Impact of omega‐6 polyunsaturated fatty acid supplementation and γ‐aminobutyric acid on astrogliogenesis through the endocannabinoid system

Neural stem cells express cannabinoid CB1 and CB2 receptors and the enzymes for the biosynthesis and metabolism of endocannabinoids (eCBs). Here we have studied the role of neural stem cell‐derived eCBs as autonomous regulatory factors during differentiation. First, we examined the effect of an indirect eCB precursor linoleic acid (LA), a major dietary omega‐6 fatty acid, on the eCB system in neural stem/progenitor cells (NSPCs) cultured in DMEM/F12 supplemented with N2 (N2/DF) as monolayer cells. LA upregulated eCB system‐related genes and 2‐arachidonoylglycerol (2‐AG), but not anandamide (AEA), levels. Glial fibrillary acidic protein (GFAP) was significantly higher under LA‐enriched conditions, and this effect was inhibited by the cannabinoid receptor type‐1 (CB1) antagonist AM251. Second, the levels of AEA and 2‐AG, as well as of the mRNA of eCB system‐related genes, were measured in NSPCs after γ‐aminobutyric acid (GABA) treatment. GABA upregulated AEA levels significantly in LA‐enriched cultures and increased the mRNA expression of the 2‐AG‐degrading enzyme monoacylglycerol lipase. These effects of GABA were reproduced under culture conditions using neurobasal media supplemented with B27, which is commonly used for neurosphere culture. GABA stimulated astroglial differentiation in this medium as indicated by increased GFAP levels. This effect was abolished by AM251, suggesting the involvement of AEA and CB1 in GABA‐induced astrogliogenesis. This study highlights the importance of eCB biosynthesis and CB1 signalling in the autonomous regulation of NSPCs and the influence of the eCB system on astrogliogenesis induced by nutritional factors or neurotransmitters, such as LA and GABA. © 2013 Wiley Periodicals, Inc.     

The effect of psychosocial stimulation on cognition and behaviour at 6 years in a cohort of term,low‐birthweight Jamaican children

Aim The aim of this study was to determine whether psychosocial stimulation up to the age of 2 years benefits cognition and behaviour at age 6 years in low‐birthweight, term‐born (LBW‐T) children (gestational age ≥37wk, birthweight <2500g), and to compare LBW‐T and normal‐birthweight (NBW) children. Method LBW‐T Jamaican infants were randomized at birth to a control group or an intervention group. Children in the intervention group received psychosocial stimulation for 2 years. LBW‐T infants were also compared with NBW infants born in the same hospital. IQ, cognitive function, and behaviour were measured at age 6 years in 109 LBW‐T infants. The LBW‐T group were divided into the intervention group (55 out of 70 enrolled, 32 females, 23 males; mean birthweight 2190g, SD 200g; and the control group (54 out of 70 enrolled, 33 females, 21 males; birthweight 2240g, SD 180g]. These were compared with 73 out of 94 enrolled NBW infants (38 females 35 males; birthweight 3130g, SD 330g). Results Among the LBW‐T children performance IQ scores were higher in the intervention group than in the control group (regression coefficient [B] 4.06, 95% confidence interval [CI] 0.01–7.98) as were visual–spatial memory scores (B 1.12, 95% CI 0.45–1.87). Children in the intervention group also exhibited fewer behavioural difficulties (B ?2.21, 95% CI ?4.13 to ?0.10) than children in the control group. Compared with NBW children, LBW‐T children in the control group had poorer selective attention (B=?3.35, 95% CI ?5.59 to ?1.26) and visual–spatial memory (B=?0.76, 95% CI ?1.54 to 0.00), but there were no differences in IQ, language, or behaviour. Interpretation Stimulation had sustained benefits in LBW‐T infants. Finding few differences between LBW‐T and NBW school‐aged children concurs with results from other developing countries.     

Outcomes of childhood epilepsy at age 33 years: A population‐based birth‐cohort study

Purpose: There is uncertainty about health and socioeconomic outcomes of children with epilepsy, knowledge of adult outcomes, and factors associated with adverse outcomes are essential to guide prognosis, improve management, and determine appropriate allocation of resources. Methods: A subgroup of 101 children with epilepsy (onset ≤ age 16 years) were previously identified and reported from the 1958 National Child Development Study (NCDS), a national United Kingdom birth cohort study. In the current study we examine outcomes of this unique childhood epilepsy subgroup at age 33 compared to unaffected NCDS cohort members in mental and general health, education and employment, marriage, and parenthood. Multivariable regression analyses were used to investigate factors (including etiology, cognitive development, parental interest, and childhood anxiety/depression at age 11 years) associated with adverse outcomes. Key Findings: Sixty‐five (66%) were still participating at 33 years. Median follow‐up after epilepsy onset was 28 years (range 17–33 years). Thirty participants [46%, 95% confidence interval (CI) 35–58] had epilepsy onset <5 years, 32 (49%, 95% CI 37–61) had “symptomatic” epilepsy, and 33 (51%, 95% CI 39–63) had idiopathic epilepsy. Thirty‐one participants (48%) reported being seen by their doctor for epilepsy in the preceding year, 27 (42%) were registered disabled, 39 (60%) had a drivers license, and 42 (65%) thought their epilepsy made it harder to get/keep a paid job. People who had childhood epilepsy had an increased risk of death [standardized mortality rate (SMR) 3.1, 95% CI 1.1–6.1]. Childhood epilepsy was associated with poor general and mental health at 33 years on univariable analyses, but not after adjusting for childhood cognitive development/comorbidities and anxiety over acceptance by peers/adults at age 11. Childhood epilepsy was an independent risk factor for not being married [odds ratio (OR) 0.45, 95% CI 0.05–0.94] or being a parent (OR 0.67, 95% CI 0.42–0.91). People with childhood epilepsy and poor cognitive development compared to those with poor cognitive development without epilepsy had a greater proportion with subsequent poor mental health (56% vs. 24%, difference in proportion 33%, 95% CI 12–50), and a lesser proportion who married (39% vs. 78%, difference in proportion −39%, 95% CI −56 to −19). Significance: Compared to the unaffected population, children with epilepsy with good cognitive development/without comorbidities have similar adult health, educational, and employment outcomes but have difficulties with establishing and maintaining personal relationships. A combination of having childhood epilepsy plus poor cognitive development is more likely to be associated with adverse outcomes compared to having poor cognitive development without childhood epilepsy. Children with epilepsy have increased risk of death compared to the rest of the population. Pharmacologic management alone is inadequate and long‐term psychosocial support is needed.     

Eating problems at age 6 years in a whole population sample of extremely preterm children

Aim The aim of this study was to investigate the prevalence of eating problems and their association with neurological and behavioural disabilities and growth among children born extremely preterm (EPC) at age 6 years. Method A standard questionnaire about eating was completed by parents of 223 children (125 males [56.1%], 98 females [43.9%]) aged 6 years who were born at 25 weeks’ gestation or earlier (mean 24.5wks, SD 0.7wks; mean birthweight 749.1g, SD 116.8g), and parents of 148 classmates born at term (66 males [44.6%], 82 females [55.4%]). All children underwent neurological, cognitive, and anthropometric assessment, and parents and teachers completed a behaviour scale. Results Eating problems were more common among the EPC than the comparison group (odds ratio [OR] 3.6, 95% confidence interval [CI] 2.1–6.3), including oral motor (OR 5.2, 95% CI 2.8–9.9), hypersensitivity (OR 3.0, 95% CI 1.6–5.6), and behavioural (OR 3.8, 95% CI 1.9–7.6) problems. Group differences were reduced after adjustment for cognitive impairment, neuromotor disability, and other behaviour problems. EPC with eating problems were shorter, lighter, and had lower mid‐arm circumference and lower body mass index (BMI) even after adjusting for disabilities, gestational age, birthweight, and feeding problems at 30 months. Interpretation Eating problems are still frequent in EPC at school age. They are only partly related to other disabilities but make an additional contribution to continued growth failure and may require early recognition and intervention.     

Weekly IM interferon beta‐1a in multiple sclerosis patients over 50 years of age

Background: Efficacy and safety data have not previously been compiled for intramuscular interferon beta‐1a (IM IFNβ‐1a) in patients with multiple sclerosis (MS) ≥ 50 years of age. We investigated the efficacy and safety of IM IFNβ‐1a in patients segregated by 50 and 40 years of age in separate meta‐analyses. Methods: The MS Clinical Research Group Study, the Controlled High‐Risk Subjects AVONEX^® (IM IFNβ‐1a) MS Prevention Study, the IFNβ‐1a European Dose‐Comparison Study, and a multicenter, open‐label antigenicity and safety study of human serum albumin‐free IM IFNβ‐1a were analyzed. Results: Overall, 906 patients (68 aged ≥ 50 years and 838 aged <50 years, or 323 aged ≥ 40 years and 583 aged <40 years) received IM IFNβ‐1a for ≥ 24 months. At baseline, patients ≥ 50 years had significantly higher Expanded Disability Status Scale scores than patients <50 years (3.4 vs. 2.8; P < 0.001), but fewer relapses in the three preceding years (2.6 vs. 3.4; P < 0.001); patients ≥ 40 years and <40 years exhibited similar differences. After 2 years of treatment, there were no significant differences in annualized relapse rate, sustained disability progression, time to sustained disability progression, or number of MRI‐identified gadolinium‐enhanced lesions between age groups in either analysis. The cumulative probability of relapse was significantly lower in patients ≥ 40 years versus patients <40 years (0.601 vs. 0.702; P < 0.001). Adverse event incidence did not differ significantly between age groups in either analysis. Conclusions: IM IFNβ‐1a is effective and well tolerated in patients with MS ≥ 40 and ≥ 50 years as well as younger patients.     

Risk of developmental delay increases exponentially as gestational age of preterm infants decreases: a cohort study at age 4 years

Aim The aim of the study was to assess the influence of decreasing gestational age on the risk of developmental delay in various domains at age 4 years among children born at a wide range of gestational ages. Method In a community‐based cohort, the parents of 1439 preterm‐born children (24 0/7 to 35 6/7wks) and 544 term‐born children (38 0/7 to 41 6/7wks’) born in 2002 and 2003 completed the Ages and Stages Questionnaire (ASQ) when their child was 3 years 7 months to 4 years 1 month old. The prevalence rates of abnormal scores on the ASQ‐total problems scale were compared in preterm and term‐born children and the resulting odds ratios for gestational age groups were calculated and adjusted for social and biological covariates. Results The prevalence rates of abnormal scores on the ASQ‐total problems scale increased with decreasing gestational age: from 4.2% among term‐born children to 37.5% among children born at 24–25 weeks’ gestation (p<0.001). The risk of an abnormal ASQ‐total score increased exponentially with decreasing gestational age compared with children born at term (odds ratio per week of gestation 1.14, 95% confidence interval 1.09–1.19). A similar exponential pattern was seen on all underlying ASQ domains, both before and after adjustment. Interpretation The risk of developmental delay increases exponentially with decreasing gestational age below 36 weeks’ gestation on all developmental domains of the ASQ. Adjustment for covariates did not alter the pattern of exponential increase in developmental risk with decreasing gestational age. We speculate that both direct perinatal cerebral injuries and tropic and maturational brain disturbances are involved.     

Spinal cord injuries in young children: a review of children injured at 5 years of age and younger

Aim To determine the epidemiology and complications of spinal cord injuries (SCIs) in children injured at 5 years of age and younger who were seen between 1981 and 2008 at a children’s hospital in the USA. Method Complications studied were scoliosis, hip dysplasia, latex allergies, autonomic dysreflexia, pressure ulcers, spasticity, deep venous thrombosis, and kidney stones. Demographic and injury‐related factors included age at injury, etiology, level of injury, American Spinal Injury Association Impairment Scale (AIS), and SCIs without radiological abnormalities (SCIWORA). Results Of the 159 individuals seen (92 males, 67 females) median age at injury was 2 years (range 0y–5y 11mo). Forty‐nine percent were injured in vehicular accidents, 60% had complete injuries, 66% had paraplegia, and 72% had SCIWORA. Ninety‐six percent developed scoliosis, 57% had hip dysplasia, and 7% had latex allergy. Thirty‐four percent with injuries at or above T6 experienced autonomic dysreflexia, 41% developed pressure ulcers, and 61% experienced spasticity. Of those without bowel or bladder control, 82% were on intermittent catheterization and 69% were on a bowel program. Median age of initiating wheelchair use was 3 years 4 months (range 1y 2mo–12y 5mo). Twenty‐four were community ambulators, and they were more likely to have AIS D lesions (half the key muscle functions below the level of injury have a muscle grade 3 or greater) and less likely to have skeletal complications. Interpretation The epidemiology, complications, and manifestations of SCIs in children injured at a young age are unique and differ distinctively from adolescent and adult‐onset SCIs.     

Within‐drug benefit‐risk evaluation of olanzapine long‐acting injection at one and two years of treatment

We sought to evaluate the within‐drug benefit‐risk of olanzapine long‐acting injection (LAI) using both quantitative and qualitative methods. Subjects included 1192 adult patients with schizophrenia or schizoaffective disorder who participated in clinical trials with the opportunity for at least two years of continuous treatment with olanzapine LAI (45–405 mg every two to four weeks). Using the Benefit Risk Action Team (BRAT) framework, we evaluated frequency versus duration of benefits and risks commonly observed with atypical antipsychotics. We then used the Transparent Uniform Risk/Benefit Overview (TURBO) method, which weighs the drug's two most medically serious and/or frequent adverse events versus its primary benefit (effectiveness) and an ancillary benefit. The most frequent events among all patients were remaining free of relapse (91.4% for an average of 306 days at one year, 88.4% for 546 days at two years) and symptomatic remission (81.7% for an average of 239 days at one year, 84.1% for 438 days at two years). One‐ and two‐year incidence of ≥7% weight gain was 33.3% and 41.7%. Incidences for sexual dysfunction, hyperprolactinemia, and post‐injection delirium/sedation syndrome (PDSS) were <2%. TURBO ratings unanimously selected PDSS and weight gain as key risks and resulted in an average score in the acceptable benefit‐risk balance range. Copyright © 2014 John Wiley & Sons, Ltd.     

Clinico‐electrophysiological findings and prognosis of Guillain‐Barré syndrome – 10 years’ experience

Soysal A, Aysal F, Calıskan B, Dogan Ak P, Mutluay B, Sakallı N, Baybas S, Arpacı B. Clinico‐electrophysiological findings and prognosis of Guillain‐Barré syndrome – 10 years’ experience.
Acta Neurol Scand: 2011: 123: 181–186.
© 2010 John Wiley & Sons A/S. Objective – To assess correlation between the prognosis and epidemiological, clinical, laboratory, electrophysiological findings in patients with Guillain‐Barré syndrome (GBS). Methods – We reviewed the medical records of 104 GBS patients who were hospitalized and followed up at our outpatient clinic during October 1997–November 2007. Results – Guillain‐Barré syndrome patients were followed up with a median period of 232 days. Full recovery or minor deficits were observed in 41% of patients in the first month, 71% in the third month, 86% in the sixth month and 92% in the first year. We found that there was a correlation between Medical Research Council (MRC) sum scores at admission, clinical subtypes, respiratory distress, interference pattern and prognosis. Conclusions – Demographic, clinical and electrophysiological findings of our GBS cases were highly similar to those of the previous reports. Two of our cases were presented with preceding tuberculosis infection, which was not reported before in the literature.     

Predicting school readiness from neurodevelopmental assessments at age 2 years after respiratory distress syndrome in infants born preterm

Aim To determine whether neurodevelopmental outcomes at the age of 2 years accurately predict school readiness in children who survived respiratory distress syndrome after preterm birth. Method Our cohort included 121 preterm infants who received surfactant and ventilation and were enrolled in a randomized controlled study of inhaled nitric oxide for respiratory distress syndrome. Abnormal outcomes at the age of 2 years were defined as neurosensory disability (cerebral palsy, blindness, or bilateral hearing loss) or delay (no neurosensory disability but Bayley Scales of Infant Development mental or performance developmental index scores <70). School readiness (assessed at a mean age of 5y 6mo, SD 1y) was determined using neurodevelopmental assessments of motor, sensory, receptive vocabulary, perceptual, conceptual, and adaptive skills. Results The mean birthweight of the cohort (57 males, 64 females) was 987g (SD 374), and the mean gestational age was 27.3 weeks (SD 2.6). At the age of 2 years, the neurodevelopmental classification was ‘disabled’ in 11% and ‘delayed’ in 23%. At the age of 5 years 6 months, intensive special education was required for 11% and some special education for 21%. Disability and delay at the age of 2 years were 92% and 50% predictive of lack of school readiness respectively, whereas only 15% of children who were normal at the age of 2 years were not school ready at the later assessment. Children with delay at 2 years were more likely to need special education if they were socially disadvantaged. Interpretation Without preschool developmental supports, preterm survivors living in poverty will require more special education services.     

Outcome of late‐life depression after 3 years of sequential treatment

Objective: To study the outcome of a sequential treatment protocol in elderly, severely depressed in‐patients. Method: All 81 patients from a 12‐week double‐blind randomized controlled trial (RCT) comparing venlafaxine with nortriptyline were asked to participate in a 3 year follow‐up study. Thirty‐two patients who did not achieve remission during the RCT, entered an open sequential treatment protocol and were treated with augmentation with lithium, switch to a monoamine oxidase inhibitor or ECT. Results: Seventy‐eight of the 81 patients (96.3%) achieved a response [≥50% reduction in Montgomery Åsberg Depression Rating Scale score) and 68 patients (84%) a complete remission (final MADRS score ≤ 10) within 3 years of treatment. Greater severity and longer duration of the depressive episode at baseline predicted poor recovery. Augmentation with lithium may be the best treatment option in treatment resistant depressed elderly. Only few patients dropped‐out due to side‐effects. Conclusion: Our study demonstrates the importance of persisting with antidepressant treatment in elderly patients who do not respond to the first or second treatment.