Hypoperfusion intensity ratio correlates with angiographic collaterals in acute ischaemic stroke with M1 occlusion.

BACKGROUND AND PURPOSE: Among patients with an acute ischaemic stroke secondary to large-vessel occlusion, the hypoperfusion intensity ratio (HIR) [time to maximum (TMax) > 10 volume/TMax > 6 volume] is a strong predictor of infarct growth. We studied the correlation between HIR and collaterals assessed with digital subtraction angiography (DSA) before thrombectomy. METHODS: Between January 2014 and March 2018, consecutive patients with an acute ischaemic stroke and an M1 middle cerebral artery (MCA) occlusion who underwent perfusion imaging and endovascular treatment at our center were screened. Ischaemic core (mL), HIR and perfusion mismatch (TMax > 6 s minus core volume) were assessed through magnetic resonance imaging or computed tomography perfusion. Collaterals were assessed on pre-intervention DSA using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) scale. Baseline clinical and perfusion characteristics were compared between patients with good (ASITN/SIR score 3-4) and those with poor (ASITN/SIR score 0-2) DSA collaterals. Correlation between HIR and ASITN/SIR scores was evaluated using Pearson's correlation. Receiver operating characteristic analysis was performed to determine the optimal HIR threshold for the prediction of good DSA collaterals. RESULTS: A total of 98 patients were included; 49% (48/98) had good DSA collaterals and these patients had significantly smaller hypoperfusion volumes (TMax > 6 s, 89 vs. 125 mL; P = 0.007) and perfusion mismatch volumes (72 vs. 89 mL; P = 0.016). HIR was significantly correlated with DSA collaterals (-0.327; 95% confidence interval, -0.494 to -0.138; P = 0.01). An HIR cut-off of <0.4 best predicted good DSA collaterals with an odds ratio of 4.3 (95% confidence interval, 1.8-10.1) (sensitivity, 0.792; specificity, 0.560; area under curve, 0.708). CONCLUSION: The HIR is a robust indicator of angiographic collaterals and might be used as a surrogate of collateral assessment in patients undergoing magnetic resonance imaging. HIR <0.4 best predicted good DSA collaterals.

Population pharmacokinetics of ϵ-aminocaproic acid in adolescents undergoing posterior spinal fusion surgery.

BACKGROUND: Despite demonstrated efficacy of ϵ-aminocaproic acid (EACA) in reducing blood loss in adolescents undergoing spinal fusion, there are no population-specific pharmacokinetic data to guide dosing. The aim of this study was to determine the pharmacokinetics of EACA in adolescents undergoing spinal fusion surgery and make dosing recommendations. METHODS: Twenty children ages 12-17 years were enrolled, with 10 children in each of two groups based on diagnosis (idiopathic scoliosis or non-idiopathic scoliosis). Previously reported data from infants undergoing craniofacial surgery were included in the model to enable dosing recommendations over a wide range of weights, ages, and diagnoses. A population non-linear mixed effects modelling approach was used to characterize EACA pharmacokinetics. RESULTS: Population pharmacokinetic parameters were estimated using a two-compartment disposition model with allometrically scaled weight and an age effect on clearance. Pharmacokinetic parameters for the typical patient were a plasma clearance of 153 ml min(-1) 70 kg(-1) (6.32 ml min(-1) kg(-0.75)), intercompartmental clearance of 200 ml min(-1) 70 kg(-1) (8.26 ml min(-1) kg(-0.75)), central volume of distribution of 8.78 litre 70 kg(-1) (0.13 litre kg(-1)), and peripheral volume of distribution of 15.8 litre 70 kg(-1) (0.23 litre kg(-1)). Scoliosis aetiology did not have a clinically significant effect on drug pharmacokinetics. CONCLUSIONS: The following dosing schemes are recommended according to patient weight: weight <25 kg, 100 mg kg(-1) loading dose and 40 mg kg(-1) h(-1) infusion; weight ≤25 kg-<50 kg, 100 mg kg(-1) loading dose and 35 mg kg(-1) h(-1) infusion; and weight ≥50 kg, 100 mg kg(-1) loading dose and 30 mg kg(-1) h(-1) infusion. An efficacy trial employing this dosing strategy is warranted. CLINICAL TRIAL REGISTRATION: NCT01408823.

The five myths of MMN: redefining how to use MMN in basic and clinical research.

The goal of this review article is to redefine what the mismatch negativity (MMN) component of event-related potentials reflects in auditory scene analysis, and to provide an overview of how the MMN serves as a valuable tool in Cognitive Neuroscience research. In doing so, some of the old beliefs (five common 'myths') about MMN will be dispelled, such as the notion that MMN is a simple feature discriminator and that attention itself modulates MMN elicitation. A revised description of what MMN truly reflects will be provided, which includes a principal focus onto the highly context-dependent nature of MMN elicitation and new terminology to discuss MMN and attention. This revised framework will help clarify what has been a long line of seemingly contradictory results from studies in which behavioral ability to hear differences between sounds and passive elicitation of MMN have been inconsistent. Understanding what MMN is will also benefit clinical research efforts by providing a new picture of how to design appropriate paradigms suited to various clinical populations.

Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery.

BACKGROUND: Understanding the clinical pharmacology of the antifibrinolytic epsilon-aminocaproic acid (EACA) is necessary for rational drug administration in children. The aim of this study is to determine the pharmacokinetics (PKs) of EACA in infants aged 6-24 months undergoing craniofacial reconstruction surgery. METHODS: Cohorts of six infants were enrolled sequentially to one of the three escalating loading dose-continuous i.v. infusion (CIVI) regimens: 25 mg kg(-1), 10 mg kg(-1) h(-1); 50 mg kg(-1), 20 mg kg(-1) h(-1); 100 mg kg(-1), 40 mg kg(-1) h(-1). Plasma EACA concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population non-linear mixed effects modelling approach was used to characterize EACA PKs. RESULTS: Population PK parameters of EACA were estimated using a two-compartment disposition model with weight expressed as an allometric covariate and an age effect. The typical patient in this study had an age of 38.71 weeks and a weight of 8.82 kg. PK parameters for this typical patient were: pre-/postoperative plasma drug clearance of 32 ml min(-1) (3.6 ml kg(-1) min(-1)), inter-compartmental clearance of 42.4 ml min(-1) (4.8 ml min(-1) kg(-1)), central volume of distribution of 1.27 litre (0.14 litre kg(-1)), and peripheral volume of distribution of 2.53 litre (0.29 litre kg(-1)). Intra-operative clearance and central volume of distribution were 89% and 80% of the pre-/postoperative value, respectively. CONCLUSIONS: EACA clearance increased with weight and age. The dependence of clearance on body weight supports weight-based dosing. Based on this study, a loading dose of 100 mg kg(-1) followed by a CIVI of 40 mg kg(-1) h(-1) is appropriate to maintain target plasma EACA concentrations in children aged 6-24 months undergoing these procedures.

Functionalized solid lipid nanoparticles for transendothelial delivery.

The objectives of this study were to synthesize and characterize functionalized solid lipid nanoparticles (fSLN) to investigate their interaction with endothelial cell monolayers and to evaluate their transendothelial transport capabilities. fSLN bearing tetramethylrhodamine-isothiocyanate-labeled bovine serum albumin (TRITC-BSA) and Coumarin 6 were prepared using a single-step phase-inversion process that afforded concurrent surface modification with a variety of macromolecules such as polystyrene sulfonate (PSS), poly-L-lysine (PLL), heparin (Hep), polyacrylic acid (PAA), polyvinyl alcohol, and polyethylene glycol (PEG). TRITC-BSA/Coumarin 6 encapsulated in fSLN with composite surface functionality (PSS-PLL and PSS-PLL-Hep) were also investigated. Size and surface charge of fSLN were analyzed using dynamic light scattering and transmission electron microscopy. Transport across bovine aortic endothelial cell (BAEC) monolayers was assessed spectrophotometrically using a transwell assay, and fSLN localization at the level of the cell and permeable support was analyzed using fluorescence microscopy. fSLN with tunable size and surface functionality were successfully produced, and had significant effects on cell localization and transport. Specifically, fSLN with PSS-PLL-Hep composite surface functionalization was capable of translocating 53.2 +/- 8.7 mug of TRITC-BSA within 4 h, with fSLN-PEG, fSLN-PAA, and fSLN-PSS exhibiting near-complete apical, paracellular, and cytosolic localization, respectively. Coumarin 6 was released by fSLN as indicated by dye labeling of BAEC membranes. We have developed a rapid process for the production of fSLN bearing low- and high-molecular-weight payloads of varying physicochemical properties. These findings have impications for drug delivery and bioimaging applications, since due to tunable surface chemistry, fSLN internalization and/or translocation across intact endothelial cell monolayers is possible.

The maturation of human evoked brain potentials to sounds presented at different stimulus rates.

The current study assessed the normal development of cortical auditory evoked potentials (CAEPs) in humans presented with pure tone stimuli at relatively fast stimulus rates. Traditionally, maturation of sound processing indexed by CAEPs has been studied in paradigms using inter-stimulus intervals (ISIs) generally slower than 1 Hz. While long ISIs may enhance the amplitude of CAEP components, speech information generally occurs at more rapid rates. These slower rates of sound presentation may not accurately assess auditory cortical functions in more realistic sound environments. We examined the effect of temporal rate on the elicitation of the P1-N1-P2-N2 components to unattended sounds at four levels of stimulus onset asynchrony (SOA, onset to onset, 200, 400, 600, and 800 ms) in children grouped separately by year (ages 8, 9, 10, 11 years), in adolescents (age 16 years) and in one group of young adults (ages 22-40 years). We found that both age and stimulus rate produced profound changes in CAEP morphology. Between the ages of 8-11 years, the P1 and N2 components dominated the ERP waveform at all stimulus rates. N1, the dominant CAEP component in adults, appeared as a bifurcation in a broad positive peak at earlier ages, and did not emerge as a separate component until adolescence. While the P1-N1-P2 components are more "adult-like" than "child-like" in the adolescent subjects, the N2 component, a hallmark of the child obligatory response, was still present. Faster rates resulted in the suppression of discrete components such that by 200 ms, only P1 in the adults and adolescents, and both P1 and N2 in the youngest children were discernable. We conclude that both age and ISI are important variables in the assessment of auditory cortex function and maturation. The presence of N2 in adolescents indicates that auditory cortical maturation persists into teen years.

The development of the perceptual organization of sound by frequency separation in 5-11-year-old children.

The analysis of the auditory scene begins from the moment we hear sounds, making it possible for the infant to distinguish the mother's voice from other sounds in the environment. The purpose of the study was to determine, in two experiments, whether the frequency separation threshold, at which the perception of a mixture of sounds turns from being perceived as one stream to two streams, differs between two groups of school-aged children (ages 5-8 and 9-11 years) and adults. The results show a developmental course for the perception of auditory streams that is not simply dependent upon frequency discrimination. This suggests that maturation of the stream segregation process follows a longer developmental course than maturation of simple feature discrimination. The data indicate that the ability to hear distinct sound streams in the environment takes time to develop and becomes sharpened with experience and maturity.

"Primitive intelligence" in the auditory cortex.

The everyday auditory environment consists of multiple simultaneously active sources with overlapping temporal and spectral acoustic properties. Despite the seemingly chaotic composite signal impinging on our ears, the resulting perception is of an orderly "auditory scene" that is organized according to sources and auditory events, allowing us to select messages easily, recognize familiar sound patterns, and distinguish deviant or novel ones. Recent data suggest that these perceptual achievements are mainly based on processes of a cognitive nature ("sensory intelligence") in the auditory cortex. Even higher cognitive processes than previously thought, such as those that organize the auditory input, extract the common invariant patterns shared by a number of acoustically varying sounds, or anticipate the auditory events of the immediate future, occur at the level of sensory cortex (even when attention is not directed towards the sensory input).

Molecular pathways of adhesion in spontaneous rosetting of T-lymphocytes to the Hodgkin's cell line L428.

Spontaneous rosetting of T-lymphocytes to Reed-Sternberg cells has been observed both in vitro and in vivo but its molecular mechanism has not been defined. We have investigated such rosetting using the Hodgkin's cell line L428. L428 expresses high levels of LFA-3 and ICAM-1, both of which are ligands for T-cell adhesion. Monoclonal antibody inhibition of spontaneous rosetting indicated that it is not dependent on the T-cell receptor complex but is largely mediated by interaction of T-cell CD2 (T11/E-rosette receptor) with its ligand LFA-3 on L428 cells. Studies using an alternate assay of adhesion (conjugate formation) confirm the roles of CD2/LFA-3 and also implicate a second mode of binding via LFA-1 on T-cells to ICAM-1 on L428. These data explain the previously reported finding of T-cell rosetting with Reed-Sternberg cells as an exaggeration of normal antigen-independent T-cell adhesion.

Auditory scene analysis in school-aged children with developmental language disorders.

Natural sound environments are dynamic, with overlapping acoustic input originating from simultaneously active sources. A key function of the auditory system is to integrate sensory inputs that belong together and segregate those that come from different sources. We hypothesized that this skill is impaired in individuals with phonological processing difficulties. There is considerable disagreement about whether phonological impairments observed in children with developmental language disorders can be attributed to specific linguistic deficits or to more general acoustic processing deficits. However, most tests of general auditory abilities have been conducted with a single set of sounds. We assessed the ability of school-aged children (7-15 years) to parse complex auditory non-speech input, and determined whether the presence of phonological processing impairments was associated with stream perception performance. A key finding was that children with language impairments did not show the same developmental trajectory for stream perception as typically developing children. In addition, children with language impairments required larger frequency separations between sounds to hear distinct streams compared to age-matched peers. Furthermore, phonological processing ability was a significant predictor of stream perception measures, but only in the older age groups. No such association was found in the youngest children. These results indicate that children with language impairments have difficulty parsing speech streams, or identifying individual sound events when there are competing sound sources. We conclude that language group differences may in part reflect fundamental maturational disparities in the analysis of complex auditory scenes.

Guidelines, practice policies, and parameters: the case for geriatrics.

OBJECTIVE: As the population ages, the care of older persons becomes more important. At the same time, practice guidelines that provide recommendations for appropriate care are being published in greater numbers. The purpose of this work is to determine the proportion of guidelines that contain specific information about older persons. DESIGN: Through a random sample of published guidelines listed in the AMA Directory of Practice Parameters, 1992 Edition, we determined the proportion of guidelines that contain specific age-related information. We also determined if, over time, there was a difference in the proportion of practice guidelines containing information about older persons. RESULTS: 45.9% (95% CI, range 33.4-58.4) of guidelines that could conceivably pertain to older persons contain no age information; 24.6% (95% CI, range 13.8-35.4) of guidelines contain information only about persons less than 65 years of age; 29.5% (95% CI, range 18.1-41.0) of guidelines contain specific information about older persons. Moreover, there were no secular trends in the proportion of guidelines pertaining to older persons. CONCLUSIONS: Only a minority of practice guidelines contain information about older persons. Possible causes and solutions to this shortfall are discussed.

Dynamic sensory updating in the auditory system.

Typically, in everyday situations, auditory input is constantly changing. Change is an important cue for the auditory system, which can signal the start of new sources of information or that some action may be required. Using an event-related brain potential that can be elicited whether or not attention is focused on the sounds (the mismatch negativity, MMN) we measured the time course of the effects of contextual changes on the brain's response to the same stimulus event. The onset or cessation of a sound in a stimulus block brought about context changes. The effect of the context was observed through changes in the MMN response to a deviant event that was present throughout the sound sequence. These results suggest the existence of a dynamic system of change detection, which updates its model of the sensory input on-line as the changes occur.

Simultaneously active pre-attentive representations of local and global rules for sound sequences in the human brain.

Regular sequences of sounds (i.e., non-random) can usually be described by several, equally valid rules. Rules allowing extrapolation from one sound to the next are termed local rules, those that define relations between temporally non-adjacent sounds are termed global rules. The aim of the present study was to determine whether both local and global rules can be simultaneously extracted from a sound sequence even when attention is directed away from the auditory stimuli. The pre-attentive representation of a sequence of two alternating tones (differing only in frequency) was investigated using the mismatch negativity (MMN) auditory event-related potential. Both local- and global-rule violations of tone alternation elicited the MMN component while subjects ignored the auditory stimuli. This finding suggests that (a) pre-attentive auditory processes can extract both local and global rules from sound sequences, and (b) that several regularity representations of a sound sequence are simultaneously maintained during the pre-attentive phase of auditory stimulus processing.

Evidence that the mismatch negativity system works on the basis of objects.

The purpose of this study was to determine whether the system that underlies the mismatch negativity (MMN) of event-related potentials would operate on the basis of objects if stimuli were delivered in such a way as to create the impression of two objects. To this end, tones were alternated between ears with one combination of features for each ear. Deviant tones, which differed from the standard tones of both ears, were delivered separately to each ear. The deviants elicited MMNs only with respect to the standards of the ear to which they were delivered. The data indicate that the MMN system operated on the basis of objects and that the integration of objects occurs preattentively in the auditory system.

Predictability of stimulus deviance and the mismatch negativity.

The purpose of this study was to test the previous report that generation of the mismatch negativity (MMN) component of event-related brain potentials (ERPs) is indifferent to the predictable occurrence of stimulus deviance. A pattern of standards (S) and deviants (D) were delivered in a predictable fashion (SSSSD) at two different speeds (1.3 s and 100 ms). An MMN was obtained to the D position tone at the slow but not the fast pace. These results demonstrate that, unlike the P3 component, the MMN is sensitive to the predictable occurrence of stimulus deviance when the predictability can be detected by the brain within the estimated limits of sensory memory.

Attention affects the organization of auditory input associated with the mismatch negativity system.

The mismatch negativity (MMN), a component of event-related potentials (ERP), was used to investigate the effect of attention on auditory stream segregation. Subjects were presented with sequences of alternating high and low tones that occurred at a constant rate, which they ignored. When subjects ignored the stimuli, the three-tone standard and deviant sequences contained within the high- and low-pitched tones did not emerge and no MMNs were obtained. Subjects were then instructed to attend to the high-pitched tones of the stimulus sequences and detect the within-stream deviants. When subjects selectively attended the high-pitched tones, MMNs were obtained to the deviants within both the attended and unattended streams. These results indicate that attention can produce segregation such that the sequences of low- and high-pitched tones are available to the automatic deviance detection system that underlies the generation of the MMN. Selective attention can alter the organization of sensory input in the early stages of acoustic processing.

Feature conjunctions and auditory sensory memory.

This study sought to obtain additional evidence that transient auditory memory stores information about conjunctions of features on an automatic basis. The mismatch negativity of event-related potentials was employed because its operations are based on information that is stored in transient auditory memory. The mismatch negativity was found to be elicited by a tone that differed from standard tones in a combination of its perceived location and frequency. The result lends further support to the hypothesis that the system upon which the mismatch negativity relies processes stimuli in an holistic manner.

Temporal integration of auditory stimulus deviance as reflected by the mismatch negativity.

We recorded event-related brain potentials (ERPs) to two different infrequent deviant tones presented successively within the repetitive sequence of a standard tone. A separate mismatch negativity (MMN) component was elicited by each of the two deviants when the interval separating their onsets was 300 ms. However, only a single MMN component was elicited when the temporal separation between the onsets of the two deviants was 150 ms. Previous studies obtained similar results using two temporally separated deviations carried by a single sound. Taken together, these results support the notion of a general temporal integration mechanism in the formation of auditory events with ca. 200 ms long window.

How a community teaching hospital is changing to better serve its community.

In recent years increased attention has been focused on the importance of teaching hospitals' serving the health of their communities. A community teaching hospital may have a special impetus and some advantages because of its linkage to a defined geographic community and a traditional mission of providing clinical and other services to that community. The authors describe how their community teaching hospital, the health and education services network it belongs to, and the integrated delivery system of which it is a member work together to respond to the current challenge to provide care and education to local communities. In particular, they describe how since 1995 the hospital has used an approach (called Measurably Enhancing the Status of Health) to create and operate its new Department of Community Health and Health Studies and associated new programs to benefit the community. The new department combines innovative community outreach programs with an emphasis on the qualitative and quantitative evaluation of the these programs. There are also programs of medical education in the hospital and at the Pennsylvania State University College of Medicine, and other programs that have community educational components (e.g., a coalition to reduce the number of smokers; a center to reduce health risks and prevent disease). The authors and their hospital colleagues have found three concepts to be helpful as they reflect on what they have learned since 1995 and continue to refine their community outreach work: community, complexity, and collaboration/competition. They explain these concepts and suggest that other institutions in academic medicine may find them and the ideas and programs of their hospital useful as the seek ways to care for, educate, and measure the health status of their own communities.

Surgical outcome for resident and attending surgeons.

We asked whether surgical process and outcome differ for physicians in postgraduate training supervised by attending surgeons compared with attending surgeons alone. All appendectomies performed during a 2 year period in a 320 bed voluntary hospital where either the admitting diagnosis or the preoperative diagnosis suggested acute appendicitis were included in the study. Data were abstracted from medical records and pathology reports. One hundred fifty-four cases of primary appendectomy were reviewed. In 97 cases, 1 of 9 attending physicians was listed as chief surgeon; in 57 cases, 1 of 15 resident physicians was listed as chief surgeon. There were no significant differences between the two patient groups according to age and sex. There was no difference between attending resident physicians in accuracy of diagnosis. Despite a pathologically normal appendix, attending surgeons in six cases and residents in two cases listed a discharge diagnosis of appendicitis. The average length of stay was 8.8 days for attending surgeons' cases and 7.1 days for residents' cases (t = 1.09, p = 0.29). The postoperative complication rates were 24 percent for attendings' cases and 12 percent for residents' cases (chi-square = 2.31, p = 0.16). We conclude that there is no appreciable difference in either the process or the outcome of care for patients undergoing appendectomy whether the operation is performed by an attending physician or a resident physician supervised by an attending physician.