Using feeding to reduce pain during vaccination of formula-fed infants: a randomised controlled trial.

OBJECTIVES: To assess the effectiveness and potential side effects of formula feeding to reduce pain during vaccination among infants. STUDY DESIGN: In the setting of well-baby clinics we recruited a community-based sample of full-term born infants who were already formula fed by the choice of the parents (n=48, aged 4-10 weeks) and received their first DTaP-IPV-HepB-Hib and pneumococcal vaccinations and randomised them into two groups. To evaluate pain experienced during vaccination we compared infants who drank formula feeding before, during and after vaccination with infants who did not. Outcomes were observed cry duration and pain scores measured by means of the Neonatal Infant Pain Scale (NIPS) and the Face, Legs, Activity, Cry and Consolability (FLACC) scale. Side effects of drinking during vaccination were recorded. We performed intention-to-treat analyses using regression models, crude and adjusted for sex and age of the infant. RESULTS: Pain at the moment of the second injection did not differ between groups. Drinking infants cried 33.5 s shorter (-56.6; -10.3). In the first minute after injection drinking infants experienced a faster pain reduction on the NIPSΔt: regression coefficient 3.86 (95% CI 2.70 to 5.02) and FLACCΔt: 4.42 (95% CI 2.85 to 5.99). CONCLUSIONS: In line with findings of previous studies regarding breast feeding, formula feeding reduced vaccination pain in the recovery phase in full-term born infants receiving their first vaccinations between ages 4 and 10 weeks with no adverse effects. Professionals should discuss this non-costly and feasible pain-reducing intervention with parents of infants who receive vaccinations. TRIAL REGISTRATION NUMBER: IRCTN 31383, post-results.

Correlations of gene expression with ratings of inattention and hyperactivity/impulsivity in Tourette syndrome: a pilot study.

BACKGROUND: Inattentiveness, impulsivity and hyperactivity are the primary behaviors associated with attention-deficit hyperactivity disorder (ADHD). Previous studies showed that peripheral blood gene expression signatures can mirror central nervous system disease. Tourette syndrome (TS) is associated with inattention (IA) and hyperactivity/impulsivity (HI) symptoms over 50% of the time. This study determined if gene expression in blood correlated significantly with IA and/or HI rating scale scores in participants with TS. METHODS: RNA was isolated from the blood of 21 participants with TS, and gene expression measured on Affymetrix human U133 Plus 2.0 arrays. To identify the genes that correlated with Conners' Parents Ratings of IA and HI ratings of symptoms, an analysis of covariance (ANCOVA) was performed, controlling for age, gender and batch. RESULTS: There were 1201 gene probesets that correlated with IA scales, 1625 that correlated with HI scales, and 262 that correlated with both IA and HI scale scores (P<0.05, |Partial correlation (r(p))|>0.4). Immune, catecholamine and other neurotransmitter pathways were associated with IA and HI behaviors. A number of the identified genes (n=27) have previously been reported in ADHD genetic studies. Many more genes correlated with either IA or HI scales alone compared to those that correlated with both IA and HI scales. CONCLUSIONS: These findings support the concept that the pathophysiology of ADHD and/or its subtypes in TS may involve the interaction of multiple genes. These preliminary data also suggest gene expression may be useful for studying IA and HI symptoms that relate to ADHD in TS and perhaps non-TS participants. These results will need to be confirmed in future studies.

Altered immunoglobulin profiles in children with Tourette syndrome.

BACKGROUND: Post-infectious autoimmunity and immune deficiency have been implicated in the pathogenesis of Tourette syndrome (TS). We asked here whether B cell immunity of patients with TS differs from healthy subjects. METHODS: In two independent cross-sectional samples, we compared serum levels of IgG1, IgG2, IgG3, IgG4, IgM, IgA, and IgE in 21 patients with TS from Yale University (17 males, 4 females, 8-16 years) versus 21 healthy controls (13 males, 8 females, 7-17 years); and in 53 patients with TS from Groningen University (45 males, 8 females, 6-18 years) versus 53 healthy controls (22 males, 31 females, 6-18 years), respectively. We also investigated correlations between Ig concentrations and symptom severity. In 13 additional patients (9 males, 4 females, age range 9-14), we established Ig profiles at time points before, during, and after symptom exacerbations. RESULTS: IgG3 levels were significantly lower in Yale patients compared to healthy children (medians 0.28 versus 0.49 mg/ml, p=.04), while levels of IgG2, IgG4, and IgM in patients were lower at trend-level significance (p≤.10). Decreased IgG3 (medians 0.45 versus 0.52 mg/ml; p=.05) and IgM (medians 0.30 versus 0.38 mg/ml; p=.04) levels were replicated in the Groningen patients. Ig levels did not correlate with symptom severity. There was a trend-level elevation of IgG1 during symptom exacerbations (p=.09). CONCLUSION: These pilot data indicate that at least some patients with TS have decreased serum IgG3, and possibly also IgM levels, though only few subjects had fully expressed Ig immunodeficiency. Whether these changes are related to TS pathogenesis needs to be investigated.

Exon expression and alternatively spliced genes in Tourette Syndrome.

Tourette Syndrome (TS) is diagnosed based upon clinical criteria including motor and vocal tics. We hypothesized that differences in exon expression and splicing might be useful for pathophysiology and diagnosis. To demonstrate exon expression and alternatively spliced gene differences in blood of individuals with TS compared to healthy controls (HC), RNA was isolated from the blood of 26 un-medicated TS subjects and 23 HC. Each sample was run on Affymetrix Human Exon 1.0 ST (HuExon) arrays and on 3' biased U133 Plus 2.0 (HuU133) arrays. To investigate the differentially expressed exons and transcripts, analyses of covariance (ANCOVA) were performed, controlling for age, gender, and batch. Differential alternative splicing patterns between TS and HC were identified using analyses of variance (ANOVA) models in Partek. Three hundred and seventy-six exon probe sets were differentially expressed between TS and HC (raw P < 0.005, fold change >|1.2|) that separated TS and HC subjects using hierarchical clustering and Principal Components Analysis. The probe sets predicted TS compared to HC with a >90% sensitivity and specificity using a 10-fold cross-validation. Ninety genes (transcripts) had differential expression of a single exon (raw P < 0.005) and were predicted to be alternatively spliced (raw P < 0.05) in TS compared to HC. These preliminary findings might provide insight into the pathophysiology of TS and potentially provide prognostic and diagnostic biomarkers. However, the findings are tempered by the small sample size and multiple comparisons and require confirmation using PCR or deep RNA sequencing and a much larger patient population.

Cytokines and soluble adhesion molecules in children and adolescents with a tic disorder.

AIM: Dysregulation of the immune system may play a role in tic disorders. We screened for immune disturbances by investigating serum levels of cytokines and soluble adhesion molecules in patients with a tic disorder. METHODS: Serum levels of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, soluble IL-2 receptor (sIL2R), tumor necrosis factor (TNF)-α, interferon (IFN)-γ, soluble vascular cell adhesion molecule-1 (sVCAM-1), and intercellular adhesion molecule-1 (sICAM-1) of 66 children and adolescents with a tic disorder and 71 healthy volunteers were compared. We also addressed possible relations between concentrations of the immune markers and severity of tics and comorbid obsessive-compulsive symptoms. RESULTS: Median serum concentrations did not differ significantly between patients and healthy subjects. Serum IL-2 concentrations were positively associated with tic severity ratings; serum IL-12 concentrations negatively with severity ratings of obsessive-compulsive symptoms. CONCLUSIONS: These preliminary findings do not reveal major immune activation in children with a tic disorder but may suggest more subtle disturbances related to disease expression.

The DRD4 gene and severity of tics and comorbid symptoms: main effects and interactions with delivery complications.

In this study, we investigated the role of the dopamine receptor D4 (DRD4) 48-base pairs (bp) variable number of tandem repeats (VNTR) and perinatal adversities regarding severity of tics and comorbid symptoms in children with tic disorders. We genotyped 110 children with tics with regard to the 48-bp VNTR and assessed presence of prenatal smoking exposure, and pregnancy and delivery complications by parent questionnaires. We examined associations between 2, 3, 4, and 7 repeat (R) alleles and severity of tics and comorbid obsessive-compulsive, depressive, anxious, and autistic symptoms. Through linear regressions, we investigated whether perinatal adversities and the 2R, 3R, 4R, and 7R alleles would interact with severity ratings of tics or comorbid symptoms as outcome. Presence of a 2R allele was related to more severe obsessive-compulsive symptoms, and presence of a 3R allele to increased severity of autistic features. Pregnancy complications were associated with decreased obsessive-compulsive symptom severity, and prenatal smoking exposure to more severe depressive and autistic symptoms. In children without a 3R allele delivery complications were associated with more severe tics, but in children with a 3R variant an inverse relation between delivery complications and tic severity was found. Moreover, the relation between delivery complications and internalizing symptom severity appeared to be most pronounced in children with a 2R allele. In conclusion, this study provides evidence for a role of the 48-bp VNTR in the etiology of tic and associated disorders, and for interactions with delivery complications regarding severity of tics and co-occurring internalizing symptoms.

Role of perinatal adversities on tic severity and symptoms of attention deficit/hyperactivity disorder in children and adolescents with a tic disorder.

OBJECTIVE: To investigate the role of perinatal adversities with regard to tic severity and comorbid attention deficit/hyperactivity disorder (ADHD) symptoms in children with a tic disorder. METHODS: In 75 children and adolescents with a tic disorder, we retrospectively assessed presence of pregnancy, delivery, and postnatal complications and of prenatal exposure to smoking and alcohol. Children with and without these perinatal adversities were compared regarding tic and ADHD symptom severity. Furthermore, through linear regressions, we investigated whether perinatal adversities would interact with presence in first-degree relatives of tic or any mental disorders with the tic or ADHD measure as outcome. RESULTS: Presence of delivery complications was related to tic severity and prenatal smoking exposure to severity of comorbid ADHD symptoms. The relationship between smoking exposure in utero and ADHD symptom severity appeared to be more pronounced in children with a positive family history of mental disorders. CONCLUSION: This study provides evidence of a role for perinatal adversities in the etiology of tic disorders. Children with perinatal adversities may be vulnerable to develop more severe tics or comorbid ADHD symptoms in the presence of a positive family history of mental disorders, suggesting a role for gene-environment interactions.