The Distribution and Role of M1 and M2 Macrophages in Aneurysm Healing after Platinum Coil Embolization.

BACKGROUND AND PURPOSE: Impairment of macrophage polarization from a proinflammatory macrophage type 1 (M1) population to an anti-inflammatory macrophage type 2 (M2) population is a hallmark of poor wound healing. In this study, we aimed to evaluate the distribution of M1 and M2 macrophages and to analyze their association with healing in aneurysms embolized by endovascular coiling. MATERIALS AND METHODS: Elastase-induced aneurysms were created in female rabbits and subsequently embolized with platinum coils. Aneurysm occlusions were evaluated with angiographic imaging at 1 (n = 6), 3 (n = 5), or 6 (n = 6) months. Aneurysm tissues were harvested for histologic analysis, quantification of M1 and M2 macrophages by immunofluorescence, and collagen deposition determined by Masson trichrome staining. Histologic grading of aneurysm healing was also performed. Untreated aneurysms were used as controls (n = 6). RESULTS: The M1 macrophage population was highest at 1 month posttreatment, progressively decreasing at 3 and 6 months. The M2 macrophage population progressively increased at 3 and 6 months posttreatment. The highest collagen deposition was at 6 months posttreatment. We found a moderate-to-weak direct correlation between the percentage of M2 macrophages and collagen deposition, as well as total histologic scores overall, and a strongly positive direct correlation between the percentage of M2 macrophages and total histologic scores at 6 months posttreatment. CONCLUSIONS: Our data support the direct correlation between M2 macrophage polarization and healing in aneurysm tissues. Our results show a positive relationship between M2 macrophage populations and total histologic scores at later stages of healing after endovascular coiling. We conclude that interventions aimed at stimulating M2 macrophage expression locally may improve aneurysm healing after coil embolization.

Histologic and Biomolecular Similarities in Healing between Aneurysms and Cutaneous Skin Wounds.

The poorly understood mechanisms of aneurysm healing contribute substantially to the pressing medical problem of coiled aneurysm recanalization. Using an established saccular aneurysm model, we developed an animal model system in rabbits to study aneurysm and skin wound healing concurrently in the same animal. We found treated aneurysm healing to be similar to skin wound healing both histologically and in biomarker gene and protein expression, but in a delayed fashion.

Purinergic signaling and energy homeostasis in psychiatric disorders.

Purinergic signaling regulates numerous vital biological processes in the central nervous system (CNS). The two principle purines, ATP and adenosine act as excitatory and inhibitory neurotransmitters, respectively. Compared to other classical neurotransmitters, the role of purinergic signaling in psychiatric disorders is not well understood or appreciated. Because ATP exerts its main effect on energy homeostasis, neuronal function of ATP has been underestimated. Similarly, adenosine is primarily appreciated as a precursor of nucleotide synthesis during active cell growth and division. However, recent findings suggest that purinergic signaling may explain how neuronal activity is associated neuronal energy charge and energy homeostasis, especially in mental disorders. In this review, we provide an overview of the synaptic function of mitochondria and purines in neuromodulation, synaptic plasticity, and neuron-glia interactions. We summarize how mitochondrial and purinergic dysfunction contribute to mental illnesses such as schizophrenia, bipolar disorder, autism spectrum disorder (ASD), depression, and addiction. Finally, we discuss future implications regarding the pharmacological targeting of mitochondrial and purinergic function for the treatment of psychiatric disorders.

Effect of forage quality on digestion and performance responses of cattle to supplementation with cooked molasses blocks.

We evaluated the effect of forage quality on response of cattle to supplementation with cooked molasses blocks. In Exp. 1, 175 heifers had ad libitum access to prairie hay (5.2% CP, DM basis). Treatments were a 2 x 3 factorial: supplementation with 0 or 1.96 kg/d of alfalfa DM, and supplementation with no cooked molasses block or with a low-protein or a high-protein cooked molasses block (14.4 and 27.5% CP, respectively, DM basis). There were no significant interactions between alfalfa and cooked molasses block for intake or gain. Forage intake and ADG were increased (P < 0.05) by alfalfa supplementation. Heifers fed high-protein cooked molasses blocks gained more (P < 0.05) weight than those fed low-protein cooked molasses blocks or no cooked molasses block. Heifers fed high-protein cooked molasses blocks ate more (P < 0.05) forage than those fed low-protein cooked molasses blocks, with heifers fed no cooked molasses block being intermediate. In Exp. 2, responses to cooked molasses blocks containing 33% CP (DM basis) were measured in 18 steers fed: 1) brome (8.4% CP), 2) alfalfa (19.2% CP), or 3) brome supplemented with 1.93 kg/d of alfalfa DM. Forages were available ad libitum. Forage DM intake was not affected by cooked molasses block and was greater (P < 0.05) for alfalfa than the alfalfa/brome mix, which in turn was greater (P < 0.05) than brome. Digestibility of DM was greater (P < 0.05) for alfalfa than brome or the alfalfa/brome mix and was not affected by cooked molasses block supplementation. Supplementation with cooked molasses blocks had only small effects on intake and digestion of medium- to high-quality forages, but it improved gains and feed efficiencies of heifers fed prairie hay ad libitum, with or without supplemental alfalfa.

Hemodynamic consequences of obstructive sleep apnea.

Patients with obstructive sleep apnea demonstrate both acute and chronic hemodynamic changes attributable to their disease. Acutely, these patients experience repetitive nocturnal hemodynamic oscillations. Sudden increases in heart rate and arterial pressure occur in association with decreases in left ventricular stroke volume immediately following apnea termination. These hemodynamic changes are likely attributable primarily to the effects of oxygen desaturation and arousal, an abrupt change in state. These acute changes occur against a background of altered cardiovascular control. Patients with sleep apnea, even when sleeping without obstructions, fail to display the normal nocturnal decline in arterial pressure of 10-15% from the waking value. The absence of a nocturnal decline may have chronic consequences, such as development of left ventricular hypertrophy. Another chronic hemodynamic consequence of sleep apnea may be sustained diurnal hypertension. Epidemiologic studies suggest individuals with sleep disordered breathing are at greater risk of daytime hypertension, even after controlling for other risk factors. Although sleep apnea may contribute to pulmonary, as well as systemic hypertension, sleep apnea alone does not appear to be a cause of decompensated right heart failure. Although knowledge of the hemodynamic consequences of sleep apnea has grown in recent years, much remains to be learned.

Sleep stage influences the hemodynamic response to obstructive apneas.

Blood pressure (BP) rises at the termination of obstructive episodes in patients with sleep apnea. Although the relationship of these BP elevations to oxygen saturation (SaO2) and arousal has been explored, the influence of sleep stage is undefined. To examine the effects of sleep stage on the postapnea BP elevation, we enrolled 12 patients with obstructive sleep apnea (OSA), and successfully collected data from seven of these (all male). Subjects slept overnight in the sleep laboratory, with full sleep and respiratory monitoring. Arterial pressure was assessed continuously with a radial artery catheter (six patients) or with digital photoplethysmography (one patient). Apneas occurring in both rapid eye movement (REM) and non-rapid eye movement (NREM) sleep were matched for duration and degree of desaturation. When mean arterial pressure (MAP) at termination of apneas during NREM sleep associated with SaO2 nadirs 78 to 82% (NREM 80%) was compared with MAP following apneas in REM with the same SaO2 nadir (REM 80%), there was a significant difference (NREM 80% 122 +/- 15.3 mm Hg, REM 80% 132 +/- 11.0; p = 0.0109). We also analyzed the effect of oxygen desaturation on MAP during REM sleep, by comparing events with SaO2 nadirs of 78 to 82% with events with nadirs of < 75% (REM < 75%). In REM, further desaturation was associated with significant lengthening of the obstructive episodes and significantly higher postapnea BP increases (REM 75% 143 +/- 19.9 mm Hg, p = 0.0392). We conclude that sleep stage alters the hemodynamic response to obstructive apneas during sleep.

Decrease in ventricular stroke volume at apnea termination is independent of oxygen desaturation.

Patients with obstructive sleep apnea experience nocturnal hemodynamic oscillations in association with repetitive respiratory events. Apnea termination (recovery) is accompanied by the nadir of arterial O2 saturation (SaO2), changes in intrathoracic pressure, and arousal from sleep. To investigate separately the contributions of hypoxemia and of arousal from sleep to changes in cardiac function, we continuously measured left ventricular stroke volume (LVSV) and mean arterial pressure (MAP) in eight subjects with severe obstructive sleep apnea (apnea-hypopnea index > 30 events/h associated with SaO2 < or = 82%) during two experimental conditions: 1) subjects slept without intervention for 1-2 h and then supplemental O2 was administered to maintain SaO2 > or = 90% (mean SaO2 nadir 92.7%) throughout the apnea-recovery cycle and 2) upper airway obstructions were abolished using nasal continuous positive airway pressure and subjects were aroused from sleep by an auditory signal. Recovery was associated with an increase in MAP and a decrease in LVSV both with and without supplemental O2. Arousal from sleep on nasal continuous positive airway pressure reproduced the postapneic elevation of MAP but not a decrease in cardiac function of the magnitude that occurred at apnea termination. We conclude that elevation of blood pressure and reduction of LVSV that occurred at apnea termination may be due to different physiological mechanisms.

Systemic blood pressure elevation after airway occlusion during NREM sleep.

Increases in arterial pressure follow obstructive sleep apneas even in the absence of hypoxemia. These blood pressure (BP) elevations could be caused by arousal from sleep, resumption of ventilation, or abrupt changes of intrathoracic pressure (ITP). To better define the relative contributions of each of these factors to the BP elevations, we designed two protocols employing six normal subjects isolating the effects of arousal from those of ventilation and ITP. BP (Penaz method), sleep stage, air flow, and esophageal pressure (Pes) were monitored. Episodically, a stopcock was closed, occluding the inspiratory circuit. In Experiment 1, data were recorded on tape. Occlusions were initiated during Stage 2 NREM sleep and released coincident with arousal. Subjects were than awakened and instructed to trace the displayed, taped Pes profile creating occlusions of identical duration to those recorded during sleep. In five subjects, the mean BP elevation (preocclusion to peak) associated with occlusion release upon arousal was 19.0 +/- 5.1 mm Hg, whereas the analogous rise for matched awake occlusions was 5.4 +/- 4.8 mm Hg (p = 0.027). In Experiment 2, occlusion release was delayed 6 to 12 s after arousal. In five subjects, these occlusions were associated with BP elevations that peaked coincident with arousal, not with resumption of ventilation (mean increase, 18.0 +/- 10.4 mm Hg). We conclude that under the conditions of these experiments, BP elevations after airway occlusion during sleep are attributable more to arousal than to resumption of ventilation.

Stroke volume and cardiac output decrease at termination of obstructive apneas.

Patients with obstructive sleep apnea (OSA) experience repetitive nocturnal oscillations of systemic arterial pressure that occur in association with changes in respiration and changes in sleep state. To investigate cardiac function during the cycle of obstruction (apnea) and resumption of ventilation (recovery), we continuously measured left ventricular stroke volume (LVSV) and mean arterial blood pressure (MAP) during non-rapid-eye-movement sleep in six males with severe OSA (apnea/hypopnea index > or = 30 events/h associated with oxygen saturation < 82%). LVSV was assessed continuously using an ambulatory ventricular function monitor (VEST; Capintec). The apnea-recovery cycle was divided into three phases: 1) early apnea (EA), 2) late apnea (LA), and 3) recovery (Rec). In all subjects recovery was associated with an abrupt decrease in LVSV [54.0 +/- 14.5 (SD) ml] compared with either EA (91.4 +/- 14.7 ml; P < 0.001) or LA (77.1 +/- 15.2 ml; P < 0.005). Although heart rate increased with recovery, the increase was not sufficient to compensate for the decrease in LVSV so that cardiac output (CO) fell (EA: 6,247 +/- 739 ml/min; LA: 5,741 +/- 1,094 ml/min; Rec: 4,601 +/- 1,249 ml/min; EA vs. Rec, P < 0.01; LA vs. Rec, P < 0.025). Recovery was also associated with a significant increase in MAP. We speculate that such abrupt decreases in LVSV and CO at apnea termination, occurring coincident with the nadir of oxygen saturation, may further compromise tissue oxygen delivery.

Upper airway anesthesia delays arousal from airway occlusion induced during human NREM sleep.

Six healthy subjects (5 males and 1 female, 26-40 yr old) were studied during non-rapid-eye-movement (NREM) sleep to assess the role of upper airway (UA) afferents in the arousal response to induced airway occlusion. Subjects wore an airtight face mask attached to a low-resistance one-way valve. A valve in the inspiratory circuit allowed instantaneous inspiratory airway occlusion and release; the expiratory circuit remained unoccluded at all times. Each subject was studied during two nights. On one night, occlusions were created during stable stage 2 NREM sleep before and after application of 4% lidocaine to the oral and nasal mucosa. On the other night, the protocol was duplicated with saline ("sham anesthesia") rather than lidocaine. The order of nights was randomized. Occlusions were sustained until electroencephalographic arousal. Three to 12 occlusions were performed in each subject for each of the four parts of the protocol (pre- and post-lidocaine, pre- and post-saline). The auditory threshold for arousal (1,500-Hz tone beginning at 30 dB) was also tested before and after UA lidocaine. For the group, arousal time after UA anesthesia was prolonged compared with preanesthesia arousal time (P less than 0.001); arousal time after sham anesthesia did not significantly increase from before sham anesthesia (P = 0.9). The increase in arousal time with UA anesthesia was greater than the increase with sham anesthesia (P less than 0.001). The auditory arousal threshold did not increase after UA anesthesia. Inspiratory mask pressure, arterial O2 saturation of hemoglobin, and end-tidal PCO2 during occlusions were similar before and after UA anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenylephrine-induced hypertension acutely decreases genioglossus EMG activity in awake humans.

To investigate the relationship between systemic blood pressure (BP) and upper airway dilator muscle activity, we recorded genioglossus electromyograms (EMGgg) during pharmacologically induced acute increases in BP in five healthy humans (ages 27-40 yr). EMGgg was measured with perorally placed fine-wire electrodes; phasic EMGgg was expressed as percentage of baseline activity. Subjects were studied supine, awake, and breathing through a face mask with their mouths taped. End-tidal PCO2 was monitored with a mass spectrometer; minute ventilation was measured with a pneumotachograph. Digital BP was monitored continuously with the Penaz method (Finapres, Ohmeda). Mean arterial pressure (MAP) at baseline was 89 +/- 6 (SD) mmHg. Phenylephrine was infused until MAP reached 15-25 mmHg above baseline (107 +/- 7 mmHg). Recording was continued until MAP returned to baseline (90 +/- 7 mmHg). Elevated BP was associated with a significantly decreased phasic EMGgg (P less than 0.005). With return of MAP to baseline, phasic EMGgg returned toward normal (P less than 0.01). Minute ventilation and end-tidal PCO2 did not differ among conditions. Genioglossus activity appears to be influenced by acute changes in systemic BP. We speculate that BP elevations accompanying obstructive apneas during sleep may decrease upper airway tone and facilitate subsequent apneas.

Effect of chest wall vibration on breathlessness in normal subjects.

This study evaluated the effect of chest wall vibration (115 Hz) on breathlessness. Breathlessness was induced in normal subjects by a combination of hypercapnia and an inspiratory resistive load; both minute ventilation and end-tidal CO2 were kept constant. Cross-modality matching was used to rate breathlessness. Ratings during intercostal vibration were expressed as a percentage of ratings during the control condition (either deltoid vibration or no vibration). To evaluate their potential contribution to any changes in breathlessness, we assessed several aspects of ventilation, including chest wall configuration, functional residual capacity (FRC), and the ventilatory response to steady-state hypercapnia. Intercostal vibration reduced breathlessness ratings by 6.5 +/- 5.7% compared with deltoid vibration (P less than 0.05) and by 7.0 +/- 8.3% compared with no vibration (P less than 0.05). The reduction in breathlessness was accompanied by either no change or negligible change in minute ventilation, tidal volume, frequency, duty cycle, compartmental ventilation, FRC, and the steady-state hypercapnic response. We conclude that chest wall vibration reduces breathlessness and speculate that it may do so through stimulation of receptors in the chest wall.

Phasic electromyographic activity of the genioglossus increases in normals during slow-wave sleep.

Obstructive apneas occur infrequently during Stage 3-4 NREM sleep (SWS), even in patients with severe obstructive sleep apnea. To investigate whether upper airway (UA) dilator muscle activity preferentially increases during SWS as a partial explanation for this phenomenon, we measured phasic electromyogram activity of the genioglossus muscle (EMGgg) during continuous Stage 2 NREM sleep and SWS in 5 healthy males. Subjects were studied supine during a complete cycle of nocturnal NREM sleep after partial sleep deprivation. EMGgg was measured with perorally inserted bipolar electrodes, and quantified as peak phasic inspiratory activity during all continuous epochs of NREM sleep. We found EMGgg to be increased during SWS relative to stage 2 sleep by a mean of 58% among all subjects (P = 0.02); neither end-tidal PCO2 nor inspired minute ventilation varied between these sleep stages. Upper airway resistance, measured in 3 of the subjects on a separate study night, was not different between SWS and Stage 2 sleep. We speculate that the increase in phasic EMGgg during SWS in our normal subjects may reflect a mechanism whereby UA patency tends to be preserved during this stage.

Hypoxemia alone does not explain blood pressure elevations after obstructive apneas.

In patients with obstructive sleep apnea (OSA), substantial elevations of systemic blood pressure (BP) and depressions of oxyhemoglobin saturation (SaO2) accompany apnea termination. The causes of the BP elevations, which contribute significantly to nocturnal hypertension in OSA, have not been defined precisely. To assess the relative contribution of arterial hypoxemia, we observed mean arterial pressure (MAP) changes following obstructive apneas in 11 OSA patients during non-rapid-eye-movement (NREM) sleep and then under three experimental conditions: 1) apnea with O2 supplementation; 2) hypoxemia (SaO2 80%) without apnea; and 3) arousal from sleep with neither hypoxemia nor apnea. We found that apneas recorded during O2 supplementation (SaO2 nadir 93.6% +/- 2.4; mean +/- SD) in six subjects were associated with equivalent postapneic MAP elevations compared with unsupplemented apneas (SaO2 nadir 79-82%): 18.8 +/- 7.1 vs. 21.3 +/- 9.2 mmHg (mean change MAP +/- SD); in the absence of respiratory and sleep disruption in eight subjects, hypoxemia was not associated with the BP elevations observed following apneas: -5.4 +/- 19 vs. 19.1 +/- 7.8 mmHg (P less than 0.01); and in five subjects, auditory arousal alone was associated with MAP elevation similar to that observed following apneas: 24.0 +/- 8.1 vs. 22.0 +/- 6.9 mmHg. We conclude that in NREM sleep postapneic BP elevations are not primarily attributable to arterial hypoxemia. Other factors associated with apnea termination, including arousal from sleep, reinflation of the lungs, and changes of intrathoracic pressure, may be responsible for these elevations.

Effect of inspired air temperature on genioglossus activity during nose breathing in awake humans.

Experimental data suggest the presence of sensory receptors specific to the nasopharynx that may reflexly influence respiratory activity. To investigate the effects of inspired air temperature on upper airway dilator muscle activity during nose breathing, we compared phasic genioglossus electromyograms (EMGgg) in eight normal awake adults breathing cold dry or warm humidified air through the nose. EMGgg was measured with peroral bipolar electrodes during successive trials of cold air (less than or equal to 15 degrees C) and warm air (greater than or equal to 34 degrees C) nasal breathing and quantified for each condition as percent activity at baseline (room temperature). In four of the subjects, the protocol was repeated after topical nasal anesthesia. For all eight subjects, mean EMGgg was greater during cold air breathing than during baseline (P less than 0.005) or warm air breathing (P less than 0.01); mean EMGgg during warm air breathing was not significantly changed from baseline. Nasal anesthesia significantly decreased the mean EMGgg response to cold air breathing. Nasal airway inspiratory resistance, measured by posterior rhinomanometry in six subjects under similar conditions, was no different for cold or warm air nose breathing [cold 1.4 +/- 0.7 vs. warm 1.4 +/- 1.1 (SD) cmH2O.l-1.s at 0.4 l/s flow]. These data suggest the presence of superficially located nasal cold receptors that may reflexly influence upper airway dilating muscle activity independently of pressure changes in awake normal humans.

Evaluation of Abbott CMV-M enzyme immunoassay for detection of cytomegalovirus immunoglobulin M antibody.

The Abbott CMV-M enzyme immunoassay (EIA) for the qualitative determination of immunoglobulin M (IgM) antibody to cytomegalovirus in human serum was compared with the indirect fluorescent-antibody (IFA) test on 338 human serum specimens. Discordant specimens were evaluated by IFA following isolation of IgM fractions. Discordant specimens remaining after IFA testing were evaluated by an IgM-specific EIA (CYTOMEGELISA M; M.A. Bioproducts). After resolution of discordant specimens, the CMV-M EIA was 94.7% sensitive and 99.1% specific.