Neurological Deficits In Children Research Articles

Diagnostic Accuracy of Somatosensory Evoked Potential monitoring during Scoliosis correction surgery in the pediatric population: A Systematic Review (P7-4.002)

<h3>Objective:</h3> To evaluate the diagnostic accuracy of intraoperative somatosensory evoked potential (SSEP) monitoring in predicting the risk of perioperative neurological outcomes during scoliosis fusion surgery for idiopathic scoliosis (IS) in the pediatric age group (≤ 21 years). <h3>Background:</h3> Scoliosis correction surgery is the most effective treatment for pediatric IS. However, new neurological deficits during the surgery can potentially affect the outcomes of this surgery. Intraoperative neuromonitoring techniques like SSEP provide real-time information about the spinal cord and nerve roots and can be used as a reliable indicator to predict perioperative neurological deficits. <h3>Design/Methods:</h3> A systematic review of various databases to find literature on pediatric IS patients who underwent scoliosis correction with intraoperative neuromonitoring. Data collection included study design, patient demographics, procedure, neuromonitoring modalities, SSEP alarm criteria, SSEP changes (including reversible and irreversible changes), and perioperative neurological deficit. We calculated the sensitivity, specificity, and diagnostic odds ratio (DOR) of SSEP changes (total, transient, and persistent) and SSEP loss for predicting perioperative neurological deficits. <h3>Results:</h3> We included eighteen studies for our final analysis, with a total cohort of 4674 children. The incidence of a significant SSEP change was 3.1% (145/4674), while the incidence of a new neurological deficit was 1.01% (47/4674). The incidence of new neurological deficits in children with an intraoperative SSEP change was 28.28% (41/145), while it was 0.13% (6/4529) in children without an SSEP change. SSEP changes had a sensitivity of 72%, specificity of 97%, and DOR of 98.64, while SSEP loss had a sensitivity of 42%, specificity of 99.3%, and a DOR of 143.76 for predicting new neurologic deficit. Transient and Persistent SSEP changes had sensitivities of 37% and 39%, specificities of 97% and 99.2%, and DORs of 18.09 and 75.43, respectively. <h3>Conclusions:</h3> Intraoperative SSEP monitoring can predict perioperative neurological injury and help improve the surgical outcomes in pediatric scoliosis fusion surgery. <b>Disclosure:</b> Dr. Gorijala has nothing to disclose. Dr. Shaik has nothing to disclose. The institution of Dr. Thirumala has received research support from University of Pittsburgh. Dr. Anetakis has nothing to disclose. Jeffery Balzer has nothing to disclose. Donald Crammond has nothing to disclose. Dr. Shandal has nothing to disclose. Dr. Lee has nothing to disclose. The institution of Dr. Shaw has received research support from LSRS. The institution of Dr. Shaw has received research support from CSRS. The institution of Dr. Shaw has received research support from AO Spine. Dr. Shaw has received intellectual property interests from a discovery or technology relating to health care. Mr. Reddy has nothing to disclose.

Surgical treatment of tethered cord syndrome showed promising outcome in young children with short duration.

Aside from the severity, surgical interventions for the treatment of neurological dysfunctions remain controversial. This study aimed to find factors predicting the benefits of tethered cord syndrome (TCS) surgery. 80 children with TCS were included and followed up for pre- and post-operative factors along with neurophysiological analysis. Outcomes were assessed by univariate and multivariate analysis. Surgical treatment not only improved preoperative signs and symptoms in 79% of TCS patients but it showed to be an efficient procedure for the occurrence of future neurological defects. Univariate analysis also revealed that surgical intervention in TCS children (age <1 year) can modulate filar lipoma location and cutaneous abnormalities three months after surgery. Neurophysiological assessment revealed only 5.0% of surgical complications in TCS patients. Two patients had cerebrospinal fluid leakage, and two cases of CNS infection were detected. Surgical intervention is highly recommended for the prevention of neurological deficits in children with TCS. Electrophysiological monitoring revealed rare complications following the surgery.

Abstract TMP20: Performing The Pediatric National Institutions Of Health Stroke Scale Over Televideo: A Pilot Study

Introduction: Telestroke networks are widely used by stroke neurologists to rapidly assess adults presenting to remote facilities with suspected acute stroke. Televideo assessment of acute neurological deficits in children is potentially useful for children who live in remote areas, but has not been studied. This study tested the feasibility of assessing the pediatric National Institutes of Health stroke scale (PedNIHSS) by televideo in children. Methods: Children ages 2-17 years with and without strokes were recruited and examined in the outpatient neurology clinic. The PedNIHSS was performed on each child by separate neurologists; one by televideo and the other at the bedside. The total PedNIHSS, subscores and time to complete each exam were recorded. Intraclass correlation coefficients (ICC) were used to analyze inter-rater reliability. Results: Twenty children were recruited with an average range of 9.2 years (range 2-17 years). Six children had chronic stroke. By bedside exam, the total PedNIHSS score ranged from 0-8 with a mean of 1.65. By televideo, the PedNIHSS total score was identical to the bedside examination in 12/20 (60%) of the children and identical or within 1 point in 19/20 children (95%). All total PedNIHSS were scored higher by the bedside vs remote examiner in cases where there was a difference. There was excellent overall inter-rater reliability (ICC=0.92; 95% CI: 0.81, 0.97) for the total PedNIHSS when comparing bedside and video exams. In the subgroup of children less than 6 years of age, ICC was 0.88 (95% CI: 0.44-0.98). The PedNIHSS subscores with lowest reliability between exams were dysarthria, ataxia and sensory change. The average time to complete the bedside and remote examinations were 5 minutes and 7 minutes, respectively. Conclusions: It is feasible to perform the full PedNIHSS over televideo with reasonable accuracy and in a similar amount of time as compared to bedside evaluations. Limitations of this study include a small number of patients and overall low burden of neurologic deficits. Future studies focusing on children presenting with focal neurologic deficits in the acute care setting are needed to further determine the reliability of performing the PedNIHSS over televideo.

Nurses' Performance regarding Care of Infant Suffering from Hypoxic Ischemic Encephalopathy: An Educational Program

Hypoxic-ischemic encephalopathy is one of the most common causes of cerebralpalsy and other severe neurological deficits in children which occurs in 1.5/1000 live births. It iscaused by inadequate blood flow and oxygen supply to the brain resulting in focal or diffuse braininjury.

Dysmature patterns of newborn EEG recordings: Biological markers of transitory brain dysfunction or brain injury

To investigate the prognostic value of dysmature EEG patterns in term or near-term newborns. Neonates with dysmature patterns in their first neonatal EEG, assessed during a 6-year period from January 2010 to December 2015, were included in the study. Their outcomes at their follow-ups in June 2019 (at the age of 3 years or more) were assessed, and the presence of neurological deficits and/or epilepsy was noted. We identified 347 neonates with video-EEG recordings during the observed period, in which 10 neonates had dysmature patterns in their first EEG. Eight were born at term and two were born late preterms, born at the 35 and 36-week gestational age. The reasons for admission were HIE grade I in 2 patients, grade II in 6 neonates, and heart problems in 2 patients. The second EEG was recorded at different time intervals, in 7 infants between 1 and 6 weeks; three infants had second EEG much later and were excluded from the study. Six of seven infants showed normal background activity (BA), and five had sharp waves over different regions, all six had normal developmental outcomes. One child with dysrhythmic pattern in the second EEG was diagnosed with genetic encephalopathy, developed spastic cerebral palsy and died due to severe pneumonia at the age of 6 years. Dysmature patterns may reflect transitory brain dysfunctions. Neonatal EEG tests remain reliable and important diagnostic tool in the very first weeks of life, particularly due to the availability of sequential EEG recordings and interpretations.

Alterations in motor functional connectivity in Neonatal Hypoxic Ischemic Encephalopathy

ABSTRACT Background Neonatal hypoxic-ischemic encephalopathy (HIE) is the result of global hypoxic-ischemic brain injury in neonates due to asphyxia during birth and is one of the most common causes of severe, long-term neurologic deficits in children. Methods: Resting state fMRI (rs-fMRI) was used to assess potential functional disruptions in the primary and association motor areas in HIE neonates (n = 16) compared to healthy controls (n = 11). Results Results demonstrate reduced intra-hemispheric resting state functional connectivity (rs-FC) between primary motor regions (upper extremity and facial motor regions) as well as reduced inter-hemispheric rs-FC in the HIE group. In addition, HIE neonates demonstrated increased rs-FC between motor regions and frontal, temporal and parietal cortices but decreased rs-FC with the cerebellum. Discussion These preliminary results provide initial evidence for the disruption of functional communication with the motor network in neonates with HIE. Further studies are necessary to both validate these findings in a larger dataset as well as to determine if rs-fMRI measurements collected at birth may have the potential to serve as a prognostic marker in addition to the traditional combination of clinical measurements and conventional MRI.

Parenteral artemisinins are associated with reduced mortality and neurologic deficits and improved long-term behavioral outcomes in children with severe malaria

BackgroundIn 2011, the World Health Organization recommended injectable artesunate as the first-line therapy for severe malaria (SM) due to its superiority in reducing mortality compared to quinine. There are limited data on long-term clinical and neurobehavioral outcomes after artemisinin use for treatment of SM.MethodsFrom 2008 to 2013, 502 Ugandan children with two common forms of SM, cerebral malaria and severe malarial anemia, were enrolled in a prospective observational study assessing long-term neurobehavioral and cognitive outcomes following SM. Children were evaluated a week after hospital discharge, and 6, 12, and 24 months of follow-up, and returned to hospital for any illness. In this study, we evaluated the impact of artemisinin derivatives on survival, post-discharge hospital readmission or death, and neurocognitive and behavioral outcomes over 2 years of follow-up.Results346 children received quinine and 156 received parenteral artemisinin therapy (artemether or artesunate). After adjustment for disease severity, artemisinin derivatives were associated with a 78% reduction in in-hospital mortality (adjusted odds ratio, 0.22; 95% CI, 0.07–0.67). Among cerebral malaria survivors, children treated with artemisinin derivatives also had reduced neurologic deficits at discharge (quinine, 41.7%; artemisinin derivatives, 23.7%, p=0.007). Over a 2-year follow-up, artemisinin derivatives as compared to quinine were associated with better adjusted scores (negative scores better) in internalizing behavior and executive function in children irrespective of the age at severe malaria episode. After adjusting for multiple comparisons, artemisinin derivatives were associated with better adjusted scores in behavior and executive function in children <6 years of age at severe malaria exposure following adjustment for child age, sex, socioeconomic status, enrichment in the home environment, and the incidence of hospitalizations over follow-up. Children receiving artesunate had the greatest reduction in mortality and benefit in behavioral outcomes and had reduced inflammation at 1-month follow-up compared to children treated with quinine.ConclusionsTreatment of severe malaria with artemisinin derivatives, particularly artesunate, results in reduced in-hospital mortality and neurologic deficits in children of all ages, reduced inflammation following recovery, and better long-term behavioral outcomes. These findings suggest artesunate has long-term beneficial effects in children surviving severe malaria.

Electrochemical Monitoring of Manganese in Drinking Water

Low levels of Mn are essential for many metabolic processes in the human body, yet excessive exposure to this heavy metal has been correlated to neurodegenerative diseases with Parkinson’s like symptoms in adults and neurological deficits in children. Erosion of Mn rich soil and rocks and human activities directly pollute groundwater which supplies drinking water for 51% of the total US population and 99% of the rural population. Hence contaminated drinking water represents one of the major sources of Mn intake. The non-enforceable updated guideline set by the EPA is 50ppb Mn. Trace metal analytical methods such as ICP-MS and AAS are limited to centralized laboratory testing and not feasible for point-of-care. Our work is aimed at the development of an electrochemical platform for efficient and rapid Mn detection in drinking water. The core technique is Square Wave Cathodic Stripping Voltammetry (SWCSV), carried out on disposable three-electrode sensors with a platinum working electrode, platinum counter electrode and an electroplated Ag/AgCl reference electrode. A 3D printed interface integrates a small vibration motor for effective agitation of the 12µL droplet sample during the deposition phase and allows connection to a commercial potentiostat. Figure 1(a) depicts the hardware components of the platform, with an onset on the sensor configuration. First, the system performances are characterized in standard solutions. Compared to peak amplitude, peak area is found to be a more suitable indicator of Mn concentration, with a linearity of R^2=0.998 in the range 5ppb-200ppb. The introduction of an embedded agitation mechanism allows for a reduction in the limit of quantitation (LOQ) from 5ppb to 3ppb and an approximate 2.3X increase in sensitivity from 9.09nC/ppb to 20.75nC/ppb. Analysis of tap water is then performed to confirm the capabilities of the electrochemical platform in more complex matrices. With optimal SWCSV parameters a limit of quantitation of 6ppb, a sensitivity of 26.45 nC/ppb and a linearity with R^2=0.995 are achieved. The developed protocol requires minimal sample preparation of the water samples, with a 2X dilution in 0.2M Acetate Buffer to provide enough ionic strength to sustain the faradaic reactions and buffer the pH at 4.7. 3-point standard addition is executed to determine the Mn concentration in unknown specimens and performances are compared to ICP-MS on the analysis of 78 tap water and well water samples from Holliston, MA with concentrations in the range 0.03ppb-5.3ppm. 100% agreement, 70% accuracy and 91% precision were obtained. Figure 1(b) shows typical voltammograms from the measurement of the unknown sample and the 3 spikes at known Mn concentrations to implement the 3-point standard addition. To enhance monitoring of water quality in local communities and rural areas, parallelization of the measurements can further reduce the analytical time and improvements in the interface can ultimately make the devised portable and easy-to-use electrochemical station soon deployable for practical on-the-field testing. Figure 1

Selective Endothelial Hyperactivation of Oncogenic KRAS Induces Brain Arteriovenous Malformations in Mice.

Brain arteriovenous malformations (bAVMs) are a leading cause of hemorrhagic stroke and neurological deficits in children and young adults, however, no pharmacological intervention is available to treat these patients. Although more than 95% of bAVMs are sporadic without family history, the pathogenesis of sporadic bAVMs is largely unknown, which may account for the lack of therapeutic options. KRAS mutations are frequently observed in cancer, and a recent unprecedented finding of these mutations in human sporadic bAVMs offers a new direction in the bAVM research. Using a novel adeno-associated virus targeting brain endothelium (AAV-BR1), the current study tested if endothelial KRASG12V mutation induces sporadic bAVMs in mice. Five-week-old mice were systemically injected with either AAV-BR1-GFP or -KRASG12V . At 8 weeks after the AAV injection, bAVM formation and characteristics were addressed by histological and molecular analyses. The effect of MEK/ERK inhibition on KRASG12V -induced bAVMs was determined by treatment of trametinib, a US Food and Drug Administration (FDA)-approved MEK/ERK inhibitor. The viral-mediated KRASG12V overexpression induced bAVMs, which were composed of a tangled nidus mirroring the distinctive morphology of human bAVMs. The bAVMs were accompanied by focal angiogenesis, intracerebral hemorrhages, altered vascular constituents, neuroinflammation, and impaired sensory/cognitive/motor functions. Finally, we confirmed that bAVM growth was inhibited by trametinib treatment. Our innovative approach using AAV-BR1 confirms that KRAS mutations promote bAVM development via the MEK/ERK pathway, and provides a novel preclinical mouse model of bAVMs which will be useful to develop a therapeutic strategy for patients with bAVM. ANN NEUROL 2021;89:926-941.

Narrative review of stem cell therapy for ischemic brain injury.

Ischemic brain injury is a common cause of long-term neurological deficits in children as well as adults, and no efficient treatments could reverse the sequelae in clinic till now. Stem cells have the capacity of self-renewal and multilineage differentiation. The therapeutic efficacy of stem cell transplantation for ischemic brain injury have been tested for many years. The grafts could survive and mature in the ischemic brain environment. Stem cell transplantation could improve functional recovery of ischemic brain injury models in pre-clinical trials. The potential mechanisms included cell replacement, release of neurotrophic and anti-inflammatory factors, immunoregulation as well as activation of endogenous neurogenesis. Besides, many clinical trials were conducted and some of trials already had preliminary results. From the current published data, cell transplantation for clinical application is safe and feasible. No severe adverse events and tumorigenesis were reported. While the therapeutic efficacy of stem cell therapy in clinic still needs more evidences. In this review, we overviewed the studies about stem cell therapy for ischemic brain injury. Different types of stem cells used for transplantation as well as the therapeutic mechanisms were discussed in detail. The related pre-clinical and clinical trials were summarized into two separate tables. In addition, we also discussed the unsolved problems and concerns about stem cell therapy for ischemic brain injury that need to be overcome before clinic transformation.

Acute Neurological Deficits in Instrumented Pediatric Cervical Spine Fusions

Recipient: Bram Verhofste, MD Acute Neurological Deficits in Instrumented Pediatric Cervical Spine Fusions Bram P. Verhofste, MD1; Michael P. Glotzbecker, MD2; M Timothy Hresko, MD2; Patricia Miller, MS1; Craig M. Birch, MD1; Michael Troy, BS1; Nora P. O'Neill, BA1; Lawrence I. Karlin, MD2; John B. Emans, MD2; Mark R. Proctor, MD2; Daniel J. Hedequist, MD2, (1) Boston Children's Hospital, Boston, MA, (2) Boston Children's Hospital, Harvard Medical School, Boston, MA Introduction: Pediatric cervical deformity is a complex disorder often associated with neurological deterioration requiring cervical spine fusion. However, little literature exists on new perioperative neurologic deficits in children. This study describes new perioperative neurologic deficits in pediatric cervical spine instrumentation and fusion. Methods: A single-center review of pediatric cervical spine instrumentation and fusion during 2002-2018 was performed. Demographics, surgical characteristics, and neurological complications were recorded. Perioperative neurologic deficits were defined as the deterioration of preexisting neurologic function or the appearance of new neurologic symptoms. Results: A total of 184 cases (160 patients, 57% male) with an average age of 12.6 ±5.30 years were included. Instability (n=63) and deformity (n=41) were the most frequent indications. Syndromes were present in 39% (n=71). Eighty-seven (48%) children presented with preoperative neurologic deficits (16 sensory, 16 motor, and 55 combined deficits). A total of 178 (96.7%) cases improved or remained neurologically stable. New neurologic deficits occurred in six (3.3%) cases: three hemiparesis, one hemiplegia, one quadriplegia, and one quadriparesis (Table 1, Figure 1). Preoperative neurologic compromise was seen in four (67%) of these new deficits (three myelopathy, one sensory deficit) and five had complex syndromes. Three new deficits were anticipated with intraoperative neuromonitoring changes (p=0.025). Three (50.0%) patients recovered within six months and the child with quadriparesis is expected to make a complete recovery. Hemiplegia persisted in one patient and one child died due a complication related to the tracheostomy. No association was found between etiology (p=0.46), preoperative neurological symptoms (p=0.65), age (p=0.56), halo (p=0.41), EBL (p=0.09), levels fused (p=0.09), approach (p=0.07), or fusion location (p=0.37). Conclusion: An improvement of the preexisting neurologic deficit or stabilization of neurologic function was seen in 96.7% of children after cervical spine fusion. New or progressive neurologic deficits occurred in 3.3% of the patients and occurred more frequently in children with preoperative neurologic symptoms. Patients with syndromic diagnoses are at higher risk to develop a deficit, likely due to the severity of deformity and the degree of cervical instability. Long-term outcomes of new neurologic deficits are favorable and 50% experienced complete neurologic recovery within six months.

Perioperative acute neurological deficits in instrumented pediatric cervical spine fusions.

Pediatric cervical deformity is a complex disorder often associated with neurological deterioration requiring cervical spine fusion. However, limited literature exists on new perioperative neurological deficits in children. This study describes new perioperative neurological deficits in pediatric cervical spine instrumentation and fusion. A single-center review of pediatric cervical spine instrumentation and fusion during 2002-2018 was performed. Demographics, surgical characteristics, and neurological complications were recorded. Perioperative neurological deficits were defined as the deterioration of preexisting neurological function or the appearance of new neurological symptoms. A total of 184 cases (160 patients, 57% male) with an average age of 12.6 ± 5.30 years (range 0.2-24.9 years) were included. Deformity (n = 39) and instability (n = 36) were the most frequent indications. Syndromes were present in 39% (n = 71), with Down syndrome (n = 20) and neurofibromatosis (n = 12) the most prevalent. Eighty-seven (48%) children presented with preoperative neurological deficits (16 sensory, 16 motor, and 55 combined deficits).A total of 178 (96.7%) cases improved or remained neurologically stable. New neurological deficits occurred in 6 (3.3%) cases: 3 hemiparesis, 1 hemiplegia, 1 quadriplegia, and 1 quadriparesis. Preoperative neurological compromise was seen in 4 (67%) of these new deficits (3 myelopathy, 1 sensory deficit) and 5 had complex syndromes. Three new deficits were anticipated with intraoperative neuromonitoring changes (p = 0.025).Three (50.0%) patients with new neurological deficits recovered within 6 months and the child with quadriparesis was regaining neurological function at the latest follow-up. Hemiplegia persisted in 1 patient, and 1 child died due a complication related to the tracheostomy. No association was found between neurological deficits and indication (p = 0.96), etiology (p = 0.46), preoperative neurological symptoms (p = 0.65), age (p = 0.56), use of halo vest (p = 0.41), estimated blood loss (p = 0.09), levels fused (p = 0.09), approach (p = 0.07), or fusion location (p = 0.07). An improvement of the preexisting neurological deficit or stabilization of neurological function was seen in 96.7% of children after cervical spine fusion. New or progressive neurological deficits occurred in 3.3% of the patients and occurred more frequently in children with preoperative neurological symptoms. Patients with syndromic diagnoses are at higher risk to develop a deficit, probably due to the severity of deformity and the degree of cervical instability. Long-term outcomes of new neurological deficits are favorable, and 50% of patients experienced complete neurological recovery within 6 months.

Ischemic stroke and disseminated tuberculosis in a child living with human immunodeficiency virus: a case report and review of the literature

BackgroundCerebrovascular accidents are rare in children. Rates of stroke in children with human immunodeficiency virus infection are higher than in the uninfected population.Case presentationWe report the case of a 19-month-old Ethiopian boy who presented with a left-sided body weakness of sudden onset. He was also diagnosed as having human immunodeficiency virus infection. Laboratory tests showed an iron deficiency anemia and imaging revealed tuberculosis of his lungs, spleen, and abdominal lymph nodes as well as an acute ischemic stroke of the right middle cerebral artery region. His symptoms improved after anti-tuberculosis drugs, antiretroviral treatment, and iron supplementation were initiated.ConclusionsExtrapulmonary tuberculosis should be considered a cause of sudden focal neurologic deficits in children with human immunodeficiency virus infection residing in endemic countries.

Intraoperative neurophysiology monitoring in scoliosis surgery in children

ObjectiveIntraoperative neurophysiology monitoring (INM) is thought to reduce the risk of postoperative neurological deficits in children undergoing scoliosis and spine deformity surgery. INM is being used increasingly despite conflicting opinions, varied results, non-standard alarm criteria and concern regarding cost effectiveness. In this paper we present our experience with INM in scoliosis and spine deformation surgery in children, propose alert criteria and preferred anaesthetics in clinical practice. MethodsWe retrospectively analysed our experience with INM in 56 children who had 61 scoliosis and spine deformity surgeries. ResultsINM was successfully undertaken with transcranial electrical motor evoked potentials (TcMEP) and somatosensory evoked potentials. There were no injuries due to INM. Four children had 5 alerts during 4 surgeries. A postoperative deficit was seen in one child only. No new postoperative deficits were seen in any child who did not have an alert during INM. Total intravenous anaesthesia was better for INM compared to inhalational anaesthetics. ConclusionsINM is useful in scoliosis surgery; it is likely to mitigate the risk of new deficits following surgery. We recommend alert criteria for TcMEPs that include multiple facets – amplitude, stimulus paradigm, morphology. We recommend propofol and remifentanil, in preference to sevoflurane and remifentanil for anaesthesia during INM. SignificanceOur study adds to the literature supporting the role of INM in scoliosis surgery in children. We provide guidelines for alarm criteria in clinical practice and recommend the use of total intravenous anaesthesia as the preferred anaesthetic option.

Organophosphate exposures during pregnancy and child neurodevelopment: Recommendations for essential policy reforms.

In a Policy Forum, Irva Hertz-Picciotto and colleagues review the scientific evidence linking organophosphate pesticides to cognitive, behavioral, and neurological deficits in children and recommend actions to reduce exposures.

Reduced inflammation and increased endothelial activation in children with asymptomatic Plasmodium falciparum parasitemia in a low transmission area

Abstract Few studies investigate asymptomatic parasitemia (AP) and researching the mechanism by which these children remain healthy can provide novel information to understand the pathogenesis of Plasmodium falciparum malaria. We hypothesized children with AP to have higher levels of pro-inflammatory cytokines, angiogenic growth factors, and markers of endothelial activation compared to children without parasitemia. Healthy children were recruited from the community as part of a study on cognitive and neurological deficits in children with central nervous system malaria in Kampala, Uganda. Plasma was prepared from blood samples acquired at enrollment and tested using magnetic bead assay. Nested PCR was performed to detect P. falciparum DNA. Of the 211 community children (CC) samples tested, 73 CC had AP and 138 CC without parasitemia. CC with AP had lower levels of pro-inflammatory cytokines and chemokines IFN-γ (p&amp;lt;0.0001), IL-1β (p=0.0001), IL-8 (p=0.0015), MIP-1α (p=0.01), IL-12p70 (p=0.0002), and RANTES (p=0.0001), and higher levels of TNF-α (p=0.05), MIP-1β (p=0.04), and IP-10 (p=0.01) when compared to CC without parasitemia. CC with AP had lower levels of angiogenic growth factors G-CSF (p&amp;lt;0.0001) and FGF-basic (p&amp;lt;0.0001), and higher levels of markers of endothelial activation ICAM-1 (p=0.0007), VCAM-1 (p&amp;lt;0.0001), and VWF (p=0.0006). In this area of low malaria transmission, children with parasitemia have suppression of these pro-inflammatory cytokines, chemokines and angiogenic factors, but an increase in endothelial activation. Endothelial activation may be an early uniform response to P. falciparum, but symptoms may be controlled by ability to suppress the inflammatory response.

Neonatal Hypoxic-ischemic Encephalopathy: A Radiological Review.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a devastating condition that may result in death or severe neurologic deficits in children. Neuroimaging with cranial ultrasound (US), computed tomography and magnetic resonance imaging are valuable tools in the workup of patients with HIE. The pattern of brain injury depends on the severity and duration of hypoxia and degree of brain maturation. Mild to moderate HI injury results in periventricular leukomalacia and germinal matrix bleed in preterm neonates, and parasagittal watershed infarcts in full-term neonates. Severe HI injury involves deep gray matter in both term and preterm infants. Treatment of HIE is largely supportive. The current article reviews the etiopathophysiology and clinical manifestations of HIE, role of imaging in the evaluation of the condition, patterns of brain injury in term and preterm neonates, the treatment and the prognosis.

Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury

ABSTRACTPerinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy.

Quantification of 2-Hydroxyglutarate Enantiomers by Liquid Chromatography-mass Spectrometry.

Two enantiomers of 2-hydroxyglutarate (2HG), L (L2HG) and D (D2HG), are metabolites of unknown function in mammalian cells that were initially associated with separate and rare inborn errors of metabolism resulting in increased urinary excretion of 2HG linked to neurological deficits in children (Chalmers et al., 1980; Duran et al., 1980; Kranendijk et al., 2012). More recently, investigators have shown that D2HG is produced by mutant isocitrate dehydrogenase enzymes associated with a variety of human malignancies, such as acute myeloid leukemia, glioblastoma multiforme, and cholangiocarcinoma (Cairns and Mak, 2013; Dang et al., 2009; Ward et al., 2010). By contrast, we and others have shown that L2HG accumulates in response to cellular reductive stressors like hypoxia, activation of hypoxia inducible factors, and mitochondrial electron transport chain defects (Oldham et al., 2015; Reinecke et al., 2011; Intlekofer et al., 2015; Mullen et al., 2015). Each enantiomer is produced and metabolized in independent biochemical pathways in reactions catalyzed by separate enzymes and utilizing different cofactors with presumably different consequences for cellular metabolism (Kranendijk et al., 2012). Therefore, as research into the roles of D2HG and L2HG in human metabolism continues, it becomes increasingly important for investigators to consider each enantiomer independently (Struys, 2013). Several methods for quantification of biochemically relevant enantiomers in general have been developed and typically include enzymatic assays using enzymes specific for one enantiomeric species or the other, the use of chiral chromatography medium to facilitate chromatographic separation of enantiomers prior to spectroscopy, or the use of chiral derivatization reagents to convert a mixture of enantiomers to diastereomers with differing physical and chemical properties facilitating their chromatographic separation. In this protocol, we report the adaptation of a previously published derivatization method using diacetyl-l-tartaric anhydride (DATAN) for the quantification of 2HG enantiomers (Figure 1) (Oldham et al., 2015; Struys et al., 2004).

Genome-wide association study of blood lead shows multiple associations near ALAD.

Exposure to high levels of environmental lead, or biomarker evidence of high body lead content, is associated with anaemia, developmental and neurological deficits in children, and increased mortality in adults. Adverse effects of lead still occur despite substantial reduction in environmental exposure. There is genetic variation between individuals in blood lead concentration but the polymorphisms contributing to this have not been defined. We measured blood or erythrocyte lead content, and carried out genome-wide association analysis, on population-based cohorts of adult volunteers from Australia and UK (N = 5433). Samples from Australia were collected in two studies, in 1993-1996 and 2002-2005 and from UK in 1991-1992. One locus, at ALAD on chromosome 9, showed consistent association with blood lead across countries and evidence for multiple independent allelic effects. The most significant single nucleotide polymorphism (SNP), rs1805313 (P = 3.91 × 10(-14) for lead concentration in a meta-analysis of all data), is known to have effects on ALAD expression in blood cells but other SNPs affecting ALAD expression did not affect blood lead. Variants at 12 other loci, including ABO, showed suggestive associations (5 × 10(-6) > P > 5 × 10(-8)). Identification of genetic polymorphisms affecting blood lead reinforces the view that genetic factors, as well as environmental ones, are important in determining blood lead levels. The ways in which ALAD variation affects lead uptake or distribution are still to be determined.