A challenging diagnosis of narcolepsy type 2 in a patient with Duane syndrome.

Duane syndrome is a form of congenital strabismus with horizontal eye movement limitation. This may present a diagnostic challenge when assessing for rapid eye movements during stage REM utilizing PSG or MSLT. We present a case of a child with Duane syndrome who presented with excessive daytime sleepiness and underwent evaluation for hypersomnia. His eye movement limitation provided a challenge in identifying stage REM. In patients with eye movement limitations or prosthetic eyes, it is necessary to look for other features of stage REM such as low chin EMG tone and EEG pattern.

A certified child life specialist influences the emotional response during polysomnography setup.

OBJECTIVES: To examine if the presence of a certified child life specialist (CCLS) had a positive impact on patient emotion at the time of polysomnography setup and to determine the optimal timing of CCLS intervention prior to polysomnography (PSG) in our sleep center. METHODS: We implemented a study which measured the impact of a CCLS on the emotional manifestation score (EMS) of pediatric patients (4 months-17 years, median 7 years) during PSG setup. CCLS intervention was either at the time of sleep medicine consultation (daytime) or during PSG setup (evening). We used Emotional Manifestations Scores (EMS) as well as patient/caregiver satisfaction data to measure the impact of a CCLS and inform decision-making regarding ongoing employment of a CCLS in our sleep lab. RESULTS: High EMS scores were noted during PSG setup in all groups indicating the emotional distress of children undergoing PSG. The EMS improved more when CCLS was present at the time of PSG setup. Statistically significant improvements occurred in level of cooperation, pain/discomfort, and child coping. Based on the results of the study, we hired a CCLS to work in our sleep center at the time of PSG setup 2 evenings per week. CONCLUSIONS: PSG is emotionally stressful for pediatric patients as seen on EMS. A CCLS present in the evening at our sleep lab led to an improvement in EMS in children being prepared for PSG set-up. After implementation of a CCLS two nights per week in our sleep lab, parents/caregiver satisfaction scores were higher on nights a CCLS was present at setup.

Double-mode relaxation of highly deformed anisotropic vesicles.

Lipid vesicles are known to undergo complex conformational transitions, but it remains challenging to systematically characterize nonequilibrium membrane dynamics in flow. Here, we report the direct observation of anisotropic vesicle relaxation from highly deformed shapes using a Stokes trap. Vesicle shape relaxation is described by two distinct characteristic timescales governed by the bending modulus and membrane tension. Interestingly, the fast double-mode timescale is found to depend on vesicle deflation or reduced volume. Experimental results are well described by a viscoelastic model of a deformed membrane. Overall, these results show that vesicle relaxation is governed by an interplay between membrane elastic moduli, surface tension, and vesicle deflation.

Enhancing the patient and family experience during pediatric sleep studies.

STUDY OBJECTIVES: Pediatric polysomnography can result in suboptimal patient and provider (physician and advanced practice provider) experiences. We embarked on a project aimed at increasing the proportion of maximal satisfaction survey scores by a minimum of 10% in 1 year without adding personnel or major expenses. METHODS: We used a Six Sigma framework, define, measure, analyze, improve, and control (DMAIC), to conduct our analysis. For measurement, we designed a project-specific survey that was given to caregivers of children who underwent PSG in February 2018 and repeated the survey after interventions in February 2019. Lean and Six Sigma quality improvement tools were used to define important processes that influence patient satisfaction, including: supplier, input, process, output, customer, and requirements (SIPOC-R); journey mapping; 1-2-4-All brainstorming; and views solicited from our center's Patient and Family Advisory Council. We analyzed the relationships between identified processes and outcomes using usual descriptive statistics. We prioritized interventions using a Kano model and a quality function deployment (QFD) technique to rank priorities for interventions. Multiple opportunities to improve patient and family satisfaction before, during, and after a pediatric polysomnography were identified. Many were simple, one-step interventions and were implemented simultaneously. For those that required substantial training and/or scheduling changes, pilots were performed and plan, do, study, act (PDSA) cycles were used to check effectiveness. RESULTS: After implementation, top box scores rose 20%, from 51% (n = 47) in 2018 to 71% (n = 50) in 2019. CONCLUSIONS: Various quality improvement techniques employed in business, engineering, and manufacturing were used to identify and address areas of improvement in the pediatric polysomnography experience.

Conformational dynamics and phase behavior of lipid vesicles in a precisely controlled extensional flow.

Lipid vesicles play a key role in fundamental biological processes. Despite recent progress, we lack a complete understanding of the non-equilibrium dynamics of vesicles due to challenges associated with long-time observation of shape fluctuations in strong flows. In this work, we present a flow-phase diagram for vesicle shape and conformational transitions in planar extensional flow using a Stokes trap, which enables control over the center-of-mass position of single or multiple vesicles in precisely defined flows [A. Shenoy, C. V. Rao and C. M. Schroeder, Proc. Natl. Acad. Sci. U. S. A., 2016, 113(15), 3976-3981]. In this way, we directly observe the non-equilibrium conformations of lipid vesicles as a function of reduced volume ν, capillary number Ca, and viscosity contrast λ. Our results show that vesicle dynamics in extensional flow are characterized by the emergence of three distinct shape transitions, including a tubular to symmetric dumbbell transition, a spheroid to asymmetric dumbbell transition, and quasi-spherical to ellipsoid transition. The experimental phase diagram is in good agreement with recent predictions from simulations [V. Narsimhan, A. P. Spann and E. S. Shaqfeh, J. Fluid Mech., 2014, 750, 144]. We further show that the phase boundary of vesicle shape transitions is independent of the viscosity contrast. Taken together, our results demonstrate the utility of the Stokes trap for the precise quantification of vesicle stretching dynamics in precisely defined flows.

Rayleigh-Taylor instabilities in high-energy density settings on the National Ignition Facility.

The Rayleigh-Taylor (RT) instability occurs at an interface between two fluids of differing density during an acceleration. These instabilities can occur in very diverse settings, from inertial confinement fusion (ICF) implosions over spatial scales of [Formula: see text] cm (10-1,000 µm) to supernova explosions at spatial scales of [Formula: see text] cm and larger. We describe experiments and techniques for reducing ("stabilizing") RT growth in high-energy density (HED) settings on the National Ignition Facility (NIF) at Lawrence Livermore National Laboratory. Three unique regimes of stabilization are described: (i) at an ablation front, (ii) behind a radiative shock, and (iii) due to material strength. For comparison, we also show results from nonstabilized "classical" RT instability evolution in HED regimes on the NIF. Examples from experiments on the NIF in each regime are given. These phenomena also occur in several astrophysical scenarios and planetary science [Drake R (2005) Plasma Phys Controlled Fusion 47:B419-B440; Dahl TW, Stevenson DJ (2010) Earth Planet Sci Lett 295:177-186].

Fishy aroma of social status: urinary chemo-signalling of territoriality in male fathead minnows (Pimephales promelas).

Chemical structures of several urinary reproductive pheromones in fish have been identified, and their role in the chemical communication of reproductive condition is well characterized. On the contrary, the role of chemical communication in signalling of social/territorial status in fish is poorly understood. Fathead minnows are an example of a fish species whose life history traits appear conducive to evolution of chemical communication systems that confer information about social/territorial status. Male reproduction in this species is dependent upon their ability to acquire and defend a high quality nesting territory, and to attract a female to the nest. We hypothesized that fathead minnow males use visual and urine-derived chemical cues to signal territorial status. To test this hypothesis, effects of territorial acquisition on male-specific secondary sex characteristics (SSCs) and urine volumes were first assessed. Second, frequencies of male urination in varying social contexts were examined. Finally, nuclear magnetic resonance-based metabolomics was used to identify urinary metabolites that were differentially excreted in the urine of territorial versus non-territorial males. The expression of SSCs, sperm, and urine volumes increased with territory acquisition, and either remained unchanged or decreased in non-territorial males. Frequency of male urination increased significantly in the presence of females (but not males), suggesting that females are the main target of the urinary signals. Territorial and non-territorial males had distinct urinary metabolomic profiles. An unforeseen finding was that one could discern future territorial status of males, based on their initial metabolomic profiles. Bile acids and volatile amines were identified as potential chemical signals of social status in the fathead minnow. The finding that trimethylamine (a fishy smelling volatile amine) may be a social cue is particularly interesting, because it is known to bind trace amine-associated receptors, indicating that these receptors may play role in chemical signalling of social status in fish.

Concept to diagnose mix with imaging x-ray Thomson scattering.

Turbulent mixing of two fluid species is a ubiquitous problem, prevalent in systems such as inertial confinement fusion (ICF) capsule implosions, supernova remnants, and other astrophysical systems. In complex, high Reynolds number compressible high energy density (HED) flows such as these, hydrodynamic instabilities initiate the turbulent mixing process, which can then feedback and alter the mean hydrodynamic motion through nonlinear processes. In order to predict how these systems evolve under turbulent conditions, models are used. However, these models require detailed quantitative data to validate and constrain their detailed physics models as well as improve them. Providing this much needed data is currently at the forefront of HED research but is proving elusive due to a lack of available diagnostics capable of directly measuring detailed flow variables. Thomson scattering is a promising technique in this regard as it provides fundamental conditions of the flow (ρ, T, Zbar) due to its direct interaction with the small scales of the fluid or plasma and was recently considered as a possible mix diagnostic. With the development of imaging x-ray Thomson scattering (IXRTS) obtaining spatial profiles of these variables is within reach. We propose a novel use of the IXRTS technique that will provide more detailed quantitative data required for model validation in mix experiments.

Analysis of residual solvents in 2-[(18)F]FDG by GC.

A gas chromatography method has been developed for the measurement of the residual acetone, ethanol and acetonitrile in 2-deoxy-2-[(18)F] fluoro-D-glucose (2-[(18)F]FDG), in accordance with the pending FDA revision on the drug. The detections limits were 0.1 ppm for all three solvents. Good precision and linearity were obtained over ranges spanning the allowable concentration levels proposed by FDA. The amounts of the three solvents in our routine 2-[(18)F]FDG products have been found well below the maximum permissible levels. The method is very amenable to quality control testing for the radiopharmaceutical.

Noninvasive estimation of the aorta input function for measurement of tumor blood flow with.

Quantitative measurement of tumor blood flow with [15O]water can be used to evaluate the effects of tumor treatment over time. Since quantitative flow measurements require an input function, we developed the profile fitting method (PFM) to measure the input function from positron emission tomography images of the aorta. First, a [11C]CO scan was acquired and the aorta region was analyzed. The aorta diameter was determined by fitting the image data with a model that includes scanner resolution, the measured venous blood radioactivity concentration, and the spillover of counts from the background. The diameter was used in subsequent fitting of [15O]water dynamic images to estimate the aorta and background radioactivity concentrations. Phantom experiments were performed to test the model. Image quantification biases (up to 15%) were found for small objects, particularly for those in a large elliptical phantom. However, the bias in the PFM concentration estimates was much smaller (2%-6%). A simulation study showed that PFM had less bias and/or variability in flow parameter estimates than an ROI method. PFM was applied to human [11C]CO and [15O]water dynamic studies with left ventricle input functions used as the gold standard. PFM parameter estimates had higher variability than found in the simulation but with minimal bias. These studies suggest that PFM is a promising technique for the noninvasive measurement of the aorta [15O]water input function.

Kinetic analysis of the 5-HT2A ligand [11C]MDL 100,907.

The goal of this study was to develop a suitable kinetic analysis method for quantification of 5-HT2A receptor parameters with [11C]MDL 100,907. Twelve control studies and four preblocking studies (400 nmol/kg unlabeled MDL 100,907) were performed in isoflurane-anesthetized rhesus monkeys. The plasma input function was determined from arterial blood samples with metabolite measurements by extraction in ethyl acetate. The preblocking studies showed that a two-tissue compartment model was necessary to fit the time activity curves of all brain regions including the cerebellum--in other words, the need for two compartments is not proof of specific binding. Therefore, a three-tissue compartment model was used to analyze the control studies, with three parameters fixed based on the preblocking data. Reliable fits of control data could be obtained only if no more than three parameters were allowed to vary. For routine use of [11C]MDL 100,907, several simplified methods were evaluated. A two-tissue (2T') compartment with one fixed parameter was the most reliable compartmental approach; a one-compartment model failed to fit the data adequately. The Logan graphical approach was also tested and produced comparable results to the 2T' model. However, a simulation study showed that Logan analysis produced a larger bias at higher noise levels. Thus, the 2T' model is the best choice for analysis of [11C]MDL 100,907 studies.

Biologically stable [(18)F]-labeled benzylfluoride derivatives.

Use of the [(18)F]-fluoromethyl phenyl group is an attractive alternative to direct fluorination of phenyl groups because the fluorination of the methyl group takes place under milder reaction conditions. However, we have found that 4-FMeBWAY showed femur uptake equal to that of fluoride up to 30 min in rat whereas 4-FMeQNB had a significantly lower percent injected dose per gram in femur up to 120 min. For these and other benzylfluoride derivatives, there was no clear in vivo structure-defluorination relationship. Because benzylchlorides (BzCls) are known alkylating agents, benzylfluorides may be alkylating agents as well, which may be the mechanism of defluorination. On this basis, the effects of substitution on chemical stability were evaluated by the 4-(4-nitro-benzyl)-pyridine (NBP) test, which is used to estimate alkylating activity with NBP. The effect of substitution on the alkylating activity was evaluated for nine BzCl derivatives: BzCl; 3- or 4-methoxy (electron donation) substituted BzCl; 2-, 3-, or 4-nitro (electron withdrawing) substituted BzCl; and 2-, 3-, or 4-chloro (electron withdrawing) substituted BzCl. Taken together, the alkylating reactivity of 3-chloro-BzCl was the weakest. This result was then applied to [(18)F]-benzylfluoride derivatives and in vivo and in vitro stability were evaluated. Consequently, 3-chloro-[(18)F]-benzylfluoride showed a 70-80% decrease of defluorination in both experiments in comparison with [(18)F]-benzylfluoride, as expected. Moreover, a good linear relationship between in vivo femur uptake and in vitro hepatocyte metabolism was observed with seven (18)F-labeled radiopharmaceuticals, which were benzylfluorides, alkylfluorides, and arylfluorides. Apparently, the [(18)F]-fluoride ion is released by metabolism in the liver in vivo. In conclusion, 3-chloro substituted BzCls are the most stable, which suggests that 3-chloro benzylfluorides will be the most chemically stable compound. This result should be important in future design of radioligands labeled with a benzylfluoride moiety.

Brain incorporation of [1-11C]arachidonate in normocapnic and hypercapnic monkeys, measured with positron emission tomography.

Positron emission tomography (PET) was used to determine brain incorporation coefficients k* of [1-11C]arachidonate in isoflurane-anesthetized rhesus monkeys, as well as cerebral blood flow (CBF) using [15O]water. Intravenously injected [1-11C]arachidonate disappeared from plasma with a half-life of 1.1 min, whereas brain radioactivity reached a steady-state by 10 min. Mean values of k* were the same whether calculated by a single-time point method at 20 min after injection began, or by least-squares fitting of an equation for total brain radioactivity to data at all time points. k* equalled 1.1-1.2 x 10(-4) ml x s(-1) x g(-1) in gray matter and was unaffected by a 2.6-fold increase in CBF caused by hypercapnia. These results indicate that brain incorporation of [1-11C]arachidonate can be quantified in the primate using PET, and that incorporation is flow-independent.

Synthesis and evaluation of radioiodinated 6-iodo-L-DOPA as a cerebral L-amino acid transport marker.

Regioselective radioiodination of N-trifluoroacetyl 3,4-dimethoxy-6-trifluoroacetoxymercurio-L-phenylalanine ethyl ester 1 under no-carrier-added condition gave 6-[125I]iodo protected L-DOPA with a labeling efficiency of more than 85%, and no-carrier-added 6-[125I]I-L-DOPA was obtained with a radio-chemical purity of over 95% after hydrolysis and chromatography. A nonradioactive standard of 6-iodo protected L-DOPA was synthesized by the iododemercuration of 6-mercuric trifluoroacetate protected L-DOPA 1 using I2 in chloroform. 6-[125I]I-L-DOPA showed high brain accumulation and rapid blood clearance in mice. The rat brain slice studies indicated high affinity of 6-[125I]I-L-DOPA for carrier-mediated and stereoselective active transport systems. The tissue homogenate analysis revealed that most of the accumulated radioactivity was intact 6-[125I]I-L-DOPA. Thus, 6-[123I]I-L-DOPA appears to be a suitable single photon emission computed tomography (SPECT) tracer for the selective measurement of cerebral L-amino acid transport, having no affinity for dopamine metabolism.

Synthesis of polymer-bound 6-mercuric carboxylate DOPA precursors and solid phase labelling method of 6-radioiodinated L-DOPA.

In order to avoid separating unreacted mercury precursor and other mercury-containing compounds after the halodemercuration of a 6-mercury DOPA precursor, we developed a polymer-bound mercury precursor for the preparation of 6-halogenated DOPA. In this study, polymer-bound 6-mercuric carboxylate DOPA derivatives were synthesized from ion-exchange resin and Merrifield-type resin. Iododemercuration of polymer-bound 6-mercuric carboxylate DOPA derivatives gave higher yields (49-54%) compared with monomeric 6-mercuric trifluoroacetate protected DOPA. The radioiodination of the resin with no-carrier added iodine-125 afforded protected 6-[125I]I-L-DOPA with labelling efficiency of 92-97% with both polymer-bound 6-mercuric carboxylate DOPA derivatives.

Incorporation of [1-carbon-11]palmitate in monkey brain using PET.

UNLABELLED: We determined regional incorporation coefficients (k*) of plasma [1-11C]palmitate into stable brain lipids of anesthetized monkeys with PET. METHODS: Carbon-11-palmitate was injected intravenously in untreated animals and in animals pretreated with methyl palmoxirate (MEP), an inhibitor of beta-oxidation of palmitate in the brain and periphery. Plasma radioactivity was followed, and brain radioactivity was determined at various times using PET. A least-squares method was used to fit the data to an operational equation to obtain regional values of k* and of cerebral blood volume (Vb) in individual experiments. RESULTS: MEP significantly decreased the integral of plasma [11C]CO2 following 11C-palmitate infusion. Mean values of k* in monkeys not given MEP were 4.9, 4.2, 4.9, 4.0 and 2.9 x 10(-5) ml/sec.g for the temporal, frontal, parietal and occipital cortices and white matter, respectively. With the exception of k* in white matter, which was increased by MEP, k* in the other brain regions was not significantly changed by MEP. The Vb ranged from 0.035 ml/g to 0.048 ml/g in gray matter regions and equaled 0.022 ml/g in white matter. CONCLUSION: PET can be used to determine regional incorporation coefficients of 11C-palmitate into the primate brain in vivo. Combined with MEP, 11C-palmitate could be used with PET to examine regional brain phospholipid metabolism in humans in normal and pathological conditions.

Synthesis of polymer-bound 6-thiolatomercury and 6-mercuric sulfonate DOPA precursors and their halodemercuration reactivity.

Fluorodemercuration has the greatest utility for the preparation of 6-[18F]DOPA, but requires separation from unreacted mercury precursor and other mercury-containing compounds. One approach is the development of a polymer-bound mercury precursor. In this study, polymer-bound 6-thiolatomercury and 6-mercuric sulfonate DOPA derivatives, and its monomeric analogs were synthesized. Fluorodemercuration of monomeric analog of mercuric sulfonate gave half the yield (14-15%) while iododemercuration gave the same yield (38%) compared with a 6-mercuric trifluoroacetate protected DOPA. The mercuric sulfonate undergoes halodemercuration, so polymer-bound halodemercuration precursors may be useful as precursors of 6-[18F]DOPA.

Comparison of bolus and infusion methods for receptor quantitation: application to [18F]cyclofoxy and positron emission tomography.

Positron emission tomography studies with the opiate antagonist [18F]cyclofoxy ([18F]CF) were performed in baboons. Bolus injection studies demonstrated initial uptake dependent on blood flow. The late uptake showed highest binding in caudate nuclei, amygdala, thalamus, and brainstem and the least accumulation in cerebellum. By 60 min postinjection, regional brain radioactivity cleared at the same rate as metabolite-corrected plasma, i.e., transient equilibrium was achieved. Compartmental modeling methods were applied to time-activity curves from brain and metabolite-corrected plasma. Individual rate constants were estimated with poor precision. The model estimate of the total volume of distribution (VT), representing the ratio of tissue radioactivity to metabolite-corrected plasma at equilibrium, was reliably determined. The apparent volume of distribution (Va), the concentration ratio of tissue to metabolite-corrected plasma during transient equilibrium, was compared with the fitted VT values to determine if single-scan methods could provide accurate receptor measurements. Va significantly overestimated VT and produced artificially high image contrast. These differences were predicted by compartment model theory and were caused by a plasma clearance rate that was close to the slowest tissue clearance rate. To develop a simple method to measure VT, an infusion protocol consisting of bolus plus continuous infusion (B/I) of CF was designed and applied in a separate set of studies. The Va values from the B/I studies agreed with the VT values from both B/I and bolus studies. This infusion approach can produce accurate receptor measurements and has the potential to shorten scan time and simplify the acquisition and processing of scan and blood data.

PET imaging of opiate receptor binding in human epilepsy using [18F]cyclofoxy.

We used [18F]cyclofoxy (CF), a potent opiate antagonist with affinity for mu and kappa receptors, and the Scanditronix PC1024-7B PET scanner to study 14 patients with complex partial seizures (CPS), and 14 normal controls. Epileptic foci were localized by prolonged EEG-video monitoring. EEG was recorded continuously during each scan. Immediately before CF administration, [15O]labeled water was used to measure cerebral blood flow, and showed hypoperfusion ipsilateral to the EEG focus. Blood samples (corrected for radiolabeled metabolites) and tissue time-activity data were acquired over 90 min following bolus CF injection. Anatomic regions were outlined directly on the PET images. A kinetic model was used to derive the total volume of distribution (Vt) in each brain region. Specific binding (Vs) was determined by substracting non-specific binding (Vt) measured in a receptor-poor brain region (occipital cortex). Regions with high Vs included mesial temporal lobes, thalamus, basal ganglia, and frontal cortex. Individual patients appeared to have higher binding in temporal lobe ipsilateral to the EEG focus, but there was no asymmetry for the patients as a group in mean Vt or Vs in anterior mesial, posterior mesial, anterior lateral, posterior lateral temporal cortex, thalamus, basal ganglia, or, for Vt, in regions of low specific binding: occipital lobe, parietal lobe, cerebellum.

In vivo imaging of insulin receptors in monkeys using 18F-labeled insulin and positron emission tomography.

We previously described a prosthetic group methodology for incorporating 18F into peptides and showed that 18F-labeled insulin (18F-insulin) binds to insulin receptors on human cells (IM-9 lymphoblastoid cells) with affinity equal to that of native insulin (1). We now report studies using 18F-insulin with positron emission tomography to study binding to insulin receptors in vivo. Positron emission tomography scans were performed in six rhesus monkeys injected with 0.3-1.4 mCi of 18F-insulin (approximately 0.1 nmol, SA 4-11 Ci/mumol). Integrity of the tracer in blood, determined by immunoprecipitation, was 94% of control for the first 5 min and decreased to 31% by 30 min. Specific, saturable uptake of 18F was observed in the liver and kidney. Coinjection of unlabeled insulin (200 U, approximately 1 nmol) with the 18F-insulin reduced liver and increased kidney uptake of the labeled insulin. Liver radioactivity was decreased by administration of unlabeled insulin at 3 min, but not 5 min, after administration of the tracer, while some kidney radioactivity could be displaced 5 min after injection. Clearance of 18F was predominantly in bile and urine. 18F-insulin is a suitable analogue for studying insulin receptor-ligand interactions in vivo, especially in the liver and kidney.