Longitudinal Structural and Diffusion-Weighted Neuroimaging of Young Children Born Preterm.

BACKGROUND: Children born preterm are at risk for diffuse injury to subcortical gray and white matter. METHODS: We used a longitudinal cohort study to examine the development of subcortical gray matter and white matter volumes, and diffusivity measures of white matter tracts following preterm birth. Our participants were 47 children born preterm (24 to 32 weeks gestational age) and 28 children born at term. None of the children born preterm had significant neonatal brain injury. Children received structural and diffusion weighted magnetic resonance imaging scans at ages five, six, and seven years. We examined volumes of amygdala, hippocampus, caudate nucleus, putamen, thalamus, brainstem, cerebellar white matter, intracranial space, and ventricles, and volumes, fractional anisotropy, and mean diffusivity of anterior thalamic radiation, cingulum, corticospinal tract, corpus callosum, inferior frontal occipital fasciculus, inferior longitudinal fasciculus, temporal and parietal superior longitudinal fasciculus, and uncinate fasciculus. RESULTS: Children born preterm had smaller volumes of thalamus, brainstem, cerebellar white matter, cingulum, corticospinal tract, inferior frontal occipital fasciculus, uncinate fasciculus, and temporal superior longitudinal fasciculus, whereas their ventricles were larger compared with term-born controls. We found no significant effect of preterm birth on diffusivity measures. Despite developmental changes and growth, group differences were present and similarly strong at all three ages. CONCLUSION: Even in the absence of significant neonatal brain injury, preterm birth has a persistent impact on early brain development. The lack of a significant term status by age interaction suggests a delayed developmental trajectory.

Large reaction rate enhancement in formation of ultrathin AuSi eutectic layers.

Metal-semiconductor eutectic liquids play a key role in both the fundamental understanding of atomic interactions and nanoscale synthesis and catalysis. At reduced sizes they exhibit properties distinct from the bulk. In this work we show an unusual effect that the formation of AuSi eutectic liquid layers is much easier for smaller thicknesses. The alloying reaction rate is enhanced by over 20 times when the thickness is reduced from 300 to 20 nm. The strong enhancement is attributed to a strain-induced increase in the chemical potential of the solid layer prior to the alloying reaction.

A tingling sanshool derivative excites primary sensory neurons and elicits nocifensive behavior in rats.

Szechuan peppers contain hydroxy-α-sanshool that imparts desirable tingling, cooling, and numbing sensations. Hydroxy-α-sanshool activates a subset of sensory dorsal root ganglion (DRG) neurons by inhibiting two-pore potassium channels. We presently investigated if a tingle-evoking sanshool analog, isobutylalkenyl amide (IBA), excites rat DRG neurons and, if so, if these neurons are also activated by agonists of TRPM8, TRPA1, and/or TRPV1. Thirty-four percent of DRG neurons tested responded to IBA, with 29% of them also responding to menthol, 29% to cinnamic aldehyde, 66% to capsaicin, and subsets responding to two or more transient receptor potential (TRP) agonists. IBA-responsive cells had similar size distributions regardless of whether they responded to capsaicin or not; cells only responsive to IBA were larger. Responses to repeated application of IBA at a 5-min interstimulus interval exhibited self-desensitization (tachyphylaxis). Capsaicin did not cross-desensitize responses to IBA to any greater extent than the tachyphylaxis observed with repeated IBA applications. These findings are consistent with psychophysical observations that IBA elicits tingle sensation accompanied by pungency and cooling, with self-desensitization but little cross-desensitization by capsaicin. Intraplantar injection of IBA elicited nocifensive responses (paw licking, shaking-flinching, and guarding) in a dose-related manner similar to the effects of intraplantar capsaicin and serotonin. IBA had no effect on thermal sensitivity but enhanced mechanical sensitivity at the highest dose tested. These observations suggest that IBA elicits an unfamiliar aversive sensation that is expressed behaviorally by the limited response repertoire available to the animal.

Self- and cross-desensitization of oral irritation by menthol and cinnamaldehyde (CA) via peripheral interactions at trigeminal sensory neurons.

Menthol and cinnamaldehyde (CA) are plant-derived spices commonly used in oral hygiene products, chewing gum, and many other applications. However, little is known regarding their sensory interactions in the oral cavity. We used a human psychophysics approach to investigate the temporal dynamics of oral irritation elicited by sequential application of menthol and/or CA, and ratiometric calcium imaging methods to investigate activation of rat trigeminal ganglion (TG) cells by these agents. Irritancy decreased significantly with sequential oral application of menthol and CA (self-desensitization). Menthol cross-desensitized irritation elicited by CA, and vice versa, over a time course of at least 60 min. Seventeen and 19% of TG cells were activated by menthol and CA, respectively, with ∼50% responding to both. TG cells exhibited significant self-desensitization to menthol applied at a 5, but not 10, min interval. They also exhibited significant self-desensitization to CA at 400 but not 200 µM. Menthol cross-desensitized TG cell responses to CA. CA at a concentration of 400 but not 200 µM also cross-desensitized menthol-evoked responses. The results support the argument that the perceived reductions in oral irritancy and cross-interactions between menthol and CA and menthol observed (at least at short interstimulus intervals) can be largely accounted for by the properties of trigeminal sensory neurons innervating the tongue.

Self-regulation task in young school age children born preterm: Correlation with early academic achievement.

BACKGROUND: Children born preterm are at risk for difficulties in executive function (EF), however there are limited tools to assess EF in young children and it is not fully understood how these early deficits are related to emerging academic skills. AIMS: To examine (a) early EF differences in young children born preterm, (b) how a measure of behavioral self-regulation correlates with other measures of EF in children born preterm, and (c) how this measure relates to academic outcomes in children born preterm. STUDY DESIGN: Longitudinal cohort study. SUBJECTS: Thirty-three healthy children born preterm (25-32 weeks gestation) and 14 children born full term were assessed before starting kindergarten at age 5 and again at ages 6 and 7 years. OUTCOME MEASURES: Each assessment included a measure of behavioral self-regulation, the Head Toes Knees Shoulders task (HTKS), performance-based measures of EF, parent rating scales of EF and behavior problems, a measure of motor ability, and academic measures. RESULTS: Children born preterm performed worse on all measures of self-regulation, EF, parent-report, academic outcomes, and motor ability across time. The HTKS had weak to moderate correlations with parent-report and performance-based measures of EF, moderate to strong correlations with academic performance, and was not correlated with motor ability. CONCLUSION: This study shows the predictive value of early EF measures on functional academic outcomes and their potential as targets of effective interventions in this high-risk population.

A validated disease severity scoring system for adults with type 1 Gaucher disease.

PURPOSE: A validated disease severity scoring system (DS3) for Gaucher disease type 1 (GD1) is needed to standardize patient monitoring and to define patient cohorts in clinical studies. METHODS: DS3 domains were established by an expert physician group using the nominal group technique of consensus formation. Items were selected by 36 GD1 physicians. The expert group determined appropriate measurement techniques for each item. Measurements were weighted considering contributions to GD1 morbidity and mortality. Consensus Clinical Global Impression Severity scores for sample cases were compared with average DS3 scores. A minimal clinically important difference in GD1 DS3 score was calculated. RESULTS: The GD1 DS3 includes bone (42% of score), hematologic (32%), and visceral domains (26%); individual items use routine assessments, including medical history, blood chemistry, organ volume measurements, and bone evaluations (magnetic resonance imaging and dual x-ray absorptiometry). The maximum score is 19. Interrater reliability was 0.97 (Cohen's kappa). DS3 scores were highly correlated with Clinical Global Impression Severity scores (r2 = 0.89). The minimal clinically important difference was -3.2 improvement and +3.9 deterioration. CONCLUSION: This DS3 accurately quantifies GD1 status and intrapatient change over time. Testing of reliability and validity will continue to allow eventual implementation of the DS3 in clinical studies and routine practice.

Nitric oxide-evoked transient kinetics of cyclic GMP in vascular smooth muscle cells.

Cyclic-3',5'-guanosine monophosphate (cGMP) mediates the intracellular signaling cascade responsible for the nitric oxide (NO) initiated relaxation of vascular smooth muscle (VSM). However, the temporal dynamics, including the regulation of cGMP turnover, are largely unknown. Here we report new mechanistic insights into the kinetics of cGMP synthesis and hydrolysis in primary VSM cells by utilizing FRET-based cGMP-indicators [A. Honda, S.R. Adams, C.L. Sawyer, V. Lev-Ram, R.Y. Tsien, W.R. Dostmann, Proc. Natl. Acad. Sci. U S A 98 (5) (2001) 2437.]. First, 2-(N,N-Diethylamino)-diazenolate 2-oxide (DEA/NO) and 2,2'-(Hydroxynitrosohydrazono)-bis-ethanimine (DETA/NO) induced NO-concentration dependent, transient cGMP responses ("peaks") irrespective of their rates of NO release. The kinetic characteristics of these cGMP peaks were governed by the concerted action of the NO-sensitive guanylyl cyclase (GC) and phosphodiesterase type V (PDE5) as shown by their respective inhibition using 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and Sildenafil. These responses occurred in the presence of moderately elevated cGMP (5-15% FRET ratio), and thus activated PKG and phosphorylated PDE5, suggesting a prominent role for GC in the maintenance and termination of cGMP peaks. Furthermore, cGMP transients could be elicited repeatedly without apparent desensitization of GC or by suppression of cGMP via long-term PDE5 activity. These results demonstrate a continuous sensitivity of the NO/cGMP signaling system, inherent to the phasic nature of smooth muscle physiology.

Feasibility of a Clinic-Community Partnership to Treat Childhood Obesity.

BACKGROUND: "Bull City Fit" is a childhood obesity treatment partnership between Duke Children's pediatric weight management clinic and Durham Department of Parks and Recreation. OBJECTIVES: Report on feasibility and implementation, characteristics of participants, and predictors of attendance. METHODS: Mixed methods study consisting of (1) a retrospective cohort analysis (n = 171) reporting demographic, attendance, and clinical data and (2) structured focus groups among stakeholders to identify implementation facilitators and barriers. RESULTS: Higher attendance was associated with Spanish language ( P = .07), more clinic visits ( P = .03), shorter time to first attendance ( P = .06), lower child z-body mass index (BMI) at baseline ( P = .08), and lower parent BMI ( P = .02). Associations were mitigated after controlling for demographic characteristics. BMI z-score did not differ between low- and moderate/high attenders at 6 months. Family inclusion and community engagement emerged as positive themes during focus groups. CONCLUSIONS: Clinic-community partnerships engage diverse populations in fitness and nutrition activities, but no specific patient characteristics appear to predict greater attendance.

Cygnets: in vivo characterization of novel cGMP indicators and in vivo imaging of intracellular cGMP.

The second messenger cyclic guanosine 5'-monophosphate (cGMP) plays a key role in the control and regulation of a steadily increasing number of diverse physiological processes. As the appreciation of the importance of understanding the cGMP signaling pathway has grown, so has the awareness of the limited techniques with which to study the rapid intracellular cGMP kinetics. We have previously demonstrated the construction of cygnets, cGMP indicators using energy transfer comprised of cyan and yellow variants of green fluorescent protein flanked by conformationally sensitive cGMP receptor portion taken from the cGMP-dependent protein kinase. Here, we report that cGMP binds to Cygnet-2.1, utilizing ECFP and Citrine, with an apparent equilibrium-binding constant of 600 nM causing a total fluorescence intensity ratio change of 45%. In contrast, cAMP could elicit a maximal 10% change in fluorescence resonance energy transfer (FRET) ratio, demonstrating an approx 500-fold selectivity for cGMP. When expressed in vascular smooth muscle cells, cygnets demonstrated even cytosolic distribution and nuclear exclusion. Cultured rat aortic smooth muscle cells, which exhibit a noncontractile, synthetic phenotype typically seen in response to atherosclerosis or vascular injury, responded to natriuretic peptide (BNP)-mediated activation of the particulate guanylyl cyclase. In conclusion, cygnets have facilitated the temporal resolution and evaluation of the contributions of cyclases and phosphodiesterases in determining overall cGMP accumulation, and the visualization of novel spatial dynamics that will contribute to more fully understanding the role of cGMP in the mediation of smooth muscle relaxation.

Functional neuroanatomical evidence for the double-deficit hypothesis of developmental dyslexia.

The double-deficit hypothesis of dyslexia posits that both rapid naming and phonological impairments can cause reading difficulties, and that individuals who have both of these deficits show greater reading impairments compared to those with a single deficit. Despite extensive behavioral research, the brain basis of poor reading with a double-deficit has never been investigated. The goal of the study was to evaluate the double-deficit hypothesis using functional MRI. Activation patterns during a printed word rhyme judgment task in 90 children with a wide range of reading abilities showed dissociation between brain regions that were sensitive to phonological awareness (left inferior frontal and inferior parietal regions) and rapid naming (right cerebellar lobule VI). More specifically, the double-deficit group showed less activation in the fronto-parietal reading network compared to children with only a deficit in phonological awareness, who in turn showed less activation than the typically-reading group. On the other hand, the double-deficit group showed less cerebellar activation compared to children with only a rapid naming deficit, who in turn showed less activation than the typically-reading children. Functional connectivity analyses revealed that bilateral prefrontal regions were key for linking brain regions associated with phonological awareness and rapid naming, with the double-deficit group being the most aberrant in their connectivity. Our study provides the first functional neuroanatomical evidence for the double-deficit hypothesis of developmental dyslexia.

Capsaicin avoidance as a measure of chemical hyperalgesia in orofacial nerve injury models.

Many patients suffer from trigeminal neuralgia and other types of orofacial pain that are poorly treated, necessitating preclininal animal models for development of mechanisms-based therapies. The present study assessed capsaicin avoidance and other nocifensive behavioral responses in three models of orofacial nerve injury in rats: chronic constriction injury (CCI) of the mental nerves, partial tight ligation of mental nerves, and CCI of lingual nerves. We additionally investigated if nerve injury resulted in enhanced capsaicin-evoked activation of neurons in trigeminal caudalis (Vc) or nucleus of the solitary tract (NTS) based on expression of Fos-like immunoreactivity (FLI). Mental nerve CCI resulted in an enhancement of capsaicin avoidance in a two-bottle preference paradigm, while neither mental nerve injury produced thermal hyperalgesia or mechanical allodynia. CCI of lingual nerves did not affect capsaicin avoidance. Counts of FLI in Vc were significantly higher in the lingual sham and mental nerve CCI groups compared to mental shams; FLI counts in NTS did not differ among groups. Mental nerve CCI may have induced central sensitization of chemical nociception since increased capsaicin avoidance was accompanied by greater activation of Vc neurons in response to oral capsaicin.

Topical application of L-menthol induces heat analgesia, mechanical allodynia, and a biphasic effect on cold sensitivity in rats.

Menthol is used in analgesic balms and also in foods and oral hygiene products for its fresh cooling sensation. Menthol enhances cooling by interacting with the cold-sensitive thermoTRP channel TRPM8, but its effect on pain is less well understood. We presently used behavioral methods to investigate effects of topical menthol on thermal (hot and cold) pain and innocuous cold and mechanical sensitivity in rats. Menthol dose-dependently increased the latency for noxious heat-evoked withdrawal of the treated hindpaw with a weak mirror-image effect, indicating antinociception. Menthol at the highest concentration (40%) reduced mechanical withdrawal thresholds, with no effect at lower concentrations. Menthol had a biphasic effect on cold avoidance. At high concentrations (10% and 40%) menthol reduced avoidance of colder temperatures (15 degrees C and 20 degrees C) compared to 30 degrees C, while at lower concentrations (0.01-1%) menthol enhanced cold avoidance. In a -5 degrees C cold plate test, 40% menthol significantly increased the nocifensive response latency (cold hypoalgesia) while lower concentrations were not different from vehicle controls. These results are generally consistent with neurophysiological and human psychophysical data and support TRPM8 as a potential peripheral target of pain modulation.

Behavioral evidence of thermal hyperalgesia and mechanical allodynia induced by intradermal cinnamaldehyde in rats.

TRPA1 agonists cinnamaldehyde (CA) and mustard oil (allyl isothiocyanate=AITC) induce heat hyperalgesia and mechanical allodynia in human skin, and sensitize responses of spinal and trigeminal dorsal horn neurons to noxious skin heating in rats. TRPA1 is also implicated in cold nociception. We presently used behavioral methods to investigate if CA affects sensitivity to thermal and mechanical stimuli in rats. Unilateral intraplantar injection of CA (5-20%) induced a significant, concentration-dependent reduction in latency for ipsilateral paw withdrawal from a noxious heat stimulus, peaking (61.7% of pre-injection baseline) by 30 min with partial recovery at 120 min. The highest dose of CA also significantly reduced the contralateral paw withdrawal latency. CA significantly reduced mechanical withdrawal thresholds of the injected paw that peaked sooner (3 min) and was more profound (44.4% of baseline), with no effect contralaterally. Bilateral intraplantar injections of CA resulted in a significant cold hyperalgesia (cold plate test) and a weak enhancement of innocuous cold avoidance (thermal preference test). The data are consistent with roles for TRPA1 in thermal (hot and cold) hyperalgesia and mechanical allodynia.

Mustard oil enhances spinal neuronal responses to noxious heat but not cooling.

The TRPA1 agonist mustard oil (allyl isothiocyanate=AITC) induces heat hyperalgesia and mechanical allodynia in human skin and sensitizes rat spinal wide dynamic range (WDR) neuronal responses to noxious skin heating. We presently used electrophysiological methods to investigate if AITC affects the responsiveness of individual spinal WDR neurons to intense skin cooling. Recordings were made from cold-sensitive WDR neurons in lamina I and deeper dorsal horn; 21/23 also responded to noxious skin heating. Topical application of AITC excited 8/18 units and significantly enhanced their responses to noxious heat while not significantly affecting responses to the cold stimulus. Vehicle (mineral oil) had no effect on thermal responses. The data confirm a role for the TRPA1 agonist AITC in enhancing heat nociception without significantly affecting cold sensitivity.

Activation of lumbar spinal wide-dynamic range neurons by a sanshool derivative.

The enigmatic sensation of tingle involves the activation of primary sensory neurons by hydroxy-alpha-sanshool, a tingly agent in Szechuan peppers, by inhibiting two-pore potassium channels. Central mechanisms mediating tingle sensation are unknown. We investigated whether a stable derivative of sanshool-isobutylalkenyl amide (IBA)-excites wide-dynamic range (WDR) spinal neurons that participate in transmission of chemesthetic information from the skin. In anesthetized rats, the majority of WDR and low-threshold units responded to intradermal injection of IBA in a dose-related manner over a >5-min time course and exhibited tachyphylaxis at higher concentrations (1 and 10%). Almost all WDR and low-threshold units additionally responded to the pungent agents mustard oil (allyl isothiocyanate) and/or capsaicin, prompting reclassification of the low-threshold cells as WDR. The results are discussed in terms of the functional role of WDR neurons in mediating tingle sensation.