Large-scale analysis of structural brain asymmetries during neurodevelopment: Associations with age and sex in 4265 children and adolescents.

Only a small number of studies have assessed structural differences between the two hemispheres during childhood and adolescence. However, the existing findings lack consistency or are restricted to a particular brain region, a specific brain feature, or a relatively narrow age range. Here, we investigated associations between brain asymmetry and age as well as sex in one of the largest pediatric samples to date (n = 4265), aged 1-18 years, scanned at 69 sites participating in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our study revealed that significant brain asymmetries already exist in childhood, but their magnitude and direction depend on the brain region examined and the morphometric measurement used (cortical volume or thickness, regional surface area, or subcortical volume). With respect to effects of age, some asymmetries became weaker over time while others became stronger; sometimes they even reversed direction. With respect to sex differences, the total number of regions exhibiting significant asymmetries was larger in females than in males, while the total number of measurements indicating significant asymmetries was larger in males (as we obtained more than one measurement per cortical region). The magnitude of the significant asymmetries was also greater in males. However, effect sizes for both age effects and sex differences were small. Taken together, these findings suggest that cerebral asymmetries are an inherent organizational pattern of the brain that manifests early in life. Overall, brain asymmetry appears to be relatively stable throughout childhood and adolescence, with some differential effects in males and females.

Poor stimulus discriminability as a common neuropsychological deficit between ADHD and reading ability in young children: a moderated mediation model.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is frequently associated with poorer reading ability; however, the specific neuropsychological domains linking this co-occurrence remain unclear. This study evaluates information-processing characteristics as possible neuropsychological links between ADHD symptoms and RA in a community-based sample of children and early adolescents with normal IQ (⩾70). METHOD: The participants (n = 1857, aged 6-15 years, 47% female) were evaluated for reading ability (reading single words aloud) and information processing [stimulus discriminability in the two-choice reaction-time task estimated using diffusion models]. ADHD symptoms were ascertained through informant (parent) report using the Development and Well-Being Assessment (DAWBA). Verbal working memory (VWM; digit span backwards), visuospatial working memory (VSWM, Corsi Blocks backwards), sex, socioeconomic status, and IQ were included as covariates. RESULTS: In a moderated mediation model, stimulus discriminability mediated the effect of ADHD on reading ability. This indirect effect was moderated by age such that a larger effect was seen among younger children. CONCLUSION: The findings support the hypothesis that ADHD and reading ability are linked among young children via a neuropsychological deficit related to stimulus discriminability. Early interventions targeting stimulus discriminability might improve symptoms of inattention/hyperactivity and reading ability.

Inflammation, neurotrophism and oxidative stress and childhood psychopathology in a large community sample.

OBJECTIVE: To investigate the association between peripheral biomarkers and child psychopathology in a large community sample. METHOD: A total of 625 aged 6- to 13-year old subjects were recruited from a community school-based study. Psychopathology was assessed using the Child Behaviour Checklist (CBCL). Psychiatric diagnosis was evaluated using the Development and Well-Being Assessment. The following biomarkers were examined in peripheral blood: brain-derived neurotrophic factor, cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, IFN-g, and TNF-α), chemokines (eotaxin/CCL11, IP-10, MCP-1), cytokine receptors (sTNFR1 and sTNFR2), and the oxidative stress marker TBARS. RESULTS: We found significant associations between sTNFR2, eotaxin/CCL11 and CBCL total score, as well as with specific dimensions of psychopathology. There were different patterns of association between these biomarkers and psychological and behavioural symptoms in children with and without a mental disorder. TBARS, IL-6 and MCP-1 were more specific to some clusters of symptoms in children with a psychiatric diagnosis. CONCLUSION: Our data support the potential use of biomarkers, especially those involved in immune-inflammatory pathways, in investigating neurodevelopmental psychopathology. Their association with different dimensions of symptoms might be of useful when analyzing illness severity and clusters of symptoms within specific disorders.

Specificity of basic information processing and inhibitory control in attention deficit hyperactivity disorder.

BACKGROUND: Both inhibitory-based executive functioning (IB-EF) and basic information processing (BIP) deficits are found in clinic-referred attention deficit hyperactivity disorder (ADHD) samples. However, it remains to be determined whether: (1) such deficits occur in non-referred samples of ADHD; (2) they are specific to ADHD; (3) the co-morbidity between ADHD and oppositional defiant disorder/conduct disorder (ODD/CD) has additive or interactive effects; and (4) IB-EF deficits are primary in ADHD or are due to BIP deficits. METHOD: We assessed 704 subjects (age 6-12 years) from a non-referred sample using the Development and Well-Being Assessment (DAWBA) and classified them into five groups: typical developing controls (TDC; n = 378), Fear disorders (n = 90), Distress disorders (n = 57), ADHD (n = 100), ODD/CD (n = 40) and ADHD+ODD/CD (n = 39). We evaluated neurocognitive performance with a Two-Choice Reaction Time Task (2C-RT), a Conflict Control Task (CCT) and a Go/No-Go (GNG) task. We used a diffusion model (DM) to decompose BIP into processing efficiency, speed-accuracy trade-off and encoding/motor function along with variability parameters. RESULTS: Poorer processing efficiency was found to be specific to ADHD. Faster encoding/motor function differentiated ADHD from TDC and from fear/distress whereas a more cautious (not impulsive) response style differentiated ADHD from both TDC and ODD/CD. The co-morbidity between ADHD and ODD/CD reflected only additive effects. All ADHD-related IB-EF classical effects were fully moderated by deficits in BIP. CONCLUSIONS: Our findings challenge the IB-EF hypothesis for ADHD and underscore the importance of processing efficiency as the key specific mechanism for ADHD pathophysiology.

Coordinated brain development: exploring the synchrony between changes in grey and white matter during childhood maturation.

Brain development during childhood and early adolescence is characterized by global changes in brain architecture. Neuroimaging studies have revealed overall decreases in cortical thickness (CT) and increases in fractional anisotropy (FA). Furthermore, previous studies have shown that certain cortical regions display coordinated growth during development. However, there is significant heterogeneity in the timing and speed of these developmental transformations, and it is still unclear whether white and grey matter changes are co-localized. In this multimodal neuroimaging study, we investigated the relationship between grey and white matter developmental changes and asynchronous maturation within brain regions in 249 normally developing children between the ages 7-14. We used structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to analyze CT and FA, respectively, as well as their covariance across development. Consistent with previous studies, we observed overall cortical thinning with age, which was accompanied by increased FA. We then compared the coordinated development of grey and white matter as indexed by covariance measures. Covariance between grey matter regions and the microstructure of white matter tracts connecting those regions were highly similar, suggesting that coordinated changes in the cortex were mirrored by coordinated changes in their respective tracts. Examining within-brain divergent trajectories, we found significant structural decoupling (decreased covariance) between several brain regions and tracts in the 9- to 11-year-old group, particularly involving the forceps minor and the regions that it connects to. We argue that this decoupling could reflect a developmental pattern within the prefrontal region in 9- and 11-year-old children, possibly related to the significant changes in cognitive control observed at this age.

Enhancement of analgesic effect of intrathecal neostigmine and clonidine on bupivacaine spinal anesthesia.

BACKGROUND AND OBJECTIVES: Intrathecal administration of neostigmine has been shown to produce analgesia in both animals and humans. The concurrent administration of intrathecal neostigmine and clonidine has been reported to produce no neurotoxicity in sheep. The purpose of the present study was to evaluate the efficacy and safety of the combining intrathecal neostigmine and clonidine for the relief of pain in patients after cesarean delivery. METHODS: After giving their consents, 80 parturients who were scheduled for cesarean delivery during spinal anesthesia were enrolled by a double-blind randomized design into four groups: bupivacaine group (n = 20) received intrathecal (i.t.) 10 mg bupivacaine; bupivacaine + neostigmine group (n = 19) received i.t. 10 mg bupivacaine + 50 microg neostigmine; bupivacaine + clonidine group (n = 20) received i.t. 10 mg bupivacaine + 150 microg clonidine; and bupivacaine + both (n = 21) received i.t. 10 mg bupivacaine + 50 microg neostigmine + 150 microg clonidine. The maximum spread of anesthesia, duration of analgesia and motor block, vital signs, and incidence of adverse effects were recorded for 14 hours postinjection. Fifty milligrams intramuscular meperidine was given as a rescue analgesic whenever patient's pain score was greater than 5/10 by the visual analog scale. RESULTS: The demographic data were similar for all four groups. Bupivacaine + both group had a significantly higher maximum spread of anesthesia of 23.3 +/- 2.9 segments than bupivacaine group of 20.5 +/- 2.9 segment. Bupivacaine + both group showed a later onset of postsurgical pain of 6.5 +/- 1.5 hours as compared to bupivacaine group of 1.3 +/- 0.6 hours. The pain score in bupivacaine + both group was significantly lower than that of bupivacaine group during the first 10 hours. The 24-hour meperidine consumption also was lower in bupivacaine + both group than that of bupivacaine group. However, motor block was significantly prolonged from 3.5 +/- 1.1 hours in bupivacaine group to 7.1 +/- 1.6 hours in bupivacaine + both group. In addition, other side effects such as nausea and vomiting and dizziness were significantly increased in bupivacaine + both group. CONCLUSION: Our study showed that the combination of 150 microg i.t. clonidine and 50 microg neostigmine provided longer postsurgical analgesia than with either drug used alone. However, this combination also produced significantly more adverse effects of prolonged motor block and nausea and vomiting. A further study combining the two study drugs but using a lower dose of i.t. neostigmine (e.g., 25 microg) is recommended.

Mediator release in an isolated airway segment in subjects with asthma.

To determine if mediator release would occur in the airways of human subjects after exposure to a hyperosmolar stimulus, we challenged isolated airway segments in vivo with 900 mosmol sodium chloride using a specially designed double-balloon catheter. In order to determine if differences in mediator concentrations correlated with airway responsiveness or with atopy, we studied 3 separate groups: 6 atopic, asthmatic subjects; 6 atopic, nonasthmatic subjects; and 6 nonatopic, nonasthmatic normal subjects. In addition, to determine if the presence of the catheter itself was a stimulus, we studied 6 atopic, asthmatic subjects after exposure to isotonic sodium chloride alone (sham exposure). Lavage specimens were assayed for PGD2, PGF2 alpha, PGE2, TxB2, LTC4, and LTB4 by radioimmunoassay and for histamine by the modified single isotope enzymatic assay. The histamine concentration of the baseline lavage samples (bronchoalveolar lavage and isolated airway segment lavage) for the subjects with asthma were significantly greater than for the atopic or normal subjects (p less than 0.05). There was a significant negative correlation between histamine concentration in the lavage samples and the airway responsiveness of the subjects (r = -0.53, p less than 0.0001). There was a marked correlation among the concentrations of histamine, PGD2, PGF2 alpha, and TxB2 in all the lavage fluids for the subjects with asthma (p less than 0.03 for all comparisons and p less than 0.0001 for overall concordance). As a result of hyperosmolar challenge, there was a significant increase in the concentration of histamine, PGD2, and PGF2 alpha in the subjects with asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

Cutting edge: evidence for a signaling partnership between urokinase receptors (CD87) and L-selectin (CD62L) in human polymorphonuclear neutrophils.

Leukocyte urokinase plasminogen activator receptors (uPARs) cluster at adhesion interfaces and at migratory fronts where they participate in adhesion, chemotaxis, and proteolysis. uPAR aggregation triggers activation signaling even though this glycolipid-anchored protein must associate with membrane-spanning proteins to access the cell interior. This study demonstrates a novel partnership between uPAR and L-selectin in human polymorphonuclear neutrophils. Fluorescence resonance energy transfer demonstrated a direct physical association between uPAR and L-selectin. To examine the role of L-selectin in uPAR-mediated signaling, uPAR was cross-linked and intracellular Ca(2+) concentrations were measured by spectrofluorometry. A mAb reactive against the carbohydrate binding domain (CBD) of L-selectin substantially inhibited uPAR-mediated Ca(2+) mobilization, whereas mAbs against the beta(2) integrin complement receptor 3 (CR3), another uPAR-binding adhesion protein, had no effect. Similarly, fucoidan, a sulfated polysaccharide that binds to L-selectin CBD, inhibited the Ca(2+) signal. We conclude that uPAR associates with the CBD region of L-selectin to form a functional signaling complex.

The optimal dose of hyperbaric tetracaine spinal anesthesia for cesarean section.

Seventy-five term parturients undergoing cesarean section were anesthetized with 9 mg, 12 mg, 15 mg and 18 mg of tetracaine in 1.5 cc of 10% using a standardized spinal anesthetic technique. The four groups were compared for their maximal spread of anesthesia, quality of analgesia, incidence of hypotension, mgs of ephedrine used to correct hypotension, and the Apgar scores of the infant. It was found that maximal segmental spread of analgesia for 9 mg. 12 mg and 15 mg groups were not different significant regardless of height or weight. But with the 18 mg-group there was significant excessive spread of analgesia. While there was no difference in maximal spread of analgesia, there was a progressive increase in good quality of analgesia with increasing dosages. There were 67%, 81%, 96%, 100% of the patients had good analgesia for their operation in the four respective group. The percentages of hypotension were significanly more in the 15 mg and 18 mg groups. However, we did not find the hypotension in the 15 mg and 18 mg group need more ephedrine to correct than the lower dosages. In addition, all babies had good Apgar scores and there was no statistical difference among the four groups.

Fibrinogen activates NF-kappa B transcription factors in mononuclear phagocytes.

Adhesion to extracellular matrices is known to modulate leukocyte activation, although the mechanisms are not fully understood. Mononuclear phagocytes are exposed to fibrinous provisional matrix throughout migration into inflammatory foci, so this study was undertaken to determine whether fibrinogen triggers activation of NF-kappa B transcription factors. U937 cells differentiated with PMA in nonadherent culture were shown to express two fibrinogen-binding integrins, predominately CD11b/CD18, and to a lesser extent, CD11c/CD18. Cells stimulated with fibrinogen (10-100 microg/ml)/Mn2+ (50 microM) for 2 h were examined by electrophoretic mobility shift assay. NF-kappa B activation, minimal in unstimulated cells, was substantially up-regulated by fibrinogen. Fibrinogen also caused activation of AP-1, but not SP1 or cAMP response element-binding protein (CREB) factors. Blocking mAbs against CD18 and CD11b abrogated fibrinogen-induced NF-kappa B activation. To determine the effects on transcriptional regulation, U937 cells were transfected with a plasmid containing the HIV-1 enhancer (bearing two NF-kappa B sites) coupled to a chloramphenicol acetyltransferase (CAT) reporter. Cells were subsequently stimulated with 1) PMA for 24 h, inducing CAT activity by 2.6-fold, 2) fibrinogen/Mn2+ for 2 h, inducing CAT activity by 3.2-fold, or 3) costimulation with fibrinogen and PMA, inducing 5.7-fold the CAT activity induced by PMA alone. We conclude that contact with fibrinogen-derived proteins may contribute to mononuclear phagocyte activation by signaling through CD11b/CD18, resulting in selective activation of transcriptional regulatory factors, including NF-kappa B.

Familial carboxypeptidase N deficiency.

Carboxypeptidase N is a serum metalloenzyme that inactivates C3a, C4a, C5a, bradykinin, kalladin, and fibrinopeptides. Of 172 sera from patients with chronic urticaria or angioedema, one had a remarkably depressed carboxypeptidase N level (21% of normal). Of sera from 103 patients with other diseases, elevated levels were observed in cases of neoplasms, and one abnormally low value was detected in a patient with cirrhosis. The patient with a remarkably low carboxypeptidase N level was a 65-year-old man with an 11-year history of episodic angioedema occurring about 40 times per year. Inactivation of C3a and lysyl-bradykinin by his serum was markedly prolonged. Plasma histamine was elevated during attacks, but serotonin and kinin activity were not. The proband's sister had an equally depressed serum carboxypeptidase N level, and studies of other family members suggested an autosomal recessive inheritance of the enzyme deficiency.

Plasma protease inhibitor and anaphylatoxin inactivator levels in chronic urticaria/angioedema and in patients experiencing anaphylactoid reactions to radiographic contrast media.

Since a protease inhibitor or anaphylatoxin inactivator deficiency might explain why certain individuals are prone to develop chronic urticaria/angioedema or anaphylactoid reactions to radiographic contrast media, serum alpha 1-protease inhibitor, alpha 1-antichymotrypsin, alpha 2-macroglobulin, inter-alpha-inhibitor, antithrombin III, alpha 2-plasmin inhibitor, C1 inhibitor, and serum carboxypeptidase N were assessed by immunologic or functional methods. These values all were within normal limits in both groups of patients except for a low mean alpha 1-protease inhibitor level in chronic idiopathic urticaria/angioedema and cold urticaria patients and marginal decreases of alpha 1-protease and inter-alpha-inhibitor levels in radiographic contrast medium reactors. However, these abnormalities were not thought to be of pathogenetic significance.

Clustering of urokinase receptors (uPAR; CD87) induces proinflammatory signaling in human polymorphonuclear neutrophils.

Leukocytes use urokinase receptors (uPAR; CD87) in adhesion, migration, and proteolysis of matrix proteins. Typically, uPAR clusters at cell-substratum interfaces, at focal adhesions, and at the leading edges of migrating cells. This study was undertaken to determine whether uPAR clustering mediates activation signaling in human polymorphonuclear neutrophils. Cells were labeled with fluo-3/AM to quantitate intracellular Ca2+ ([Ca2+]i) by spectrofluorometry, and uPAR was aggregated by Ab cross-linking. Aggregating uPAR induced a highly reproducible increase in [Ca2+]i (baseline to peak) of 295 +/- 37 nM (p = 0.0002). Acutely treating cells with high m.w. urokinase (HMW-uPA; 4000 IU/ml) produced a response of similar magnitude but far shorter duration. Selectively aggregating uPA-occupied uPAR produced smaller increases in [Ca2+]i, but saturating uPAR with HMW-uPA increased the response to approximate that of uPAR cross-linking. Cross-linking uPAR induced rapid and significant increases in membrane expression of CD11b and increased degranulation (release of beta-glucuronidase and lactoferrin) to a significantly greater degree than cross-linking control Abs. The magnitude of degranulation correlated closely with the difference between baseline and peak [Ca2+]i, but was not dependent on the state of uPA occupancy. By contrast, selectively cross-linking uPA-occupied uPAR was capable of directly inducing superoxide release as well as enhancing FMLP-stimulated superoxide release. These results could not be duplicated by preferentially cross-linking unoccupied uPAR. We conclude that uPAR aggregation initiates activation signaling in polymorphonuclear neutrophils through at least two distinct uPA-dependent and uPA-independent pathways, increasing their proinflammatory potency (degranulation and oxidant release) and altering expression of CD11b/CD18 to favor a firmly adherent phenotype.

Dose-response studies of the suppression of whole blood histamine and basophil counts by prednisone.

If some clinical problems (e.g., radiographic contrast media reactions) arise from mediator release by circulating basophils, prednisone's capacity to prevent such is likely to be at least partly related to its suppressive effects on whole blood histamine and basophil levels. To establish an optimal dosage schedule, 15 healthy male volunteers entered a two-phased study to determine (1) the single dose of prednisone required to produce maximal suppression of histamine and basophil levels and (2) the effects of repeated prednisone doses. Parameters monitored were whole blood histamine, quantitative basophil counts, white blood cell (WBC) and differential counts, and plasma prednisone, prednisolone, and cortisol levels. Fifty milligrams prednisone suppressed whole blood histamine levels as much as a larger dose and also showed a marked effect on circulating basophils and other leukocytes. Three 50-mg prednisone doses given at 6-hr intervals had a greater effect on whole blood histamine and circulating leukocytes than fewer doses. Thus, the commonly used empirical prednisone dosage regimen is supported. One implication of the results of this study is that greater suppression of blood basophils and histamine levels might be obtained by administering the last prednisone dose about 6 hr before procedures in which a very rapid release of mediators from basophils is anticipated.

Urokinase receptor (CD87) aggregation triggers phosphoinositide hydrolysis and intracellular calcium mobilization in mononuclear phagocytes.

Leukocytes utilize urokinase receptors (uPAR; CD87) in adhesion, migration, and matrix proteolysis. uPAR aggregate at cell-substratum interfaces and at leading edges of migrating cells, so this study was undertaken to determine whether uPAR aggregation is capable of initiating activation signaling. Monocyte-like U937 cells were labeled with fluo-3-acetoxymethyl ester to quantitate intracellular Ca2+ concentrations ([Ca2+]i) by spectrofluorometry, and uPAR was aggregated by mAb cross-linking. uPAR aggregation induced highly reproducible increases in [Ca2+]i of 103.0 +/- 10.9 nM (p < 0.0001) and >3-fold increases in cellular d-myoinositol 1,4,5-trisphosphate (Ins(1,4,5)P3) levels. Similar increases in [Ca2+]i were also elicited by uPAR aggregation in human monocytes, but cross-linking a control IgG2a had no effect on [Ca2+]i. Selectively cross-linking uPA-occupied uPAR with an anti-uPA mAb produced smaller increases in [Ca2+]i, but fully saturating uPAR with exogenous uPA enhanced the [Ca2+]i response to equal the effect of aggregating uPAR directly. Increased [Ca2+]i was inhibited by thapsigargin, herbimycin A, and U73122, but only partially reduced by low extracellular [Ca2+], indicating that uPAR aggregation increases [Ca2+]i by activating phospholipase C through a tyrosine kinase-dependent mechanism, generating Ins(1,4,5)P3 and releasing Ca2+ from Ins(1,4, 5)P3-sensitive intracellular stores. Cross-linking the beta2 integrin CR3 could not duplicate the effect of uPAR cross-linking, and uPAR-triggered Ca2+ mobilization was not blocked by anti-CR3 mAbs. These results indicate that uPAR aggregation initiates phosphoinositide hydrolysis by mechanisms that are not strictly dependent on associated uPA or CR3.

[The effect of epidural anesthesia on tourniquet pain: a comparison of 2% lidocaine and 0.5% bupivacaine].

The incidence of tourniquet pain was evaluated in two groups of patients with 20 each undergoing orthopedic surgery of the lower extremities during epidural anesthesia using plain solution of either 2% lidocaine or 0.5% bupivacaine. The drugs were administered in a randomized fashion. Measurement of the levels of sensory loss to pinprick and incidence of tourniquet pain were made by blind-trust. The maximum analgesia level, time between 1st injection and onset of pain, time between tourniquet inflation and onset of pain were recorded similarly in both groups of patients. The incidence of tourniquet pain was significantly greater in patients given 2% lidocaine (40%) than in patients given 0.5% bupivacaine (10%). The incidence of pain was not related to the time of tourniquet inflation, because patients in the bupivacaine group had a significant longer duration of tourniquet inflation than did patients in the lidocaine group. The incidence of pain was also not related to tachyphylaxis, because 7 of 8 patients who complained tourniquet pain in lidocaine group received less than 3 injections for maintenance of analgesia when tourniquet pain started. In summary, it is apparent that tourniquet pain occurs less frequently when bupivacaine is employed for epidural anesthesia as compared to lidocaine.