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Biomedical subjects

Philip L Smith

Publications and source records attributed to Philip L Smith.

34 records · Page 2Linked to original sources
PubMed2004

The attentional dynamics of masked detection.

A dichoptic masking procedure was used to test whether the mask-dependent cuing effects found in luminance detection by P. L. Smith (2000a) were due to integration masking or interruption masking. Attentional cuing enhanced detection sensitivity (d') when stimuli were backwardly masked with either dichoptic or monoptic masks, whereas no cuing effect was found with unmasked stimuli, implying the mask dependencies were due to interruption of stimulus processing in visual cortex by the mask. The effect is predicted by a gated diffusion process model in which masks interrupt stimulus processing and attention controls the flow of information to a sequential-sampling decision mechanism. The model correctly predicts different patterns of performance for detection and discrimination and cuing effects in simple reaction time.

Attention↗
PubMed2004

Mask-dependent attentional cuing effects in visual signal detection: the psychometric function for contrast.

A spatial-cuing paradigm was used to test the hypothesis of Carrasco, Penpeci-Talgar, and Eckstein (2000) that the mask-dependent cuing effects found in visual signal detection by Smith (2000a) were caused by submaximal activation of the transient-orienting system. Mask-dependent cuing was found with a range of stimulus contrasts with pure peripheral cues and with the mixed central-peripheral cues of Smith (2000a), contrary to the predictions of the submaximal activation hypothesis. The use of a pedestal detection task to control spatial uncertainty showed that the cuing effect was due to signal enhancement. A model of mask-dependent cuing is described, which assumes that attention affects the rate of information accumulation from the display and that masks limit the visual persistence of the stimulus. The model correctly predicts differential mask dependencies in sensitivity for detection and discrimination and the associated patterns of response times.

Adolescent↗
PubMed2003

Impact of interrupted leptin pathways on ventilatory control.

Leptin deficiency in ob/ob mice produces marked depression of the hypercapnic ventilatory response, particularly during sleep. We now extend our previous findings to determine whether 1) leptin deficiency affects the hypoxic ventilatory response and 2) blockade of the downstream excitatory actions of leptin on melanocortin 4 receptors or inhibitory actions on neuropeptide Y (NPY) pathways has an impact on hypercapnic and hypoxic sensitivity. We have found that leptin-deficient ob/ob mice have the same hypoxic ventilatory response as weight-matched wild-type obese mice. There were no differences in the hypoxic sensitivity between agouti yellow mice and weight-matched controls, or NPY-deficient mice and wild-type littermates. Agouti yellow mice, with blocked melanocortin pathways, exhibited a significant depression of the hypercapnic sensitivity compared with weight-matched wild-type controls during non-rapid eye movement sleep (5.8 +/- 0.7 vs. 8.9 +/- 0.7 ml x min(-1) x %CO(2)(-1), P < 0.01), but not during wakefulness. NPY-deficient transgenic mice exhibited a small increase in the hypercapnic ventilatory response compared with wild-type littermates, but this was only present during wakefulness. We conclude that interruption of leptin pathways does not affect hypoxic sensitivity during sleep and wakefulness but that melanocortin 4 blockade is associated with depressed hypercapnic sensitivity in non-rapid eye movement sleep.

Animals↗
PubMed2003

Differences in sleep-induced hypoxia between A/J and DBA/2J mouse strains.

In obstructive sleep apnea, hypoxic ventilatory sensitivity may affect the degree of hypoxic stress and sleep disruption that occurs in response to upper airway obstruction. We induced (1) sleep-induced hypoxia (SIH) or (2) sleep fragmentation (SF) without hypoxia for 5 days (12-hour light/dark cycle) in two inbred mouse strains with low (A/J) and high (DBA/2J) hypoxic ventilatory sensitivities. During SIH, the time to arousal (26.4 +/- 1.1 vs. 21.3 +/- 1.5 seconds, p<0.025) and the severity of hypoxic exposure (nadir FIO2: 11.5 +/- 0.4 vs. 13.6 +/- 0.1%, p<0.002) was greater in A/J than DBA/2J mice. Furthermore, A/J mice had a greater frequency of hypoxic events (640 +/- 29 vs. 368 +/- 33 events per 24 hours, p<0.001) and total sleep time (47.5 +/- 2.8% vs. 26.5 +/- 2.4% per 24 hours, p<0.0001) during SIH than DBA/2J mice. In contrast, the event characteristics and total sleep time during SF were the same in both strains. Furthermore, in the light phase, both strains showed a longer (p<0.01) time to arousal during SIH and SF compared with the dark phase. We conclude that genetic background can influence respiratory events and sleep architecture during SIH and that the arousal threshold is subject to circadian variation. Our data imply that individuals with low hypoxic sensitivity may be at a greater risk for hypoxia-related complications of obstructive sleep apnea.

Animals↗
PubMed2003

Intermittent hypoxia increases insulin resistance in genetically obese mice.

Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J-Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 +/- 11 mg dl-1 on day 0 to 138 +/- 10 mg dl-1 on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 +/- 0.3 vs. 1.7 +/- 0.2 ng ml-1, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 +/- 136 % (P < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 +/- 1.1 ng ml-1 at baseline to 9.8 +/- 1.8 ng ml-1 at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways.

Adipose Tissue↗
PubMed2003

Tongue neuromuscular and direct hypoglossal nerve stimulation for obstructive sleep apnea.

Recent studies have shown that neuromuscular stimulation of the genioglossus muscle and direct stimulation of the hypoglossal nerve can be performed selectively and safely. Such stimulation, delivered below the arousal threshold, can modulate airflow during sleep in patients with OSA. The feasibility and potential of upper airway stimulation for the treatment of OSA have been demonstrated. Further studies and stimulation-system refinements are presently underway, with hopes of establishing upper airway stimulation as a therapeutic option for this challenging disorder.

Electric Stimulation Therapy↗
PubMed2003

In vitro metabolism of tolcapone to reactive intermediates: relevance to tolcapone liver toxicity.

Tolcapone is a catechol-O-methyltransferase (COMT) inhibitor used for control of motor fluctuations in Parkinson's disease (PD). Since its entry onto the market in 1998, tolcapone has been associated with numerous cases of hepatotoxicity, including three cases of fatal fulminant hepatic failure. The cause of this toxicity is not known; however, it does not occur with the use of the structurally similar drug entacapone. It is known that tolcapone is metabolized to amine (M1) and acetylamine (M2) metabolites in humans, but that the analogous metabolites were not detected in a limited human study of entacapone metabolism. We hypothesized that one or both of these tolcapone metabolites could be oxidized to reactive species and that these reactive metabolites might play a role in tolcapone-induced hepatocellular injury. To investigate this possibility, we examined the ability of M1 and M2 to undergo in vitro bioactivation by electrochemical and enzymatic methods. Electrochemical experiments revealed that M1 and M2 are more easily oxidized than the parent compound, in the order M1 > M2 > tolcapone. There was a general correlation between oxidation potential and the half-lives of the compounds in the presence of two oxidizing systems, horseradish peroxidase and myeloperoxidase. These enzymes catalyzed the oxidation of M1 and M2 to reactive species that could be trapped with glutathione (GSH) to form metabolite adducts (C1 and C2). Each metabolite was found to only form one GSH conjugate, and the structures were tentatively identified using LC-MS/MS. Following incubation of M1 and M2 with human liver microsomes in the presence of GSH, the same adducts were observed, and their structures were confirmed using LC-MS/MS and (1)H NMR. Experiments with chemical P450 inhibitors and cDNA-expressed P450 enzymes revealed that this oxidation is catalyzed by several P450s, and that P450 2E1 and 1A2 play the primary role in the formation of C1 while P450 1A2 is most important for the production of C2. Taken together, these data provide evidence that tolcapone-induced hepatotoxicity may be mediated through the oxidation of the known urinary metabolites M1 and M2 to reactive intermediates. These reactive species may form covalent adducts to hepatic proteins, resulting in damage to liver tissues, although this supposition was not investigated in this study.

Acetylation↗
PubMed2003

Upper airway response to electrical stimulation of the genioglossus in obstructive sleep apnea.

Contraction of the genioglossus (GG) has been shown to improve upper airway patency. In the present study, we evaluated responses in upper airway pressure-flow relationships during sleep to electrical stimulation (ES) of the GG in patients with obstructive sleep apnea. Five patients with chronically implanted hypoglossal nerve (HG) electrodes and nine patients with fine-wire electrodes inserted into the GG were studied. Airflow was measured at multiple levels of nasal pressure, and upper airway collapsibility was defined by the nasal pressure below which airflow ceased ["critical" pressure (Pcrit)]. ES shifted the pressure-flow relationships toward higher flow levels in all patients over the entire range of nasal pressure applied. Pcrit decreased similarly during both HG-ES and GG-ES (deltaPcrit was 3.98 +/- 2.31 and 3.18 +/- 1.70 cmH2O, respectively) without a significant change in upstream resistance. The site of collapse (velo- vs. oropharynx) did not influence the response to GG-ES. Moreover, ES-induced reductions in the apnea-hypopnea index of the HG-ES patients were associated with substantial decreases in Pcrit. Our findings imply that responses in apnea severity to HG-ES can be predicted by characterizing the patient's baseline pressure-flow relationships and response to GG-ES.

Adult↗
PubMed2003

A physiologic comparison of nasal and oral positive airway pressure.

STUDY OBJECTIVES: The effectiveness of nasal continuous positive airway pressure (CPAP) in treating obstructive sleep apnea (OSA) is based on raising the intramural pressure above a critical collapsing pressure of the oropharyngeal airway. It is currently unclear whether CPAP delivered orally is also capable of raising pressure in the oropharynx above the critical collapse pressure. DESIGN: We tested a novel oral CPAP device to determine whether the pressure-flow relationships are similar to nasal CPAP and whether the device alters these relationships. Patients were selected based on having moderately severe apnea and were randomized to nasal CPAP, nasal CPAP with oral device, or oral CPAP. SETTING: Johns Hopkins University, The Johns Hopkins Asthma and Allergy Center, Baltimore, MD. PATIENTS: Five men and two women with OSA were studied. INTERVENTIONS: Individual pressure-flow curves were constructed during the application of nasal or oral CPAP. RESULTS: We found the following: (1) a similar effective pressure eliminated inspiratory flow limitation for the nasal or oral CPAP; (2) as pressure in the nose or mouth was lowered below the effective pressure, a linear pressure-flow curve was obtained and a critical closing pressure was described; (3) similar mean (+/- SD) critical pressures of -0.3 +/- 5.3, 1.7 +/- 4.0, and 0.5 +/- 2.8 cm H(2)O, respectively, occurred for nasal CPAP, nasal CPAP with the oral device in place, and oral CPAP conditions (p > 0.1); and (4) the comparable mean values for upstream resistance were 27.8 +/- 19, 19.1 +/- 8.3, and 26.5 +/- 26.7 cm H(2)O/L/s, respectively, for the above three conditions (p > 0.1). CONCLUSIONS: We concluded that comparable upper airway pressure-flow relationships were obtained during oral and nasal breathing. Moreover, effective treatment pressure is obtained when constant pressure is applied through either the nasal or oral route.

Adult↗
PubMed2002

Phenotypic differences in the hemodynamic response during REM sleep in six strains of inbred mice.

The pattern of cardiovascular changes that occur at nighttime can have an impact on morbidity and mortality. Rapid-eye-movement (REM) sleep, in particular, represents a period of increased risk due to marked cardiovascular instability. We hypothesized that genetic differences between inbred strains of mice would affect the phenotypic expression of cardiovascular responses that occur in REM sleep. We monitored polysomnography and arterial blood pressure (P(SA)) simultaneously in six inbred strains of mice as they naturally cycled through sleep/wake states. Two strains elevated their P(SA) above non-REM (NREM) levels for 57.9 +/- 6.6% (BALB/cJ) and 51.8 +/- 8.4% (DBA/2J) of the REM period and exhibited a significant (P < 0.05) number of P(SA) surges greater than 10 mmHg (0.78 +/- 0.36 surges/min for BALB/cJ; 0.63 +/- 0.13 surges/min for DBA/2J). Despite similar P(SA) responses, the DBA/2J strain exhibited a decreased heart rate and the BALB/cJ strain exhibited an increased heart rate during REM sleep. The four other strains (A/J, C57BL/6J, C3H/HeJ, and CBA/J) exhibited a significant hypotensive response associated with no change in heart rate in three of the strains and a significant decrease in heart rate in the A/J strain. The overall variability in P(SA) during REM sleep was significantly greater in the C3H/HeJ strain (26.8 +/- 2.0 mmHg; P < 0.0125) compared with the other five strains. We conclude that genetic background contributes to the magnitude, variability, and arterial baroreceptor buffering capacity of cardiovascular responses during REM sleep.

Animals↗
PubMed2002

The association between daytime sleepiness and sleep-disordered breathing in NREM and REM sleep.

BACKGROUND: Daytime sleepiness is common in patients with sleep-disordered breathing. Although respiratory events during sleep are associated with the occurrence of daytime sleepiness, the differential impact of these events during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep on daytime sleepiness has not been well characterized. STUDY OBJECTIVES: To determine the effect of respiratory events during REM sleep and NREM sleep on daytime sleepiness, as assessed by the multiple sleep latency test (MSLT). DESIGN: Cross-sectional study. SETTING: University-based sleep disorders laboratory. PARTICIPANTS: Patients referred for polysomnography and daytime MSLT (n=1,821). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The study sample was initially divided into quartiles based on the level of the apnea-hypopnea index (AHI) during NREM sleep. Within the first NREM-AHI quartile (NREM-AHI < 8.3 events/hr), the association between REM-related respiratory events and daytime sleepiness was examined using the method of Kaplan-Meier analysis and Cox proportional hazards regression. After adjusting for age, gender, body mass index, and the duration of NREM and REM sleep, REM-AHI was not associated with daytime sleepiness (Relative Risk: 1.01; 95%CI: 0.94-1.10). Similarly, no significant association was observed between REM-AHI and the MSLT in patients within the second through fourth NREM-AHI quartiles. In contrast, increasing severity of disordered breathing during NREM sleep was associated with daytime sleepiness. For a 10-point increase in NREM-AHI, the adjusted relative risks for daytime sleepiness in the second through fourth NREM-AHI quartile were 1.21 (95%CI: 1.01-1.46), 1.20 (95%CI: 1.05-1.37), and 1.10 (95%CI: 1.04-1.16), respectively. CONCLUSION: Sleep-disordered breathing during NREM sleep, but not REM sleep, is associated with increased risk of daytime sleepiness.

Adult↗
PubMed2002

Sleep-disordered breathing and insulin resistance in middle-aged and overweight men.

Sleep-disordered breathing is a prevalent condition associated with impairment of daytime function and may predispose individuals to metabolic abnormalities independent of obesity. The primary objective of this study was to determine the metabolic consequences and community prevalence of sleep-disordered breathing in mildly obese, but otherwise healthy, individuals. One hundred and fifty healthy men, without diabetes or cardiopulmonary disease, were recruited from the community. Measurements included polysomnography, a multiple sleep latency test, an oral glucose tolerance test, determination of body fat by hydrodensitometry, and fasting insulin and lipids. The prevalence of sleep-disordered breathing, depending on the apnea-hypopnea index (AHI) cutoff, ranged from 40 to 60%. After adjusting for body mass index (BMI) and percent body fat, an AHI gt-or-equal, slanted 5 events/h was associated with an increased risk of having impaired or diabetic glucose tolerance (odds ratio, 2.15; 95% CI, 1.05-4.38). The impairment in glucose tolerance was related to the severity of oxygen desaturation (DeltaSa(O(2))) associated with sleep-disordered breathing. For a 4% decrease in oxygen saturation, the associated odds ratio for worsening glucose tolerance was 1.99 (95% CI, 1.11 to 3.56) after adjusting for percent body fat, BMI, and AHI. Multivariable linear regression analyses revealed that increasing AHI was associated with worsening insulin resistance independent of obesity. Thus, sleep-disordered breathing is a prevalent condition in mildly obese men and is independently associated with glucose intolerance and insulin resistance.

Adult↗
PubMed2002

Synthesis of analogs of L-valacyclovir and determination of their substrate activity for the oligopeptide transporter in Caco-2 cells.

L-Valacyclovir, a prodrug of acyclovir, is a substrate for the peptide transporter (PepT1) in the intestinal mucosa, which accounts for its higher than expected oral bioavailability. The substrate activity of L-valacyclovir for PepT1 is surprising, particularly when one considers that the molecule has the structural features of a nucleoside rather than a peptide. In an attempt to better understand the structure-transport relationships (STR) for the interactions of L-valacyclovir with PepT1, analogs of this molecule with structural changes in the guanine moiety were synthesized and their substrate activity for PepT1 in Caco-2 cell monolayers was determined. The analogs synthesized include those that had the guanine moiety of L-valacyclovir substituted with purine, benzimidazole, and 7-azaindole. All three analogs (purine, benzimidazole, and 7-azaindole) exhibited affinity for PepT1 in binding studies, but only the purine analog (as the L-valine ester) showed PepT1-associated transcellular transport across Caco-2 cell monolayers. The benzimidazole and 7-azaindole analogs (as their L-valine esters) were rapidly metabolized by esterase when applied to the apical surface of Caco-2 cells, which probably explains their low penetration as the intact prodrugs via PepT1.

Acyclovir↗
PubMed2002

Evaluation of muscarinic agonist-induced analgesia in muscarinic acetylcholine receptor knockout mice.

Centrally active muscarinic agonists display pronounced analgesic effects. Identification of the specific muscarinic acetylcholine receptor (mAChR) subtype(s) mediating this activity is of considerable therapeutic interest. To examine the roles of the M(2) and M(4) receptor subtypes, the two G(i)/G(o)-coupled mAChRs, in mediating agonist-dependent antinociception, we generated a mutant mouse line deficient in both M(2) and M(4) mAChRs [M(2)/M(4) double-knockout (KO) mice]. In wild-type mice, systemic, intrathecal, or intracerebroventricular administration of centrally active muscarinic agonists resulted in robust analgesic effects, indicating that muscarinic analgesia can be mediated by both spinal and supraspinal mechanisms. Strikingly, muscarinic agonist-induced antinociception was totally abolished in M(2)/M(4) double-KO mice, independent of the route of application. The nonselective muscarinic agonist oxotremorine showed reduced analgesic potency in M(2) receptor single-KO mice, but retained full analgesic activity in M(4) receptor single-KO mice. In contrast, two novel muscarinic agonists chemically derived from epibatidine, CMI-936 and CMI-1145, displayed reduced analgesic activity in both M(2) and M(4) receptor single-KO mice, independent of the route of application. Radioligand binding studies indicated that the two CMI compounds, in contrast to oxotremorine, showed >6-fold higher affinity for M(4) than for M(2) receptors, providing a molecular basis for the observed differences in agonist activity profiles. These data provide unambiguous evidence that muscarinic analgesia is exclusively mediated by a combination of M(2) and M(4) mAChRs at both spinal and supraspinal sites. These findings should be of considerable relevance for the development of receptor subtype-selective muscarinic agonists as novel analgesic drugs.

Analgesia↗
PubMed2002

Modulation of upper airway collapsibility during sleep: influence of respiratory phase and flow regimen.

We hypothesized that upper airway collapsibility is modulated dynamically throughout the respiratory cycle in sleeping humans by alterations in respiratory phase and/or airflow regimen. To test this hypothesis, critical pressures were derived from upper airway pressure-flow relationships in six tracheostomized patients with obstructive sleep apnea. Pressure-flow relationships were generated by varying the pressure at the trachea and nose during tracheostomy (inspiration and expiration) (comparison A) and nasal (inspiration only) breathing (comparison B), respectively. When a constant airflow regimen was maintained throughout the respiratory cycle (tracheostomy breathing), a small yet significant decrease in critical pressure was found at the inspiratory vs. end- and peak-expiratory time point [7.1 +/- 1.6 (SE) to 6.6 +/- 1.9 to 6.1 +/- 1.9 cmH(2)O, respectively; P < 0.05], indicating that phasic factors exerted only a modest influence on upper airway collapsibility. In contrast, we found that the inspiratory critical pressure fell markedly during nasal vs. tracheostomy breathing [1.1 +/- 1.5 (SE) vs. 6.1 +/- 1.9 cmH(2)O; P < 0.01], indicating that upper airway collapsibility is markedly influenced by differences in airflow regimen. Tracheostomy breathing was also associated with a reduction in both phasic and tonic genioglossal muscle activity during sleep. Our findings indicate that both phasic factors and airflow regimen modulate upper airway collapsibility dynamically and suggest that neuromuscular responses to alterations in airflow regimen can markedly lower upper airway collapsibility during inspiration.

Adult↗