecurity, as well as a heightened awareness and policy change to alleviate experiences of food insecurity., Competing Interests: No competing financial interests exist., (© Veronica C. Pasha et al., 2024; Published by Mary Ann Liebert, Inc.)

Background: The COVID-19 pandemic had its first peak in the United States between April and July of 2020, with incidence and prevalence rates of the virus the greatest in the northeastern coast of the country. At the time of study implementation, there were few studies capturing the perspectives of nurses working the frontlines of the pandemic in any setting as research output in the United States focused largely on treating the disease., Objective: The purpose of this study was to capture the perspectives of nurses in the United States working the frontlines of the COVID-19 pandemic's first wave. We were specifically interested in examining the impact of the pandemic on nurses' roles, professional relationships, and the organizational cultures of their employers., Design: We conducted an online qualitative study with a pragmatic design to capture the perspectives of nurses working during the first wave of the United States COVID-19 pandemic. Through social networking recruitment, frontline nurses from across the country were invited to participate. Participants provided long form, text-based responses to four questions designed to capture their experiences. A combination of Latent Dirichlet Allocation--a natural language processing technique--along with traditional summative content analysis techniques were used to analyze the data., Setting: The United States during the COVID-19 pandemic's first wave between May and July of 2020., Results: A total of 318 nurses participated from 29 out of 50 states, with 242 fully completing all questions. Findings suggested that the place of work mattered significantly in terms of the frontline working experience. It influenced role changes, risk assumption, interprofessional teamwork experiences, and ultimately, likelihood to leave their jobs or the profession altogether. Organizational culture and its influence on pandemic response implementation was a critical feature of their experiences., Conclusions: Findings suggest that organizational performance during the pandemic may be reflected in nursing workforce retention as the risk for workforce attrition appears high. It was also clear from the reports that nurses appear to have assumed higher occupational risks during the pandemic when compared to other providers. The 2020 data from this study also offered a number of signals about potential threats to the stability and sustainability of the US nursing workforce that are now manifesting. The findings underscore the importance of conducting health workforce research during a crisis in order to discern the signals of future problems or for long-term crisis response., Tweetable Abstract: Healthcare leaders made the difference for nurses during the pandemic. How many nurses leave their employer in the next year will tell you who was good, who wasn't., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA) has revolutionized the diagnostic approach to mediastinal diseases. Lesions located lateral to the pulmonary artery (trans-PA, Station 5), or in the lumen of the PA (intra-PA) are in the 'blind-spot' of EBUS., Objectives: We describe a case series where EBUS guided trans-pulmonary or intra-pulmonary aspiration (EBUS-TIPNA) was used for diagnosis., Methods: Retrospective analysis of 10 patients who had EBUS-TIPNA over 3 years in 2 centres. The inclusion criteria included patients with station 5 lesions, or intrapulmonary artery lesions, where no other option was possible., Results: The study included 4 males and 6 females, mean age 52 years, with 7 trans-PA and 3 intra-PA lesions. Adequacy was seen in 10/10, and a definitive diagnosis was made in 9/10 patients. There were no procedure-related complications., Conclusion: EBUS-TIPNA can be done as a safe and successful procedure and adds to the armamentarium of Convex Probe-EBUS (CP-EBUS), in carefully selected patients., (© 2018 John Wiley & Sons Ltd.)

Background: Prolonged air leak (PAL) is a life-threatening condition that can present either as bronchopleural fistula, or alveolar-pleural fistula (APF). Although numerous bronchoscopic treatments are described, they are either expensive, not widely available in the developing world or have limited success. We describe our experience with a novel customized endobronchial silicone blocker (CESB) for PAL treatment., Methods: This is a retrospective study of PAL patients who underwent CESB placement. The air leak was localized using a balloon occlusion test. The CESB was uniquely designed by molding silicone stent pieces into a conical shape, deployed with rigid bronchoscopy into the appropriate segment, and reinforced with cyanoacrylate glue to prevent migration. In patients with APF, pleurodesis was performed after leak resolution to prevent recurrence. Following this, the CESB was removed after 6 weeks., Results: Forty-nine CESBs were placed in 31 patients (25 male individuals, 6 female individuals) with mean age of 49.7±19.7 years. The PALs included APF (n=16), bronchopleural fistula (n=14), and airway-mediastinal fistula (n=1). The average diameter of the CESB used was 7.9±2.9 mm. There was resolution of the PAL in 26 of 31 patients (84%). The CESB migrated in 5 patients with no adverse events. Pleurodesis was performed in 13 of 16 patients with APF, to prevent recurrence. No other significant complications were observed., Conclusions: CESBs represent a safe, effective, and innovative approach in the management of PAL. They should be considered in patients who are not surgical candidates, fail surgery, or those who have a recurrence following surgery.

Background: Current histopathological classification and TNM staging have limited accuracy in predicting survival and stratifying patients for appropriate treatment. The goal of the study is to determine whether the expression pattern of functionally important regulatory proteins can add additional values for more accurate classification and prognostication of non-small lung cancer (NSCLC)., Methods: The expression of 108 proteins and phosphoproteins in 30 paired NSCLC samples were assessed using Protein Pathway Array (PPA). The differentially expressed proteins were further confirmed using a tissue microarray (TMA) containing 94 NSCLC samples and were correlated with clinical data and survival., Results: Twelve of 108 proteins (p-CREB(Ser133), p-ERK1/2(Thr202/Tyr204), Cyclin B1, p-PDK1(Ser241), CDK4, CDK2, HSP90, CDC2p34, β-catenin, EGFR, XIAP and PCNA) were selected to build the predictor to classify normal and tumor samples with 97% accuracy. Five proteins (CDC2p34, HSP90, XIAP, CDK4 and CREB) were confirmed to be differentially expressed between NSCLC (n=94) and benign lung tumor (n=19). Over-expression of CDK4 and HSP90 in tumors correlated with a favorable overall survival in all NSCLC patients and the over-expression of p-CREB(Ser133) and CREB in NSCLC correlated with a favorable survival in smokers and those with squamous cell carcinoma, respectively. Finally, the four proteins (CDK4, HSP90, p-CREB and CREB) were used to calculate the risk score of each individual patient with NSCLC to predict survival., Conclusion: In summary, our data demonstrated a broad disturbance of functionally important regulatory proteins in NSCLC and some of these can be selected as clinically useful biomarkers for diagnosis, classification and prognosis.

Dedicated linear endobronchial ultrasound (EBUS) is an established modality in sampling central pulmonary lesions, mediastinal and hilar lymph nodes to diagnose and stage lung malignancies as well as evaluate a number of inflammatory conditions. In addition, power Doppler modality of EBUS allows for vascular evaluation. We describe a case where EBUS visualized a submucosal lesion within a vascular malformation, which was eventually proven to be a carcinoid tumor. Computed tomographic scan of the chest failed to differentiate the 2 structures and bronchoscopy showed no endobronchial component. This case underscores the added diagnostic capabilities of endobronchial Doppler ultrasonography. We suggest considering EBUS in investigating central opacities associated with vascular features within the lung parenchyma when technically feasible.

Sphingomyelin (SM), a major sphingolipid in the lipid raft microdomains of the cell membrane, is synthesized by plasma membrane-bound sphingomyelin synthase 2 (SMS2). SMS2 is required for the maintenance of plasma membrane microdomain fluidity and receptor-mediated responses to inflammation in macrophages. However, the exact mechanism of SMS2 activation in endothelial barrier disruption and lung injury is not fully understood. To define the role of SMS activation in lung injury, we hypothesized that the inhibition of SM synthesis may provide protection against acute lung injury (ALI) by preserving endothelial barrier function. Using SMS2-silencing RNA (siRNA) treatment in human pulmonary endothelial cells (HPAECs) and tricyclodecan-9-yl-xanthogenate (D609), a competitive inhibitor of SMS, and phosphatidylcholine-specific phospholipase C in a murine model of bacterial LPS injury, we studied the role of sphingomyelin synthesis in ALI. Results show that pretreating mice with D609 significantly attenuated LPS-induced lung injury, as measured by a significant decrease in wet to dry ratio, bronchoalveolar lavage fluid cell and protein counts, and myeloperoxidase activity in lung tissue. Similarly, LPS-induced endothelial barrier disruption was significantly reduced in HPAECs pretreated with D609 or SMS2 siRNA, as demonstrated by an increase in paracellular integrity on an FITC-dextran assay, by the inhibition of LPS-induced stress fibers, and by the formation of cortical actin rings and lamellipodia at the periphery. These results indicate that D609 attenuates LPS-mediated endothelial barrier dysfunction and lung injury in mice through inhibition of SMS, suggesting a novel and essential role of SMS inhibition in modulating endothelial barrier integrity via actin cytoskeletal activation, with a potential therapeutic role in ALI.

Endobronchial stents have been used occasionally to treat benign conditions such as tracheobronchomalacia (TBM). This report describes a unique case of a patient with crescentic TBM in whom Dynamic Y stent was placed on 2 separate occasions to control symptoms and resulted in identical posterior wall stent fractures within a year of stent placement, both times. A silicone Y stent was substituted for the dynamic stent, and it has been effective in controlling symptoms for 9 months without complications. A literature review of cases of fractured Dynamic Y stents is made and factors affecting the choice of stent type for crescentic TBM are explored.

Chronic Obstructive Pulmonary Disease (COPD) frequently has a significant impact on patients' everyday activity. Because of this, accurate measurement of daily activity is of particular interest. Although accelerometers are an objective means of measuring daily activity, these devices sense vibrations and erroneously score motor vehicle travel (MVT) as moderate physical activity. It is the objective of this study to develop a new method to analyze accelerometry data that would accurately classify MVT as non-acceleration, or sitting/standing. As sitting/standing has a different pattern of count-to-count variability than walking, we hypothesized that a rolling standard deviation (RSD), which is a measurement of volatility in the data, would more accurately classify periods of MVT than analysis based on activity counts alone. Twenty-two subjects with COPD were studied. A training set of 15% of the dataset was used to establish an RSD-threshold during MVT based on the upper 95%-confidence interval. The accuracy of the RSD thresholds were tested and presented as sensitivity, specificity and receiver operating curves. Results demonstrated high sensitivity and specificity suggesting that the RSD not only accurately classified MVT, but had a low rate of misclassification. The RSD analysis scored more MVT as sitting/standing than assessment by VMU alone. The accuracy of accelerometers to define the profile of daily activity in sedentary populations, such as those with COPD, is greatly improved.

Background: The frequency of oxygen desaturation during daily activities in chronic obstructive pulmonary disease (COPD) is poorly defined. The BODE index predicts survival in COPD. The purpose of this study was to determine the relationship between BODE scores and oxygen saturation during daily activities., Methods: Seventy-eight patients with COPD (FEV(1) = 37%) underwent ambulatory oximetry and activity monitoring. We defined four activity categories: Walking, Slow-Intermittent-Walking (SIW), Active-Not-Walking (ANW), and Rest. We quantified oxygen desaturation during activity using a desaturation index (DSI = % time oxygen saturation <90%). BODE scores were categorized into three groups: group I (0-3), II (4-6), and III (7-10)., Results: The percentage of patients demonstrating oxygen desaturation (DSI ≥ 10%) during each activity was 55% for Walking, 35% for SIW, 15% for ANW, and 28% for Rest. There was a strong association between BODE score and desaturation for Walking and SIW. During Walking, 21, 44, and 86% of patients in BODE groups I, II, and III, respectively, demonstrated desaturation. The DSI for Walking and SIW was increased in patients in BODE groups II and III compared to group I (P < 0.006, P < 0.007, respectively). BODE score was also linked to long-term oxygen therapy (LTOT) usage; the majority of patients not on LTOT (89%) had a BODE score <7. The majority of patients on LTOT (84%) demonstrated desaturation during Walking, but 42% of patients not on LTOT also demonstrated desaturation. In this subgroup of patients not on LTOT, all patients with a BODE score ≥ 7 demonstrated desaturation during Walking., Conclusions: The link between the BODE index and oxygen desaturation during daily activities suggests that desaturation is linked to disease severity. Our data suggest that patients with a BODE score ≥ 7 should be evaluated for desaturation during daily activities. Use of the BODE index to screen for exertional desaturation may have value as a tool that can lead to the earlier identification of patients who may be candidates for LTOT.

Sphingomyelin synthase (SMS) catalyzes the synthesis of sphingomyelin (SM) and is required for maintenance of plasma membrane microdomain fluidity. Of the two isoforms of mammalian SMS, SMS1 is mostly present in the trans-Golgi apparatus, whereas SMS2 is predominantly found at the plasma membrane. SMS2 has a role in receptor mediated response to inflammation in macrophages, however, the role of SMS2 in vascular permeability, pulmonary edema, and lung injury have not been investigated. To define the role of SMS activation in lung injury, we utilized a lipopolysaccharide (LPS)-induced lung edema model. SMS activity was measured and correlated with the severity of lung injury. Within 4 h of LPS treatment, SMS activity was increased significantly and remained upregulated up to 24 h. Comparison of LPS-induced lung injury in SMS2 knockout (SMS2(-/-)) and wild-type littermate control mice showed that inflammation, cytokine induction, and lung injury were significantly inhibited in SMS2(-/-) mice. Our results suggest that a deficiency of SMS2 can diminish the extent of pulmonary edema and lung injury. Furthermore, we show that depletion of SMS2 was sufficient to decrease MAP kinase-JNK activation, severity of LPS-induced pulmonary neutrophil influx, and inflammation, suggesting a novel role of SMS2 activation in lung injury.

Malignant primary tracheal tumors are extremely rare. The most common malignant primary tracheal tumors are squamous cell carcinoma and adenoid cystic carcinomas. In this brief report, we describe a patient who presented with a primary papillary squamous cell carcinoma in-situ at multiple areas in the trachea with a significant airway obstruction. Our case was successfully managed using a combination of electrocautery and argon photocoagulation for endotracheal ablation of the tumor and adjuvant external beam radiotherapy.

Purpose: Patients with chronic obstructive pulmonary disease with a low profile of daily activity have poor health outcomes. Although walking is a common activity, it may not be the most relevant physical activity to measure in this population. It was the purpose of this study to determine the accelerometer-defined thresholds that discriminate a range of daily activities and use these thresholds to assess activity profiles among stages of disease severity., Methods: Subjects with chronic obstructive pulmonary disease (N = 57) completed a standardized sequence of activities that comprised sitting, standing, and walking while wearing an accelerometer on the waist and an actigraph on the wrist. Using a calibration procedure, accelerometer output was translated into speeds. Speeds were estimated for each interval in the testing sequence. Walking and nonacceleration thresholds were derived from the intervals to define 4 activity categories: walking, slow/intermittent walking, active-not-walking, and rest. Subjects wore the 2 devices for 2 days. Accelerometer output was then classified into 1 of the activity categories. Percent time spent in activity categories and speeds generated were compared among Global Initiative for Obstructive Lung Disease (GOLD) stages., Results: The waist-worn accelerometer accurately estimated speeds. Speed thresholds for walking and nonacceleration were 0.70 mph and 0.25 mph, respectively. Among GOLD stages, those with more severe obstruction spent less time in the walking categories and generated slower speeds., Conclusions: The accuracy of these methods to detect a range of physical activities enhances the utility of accelerometers in comparing daily activity in sedentary populations. Measurements of the more subtle activities offer an appealing new area of study.

Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity and mortality. Its possible association with obstructive sleep apnea is a major cause of concern for clinicians. As the prevalence of both COPD and sleep apnea continues to rise, further investigation of this interaction is needed. In addition, COPD patients are at risk for hypoventilation during sleep due to the underlying respiratory dysfunction. In this study, 13 COPD subjects and 13 non-COPD control subjects were compared for the presence and severity of obstructive sleep apnea and nocturnal hypoventilation. All 26 subjects had presented to a sleep clinic and showed no signs of daytime hypoxemia. After matching for BMI and age, COPD subjects had a similar prevalence of sleep apnea with a lower degree of severity compared to the control subjects. However, less severe events, such as RERA, occurred at similar rates between the two groups. There was no significant difference between groups in the magnitude of oxyhemoglobin desaturation during sleep. Interestingly, severity and presence of nocturnal hypoxemia correlated with that of sleep apnea in the control group, but not in the COPD subjects. In conclusion, COPD without daytime hypoxemia was not a risk factor for sleep apnea or nocturnal hypoventilation in this study.

Post-obstructive pneumonia is the result of airway obstruction, commonly due to lung cancer. The majority of patients with lung cancer are non-operable and incurable at initial presentation. The clinical course of these patients is steadily downhill with complicating events such as post-obstructive pneumonia, respiratory failure, pleural effusion, and severe debilitation. Non-invasive conventional options for post-obstructive pneumonia include broad-spectrum antibiotics, combined with attempts at relieving the obstruction using radiation therapy. There is scant literature on the natural course of post-obstructive pneumonia, disease resolution, and optimal treatment. With the recent surge in technologic advances in interventional pulmonology, multiple airway recanalizaton options are now available. In this paper, we describe the causes of post-obstructive pneumonia, and the role of interventional pulmonary procedures in -establishing an open airway.

The effect of alkaline stress, or an increase in extracellular pH (pHext), on cell viability is poorly defined. Human pulmonary artery endothelial cells (HPAEC) were subjected to alkaline stress using different methods of increasing pHext. Viability and mode of cell death following alkaline stress were determined by assessing nuclear morphology, ultrastructural features, and caspase-3 activity. Incubation of monolayers in media set to different pHext values (7.4-8.4) for 24-h induced morphological changes suggesting apoptosis (35-45% apoptotic cells) following severe alkaline stress. The magnitude of apoptosis was related to the severity of alkaline stress. These findings were confirmed with an assessment of ultrastructural changes and caspase-3 activation. While there was no difference in the intracellular calcium level ([Ca(2+)](i)) in monolayers set to pHext 7.4 versus 8.4 following the first hour of alkaline stress, blockade of calcium uptake with the chelator, EGTA, potentiated the magnitude of apoptosis under these conditions. Potentiation of apoptosis was reduced by calcium supplementation of the media. Finally, alkaline stress was associated with an increase in intracellular pH. This is the first report of apoptosis following alkaline stress in endothelial cells in the absence of other cell death stimuli.

Tuberculosis (TB) persists as a worldwide health crisis. Nearly one third of the world's population is infected with TB and it remains a critical public health issue. In the past two decades, international efforts have focused on improving identification of those infected with TB as well as supporting molecular microbiologists in developing better diagnostic techniques. Furthermore, implementation of programs such as directly observed therapy have assisted more patients in receiving and completing therapy. This review aims to identify some of the more relevant findings in the field of TB over the past few years with a special emphasis on TB in urban communities.

We investigated the effect of altered extracellular pH, mitochondrial function, and ATP content on development of apoptosis in human pulmonary artery endothelial cells after treatment with staurosporine (STS). STS produced a concentration- and time-dependent increase in caspase-3 activity in pH 7.4 medium that reached a peak at 6 h. The increase in caspase activity was associated with significant DNA fragmentation. Fluorescent imaging of treated monolayers in pH 7.4 medium with Hoechst-33342-propidium iodide demonstrated a large percentage of apoptotic cells ( approximately 40%) with no evidence of necrosis. Caspase activity, DNA fragmentation, and percentage of apoptotic cells were reduced after STS treatment in acidic media (pH 7.0 and 6.6). The Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-AM inhibited STS-induced apoptosis, whereas the rise in intracellular Ca2+concentration in STS-treated cells in pH 7.4 medium was reduced in pH 7.0 medium. These results suggest that one mechanism for inhibitory effects of acidosis may be a pH-induced alteration in Ca2+ signaling. Treatment with STS in the presence of oligomycin (10 microM), an inhibitor of the mitochondrial F(0)F(1)-ATPase, in glucose-free media abolished caspase activation and DNA fragmentation in association with severe ATP depletion ( approximately 2% of control cells). Imaging demonstrated a change in the mode of cell death from apoptosis to necrosis under these conditions. This change was linked to the level of ATP depletion, because STS treatment in the absence of glucose or the presence of oligomycin in media with glucose still leads to apoptosis in the presence of only moderate ATP depletion. These results demonstrate that pH, mitochondrial function, and ATP supply are important variables that regulate STS-induced apoptosis in human pulmonary artery endothelial cells.

We investigated the effect of changes in intracellular pH (pHi) and Na/H antiport activity on intracellular oxidant production in human pulmonary artery endothelial cells (HPAEC) following disruption of cellular metabolism. Oxidant production was measured with oxidant-sensitive probes (2',7'-dichlorofluorescein diacetate [H2DCF], dihydroethidium [DHE]) following treatment with inhibitors of mitochondrial electron transport and glycolysis (antimycin/2-deoxyglucose, A/D). A/D treatment increased oxidant production in a dose-dependent fashion over 2 hours. Omission of 2-deoxyglucose did not alter the magnitude of oxidant production. Inhibition at more proximal sites in the mitochondrial electron transport chain inhibited oxidant production. These data suggested that the mitochondrial electron transport chain was the source of oxidant production. Fluorescent imaging experiments confirmed the mitochondrial origin of the increased oxidant production under these conditions. Maneuvers that reduced pHi and inhibited Na/H exchange (acidosis, specific Na/H exchange inhibitors) attenuated oxidant production, whereas maneuvers that raised pHi (monensin) potentiated oxidant production. The results with the pH-insensitive probe (DHE) confirmed that oxidant production was pH-dependent. Oxidant production preceded significant loss of cell viability at 6 h following A/D treatment. These results demonstrate that oxidant production following inhibition of mitochondrial electron transport in HPAEC is pH-dependent and may contribute to endothelial cell injury by increasing endogenous oxidative stress.

We investigated the role of intracellular pH (pH(i)) and Na/H exchange in cell death in human pulmonary artery endothelial cells (HPAEC) following a metabolic insult (inhibition-oxidative phosphorylation, glycolysis). Metabolic inhibition in medium at pH 7. 4 decreased viability (0-15% live cells) over 6 h. Cell death was attenuated by maneuvers that decreased pH(i) and inhibited Na/H exchange (acidosis, Na/H antiport inhibitors). In contrast, cell death was potentiated by maneuvers that elevated pH(i) or increased Na/H exchange (monensin, phorbol ester treatment) before the insult. HPAEC demonstrated a biphasic pH(i) response following a metabolic insult. An initial decrease in pH(i) was followed by a return to baseline over 60 min. Maneuvers that protected HPAEC and inhibited Na/H exchange (acidosis, Na(+)-free medium, antiport inhibitors) altered this pattern. pH(i) decreased, but no recovery was observed, suggesting that the return of pH(i) to normal was mediated by antiport activation. Although Na/H antiport activity was reduced (55-60% of control) following a metabolic insult, the cells still demonstrated active Na/H exchange despite significant ATP depletion. Phorbol ester pretreatment, which potentiated cell death, increased Na/H antiport activity above the level observed in monolayers subjected to a metabolic insult alone. These results demonstrate that HPAEC undergo a pH-dependent loss of viability linked to active Na/H exchange following a metabolic insult. Potentiation of cell death with phorbol ester treatment suggests that this cell death pathway involves protein kinase C-mediated phosphorylation events.

Background: The benefits of long-term oxygen supplementation in COPD patients with hypoxemia are well established. The standard approach to prescribing oxygen uses a static assessment of oxygen requirements in a hospital or clinic setting. The assumption behind this approach is that patients will maintain a "therapeutic" hemoglobin oxygen saturation (SpO2) in the outpatient setting. We questioned the validity of this assumption, and hypothesized that many patients may demonstrate significant oxygen desaturation during normal activities of daily living. STUDY DESIGN, METHODS, AND MEASUREMENTS: We determined if oxygen supplementation maintained a therapeutic SpO2 level in patients with COPD (n = 27), using the technique of ambulatory oximetry monitoring (AOM). AOM consisted of using a portable oximeter to monitor SpO2, pulse rate, and patient activity while patients were engaged in normal activities of daily living over an extended time period (approximately 18 h). The portable oximeter collected and stored these data every 15 s over the monitored time period. Each AOM recording was manually scored for desaturation events and other key variables, including average SpO2 over the monitoring period, the average number of desaturation events per hour, and the percentage of monitored time deleted secondary to artifacts., Setting: University-affiliated Veterans Affairs Medical Center., Patients: All subjects were patients with stable COPD with no recent history of hospitalization or exacerbation of their lung disease., Results: This cohort of patients demonstrated a surprising frequency of desaturation below the recommended target SpO2 value (90%), which averaged approximately 25% of AOM recording time. There was wide variability among patients in the percentage of time SpO2 was below the target value (range, 3 to 67% of AOM recording time). Motion artifact on the AOM recordings was not a major problem; an average of 8% of the recording time was deleted secondary to artifacts in this patient cohort., Conclusions: The results demonstrate that AOM is feasible and accurate with an acceptable level of motion artifact. These results also suggest that the standard approach for prescribing oxygen may lead to subtherapeutic SpO2 values in the outpatient setting. AOM holds promise as a tool to monitor the adequacy of oxygen prescriptions in the outpatient setting in patients with lung disease.

Little is known about the effects of prolonged hypoxic exposure on membrane ion transport activity. The Na+/H+ antiport is an ion transport site that regulates intracellular pH in mammalian cells. We determined the effect of prolonged hypoxic exposure on human pulmonary arterial endothelial cell antiport activity, gene expression, and localization. Monolayers were incubated under hypoxic or normoxic conditions for 72 h. Antiport activity was determined as the rate of recovery from intracellular acidosis. Antiport isoform identification and gene expression were determined with RT-PCR and Northern and Western blots. Antiport localization and F-actin cytoskeleton organization were defined with immunofluorescent staining. Prolonged hypoxic exposure decreased antiport activity, with no change in cell viability compared with normoxic control cells. One antiport isoform [Na+/H+ exchanger isoform (NHE) 1] that was localized to the basolateral cell surface was present in human pulmonary arterial endothelial cells. Hypoxic exposure had no effect on NHE1 mRNA transcript expression, but NHE1 protein expression was upregulated. Immunofluorescent staining demonstrated a significant alteration of the F-actin cytoskeleton after hypoxic exposure but no change in NHE1 localization. These results demonstrate that the decrease in NHE1 activity after prolonged hypoxic exposure is not related to altered gene expression. The change in NHE1 activity may have important consequences for vascular function.

Apoptosis may be important in the exacerbation of endothelial cell injury or limitation of endothelial cell proliferation. We have found that extracellular ATP (exATP) and adenosine cause endothelial apoptosis and that the development of apoptosis is linked to intracellular metabolism of adenosine [Dawicki, D. D., D. Chatterjee, J. Wyche, and S. Rounds. Am. J. Physiol. 273 (Lung Cell Mol. Physiol. 17): L485-L494, 1997]. In the present study, we investigated the mechanism of this effect. We found that exATP, adenosine, and the S-adenosyl-L-homocysteine (SAH) hydrolase inhibitor MDL-28842 caused apoptosis and decreased the ratio of S-adenosyl-L-methionine to SAH compared with untreated control cells. Using release of soluble [3H]thymidine as a measure of DNA fragmentation, we found that the effect of adenosine on soluble DNA release was potentiated by coincubation with homocysteine. These results suggest that the mechanism of exATP- and adenosine-induced endothelial cell apoptosis involves inhibition of SAH hydrolase. exATP-induced apoptosis was enhanced by an inhibitor of adenosine deaminase, whereas exogenous adenosine-induced apoptosis was partially inhibited by an adenosine deaminase inhibitor. These results suggest that adenosine deaminase may also be involved in the mechanism of adenosine-induced endothelial cell apoptosis. Adenosine and MDL-28842 caused intracellular acidosis as assessed with the fluorescent probe 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. The cell-permeant base chloroquine prevented adenosine-induced acidosis but not apoptosis. Thus, although intracellular acidosis is associated with adenosine-induced apoptosis, it is not necessary for this effect. We speculate that exATP- and adenosine-induced endothelial cell apoptosis may be due to an inhibition of methyltransferase(s) activity. Purine-induced endothelial cell apoptosis may be important in limiting endothelial cell proliferation after vascular injury.

Bovine (BPAEC) and human (HPAEC) pulmonary artery endothelial cell monolayers were incubated with either ATP, ATP analogues, or UTP, followed by measurement of intracellular pH (pHi) and the rate of recovery from acidosis. ATP increased baseline pHi and the rate of acid recovery in BPAEC. This response was inhibited by the amiloride analogue, methyisobutylamiloride, demonstrating that activation of the Na+/H+ antiport was responsible for the increase in baseline pHi and the recovery from acidosis. This response had the features of both a P2Y and P2U purinergic receptor, based on the responses to a series of ATP analogues and UTP. In contrast, none of the nucleotides had any significant effect on pHi and Na+/H+ antiport activity in HPAEC. This difference in the response to extracellular nucleotides was not due to a difference in ATP metabolism between cell types, since the ectonucleotidase-resistant analogue. ATP gamma S, also had no effect on HPAEC. Analogues of cAMP had no effect on pHi or acid recovery in either cell type. Incubation of BPAEC and HPAEC with the photoaffinity ligand [32P] 8-AzATP indicated that both BPAEC and HPAEC possess an ATP-binding protein of 48 kDa. However, BPAEC exhibited an additional binding protein of 87 kDa. Thus, the contrasting response to extracellular ATP between bovine and human pulmonary artery endothelial cells may be related to differences in the signal transduction pathway leading to antiport activation, including different ATP-binding sites on the cell membrane.

The Na/K pump is critically important in maintenance of cell homeostasis in the face of injury. Little is known about the regulation of endothelial cell Na/K-pump activity. We previously reported that short-term (30-minute) oxidant-induced endothelial cell perturbation increased Na/K-pump activity in intact monolayers of bovine pulmonary artery endothelial cells (BPAECs). In this study we investigated the mechanism of oxidant-induced increases in endothelial Na/K-pump activity, focusing on short-term modulation of alpha1-pump subunit. By using immunofluorescence microscopy and confocal scanning laser microscopy, we found alpha1 subunit on both apical and basal aspects of BPAECs without polarized distribution. Short-term (30-minute) incubation of PAEC monolayers with H2O2 (1 mmol/L) did not change the relative amounts of alpha1 subunit in membrane fractions, as assessed by immunoblotting. Phosphorylation of the alpha1 subunit also was not affected by H2O2 treatment. Because protein kinases have been reported to alter Na/K-pump activity in several tissues and because H2O2 has been reported to increase PKC activity of endothelial cells, we determined the effects of inhibition and activation of protein kinase C (PKC) on Na/K-pump activity quantitated as ouabain-inhibitable uptake of 86Rb. We also determined the effects of PKC activation and inhibition on H2O2-induced increases in Na/K-pump activity. Inhibitors of PKC increased Na/K-pump activity over a 30-minute period in intact monolayers. Inhibition or depletion of PKC did not prevent H2O2-induced increases in pump activity. These results indicate that PKC is an endogenous regulator of pulmonary artery endothelial cell Na/K-pump activity but that the effects of H2O2 are not mediated by activation of PKC or by changes in the expression or phosphorylation of alpha1 subunit.

Little is known about the mechanisms of altered cell membrane function after hyperoxic exposure. We determined the effects of hyperoxic exposure and exogenous oxidant stress with xanthine/xanthine oxidase (X/XO) on Na+/H+ antiport activity. Pulmonary artery endothelial cell monolayers were incubated in 95% O2/5% CO2 (24 to 72 hours) simultaneously with controls placed in 21 % O2/5% CO2. Monolayers were then incubated for 2 hours in MEM with or without X/XO (100 micromol/L X; 0.01 U/ml XO). Antiport activity was determined as the rate of recovery from intracellular acidosis by measurement of intracellular pH (pH,) with 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF). Hyperoxic exposure (72 hours) decreased Na+/H+ antiport activity as compared with that in control monolayers. Exogenous oxidant stress also decreased antiport activity in both control and hyperoxic cells, but this effect was more pronounced in hyperoxic cells at all time points. These changes occurred in the absence of overt cytotoxicity. Incubation with antioxidants (polyethylene glycol-superoxide dismutase (PEG-SOD), PEG-catalase, vitamin E), N-acetylcysteine, or phospholipase A2 (PLA2) inhibitors did not prevent the decrease in antiport activity after hyperoxic exposure. Conditioned medium experiments demonstrated that the diminished antiport activity was not related to release of a soluble mediator after hyperoxic exposure. These findings suggest that the diminished Na+/H+ antiport activity represents a sublethal form of membrane dysfunction that may be a component of the increased endothelial cell susceptibility to injury after hyperoxic exposure.

The fluoroprobe sodiumbinding benzofuran isophthalate (SBFI) is used to measure intracellular cytosolic sodium concentration ([Na]i). A problem with the use of this probe is the difficulty in loading it into cells. ATP reversibly increases membrane permeability of some cells via activation of receptors of the tetrabasic form of ATP (ATP4-). We investigated the effect of ATP-induced membrane permeabilization on loading of the acetoxymethyl ester (AM) form of SBFI (SBFI-AM) into bovine pulmonary arterial endothelial cells. Monolayers were incubated in a series of solutions that reversibly opened pores, loaded the fluoroprobe, and finally sealed the proes. ATP (1-5 mM) or 3'-O-(4-benzoyl)benzoyl-ATP (0.1-1 mM), an analogue 30-100x more specific for ATP4- receptors, was utilized to permeabilize the cell membrane. The signal-to-background ratio of the intracellular SBFI fluorescent signal was used as an indicator of the effectiveness of dye loading. ATP and 3'-O-(4-benzoyl)benzoyl-ATP significantly increased the signal-to-background ratio compared with the values obtained with the standard dye-loading procedure without ATP, indicating that permeabilization increased SBFI-AM entry into the cells. The permeabilization procedure produced a small decrease in cell viability, as determined with a fluorescent viability assay (ethidium dimer uptake), compared with the standard method of loading SBFI-AM. We used the procedure to measure baseline [Na]i and changes in [Na]i after the administration of ouabain (10(-4) M) and monensin (10(-5) M). Baseline [Na]i with this procedure (19.7 +/- 2.7 mM; n = 15 monolayers) was similar to measurements made in other cell types with the standard method of loading the probe. We conclude that 1) the ATP-induced permeabilization technique is an improved dye-loading method for SBFI-AM in endothelial cell monolayers that facilitates measurement of [Na]i and 2) these data suggest the presence of an ATP4 pore-forming mechanism in this cell type.

We determined the effects of oxidant stress by the use of tert-butyl hydroperoxide (t-BOOH) on Na+/H+ exchange in pulmonary artery endothelial cells. Monolayers were exposed to the hydroperoxide, followed by measurement of intracellular pH and the rate of recovery from acidosis by utilizing the pH-sensitive probe 2',7'-bis(carboxyethyl)-5(6)- carboxyfluorescein. t-BOOH (0.4 mM) decreased the rate of acid recovery after a 2-h exposure without evidence of overt cytotoxicity (51Cr-release assay). Glutathione repletion (N-acetyl-L-cysteine) abolished the effect of the hydroperoxide. Lowering intracellular glutathione with buthionine sulfoximine decreased the acid recovery rate at a dose of t-BOOH (0.04 mM) that was not normally associated with a change in this parameter. Preincubation with vitamin E had no protective effect. Dithiothreitol abolished the effect of the hydroperoxide, suggesting oxidation of protein sulfhydryl groups as a mechanism for the altered kinetics of acid recovery. There was no difference in cell buffering capacity between control and treated monolayers. The findings suggest that the decrease in Na+/H+ antiport activity in this model of oxidant stress represents an early perturbation of membrane function and illustrate the role of the glutathione redox system in maintaining the functional integrity of the Na+/H+ antiport in these cells.

Oxidant injury to pulmonary vascular endothelium is an important factor in the pathogenesis of acute lung injury. Oxidant injury to other cell types has been reported to alter the function of Na-K-adenosinetriphophatase (ATPase) an enzyme important in maintenance of cellular ionic homeostasis and in transport of ions across biological membranes. We investigated the effect of H2O2 (0.001-10 mM) or xanthine (X) (15.2 micrograms/ml) plus xanthine oxidase (XO) (0.0153 U/ml) on the Na-K pump activity of cultured bovine pulmonary arterial endothelial cells (PAECs). We used a functional assay, using 86RbCl as a tracer for K+ and expressing Na-K pump activity as ouabain-inhibitable K+ uptake. Our results demonstrate that H2O2 and X/XO stimulate Na-K pump activity of bovine PAECs, an effect prevented by catalase. In addition, we assessed the affinity, number, and turnover of [3H]ouabain binding sites on intact endothelial monolayers and found that H2O2 increased affinity to [3H]ouabain, decreased the number of binding sites, and increased the rate of pump turnover. Influx of 22Na increased in response to a nonlytic concentration of H2O2. Cell injury, as assessed by 51Cr release, adherent cell number, and phase-microscopic morphology, was not observed after 30-min incubations with the lowest dose (1 mM) of H2O2 effective in stimulating Na-K pump activity, or after incubation with X/XO. Na-K pump inhibition by ouabain significantly increased the 51Cr release caused by H2O2 or by X/XO, suggesting that the increase in Na-K pump activity may be a compensatory response to the cellular alterations produced by H2O2. Incubation with H2O2 decreased cell ATP content, an effect which was not prevented by coincubation with ouabain. In summary, these results show that H2O2 increases Na-K pump activity of PAECs, an effect mediated, at least in part, by increased intracellular [Na] and by an increased rate of pump turnover. It is possible that the increased pump activity may be an early marker of endothelial cell perturbation.

The polyene antibiotic amphotericin B has been implicated in vascular injury in human subjects and lung injury in an animal model. Our objective was to determine whether amphotericin B directly injures endothelial cells and to investigate several possible mechanisms of injury. Confluent cultures of bovine endothelial cells were incubated with different concentrations of amphotericin B for varying time periods. Injury was assessed by using a chromium 51 release assay, adherent cell counts, and morphologic changes in the endothelial cell monolayers by phase microscopy. Amphotericin B increased 51Cr release in a dose- and time-dependent fashion. Corresponding to changes in 51Cr release, amphotericin B decreased adherent cell counts and disrupted the monolayers. Incubation with vehicle alone (sodium desoxycholate, 8.2 micrograms/ml) did not alter any of these parameters. Incubation of cells with a dose of antibiotic (1 micrograms/ml), which did not produce overt cell injury, significantly increased membrane permeability to K+ ions and activated the sodium/potassium adenosine triphosphatase (Na/K ATPase). Inhibition of the ATPase at this same antibiotic concentration (1 micrograms/ml) produced endothelial cell injury equivalent to the magnitude of injury observed with high doses of the antibiotic (10 micrograms/ml). In the presence of 10% fetal calf serum, the injury at 24 hours was significantly attenuated. This protective effect could not be attributed to binding of the drug by albumin because varying concentrations of bovine serum albumin in minimal essential medium without other serum constitutents had no effect on the magnitude of injury. Incubation of cells with several exogenous oxygen radical scavengers (dimethylthiourea, catalase, and mannitol) or a decrease in ambient oxygen tension during antibiotic exposure did not alter the magnitude of injury. The results demonstrate that amphotericin B directly injures endothelial cells in a dose- and time-dependent manner and demonstrate the importance of the Na/K ATPase for the maintenance of normal endothelial cell function and viability in response to this form of injury.

The objective of this study was to determine the effects of Na-K-adenosinetriphosphatase (ATPase) inhibition on aspects of vascular reactivity in rat pulmonary artery, including resting tone and catecholamine reactivity, loss of reactivity to repeated catecholamine stimulation, and contraction-relaxation kinetics. The effect of ATPase inhibition on resting tone and catecholamine reactivity was determined by comparing the responses to 10(-4) and 10(-3) M ouabain (Oua-4, Oua-3), 10(-4) M tyramine, and 10(-6) M norepinephrine (NE) pre- and postouabain. Loss of responsiveness to NE was induced by repeated cumulative doses of NE (NE I, NE II) with 60 min between exposures. ATPase inhibition was superimposed on this loss of reactivity by 1) administration of Oua-4 or Oua-3 15 min before NE II, 2) incubation in K(+)-free solution 15 min before NE II, and 3) incubation in K(+)-free solution 15 min before NE I for the entire protocol. The effect of ATPase inhibition on the response pattern after repetitive dosing with phenylephrine (PE) and KCl was also determined. To correlate ATPase activity with the loss of reactivity after catecholamine stimulation, we measured ATPase activity (86Rb uptake) at different time points after repeated NE administration. The effect of ATPase inhibition on contraction-relaxation rates after catecholamine stimulation was determined by analyzing the response to repeated single doses of NE in normal salt solution and after incubation in K(+)-free solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Pregnancy is a state of altered pulmonary vascular reactivity, but the conclusions about changes in reactivity have varied with the agents or species chosen for study. The present study was designed as a comprehensive analysis of pregnancy-induced and gender-related differences in pulmonary vascular reactivity in one species. Using an isolated perfused feline lung preparation, the pulmonary vascular responses to angiotensin II, serotonin, histamine, epinephrine, norepinephrine, and acute hypoxia (FIO2, 8%) were compared between males, females, and pregnant females. Vascular reactivity (maximum response) and drug sensitivity (ED50) were compared using cumulative dose-response data for each pharmacological agent. The results demonstrate that (1) reactivity to angiotensin II, serotonin, epinephrine, and acute hypoxia is decreased during pregnancy, while the response to norepinephrine remain unchanged, (2) drug sensitivity is unchanged with serotonin and the catecholamines, increased with histamine, and decreased with angiotensin II, and (3) the responses to acute hypoxia and histamine have significant gender-related differences in reactivity independent of the changes observed during pregnancy.

The present study investigated the effects of repetitive exposure to a select group of biogenic amines (epinephrine, norepinephrine, histamine, and serotonin) on pulmonary vascular reactivity by constructing and analyzing a set of four sequential cumulative dose-response curves to one biogenic amine in the isolated blood-perfused left lower lobe of the cat lung in vivo. The dose-response curves were obtained under conditions of constant flow, insuring that the observed pressure changes in the lobe were pressor responses resulting from vasoconstriction rather than flow-related changes. Histamine and epinephrine demonstrated a progressive loss of initial vasoconstrictor activity, whereas the responses to serotonin remained unchanged after repetitive exposure. Norepinephrine demonstrated two different patterns of response, depending on the dose range employed; norepinephrine (0.068-2.27 nmol/ml) demonstrated a loss of the original vasoconstrictor activity, in a pattern similar to histamine and epinephrine, while higher doses of norepinephrine (0.34-9.1 nmol/ml) demonstrated no change in activity with a left shift in the concentration at which the maximal responses occurred, suggesting an increase in sensitivity as a result of repeated exposure. These results were obtained in the absence of significant alterations of arterial blood gases, changes in base-line tone in the experimental left lower lobe, or the development of severe pulmonary edema. These data suggest that only the agents that are capable of stimulating antagonistic vasoconstrictor and vasodilator receptors demonstrated a loss of pulmonary vasoconstrictor activity, which may result from a functional shift in the balance of antagonistic receptor activity with continued exposure.

The pulmonary vascular responses to histamine, epinephrine, and norepinephrine demonstrate tachyphylaxis following repetitive exposure in the isolated blood-perfused cat lung. In the present study, we tested the hypothesis that this phenomenon was related to a change in the balance of antagonistic receptor activity. The protocol consisted of 5 consecutive dose-response maneuvers (DR I to V) to 1 amine in each animal separated by 1 h. Once the loss of the initial vasoconstrictor activity had occurred (DR I to IV), the animal was given a receptor blocking agent, either the beta blocker propranolol or the H2 blocker cimetidine, prior to a final dose-response maneuver (DR V). The dose-response relationships were analyzed in terms of 3 parameters: maximum response, slope, and ED50. All the experiments with norepinephrine (n = 6), epinephrine (n = 10), and histamine (n = 25) demonstrated a progressive loss of vasopressor activity as shown by reductions in the maximum response and slope between DR I to IV. In addition, histamine demonstrated a significant increase in ED50 from DR I to IV, which suggested a loss of sensitivity. The loss of vasoconstrictor activity to histamine and the catecholamines was restored by the administration of propranolol prior to DR V. In contrast, cimetidine did not restore the initial vasopressor activity of histamine. The loss of reactivity to histamine was not secondary to changes in circulating catecholamine levels, because the plasma catecholamine levels before DR I and immediately following DR V in a subset of animals (n = 5) were within the reported normal range for this species.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of age on the pulmonary vascular responses to histamine (HIST), norepinephrine (NE), 5-hydroxytryptamine (5-HT), and KCl were studied in isolated, perfused lungs from juvenile (7-wk-old), adult (14-wk-old), and mature adult (28-wk-old) normoxic rats and compared with age-matched rats exposed to chronic hypoxia for either 14 or 28 days. Chronic hypoxia changed vasoconstriction to HIST and NE to vasodilation in lungs from juvenile and adult rats. Mature adult lungs only vasoconstricted to these amines in both control and hypoxic animals. Pressor responses to 5-HT were not affected by chronic hypoxia regardless of age group. Pressor responses to KCl were also not altered by hypoxia, but lungs from older rats showed greater control responsiveness to KCl compared with lungs from juveniles. Only lungs from juvenile animals developed significant elevations of base-line resistance as a result of hypoxic exposure. To investigate the contribution of H1-, H2-, and beta-receptors in these changes, we employed chlorpheniramine, metiamide, and propranolol, respectively, as blocking agents in another series of experiments. Chlorpheniramine either reduced vasoconstriction or increased vasodilation to HIST in lungs from both control and hypoxic animals, whereas metiamide was without effect. Propranolol either increased vasoconstriction or reversed vasodilation to HIST and NE in all lungs studied. The present data demonstrate the important interaction between chronic hypoxia and age that can alter pulmonary vascular tone and reactivity. The inverse relationship between age and elevation of pulmonary vascular resistance after chronic hypoxic exposure may be the key element that changes pulmonary vascular reactivity observed during hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of acute hypoxia on the pressor responses to five biogenic amines were studied in isolated blood-perfused cat lungs. Hypoxia (Po2 = 46 +/- 2 Torr) reduced the pressor responses to phenylephrine while changing the pressor responses to epinephrine and norepinephrine to vasodilation. Hypoxia reduced the pressor responses to histamine, and these reductions were preceded by small but significant vasodilations. Hypoxia had no effect on the pressor responses to serotonin. These changes in pulmonary vasoactivity were reversed on reoxygenation, independent of changes in base-line tone and not correlated with circulating catecholamines. We also examined the effects of hypoxia on the pressor responses to norepinephrine during beta-blockade with propranolol and then alpha-blockade with dibenzyline. The vasodilation produced during hypoxia by norepinephrine was blocked by propranolol, and vasoconstriction reappeared. When alpha-blockade was then established, vasodilation to norepinephrine reemerged during hypoxia. These results demonstrate that hypoxia produces changes in pulmonary vascular responsiveness that are acute in nature and reversible. Although the cellular nature of these changes is unknown, the data suggest that hypoxia produces acute shifts in antagonistic adrenergic receptor activity by either 1) reducing alpha- or increasing beta-receptor activity or 2) acutely changing adrenergic receptor conformation, affinity, or efficacy, such that beta-activity prevails.

Past work in the isolated perfused cat lung has shown that acute hypoxia (H) changes the response to norepinephrine (NE) from vasoconstriction to vasodilation but has no effect on the response to serotonin (S). These results could be related to the increase in pulmonary arterial pressure or vascular resistance during the hypoxic pressor response or a direct effect of H. We addressed this question, in the same preparation, by comparing responses to NE under four conditions in each experimental animal (n = 12): 1) NE infused during normoxia; 2) NE infused after vascular resistance (Rpv) was increased with serotonin; 3) NE infused after Rpv was increased by H; 4) NE infused after lobar pressure was raised by an increase in flow (P/F). PO2 values during H were varied (27-56 Torr). S and H produced a 137 +/- 35 and 43 +/- 8% delta Rpv increase in lobar vascular resistance, respectively. P/F increased lobar pressure 91 +/- 10%. Only NE infusion during H demonstrated significant differences in lobar pressure and Rpv compared with control normoxic periods. There was no correlation between responses to NE during S, H, and P/F and degree to which each stimulus increased Rpv or lobar pressure (r = 0.003, 0.28, 0.24). A significant relationship between response to NE during H vs. PO2 during H was observed (r = 0.78; P less than 0.001). In a subset of animals, we repeated the infusion of NE during H and P/F post-beta-blockade. The decrease in vascular response to NE during H and the correlation of PO2 with NE response were abolished (n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)

Cross-sectional analysis of CBF values was carried out among 668 volunteers and patients. Subjects were subdivided according to age, gender, and degree of cerebrovascular disease, ranging from healthy volunteers with or without risk factors for stroke to patients with multi-infarct dementia. Four-year longitudinal analysis was also carried out on 230 individuals from the original sample. Decrements in CBF values were evidenced by both cross-sectional and longitudinal analysis in relation to advancing age, progressive cerebrovascular disease, and dementia. Regional, age-related CBF declines in healthy volunteers were heterogeneous, possibly related to changes in levels of functional activity within different brain regions.