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Biomedical subjects

Philip L Smith

Publications and source records attributed to Philip L Smith.

At least 19 recordsLinked to original sources

Dual diffusion model for single-cell recording data from the superior colliculus in a brightness-discrimination task.

Monkeys made saccades to one of two peripheral targets based on the brightness of a central stimulus. Task difficulty was manipulated by varying the ratio of stimulus black-and-white pixels. Correct response probability for two monkeys varied directly with difficulty. Deep layer SC neurons exhibited robust presaccadic activity the magnitude of which was unaffected by task difficulty when the stimulus specified a saccade toward a target within the neuron's response field. Activity after stimuli specifying saccades to targets outside the response field was affected by task difficulty, increasing as the task became more difficult. A quantitative model derived from studies of human decision-making was fit to the behavioral data. The model assumes that information from the stimulus drives two independent diffusion processes. Simulated paths from the model were compared with neuron activity, assuming that firing rate is linearly related to position in the accumulation process. The firing rate data show delayed availability of discriminative information for fast, intermediate, and slow decisions when activity is aligned on the stimulus and very small differences in discriminative information when aligned on the saccade. The model produces exactly these patterns of results. The accumulation process is highly variable, allowing the process both to make errors, as is the case for the behavioral performance, and also to account for the firing rate results. Thus the dual diffusion model provides a quantitative account for both the behavior in a simple decision-making task as well as the patterns of activity in competing populations of neurons.

Animals↗

Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia.

Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH) and associated with dysregulation of lipid metabolisms and atherosclerosis. Causal relationships between OSA and metabolic abnormalities have not been established because of confounding effects of underlying obesity. The goal of the study was to determine if CIH causes lipid peroxidation and dyslipidemia in the absence of obesity and whether the degrees of dyslipidemia and lipid peroxidation depend on the severity of hypoxia. Lean C57BL/6J mice were exposed to CIH for 4 wk with a fractional inspired O2 (FI(O2)) nadir of either 10% (moderate CIH) or 5% (severe CIH). Mice exposed to severe CIH exhibited significant increases in fasting serum levels of total cholesterol (129 +/- 2.9 vs. 113 +/- 2.8 mg/dl in control mice, P < 0.05) and low-density lipoprotein cholesterol (85.7 +/- 8.9 vs. 56.4 +/- 9.7 mg/dl, P < 0.05) in conjunction with a 1.5- to 2-fold increase in lipoprotein secretion, and upregulation of hepatic stearoyl coenzyme A desaturase 1 (SCD-1). Severe CIH also markedly increased lipid peroxidation in the liver (malondialdehyde levels of 94.4 +/- 5.4 vs. 57.4 +/- 5.2 nmol/mg in control mice, P < 0.001). In contrast, moderate CIH did not induce hyperlipidemia or change in hepatic SCD-1 levels but did cause lipid peroxidation in the liver at a reduced level relative to severe CIH. In conclusion, CIH leads to hypercholesterolemia and lipid peroxidation in the absence of obesity, and the degree of metabolic dysregulation is dependent on the severity of the hypoxic stimulus.

Animals↗

Neuromechanical control of upper airway patency during sleep.

Obstructive sleep apnea is caused by pharyngeal occlusion due to alterations in upper airway mechanical properties and/or disturbances in neuromuscular control. The objective of the study was to determine the relative contribution of mechanical loads and dynamic neuromuscular responses to pharyngeal collapse during sleep. Sixteen obstructive sleep apnea patients and sixteen normal subjects were matched on age, sex, and body mass index. Pharyngeal collapsibility, defined by the critical pressure, was measured during sleep. The critical pressure was partitioned between its passive mechanical properties (passive critical pressure) and active dynamic responses to upper airway obstruction (active critical pressure). Compared with normal subjects, sleep apnea patients demonstrated elevated mechanical loads as demonstrated by higher passive critical pressures [-0.05 (SD 2.4) vs. -4.5 cmH2O (SD 3.0), P = 0.0003]. Dynamic responses were depressed in sleep apnea patients, as suggested by failure to lower their active critical pressures [-1.6 (SD 3.5) vs. -11.1 cmH2O (SD 5.3), P < 0.0001] in response to upper airway obstruction. Moreover, elevated mechanical loads placed some normal individuals at risk for sleep apnea. In this subset, dynamic responses to upper airway obstruction compensated for mechanical loads and maintained airway patency by lowering the active critical pressure. The present study suggests that increased mechanical loads and blunted neuromuscular responses are both required for the development of obstructive sleep apnea.

Adult↗

Dynamic modulation of upper airway function during sleep: a novel single-breath method.

To examine the dynamic modulation of upper airway (UA) function during sleep, we devised a novel approach to measuring the critical pressure (Pcrit) within a single breath in tracheostomized sleep apnea patients. We hypothesized that the UA continuously modulates airflow dynamics during transtracheal insufflation. In this study, we examine tidal pressure-flow relationships throughout the respiratory cycle to compare phasic differences in UA collapsibility between closure and reopening. Five apneic subjects (with tracheostomy) were recruited (2 men, 3 women; 18-50 yr; 20-35 kg/m2; apnea-hypopnea index >20) for this polysomnographic study. Outgoing airflow through the UA (face mask pneumotachograph) and tracheal pressure were recorded during brief transtracheal administration of insufflated airflow via a catheter. Pressure-flow relationships were generated from deflation (approaching Pcrit) and inflation (after Pcrit) of the UA during non-rapid eye movement sleep. During each breath, UA function was described by a pressure-flow relationship that defined the collapsibility (Pcrit) and upstream resistance (Rus). UA characteristics were examined in the presence and absence of complete UA occlusion. We demonstrated that Pcrit and Rus changed dynamically throughout the respiratory cycle. The UA closing pressure (4.4 +/- 2.0 cm H2O) was significantly lower than the opening pressure (10.8 +/- 2.4 cm H2O). Rus was higher for deflation (18.1 +/- 2.4 cm H2O x l(-1) x s) than during inflation (7.5 +/- 1.9 cm H2O x l(-1) x s) of the UA. Preventing occlusion decreases UA pressure-flow loop hysteresis by approximately 4 cm H2O. These findings indicate that UA collapsibility varies dynamically throughout the respiratory cycle and that both local mechanical and neuromuscular factors may be responsible for this dynamic modulation of UA function during sleep.

Adolescent↗

Tetraoxane antimalarials and their reaction with Fe(II).

Mixed tetraoxanes 5a and 13 synthesized from cholic acid and 4-oxocyclohexanecarboxylic acid were as active as artemisinin against chloroquine-susceptible, chloroquine-resistant, and multidrug-resistant Plasmodium falciparum strains (IC50, IC90). Most active 13 is metabolically stable in in vitro metabolism studies. In vivo studies on tetraoxanes with a C(4' ') methyl group afforded compound 15, which cured 4/5 mice at 600 and 200 mg.kg-1.day-1, and 2/5 mice at 50 mg.kg-1.day-1, showing no toxic effects. Tetraoxane 19 was an extremely active antiproliferative with LC50 of 17 nM and maximum tolerated dose of 400 mg/kg. In Fe(II)-induced scission of tetraoxane antimalarials only RO* radicals were detected by EPR experiments. This finding and the indication of Fe(IV)=O species led us to propose that RO* radicals are probably capable of inducing the parasite's death. Our results suggest that C radicals are possibly not the only lethal species derived from peroxide prodrug antimalarials, as currently believed.

Animals↗

Childhood obstructive sleep apnea associates with neuropsychological deficits and neuronal brain injury.

BACKGROUND: Childhood obstructive sleep apnea (OSA) is associated with neuropsychological deficits of memory, learning, and executive function. There is no evidence of neuronal brain injury in children with OSA. We hypothesized that childhood OSA is associated with neuropsychological performance dysfunction, and with neuronal metabolite alterations in the brain, indicative of neuronal injury in areas corresponding to neuropsychological function. METHODS AND FINDINGS: We conducted a cross-sectional study of 31 children (19 with OSA and 12 healthy controls, aged 6-16 y) group-matched by age, ethnicity, gender, and socioeconomic status. Participants underwent polysomnography and neuropsychological assessments. Proton magnetic resonance spectroscopic imaging was performed on a subset of children with OSA and on matched controls. Neuropsychological test scores and mean neuronal metabolite ratios of target brain areas were compared. Relative to controls, children with severe OSA had significant deficits in IQ and executive functions (verbal working memory and verbal fluency). Children with OSA demonstrated decreases of the mean neuronal metabolite ratio N-acetyl aspartate/choline in the left hippocampus (controls: 1.29, standard deviation [SD] 0.21; OSA: 0.91, SD 0.05; p = 0.001) and right frontal cortex (controls: 2.2, SD 0.4; OSA: 1.6, SD 0.4; p = 0.03). CONCLUSIONS: Childhood OSA is associated with deficits of IQ and executive function and also with possible neuronal injury in the hippocampus and frontal cortex. We speculate that untreated childhood OSA could permanently alter a developing child's cognitive potential.

Adolescent↗

Intermittent hypoxia causes REM sleep deficits and decreases EEG delta power in NREM sleep in the C57BL/6J mouse.

BACKGROUND AND PURPOSE: Obstructive sleep apnea (OSA) severely impairs sleep architecture. We hypothesized that both intermittent hypoxia (IH) and non-hypoxic arousals of OSA result in significant disruption of non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS). PATIENTS AND METHODS: Polysomnography was performed in C57BL/6J mice (n=5) exposed to IH (cycling of FIO2 from 20.9 to 5.0%) or sleep fragmentation (SF: high flow air blasts) throughout the 12-h light phase over 5 consecutive days. RESULTS: Both IH and SF induced arousals from sleep. On Day 1 of exposure, total NREMS during the light phase decreased comparably during IH (44.1+/-7.8%/12h, P<0.05) and SF (43.7+/-3.3%/12h, P<0.05) but returned to baseline levels of 62.0+/-7.8%/12h by Day 5 of exposure under both conditions. During IH, however, the electroencephalographic (EEG) delta power of NREMS remained impaired throughout the 5-day period of IH with a nadir of 65.4+/-5.6% relative to baseline (P=0.01), and REMS was effectively abolished during the light phase. In contrast, SF did not cause a significant reduction in either EEG delta power or REMS during the light phase. CONCLUSIONS: Thus, hypoxic exposure, but not arousals, caused overall deficits in the EEG delta power of NREMS and marked deficits in the total amount of REMS. We propose that hypoxic arousals may have a more severe impact on sleep architecture in patients with OSA than non-hypoxic arousals.

Animals↗

Intermittent hypoxia induces hyperlipidemia in lean mice.

Obstructive sleep apnea, a syndrome leading to recurrent intermittent hypoxia (IH), has been associated previously with hypercholesterolemia, independent of underlying obesity. We examined the effects of experimentally induced IH on serum lipid levels and pathways of lipid metabolism in the absence and presence of obesity. Lean C57BL/6J mice and leptin-deficient obese C57BL/6J-Lep(ob) mice were exposed to IH for five days to determine changes in serum lipid profile, liver lipid content, and expression of key hepatic genes of lipid metabolism. In lean mice, exposure to IH increased fasting serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, phospholipids (PLs), and triglycerides (TGs), as well as liver TG content. These changes were not observed in obese mice, which had hyperlipidemia and fatty liver at baseline. In lean mice, IH increased sterol regulatory element binding protein 1 (SREBP-1) levels in the liver, increased mRNA and protein levels of stearoyl-coenzyme A desaturase 1 (SCD-1), an important gene of TG and PL biosynthesis controlled by SREBP-1, and increased monounsaturated fatty acid content in serum, which indicated augmented SCD-1 activity. In addition, in lean mice, IH decreased protein levels of scavenger receptor B1, regulating uptake of cholesterol esters and HDL by the liver. We conclude that exposure to IH for five days increases serum cholesterol and PL levels, upregulates pathways of TG and PL biosynthesis, and inhibits pathways of cholesterol uptake in the liver in the lean state but does not exacerbate the pre-existing hyperlipidemia and metabolic disturbances in leptin-deficient obesity.

Animals↗

Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice.

Obstructive sleep apnea (OSA), a condition tightly linked to obesity, leads to chronic intermittent hypoxia (CIH) during sleep. There is emerging evidence that OSA is independently associated with insulin resistance and fatty liver disease, suggesting that OSA may affect hepatic lipid metabolism. To test this hypothesis, leptin-deficient obese (ob/ob) mice were exposed to CIH during the light phase (9 AM-9 PM) for 12 wk. Liver lipid content and gene expression profile in the liver (Affymetrix 430 GeneChip with real-time PCR validation) were determined on completion of the exposure. CIH caused a 30% increase in triglyceride and phospholipid liver content (P < 0.05), whereas liver cholesterol content was unchanged. Gene expression analysis showed that CIH upregulated multiple genes controlling 1) cholesterol and fatty acid biosynthesis [malic enzyme and acetyl coenzyme A (CoA) synthetase], 2) predominantly fatty acid biosynthesis (acetyl-CoA carboxylase and stearoyl-CoA desaturases 1 and 2), and 3) triglyceride and phospholipid biosynthesis (mitochondrial glycerol-3-phosphate acyltransferase). A majority of overexpressed genes were transcriptionally regulated by sterol regulatory element-binding protein (SREBP) 1, a master regulator of lipogenesis. A 2.8-fold increase in SREBP-1 gene expression in CIH was confirmed by real-time PCR (P = 0.001). Expression of major genes of cholesterol biosynthesis, SREBP-2 and 3-hydroxy-3-methylglutaryl-CoA reductase, was unchanged. In conclusion, we have shown that CIH may exacerbate preexisting fatty liver of obesity via upregulation of the pathways of lipid biosynthesis in the liver.

Animals↗

In vitro metabolism of phenoxypropoxybiguanide analogues in human liver microsomes to potent antimalarial dihydrotriazines.

Phenoxypropoxybiguanides, such as 1 (PS-15), are prodrugs analogous to the relationship of proguanil and its active metabolite cycloguanil. Unlike cycloguanil, however, 1a (WR99210), the active metabolite of 1, has retained in vitro potency against newly emerging antifolate-resistant malaria parasites. Unfortunately, manufacturing processes and gastrointestinal intolerance have prevented the clinical development of 1. In vitro antimalarial activity and in vitro metabolism studies have been performed on newly synthesized phenoxypropoxybiguanide analogues. All of the active dihydrotriazine metabolites exhibited potent antimalarial activity with in vitro IC(50) values less than 0.04 ng/mL. In vitro metabolism studies in human liver microsomes identified the production of not only the active dihydrotriazine metabolite, but also a desalkylation on the carbonyl chain, and multiple hydroxylated metabolites. The V(max) for production of the active metabolites ranged from 10.8 to 27.7 pmol/min/mg protein with the K(m) ranging from 44.8 to 221 microM. The results of these studies will be used to guide the selection of a lead candidate.

Animals↗

Moments in time: metacognition, trust, and outcomes in dyadic negotiations.

This research tested the relationships between turning points, cognitive and affective trust, and negotiation outcomes. After completing a simulated negotiation, participants identified turning points from videotape. Turning points were then classified as substantive (interest, offer), characterization (positive, negative), or procedural (positive, negative). Prenegotiation affective trust predicted subsequent turning points, whereas prenegotiation cognitive trust did not, suggesting that different cues influence the two types of trust. Postnegotiation cognitive trust was increased by the occurrence of interest, positive characterization, and positive procedural turning points and decreased by negative characterization turning points. Affective trust was increased by positive procedural turning points. Finally, interest turning points resulted in higher joint outcomes, whereas negative characterization turning points resulted in lower joint outcomes. We conclude that there are two paths to building trust and increasing joint gain, one through insight and one through signaling good faith intentions.

Adult↗

9th International drug delivery technologies & deal-making summit.

SRI's 9th International drug delivery summit analysed the current position of drug delivery technologies within the pharmaceutical industry. The classical position of drug delivery as a tool in life cycle management is currently expanding into the primary formulations or even into enabling positions. Using drug delivery as a platform for drug development or redevelopment was recognised as a trend in the industry which is supported by the rapidly growing portion of drug delivery enhanced products already sold as well as by industry initiatives supporting future growth of the sector.

Drug Delivery Systems↗

Michael addition reactions with eta2-coordinated anisoles: controlling the stereochemistry of the para and benzylic carbons.

Several eta(2)-coordinated anisole complexes were treated with various Michael acceptors in the presence of a Lewis or Bronsted acid to generate stable 4H-anisolium complexes. These reactions were found to proceed with high stereochemical control with predictable outcomes, provided that the moderate acid (NH(2)Ph(2))OTf was used and the complex was dissolved in an acidic solution. The stereochemistry is shown to originate from an unexpectedly high preference for one coordination diastereomer of the anisole complex in the solid state and a Diels-Alder like transition state for the Michael reaction.

Anisoles↗

Differences in patient and bed partner-assessed quality of life in sleep-disordered breathing.

Sleep-disordered breathing (SDB) is associated with daytime sleepiness and impaired quality of life. Clinical experience suggests that there is a discrepancy between the information provided by the patient and the bed partner. Although this discrepancy is widely recognized, it is not known whether there are differences in quality of life ratings as reported by the patient and by the bed partner on the patient's behalf. Using the Short-Form 36 to assess quality of life in 122 patients with SDB (apnea-hypopnea index > or = 5 events/hour), this study found that patients with SDB generally rate their quality of life higher than their respective bed partners. Systematic differences existed between the two raters in the following Short-Form 36 domains: physical functioning, general health, and vitality. Moreover, male patients reported a higher functional status compared with female patients relative to their respective bed partners. In contrast, no differences were noted between self and bed partner quality of life in normal subjects (n = 15) without SDB (apnea-hypopnea index < 5 events/hour) recruited from the general community. This study suggests that systematic differences exist between patient- and bed partner-assessed quality of life in SDB. Bed partner ratings provide supplemental information on quality of life impairment in SDB.

Adult↗

A simplified method for measuring critical pressures during sleep in the clinical setting.

Upper airway critical pressure measurements correlate with the degree of upper airway obstruction during sleep and may have a role in the diagnosis and treatment of obstructive sleep apnea. Nevertheless, the utility of the critical pressure has not yet been realized in the clinical setting because significant technical expertise is still required for the acquisition and analysis of pressure-flow data. Using segmented regression, we developed and validated a simplified approach to analyze the pressure-flow relationship and to determine the effects of protocol-related factors in 44 subjects with sleep apnea. When compared with expert visual analysis, segmented regression method was found to accurately determine the critical pressure (-0.98 +/- 2.47 cm H(2)O vs. -1.07 +/- 2.47 cm H(2)O, respectively; p = 0.46). Furthermore, it was found that two series of measurements acquired at varying nasal pressure levels with two or more breaths per level were sufficient to determine the critical pressure with a minimum of variability. Therefore, this analytic approach has the potential for standardizing and simplifying the ascertainment of the critical pressure for studies examining the effect of therapeutic devices and agents on upper airway collapsibility during sleep.

Airway Resistance↗

Psychology and neurobiology of simple decisions.

Patterns of neural firing linked to eye movement decisions show that behavioral decisions are predicted by the differential firing rates of cells coding selected and nonselected stimulus alternatives. These results can be interpreted using models developed in mathematical psychology to model behavioral decisions. Current models assume that decisions are made by accumulating noisy stimulus information until sufficient information for a response is obtained. Here, the models, and the techniques used to test them against response-time distribution and accuracy data, are described. Such models provide a quantitative link between the time-course of behavioral decisions and the growth of stimulus information in neural firing data.

Action Potentials↗

Attention orienting and the time course of perceptual decisions: response time distributions with masked and unmasked displays.

Mask-dependent cuing effects, like those previously found in yes-no detection, were found in a task in which observers judged the orientations of orthogonally-oriented Gabor patches presented at cued or uncued locations. Attentional cues enhanced sensitivity for masked, but not unmasked, stimuli. Responses were faster to cued than to uncued stimuli, irrespective of masking. The distributions of response times and accuracy were well described by a diffusion process model of decision making. Mask-dependent cuing was explained by an orienting model in which: (a) decisions are based on stable stimulus representations in visual short term memory that determine the rate of evidence accumulation in the diffusion process; (b) inattention delays the entry of stimuli into short term memory, and (c) masks limit the visual persistence of stimuli.

Attention↗

A comparison of sequential sampling models for two-choice reaction time.

The authors evaluated 4 sequential sampling models for 2-choice decisions--the Wiener diffusion, Ornstein-Uhlenbeck (OU) diffusion, accumulator, and Poisson counter models--by fitting them to the response time (RT) distributions and accuracy data from 3 experiments. Each of the models was augmented with assumptions of variability across trials in the rate of accumulation of evidence from stimuli, the values of response criteria, and the value of base RT across trials. Although there was substantial model mimicry, empirical conditions were identified under which the models make discriminably different predictions. The best accounts of the data were provided by the Wiener diffusion model, the OU model with small-to-moderate decay, and the accumulator model with long-tailed (exponential) distributions of criteria, although the last was unable to produce error RTs shorter than correct RTs. The relationship between these models and 3 recent, neurally inspired models was also examined.

Choice Behavior↗