Mild Delay Research Articles

A Phenotype of Childhood Autism Is Associated with Preexisting Maternal Anxiety and Depression.

This study explored whether ASD phenotypes in the child were associated with a history of anxiety or depression in the mother. We hypothesized that an ASD profile in children characterized by mild delays and increased rates of dysregulation would be associated with preexisting maternal anxiety or depression. Participants were 672 preschool children with ASD and their mothers. Children were classified as ASD after a comprehensive developmental evaluation. Mothers reported whether a healthcare provider ever diagnosed them with anxiety or depression before the birth of their child. Four child ASD phenotypes were derived from latent class analysis: Mild Language Delay with Cognitive Rigidity (Type 1), Significant Developmental Delay with Repetitive Motor Behaviors (Type 2), General Developmental Delay (Type 3), and Mild Language and Motor Delay with Dysregulation (i.e., aggression, anxiety, depression, emotional reactivity, inattention, somatic complaints, and sleep problems) (Type 4). Type 2 ASD served as the referent category in statistical analyses. Results showed that 22.6% of mothers reported a diagnosis of anxiety or depression before the birth of their child. Maternal anxiety or depression was associated with 2.7 times the odds (95% confidence interval: 1.4, 5.3) of Type 4 or Dysregulated ASD in the child; maternal anxiety and depression was associated with 4.4 times the odds (95% confidence interval: 1.4, 14.0) of Type 4 or Dysregulated ASD in the child. Our findings suggest an association between Dysregulated ASD in the child and anxiety and depression in the mother. These findings can enhance screening methods and inform future research efforts.

Monosomy chromosome 21 compensated by 21q22.11q22.3 duplication in a case with small size and minor anomalies

BackgroundPartial monosomy 21 is a rare finding with variable sizes and deletion breakpoints, presenting with a broad spectrum of phenotypes.Case presentationWe report a 10-month-old boy with short stature, minor anomalies and mild motor delay. The patient had a monosomy 21 and duplication of the 21q22.11q22.3 region on the remaining derivative chromosome 21 which represents a partial 21q uniparental disomy of paternal origin, upd(21q22.11q22.3)pat. The abnormalities were characterized by karyotyping, FISH, chromosomal microarray, and genotyping.ConclusionsThis is the first case showing a monosomy 21 compensated by upd(21q22.11q22.3) as a mechanism of genomic rescue. Because there is no strong evidence showing imprinting on chromosome 21, the uniparental disomy itself is not associated with abnormal phenotype but has reduced phenotype severity of monosomy 21. We reviewed the previously published cases with isolated 21q deletions and identified a common deletion of 5.7 Mb associated with low birth weight, length and head circumference in the 21q21.2 region.

Phenotype study of SCN2A gene related epilepsy

Objective: To summarize the phenotype of epileptic children with SCN2A mutations. Methods: Epileptic patients who were treated in the Pediatric Department of Peking University First Hospital from September 2006 to October 2017 and detected with SCN2A mutations by targeted next-generation sequencing were enrolled. Clinical manifestations of all patients were analyzed retrospectively. Results: A total of 21 patients (16 boys and 5 girls) with SCN2A mutations were collected. Twenty-one SCN2A mutations were identified. Ten patients had mutations inherited from one of their parents and 11 patients had de novo mutations. The age of epilepsy onset was from 2 days to 2 years and 6 months: six patients with seizure onset in neonates (29%) , six patients with seizure onset between 1 month and 3 months of age (29%), three patients with seizure onset between 4 months and 6 months of age, two patients with seizure onset between 7 months and one year of age, and four patients with seizure onset beyond one year of age. Multiple seizure types were observed. The focal seizure was the most common seizure type which was observed in 18 patients (86%) . Spasm seizure was observed in 6 patients (29%) . Other seizure types were rare. In 19 patients, seizures manifested in clusters (90%) . In 3 patients, seizures manifested fever-sensitive. Nine of ten patients with inherited SCN2A mutations had normal development. However, all patients with de novo SCN2A mutations had mild or severer development delay. In 21 patients with SCN2A mutations, five were diagnosed with benign familial infantile epilepsy, 3 with benign familial neonatal-infantile epilepsy, 3 with Ohtahara syndrome, 3 with West syndrome, 2 with encephalopathy with early infantile onset epilepsy, one with febrile seizures plus, one with Dravet syndrome, one with encephalopathy with childhood-onset epilepsy, one with autism with epilepsy and one with intellectual disability with epilepsy. Conclusions: The clinical features of patients with SCN2A mutations include that main seizure onset is the neonate and early infancy, and the main seizure type is the focal seizure, manifested in clusters. The large spectrum of SCN2A-related epilepsy, which not only includes epilepsy with a comparatively favorable prognosis, but also epileptic encephalopathy. De novo mutations often lead to severe phenotype with development delay.

Post-stroke dysphagia: novel treatment approaches

The paper presents the results of examination and treatment in patients in the early recovery period of ischemic stroke. It considers the concurrent use of drug and speech therapies to improve the rehabilitation of patients with post-stroke speech and swallowing disorders. Objective : to identify the role of speech-language therapy and neuropsychology sessions in the treatment of speech and swallowing disorders in the early recovery period of ischemic hemispheric stroke. Patients and methods . A total of 45 patients (32 (71%) men and 13 (29%) women) with a 2–3-month history of ischemic hemispheric stroke were examined. The follow-up period was 2 months. The patients were divided in two groups. Group 1 (a study group) included 30 patients who received combination therapy (drug treatment; sessions with a speech-language pathologist; and compensatory treatments for restoring swallowing function). All the patients had moderate dysphagia accompanied by speech disorders. Moderate sensorimotor aphasia was observed in 15 patients; moderate dysarthria was also seen in 15 patients. Vinpocetine (Cavinton®) and its dispersible tablets (Cavinton® Comfort) were chosen as an agent for vasoactive therapy. Group 2 (a comparison group) consisted of 15 patients with dysphagia who had only standard therapy and speech therapy sessions. There was sensorimotor aphasia in 2 (4%) patients and dysarthria in 13 (29%). A complex psychological and logopedic examination was carried out using the Mann Assessment of Swallowing Ability (MASA), dysarthria assessment, and the scale designed by L.I. Vasserman for estimating the degree of speech disorders in patients with local brain injuries. Results and discussion . Posttreatment swallowing function improved in all the 45 patients; however, more pronounced positive changes were recorded in the patients of Group 1 (p< 0.05). Survey data, possible diet modification, better patient communications, improved quality of life in the patients, and the opinions of their relatives and medical staff served as criteria for the effectiveness of the model used to recover swallowing function. A subjective improvement showed itself as an increased ability to initialize the pharyngeal phase of swallowing in 25 (56%) patients and none mild delays (up to 5 sec) in the movement of a food bolus in the oral cavity in 10 (22%) patients and in the intake of the food of different consistency in 10 (22%). After a treatment cycle in Group 1, the number of patients with mild dysphagia increased up to 30%; moderate swallowing disorders were present in 63% of patients, which required that medical and speech correction should be continued. A significant improvement in swallowing function was noted in 10% of Group 1 patients with medium-sized cortical and cortical-subcortical lesions; a moderate improvement was seen in 67% with medium and small cerebral foci at the same location. At the same time, in Group 2 there were insignificant positive changes only in 20% of patients, most of whom had dysarthria. Conclusion. The high incidence of post-stroke makes it reasonable to use speech therapy methods in a set of multidisciplinary specialized types of care. This care should be personalized; prescribing easy-to-swallow dispersible drugs plays an important role in this case. This will improve quality of life in the patient and protect him from unwanted complications.

Microduplication in the 2p16.1p15 chromosomal region linked to developmental delay and intellectual disability

BackgroundSeveral patients with the 2p16.1p15 microdeletion syndrome have been reported. However, microduplication in the 2p16.1p15 chromosomal region has only been reported in one case, and milder clinical features were present compared to those attributed to 2p16.1p15 microdeletion syndrome. Some additional cases were deposited in DECIPHER database.Case presentationIn this report we describe four further cases of 2p16.1p15 microduplication in four unrelated probands. They presented with mild gross motor delay, delayed speech and language development, and mild dysmorphic features. In addition, two probands have macrocephaly and one a congenital heart anomaly. Newly described cases share several phenotype characteristics with those detailed in one previously reported microduplication case.ConclusionThe common features among patients are developmental delay, speech delay, mild to moderate intellectual disability and unspecific dysmorphic features. Two patients have bilateral clinodactyly of the 5th finger and two have bilateral 2nd-3rd toes syndactyly. Interestingly, as opposed to the deletion phenotype with some cases of microcephaly, 2 patients are reported with macrocephaly. The reported cases suggest that microduplication in 2p16.1p15 chromosomal region might be causally linked to developmental delay, speech delay, and mild intellectual disability.

Neurodesarrollo en trillizos a los 2 años de vida de acuerdo al método de embarazo

BackgroundMultiple pregnancies, prematurity, low birth weight and intrauterine growth restriction are important risk factors for adverse neurodevelopmental throughout the world. Material and methodsAn observational, retrospective, and analytical study was conducted on a cohort of triplets born by different pregnancy methods. They were assessed using the Mayo Clinic neurological assessment, neurobehavioural evaluation, Bayley psychomotor assessment, human communication, and hearing and language at 2 years of life. ResultsA total of 82 sets of triplets were included in the analysis. In the neurological examination at two years, behavioural problems stand out, being 10.6% for spontaneous pregnancies. In the neurobehavioural assessment, 16% presented with a mild delay, 3.4% moderate, and severe delay only in 0.8%. The percentage for hearing loss in general was low, being superficial in one patient, with mild hearing loss in one, and another with profound hearing loss. The language for the entire sample was at a mean of 21.2 months. For the Bayley scale, the mean mental index was 83.6, and for the psychomotor index it was 82.7. ConclusionsThere were no statistical differences in relation to neurodevelopment and pregnancy methods. The only differences were found in the Bayley assessment for those born by ovulation inducers. The results of neurodevelopment in general were favourable. Cerebral palsy only occurred in 1.2%, with behavioural problems predominating in 6.8%.

T87. EEG and simultaneously recorded SEPs in evaluation of newborns with hypoxic ischemic encephalopathy or stroke in the NICU

Introduction Differential diagnostics and outcome prediction in newborns presenting with seizures or encephalopathy remain difficult in the bedside. The objectives of the present study were (i) to determine the accuracy of simultaneously recorded EEG and somatosensory evoked potentials (SEPs) in differentiating between hypoxic-ischemic encephalopathy (HIE) and stroke as the underlying etiology of neonatal seizures or encephalopathy and (ii) to determine the accuracy of EEG and SEPs and their combination for predicting outcome in newborns with HIE or stroke. Methods The study comprised of 133 newborns (gestational age > 34 weeks) that underwent a clinically indicated EEG and simultaneous SEPs in the acute phase of their illness. 102 of the newborns had HIE and 31 had stroke. EEG background was scored as continuous (sleep stages identifiable and EEG continuous at least in active sleep or awake state) or discontinuous (sleep stages not identifiable and EEG not continuous at any time during the recording). The SEPs were classified as bilaterally absent, unilaterally absent, or bilaterally present. Outcome was evaluated from medical records at approximately 1–1.5 years age. Death, cerebral palsy, severe mental retardation, and epilepsy were considered as unfavorable outcomes. Normal or mildly abnormal development (e.g. mild motor or language delay) were considered as favorable outcomes. Results The combinations of EEG and SEP abnormalities were indicative of etiology (HIE vs stroke) and predictive of outcome. If the EEG was discontinuous, the etiology was always HIE (33 newborns) regardless of SEPs. Furthermore, if the EEG was continuous, but SEPs were uni- (9 newborns) or bilaterally (1 newborn) absent, the etiology was always stroke. Normal SEPs and continuous EEG occurred in 69 newborns with HIE and 21 newborns with stroke, and hence in these newborns the distinction between the etiologies could not be made with the present EEG-SEP criteria. This combination was, however, highly predictive of a favorable outcome regardless of the etiology: The outcome was favorable in 67/69 of those HIE and 20/21 of those with stroke. On the contrary, bi- or unilaterally absent SEPs were associated with poor outcome in all newborns with HIE (22/22) and all but two newborns with stroke (8/10). Furthermore, in newborns with HIE, even if the EEG was discontinuous but SEPs were bilaterally present, the outcome was likely to be favorable (8/11 newborns). Conclusion EEG-SEP is useful in bedside differential diagnostics between HIE and stroke in newborns presenting with seizures or general signs of encephalopathy. Furthermore, EEG-SEP is accurate in outcome prediction in both etiologies.

No evidence of obstetrical adverse events after hyperimmune globulin application for primary cytomegalovirus infection in pregnancy: experience from a single centre

To determine the frequency of obstetrical adverse events and clinical outcome in infants following antenatal hyperimmune globulin (HIG) treatment for primary cytomegalovirus (CMV) infection in pregnancy. Data from 50 women including three twin pregnancies were retrospectively evaluated. Primary infection was defined by seroconversion or the presence of CMV-specific IgM and low IgG avidity. All women received two or more infusions of HIG (200U/kg). Congenital CMV (cCMV) infection was diagnosed by detection of CMV in amniotic fluid and/or neonatal urine. We compared gestational age (GA) at birth, head circumference (HC) and birth weight (BW) of infants in our study cohort with those of live-born infants delivered in our clinic between 2015 and 2016. Median gestational age at time of maternal CMV diagnosis was 13weeks. One-hundred-forty-one maternal HIG doses were given. No HIG-related severe adverse reactions occurred. Preterm birth rate was 4.2% (2/47) in singleton pregnancies. None of the neonates had birth weight or head circumference<3rd percentile (<3P) for gestational age. There was no statistically significant difference regarding GA, BW and HC between our study cohort and the total population of live-born infants. The frequency of CMV-related sequelae in infants with cCMV infection was 10.5% (2/19) (one with bilateral hearing loss and one with mild motoric delay), both cases following first trimester maternal infection. Antenatal HIG treatment was well tolerated and not associated with prematurity or decreased birth weight. HIG application might have a favorable effect on the clinical course of congenital CMV infection.

Associations between parental broader autism phenotype and child autism spectrum disorder phenotype in the Study to Explore Early Development.

The autism spectrum disorder phenotype varies by social and communication ability and co-occurring developmental, behavioral, and medical conditions. Etiology is also diverse, with myriad potential genetic origins and environmental risk factors. Examining the influence of parental broader autism phenotype-a set of sub-clinical characteristics of autism spectrum disorder-on child autism spectrum disorder phenotypes may help reduce heterogeneity in potential genetic predisposition for autism spectrum disorder. We assessed the associations between parental broader autism phenotype and child phenotype among children of age 30-68 months enrolled in the Study to Explore Early Development (N = 707). Child autism spectrum disorder phenotype was defined by a replication of latent classes derived from multiple developmental and behavioral measures: Mild Language Delay with Cognitive Rigidity, Mild Language and Motor Delay with Dysregulation (e.g. anxiety/depression), General Developmental Delay, and Significant Developmental Delay with Repetitive Motor Behaviors. Scores on the Social Responsiveness Scale-Adult measured parent broader autism phenotype. Broader autism phenotype in at least one parent was associated with a child having increased odds of being classified as mild language and motor delay with dysregulation compared to significant developmental delay with repetitive motor behaviors (odds ratio: 2.44; 95% confidence interval: 1.16, 5.09). Children of parents with broader autism phenotype were more likely to have a phenotype qualitatively similar to broader autism phenotype presentation; this may have implications for etiologic research.

Neurodevelopmental outcome in very preterm and very-low-birthweight infants born over the past decade: a meta-analytic review.

The purpose of this systematic review was to provide an up-to-date global overview of the separate prevalences of motor and cognitive delays and cerebral palsy (CP) in very preterm (VPT) and very-low-birthweight (VLBW) infants. A comprehensive search was conducted across four databases. Cohort studies reporting the prevalence of CP and motor or cognitive outcome from 18months corrected age until 6years of VPT or VLBW infants born after 2006 were included. Pooled prevalences were calculated with random-effects models. Thirty studies were retained, which included a total of 10293 infants. The pooled prevalence of cognitive and motor delays, evaluated with developmental tests, was estimated at 16.9% (95% confidence interval [CI] 10.4-26.3) and 20.6% (95% CI 13.9-29.4%) respectively. Mild delays were more frequent than moderate-to-severe delays. Pooled prevalence of CP was estimated to be 6.8% (95% CI 5.5-8.4). Decreasing gestational age and birthweight resulted in higher prevalences. Lower pooled prevalences were found with the Third Edition of the Bayley Scales of Infant Development than with the Second Edition. Even though neonatal intensive care has improved over recent decades, there is still a wide range of neurodevelopmental disabilities resulting from VPT and VLBW births. However, pooled prevalences of CP have diminished over the years. The Bayley Scales of Infant and Toddler Development, Third Edition reported lower pooled prevalences of motor and cognitive delays than the Second Edition. The pooled prevalence of cerebral palsy in infants born extremely preterm was reduced compared with previous meta-analyses.

Repolarisation anomalies and rhabdomyolysis

Acute rhabdomyolysis is a rare but potentially severe disease in childhood. Inherited metabolic disorders have to be searched for. Significant repolarisation abnormalities have been described in patients with acute rhabdomyolysis and TANGO2 mutation involved in the Golgi apparatus. Between 12/2013 and 01/2017, 4 children (mean age 3,5 years at first crisis) presented in our department with 1 to 3 acute severe rhabdomyolysis crises (CPK > 10,000 UI/L) associated with significant ECG anomalies. All 4 had neurodevelopmental delay (from mild speech delay to spastic tetraparesia, with microcephaly). Rhabdomyolysis occurred after acute viral illnesses or unusual fasting and were associated with neurological deterioration. Cardiac anomalies included significant lengthening of QT and QTc interval in all 4, concomitant bradycardia and life-threatening “torsades de pointe” in patient 1, left bundle branch bloc in patient 3 and ventricular arrhythmia and cardiac arrest in patient 4 ( Fig. 1 ). ECG anomalies were maximal around 10 days after the beginning of crisis and slightly delayed from the peak CPK level. Ventricular dysfunction was associated in patient 2 (mild) and in patient 3 (severe requiring inotrope support). Cardiac anomalies regressed completely in all between the rhabdomyolysis crises. Patient 1 died while admitted for her 3rd rhabdomyolysis crisis, with severe neurological worsening, prolonged QT but no ventricular arrhythmia. TANGO2 mutation was confirmed in patient 1, suspected but not yet confirmed for the 3 others. Ventricular conduction and function have to be explored in children with acute rhabdomyolysis in the setting of neurodevelopmental delay. TANGO2 mutations may be responsible. The cardiac disorders are rapidly progressive, potentially life-threatening but reversible. The mechanism and treatment are poorly defined.

The Role of Phonological Working Memory and Environmental Factors in Lexical Development in Italian-Speaking Late Talkers: A One-Year Follow-Up Study.

This follow-up study assessed (a) the influence of phonological working memory (pWM), home literacy environment, and a family history of linguistic impairments in late talkers (LTs); (b) the diagnostic accuracy of a task of nonword repetition (NWR) in identifying LTs; and (c) the persistence of lexical weaknesses after 10 months. Two hundred ninety-three children were assessed at approximately 32 (t1) and 41 (t2) months. At t1, they were administered the Italian adaptation of the Language Development Survey, an NWR task (used to assess pWM), and questionnaires assessing home literacy environment and family history of language impairments. Thirty-three LTs were identified. The linguistic skills of the participants were evaluated at t2 by administering tasks assessing Articulation, Naming, Semantic Fluency, and Lexical Comprehension. At t2, LTs performed more poorly as compared with age-matched typically developing peers in articulatory and naming skills, had reduced lexical comprehension abilities, and had limited lexical knowledge. Their performance on the NWR task at t1 correlated with the extension of their vocabularies at t2 (as estimated with a Semantic Fluency task). The Language Development Survey recently adapted to Italian is sensitive to LTs. Former LTs still have a mild lexical delay at approximately 40 months. As an indirect measure of pWM, the task of NWR is an early indicator of future lexical deficits.

The Relationship Between Motor Delays and Language Development in Very Low Birthweight Premature Children at 18 Months Corrected Age.

The aim of this study is to determine if there is a specific association between motor delays and receptive and expressive language function, respectively, in prematurely born children. Retrospective data review: 126 premature children ≤ 1,250-g birthweight from English-speaking families were evaluated on motor development (normal, mild delay, and moderate-severe delay) and the cognitive and language scales of the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley, 2006) at 18 months corrected age. Cognitive scores were categorized as normal, suspect, and abnormal. Gender, demographic, and perinatal variables were recorded and analyzed with respect to motor category. Lower birthweight, chronic need for oxygen, severe intraventricular hemorrhage, and intestinal infection/inflammation were related to poorer motor development. On receptive language, the normal motor group attained significantly higher scores than the moderate-severe motor group but did not differ significantly from the mild delay motor group. On expressive language, the normal motor group had significantly higher scores than both the mild and moderate-severe groups. Girls performed better than boys on receptive and expressive language, but there was no significant interaction between gender and motor category on any of the Bayley scores. Cognitive, but not motor, category significantly contributed to variance of receptive language scores; cognitive and motor category each independently contributed to the variance in expressive language. Findings suggest that motor control areas of the brain may be implicated in expressive language development of premature children. Further research is needed to determine the underlying factors for the association between motor and expressive language function.

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction.

The role of PI3K in leptin physiology has been difficult to determine due to its actions downstream of several metabolic cues, including insulin. Here, we used a series of mouse models to dissociate the roles of specific PI3K catalytic subunits and of insulin receptor (InsR) downstream of leptin signaling. We show that disruption of p110α and p110β subunits in leptin receptor cells (LRΔα+β) produces a lean phenotype associated with increased energy expenditure, locomotor activity, and thermogenesis. LRΔα+β mice have deficient growth and delayed puberty. Single subunit deletion (i.e., p110α in LRΔα) resulted in similarly increased energy expenditure, deficient growth, and pubertal development, but LRΔα mice have normal locomotor activity and thermogenesis. Blunted PI3K in leptin receptor (LR) cells enhanced leptin sensitivity in metabolic regulation due to increased basal hypothalamic pAKT, leptin-induced pSTAT3, and decreased PTEN levels. However, these mice are unresponsive to leptin's effects on growth and puberty. We further assessed if these phenotypes were associated with disruption of insulin signaling. LRΔInsR mice have no metabolic or growth deficit and show only mild delay in pubertal completion. Our findings demonstrate that PI3K in LR cells plays an essential role in energy expenditure, growth, and reproduction. These actions are independent from insulin signaling.

Growth trajectory and neurodevelopmental outcome in infants with congenital diaphragmatic hernia

PurposeThe purpose of this study was to evaluate the impact of impaired growth on short-term neurodevelopmental (ND) outcomes in CDH survivors. MethodsBetween 9/2005–12/2014, 84 of 215 (39%) CDH survivors underwent ND assessment at 12months of age using the BSID-III. ResultsMean cognitive, language, and motor scores were 92.6±13.5, 87.1±11.6, and 87.0±14.4, respectively (normal 100±15). 51% of patients scored 1 SD below the population mean in at least one domain, and 13% scored 2 SD below the population mean.Group-based trajectory analysis identified two trajectory groups (‘high’ and ‘low’) for weight, length, and head circumference (HC) z-scores. (Fig. 1) 74% of the subjects were assigned to the ‘high’ trajectory group for weight, 77% to the ‘high’ height group, and 87% to the ‘high’ HC group, respectively. In multivariate analysis, longer NICU stay (p<0.01) was associated with lower cognitive scores. Motor scores were 11 points higher in the ‘high’ HC group compared to the ‘low’ HC group (p=0.05). Motor scores were lower in patients with longer NICU length of stay (p<0.001). ConclusionsAt 1 year, half of CDH survivors had a mild delay in at least one developmental domain. Low HC trajectory was associated with worse neurodevelopmental outcomes. Type of studyPrognosis Study/Retrospective Study. Level of evidenceLevel II.

Mild acidosis delays neutrophil apoptosis via multiple signaling pathways and acts in concert with inflammatory mediators.

Accumulating evidence indicates development of local extracellular acidosis in inflamed tissues in response to infection and tissue injury. Activation of infiltrating neutrophils contributes to a transient decrease in pH, which, in turn, triggers innate immunity. In this study, we investigated the impact of extracellular acidosis on neutrophil apoptosis, a critical determinant of the outcome of the inflammatory response and analyzed the underlying signaling pathways. Culture of human isolated neutrophils in mildly acidotic conditions (pH 6.5-7.0) resulted in activation of NF-κB; intracellular accumulation of cAMP; and phosphorylation of Akt, ERK, and p38 MAPK; and preservation of Mcl-1 expression. Consequently, extracellular acidosis prevented disruption of mitochondrial transmembrane potential and translocation of cytochrome c and apoptosis-inducing factor from the mitochondria to cytoplasm and nuclei, respectively and inhibited caspase-3 activity. Pharmacological inhibition of ERK, PI3K, NF-κB, or PKA partially reversed survival cues by extracellular acidosis and redirected neutrophils to apoptosis. Conversely, dibutyryl cAMP (100-500 μM) delayed apoptosis of neutrophils cultured at pH 7.4. Extracellular acidosis-generated survival cues were additive to the potent prosurvival signals from bacterial DNA, LPS, modified C-reactive protein, and serum amyloid A. Acidosis increased CpG DNA uptake by neutrophils and augmented phosphorylation of ERK and Akt, leading to preservation of Mcl-1 expression. Our results identified extracellular acidosis as a survival signal for neutrophils by suppressing the constitutive apoptotic machinery and suggest that transient decreases in local pH can enhance neutrophil responses to inflammatory stimuli, thereby contributing to amplification or prolongation of the inflammatory response.

Effect of breastfeeding on the behavioral development of infants and children: a birth cohort study in Ma'anshan

Objective: To discuss the relationship between breastfeeding and the behavioral development of infants and children. Methods: Based on the Ma'anshan Birth Cohort Study, there were 3 474 pregnant women recruited from Ma'anshan Maternal and Child Care Center between May 2013 and September 2014, including 3 273 singleton live births. Follow up the infants to the age of 18 months old. Excluded the infants with incomplete information of breastfeeding and who did not finish the ASQ-3 evaluation in 6 months old and 18 months old, 2 404 valid subjects were included in the study. The information of demographic characteristics, deliver, infants and breastfeeding was collected. The behavioral development were evaluated by the third edition of Ages and Stages Questionnaire (ASQ-3) at 6 months old and 18 months old, and the effect of breastfeeding on behavioral development among infants and children were analyzed by multivariable logistic regression model. Results: The intensity of breastfeeding of infants within 6 months old was (26.56±10.56). The rate of breastfeeding as pure or major intake for infants between 0-5 months old were separately 54.2% (1 303), 54.0% (1 298). 54.0% (1 297), 50.5% (1 213), 34.4% (827) and 9.9% (237). After age, pre-pregnant BMI, intelligence, delivery mode, gender, gestational age, birth weight and family economic status adjusted, compared to never-breastfeeding, continuous breastfeeding for 1-3 months could protect children from severe developmental delay in fine motor domain aged 6 months old (RR=0.36, 95%CI: 0.17-0.79), communication domain aged 18 months old (RR=0.27, 95%CI: 0.08-0.88), and social domain aged 18 months old (RR=0.36, 95%CI: 0.21-0.63). Compared to never-breastfeeding, continuous breastfeeding for more than 4 months could protect children from severe developmental delay in fine motor domain aged 6 months old (RR=0.58, 95%CI: 0.34-0.97), communication domain (RR=0.57, 95%CI: 0.39-0.83) and mild developmental delay (RR=0.65, 95%CI: 0.48-0.87) aged 18 months old and fine motor domain (RR=0.57, 95%CI: 0.39-0.83) aged 18 months old and social domain aged 18 months old (RR=0.57, 95%CI: 0.39-0.83). With the breastfeeding intensity rising, there were less children evaluated as severe development delay in communication domain aged 6 months old, communication, fine motor and problem-solving domains aged 18 months old, with RR (95%CI) at 0.98 (0.96-1.00), 0.96 (0.93-0.99), 0.98 (0.97-1.00) and 0.98 (0.96-1.00); and less children evaluated as mild development delay in communication domain aged 18 months old with RR (95%CI) at 0.99 (0.98-1.00). Conclusion: Breastfeeding with longer duration and increased intensity could promote better development in children.

Homogeneous Subgroups of Young Children with Autism Improve Phenotypic Characterization in the Study to Explore Early Development.

The objective of this study was to identify homogenous classes of young children with autism spectrum disorder (ASD) to improve phenotypic characterization. Children were enrolled in the Study to Explore Early Development between 2 and 5years of age. 707 children were classified with ASD after a comprehensive evaluation with strict diagnostic algorithms. Four classes of children with ASD were identified from latent class analysis: mild language delay with cognitive rigidity, mild language and motor delay with dysregulation, general developmental delay, and significant developmental delay with repetitive motor behaviors. We conclude that a four-class phenotypic model of children with ASD best describes our data and improves phenotypic characterization of young children with ASD. Implications for screening, diagnosis, and research are discussed.

Standing intraoral extractions of cheek teeth aided by partial crown removal in 165 horses (2010-2016).

Diseased cheek teeth in horses often require invasive extraction techniques that carry a high rate of complications. Techniques and instrumentation were developed to perform partial crown removal to aid standing intraoral extraction of diseased cheek teeth in horses. To analyse success rates and post-surgical complications in horses undergoing cheek teeth extraction assisted by partial crown removal. Retrospective cohort study. This study included 165 horses with 194 diseased cheek teeth that were extracted orally assisted by partial crown removal between 2010 and 2016. Medical records were analysed, including case details, obtained radiographs, surgical reports and follow-up information. Follow-up information (≥2 months) was obtained for 151 horses (91.5%). There were 95 horses examined post-operatively by the authors and, 16 horses by the referring veterinarian; in 40 horses, post-operative follow up was obtained by informal telephone interviews with the owner. Successful standing intraoral extraction of cheek teeth was obtained in 164/165 horses (99.4%). Twenty-five of these horses (15.2%) required additional intraoral extraction methods to complete the extraction, including minimally invasive transbuccal approach (n = 21) and tooth sectioning (n = 4). There was one (0.6%) horse with intraoral extraction failure that required standing repulsion to complete the extraction. The intraoperative complication of fractured root tips occurred in 11/165 horses (6.7%). Post-operative complications occurred in 6/165 horses (3.6%), including alveolar sequestra (n = 4), mild delay of alveolar healing at 2 months (n = 1), and development of a persistent draining tract secondary to a retained root tip (n = 1). Specialised instrumentation and additional training in the technique are recommended to perform partial crown removal in horses. Horses with cheek teeth extraction by partial crown removal have an excellent prognosis for a positive outcome. The term partial coronectomy is proposed for this technique.

Contrasting Phenotypes in Resistance to Thyroid Hormone Alpha Correlate with Divergent Properties of Thyroid Hormone Receptor α1 Mutant Proteins.

Background: Resistance to thyroid hormone alpha (RTHα), a disorder characterized by tissue-selective hypothyroidism and near-normal thyroid function tests due to thyroid receptor alpha gene mutations, is rare but probably under-recognized. This study sought to correlate the clinical characteristics and response to thyroxine (T4) therapy in two adolescent RTHα patients with the properties of the THRA mutation, affecting both TRα1 and TRα2 proteins, they harbored.Methods: Clinical, auxological, biochemical, and physiological parameters were assessed in each patient at baseline and after T4 therapy.Results: Heterozygous THRA mutations occurring de novo were identified in a 17-year-old male (patient P1; c.788C>T, p.A263V mutation) investigated for mild pubertal delay and in a 15-year-old male (patient P2; c.821T>C, p.L274P mutation) with short stature (0.4th centile), skeletal dysplasia, dysmorphic facies, and global developmental delay. Both individuals exhibited macrocephaly, delayed dentition, and constipation, together with a subnormal T4/triiodothyronine (T3) ratio, low reverse T3 levels, and mild anemia. When studied in vitro, A263V mutant TRα1 was transcriptionally impaired and inhibited the function of its wild-type counterpart at low (0.01–10 nM) T3 levels, with higher T3 concentrations (100 nM–1 μM) reversing dysfunction and such dominant negative inhibition. In contrast, L274P mutant TRα1 was transcriptionally inert, exerting significant dominant negative activity, only overcome with 10 μM of T3. Mirroring this, normal expression of KLF9, a TH-responsive target gene, was achieved in A263V mutation-containing peripheral blood mononuclear cells following 1 μM of T3 exposure, but with markedly reduced expression levels in L274P mutation-containing peripheral blood mononuclear cells, even with 10 μM of T3. Following T4 therapy, growth, body composition, dyspraxia, and constipation improved in P1, whereas growth retardation and constipation in P2 were unchanged. Neither A263V nor L274P mutations exhibited gain or loss of function in the TRα2 background, and no additional phenotype attributable to this was discerned.Conclusions: This study correlates a milder clinical phenotype and favorable response to T4 therapy in a RTHα patient (P1) with heterozygosity for mutant TRα1 exhibiting partial, T3-reversible, loss of function. In contrast, a more severe clinical phenotype refractory to hormone therapy was evident in another case (P2) associated with severe, virtually irreversible, dysfunction of mutant TRα1.