Microstructural abnormalities found in uncinate fasciculus and superior cerebellar tracts in children with global developmental delay: a feasibility study.

AIM: To evaluate the microstructural abnormalities of the white matter tracts (WMT) using diffusion tensor imaging (DTI) in children with global developmental delay (GDD). MATERIALS AND METHODS: Sixteen children with GDD underwent magnetic resonance imaging (MRI) and cross-sectional DTI. Formal developmental assessment of all GDD patients was performed using the Mullen Scales of Early Learning. An automated processing pipeline for the WMT assessment was implemented. The DTI-derived metrics of the children with GDD were compared to healthy children with normal development (ND). RESULTS: Only two out of the 17 WMT demonstrated significant differences (p<0.05) in DTI parameters between the GDD and ND group. In the uncinate fasciculus (UF), the GDD group had lower mean values for fractional anisotropy (FA; 0.40 versus 0.44), higher values for mean diffusivity (0.96 versus 0.91×10-3 mm2/s) and radial diffusivity (0.75 versus 0.68×10-3 mm2/s) compared to the ND group. In the superior cerebellar peduncle (SCP), mean FA values were lower for the GDD group (0.38 versus 0.40). Normal myelination pattern of DTI parameters was deviated against age for GDD group for UF and SCP. CONCLUSION: The UF and SCP WMT showed microstructural changes suggestive of compromised white matter maturation in children with GDD. The DTI metrics have potential as imaging markers for inadequate white matter maturation in GDD children.

Predictors of parenting stress in mothers of children with spina bifida.

STUDY DESIGN: Prospective cross-sectional multidimensional study using clinical assessment and standard measures. OBJECTIVES: To determine the medical and social factors associated with parenting stress among mothers of children with spina bifida. SETTING: Spina bifida clinics of two tertiary hospitals in urban Kuala Lumpur, Malaysia. METHODS: A total of 81 mothers of children aged 1-18 years completed the Parenting Stress Index-Short Form (PSI/SF). Each child's adaptive skills were assessed using the Vineland Adaptive Behaviour Scales (VABS), Interview Edition. Medical and social data were obtained from direct interviews and case note reviews. Hierarchical multiple regression analysis was used to investigate factors that were determinants for high scores in the parental distress (PD), difficult child (DC) and parent-child dysfunctional interaction (P-CDI) subdomains of the PSI/SF. Results were expressed as beta coefficient (ß) and 95% confidence intervals (95% CIs). RESULTS: Single-parent families (ß 8.6, 95% CI 3.4-13.9) and the need for clean intermittent catheterization of bladder (ß 3.5, 95% CI 0.7-6.2) were associated with high PD scores. Clean intermittent catheterization (ß 3.0, 95% CI 0.5-5.5) was associated with higher DC scores. Lower composite VABS scores (ß -0.08, 95% CI -0.02 to -0.15) and mother as the sole caregiver (ß 2.6, 95% CI 0.15-4.96) was associated with higher P-CDI scores. CONCLUSION: The need for clean intermittent catheterization was the only medical factor associated with parenting stress in mothers of children with spina bifida. This was mediated by single parenthood, caregiver status and the child's adaptive skills.

2-[18F]-2-deoxy-D-glucose (FDG) uptake in human tumor cells is related to the expression of GLUT-1 and hexokinase II.

BACKGROUND: The uptake of 2-[18F]-2-deoxy-D-glucose ((18)F-FDG) is widely used as a marker of increased glucose metabolism to monitor progression of cancers with positron emission tomography (PET). Many tumors have been shown to overexpress facilitated glucose transporters, especially GLUT-1 and a glycolytic enzyme, hexokinase II. PURPOSE: To define whether a quantitative relationship exists between the expression levels of GLUT-1 and hexokinase II, and (18)F-FDG uptake in human cancer xenografts. MATERIAL AND METHODS: We determined the expression levels of both GLUT-1 and hexokinase II in normal cells and in five different human cancer cell lines (AGS, A431, A549, Colo 320 HSR, and HepG2) using Western blot analysis. In vitro assays of 18F-FDG uptake in cultures were performed, and subsequently representative cell lines were inoculated onto the flanks of severe combined immunodeficient (SCID) mice. To establish an orthotopic model of human hepatocellular carcinoma (HCC), cells were injected into the intraportal vein of SCID mice. (18)F-FDG uptake in vivo was assessed by subjecting mice to PET imaging. RESULTS: All cell lines were shown to express higher amounts of GLUT-1 and hexokinase II compared with fibroblast controls. Our results from in vitro (18)F-FDG uptake assays also correlated with the Western blot results. All xenografts gave highly positive results at microPET imaging, and a strong correlation (R(2)=0.88, P<0.001) was found between the maximum standardized uptake values (SUV(max)) and the expression of GLUT-1 proteins. CONCLUSION: Our data indicate that the expression levels of GLUT-1 and hexokinase II as well as in vitro assays of FDG uptake serve as good screening tests to evaluate the feasibility of cell lines to be further developed into xenograft cancer models for small-animal PET imaging.

MTHFR C677T polymorphism as a risk factor of neural tube defects in Malay: a case control study.

Major congenital malformations occur in about 3% of newborn. Several studies have suggested that homozygosity for the C677T methylenetetrahydrofolate reductase (MTHFR) variant is a potential risk factor for neural tube defects (NTDs). It has been hypothesized that the maternal folic acid supplementation prevents NTDs by partially correcting reduced MTHFR activity associated with the variant form of the enzyme. This association has not been found in some ethnic groups. In this study, we attempted to assess the association between NTDs and MTHFR C677T in Malaysian Malay population. Results show that MTHFR 677TT genotype was absent in both patient and control groups.

The impact of epilepsy on academic achievement in children with normal intelligence and without major comorbidities: A systematic review.

PURPOSE: To systematically examine published literature which assessed the prevalence of academic difficulties in children with epilepsy (CWE) of normal intelligence, and its associating factors. METHODS: A search was conducted on five databases for articles published in English from 1980 till March 2015. Included were studies who recruited children (aged 5-18 years), with a diagnosis or newly/recurrent epilepsy, an intelligent quotient (IQ) of ≥70 or attending regular school, with or without a control group, which measured academic achievement using a standardised objective measure, and published in English. Excluded were children with learning difficulties, intellectual disabilities (IQ<70) and other comorbidities such as attention deficits hyperactive disorder or autism. Two pairs of reviewers extracted the data, and met to resolve any differences from the data extraction process. RESULTS: Twenty studies were included. The majority of the studies assessed "low achievement" whist only two studies used the IQ-achievement discrepancy definition of "underachievement". Fourteen studies (70%) reported that CWE had significantly lower academic achievement scores compared to healthy controls, children with asthma or reported norms. The remaining six studies (30%) did not report any differences. CWE had stable academic achievement scores over time (2-4 years), even among those whose seizure frequency improved. Higher parental education and children with higher IQ, and had better attention or had a positive attitude towards epilepsy, were associated with higher academic achievement score. Older children were found to have lower academic achievement score. CONCLUSIONS: In CWE of normal intelligence, the majority of published literature found that academic achievement was lower than controls or reported norms. The high percentages of low achievement in CWE, especially in the older age group, and the stability of scores even as seizure frequency improved, highlights the need for early screening of learning problems, and continued surveillance.

Turn-around-time of radiographs in a neonatal intensive care unit.

A quality assurance study was carried out prospectively in two phases at the Neonatal Intensive Care Unit (NICU) of Hospital Universiti Kebangsaan Malaysia. The objectives of the study were to determine the turn-around-time (TAT) of radiographs requested for infants undergoing intensive care treatment in the NICU and the effects of a standard operating procedure introduced based on initial findings of first phase of the study on subsequent TAT. The TAT was defined as the time taken for the radiograph to be ready for viewing after the attending doctor had requested for it to be done on an infant. During phase one of the study, none of the requested radiographs was ready to be viewed by the doctors within the standard TAT of 45 minutes. The problems identified were ward staffs delay in sending request forms to the radiology department, radiographers' delay in shooting and processing the films, and delay by NICU porter in collecting the processed films. Based on these findings, a standard operating procedure (SOP) was drawn up jointly by the staff of NICU and Department of Radiology. During phase two of the study conducted at one month after implementation of the SOP, there was a reduction of TAT by 50%. However, only 3 (4.3%) of the radiographs achieved the standard TAT. The main problems identified during phase two were delay in sending request forms and in collecting processed radiographs by the porter system. The dismal TAT of radiographs in NICU was related primarily to human behaviour. Besides continuous staff education, replacement of the porter system with electronic system may improve the TAT.

Haemophilus influenzae meningitis in Malaysia.

OBJECTIVE: To determine the pattern of postneonatal childhood meningitis in Malaysia. METHODS: Retrospective cross-sectional study involving five pediatric departments in Malaysia. RESULTS: There were 435 cases of clinical meningitis admitted to the five centers. More than 90% of the patients were <5 years old, and one-half were <6 months of age. The estimated overall incidence of childhood meningitis in the first 5 years of life was 76.7 per 100000 per year. However, of the 435 cases only 71 (16.3%) fulfilled laboratory diagnostic criteria and in only 58 of these was an organism isolated. Nearly one-half (48%) of all bacteriologically proved cases were caused by Haemophilus influenzae type b (Hib). The mortality rate was 12.5% and 21 patients (30%) suffered neurologic sequelae. CONCLUSIONS: More than one-half of all cases of culture-positive childhood bacterial meningitis were caused by Hib, although successful isolation of a pathogen occurred in only a small proportion of cases. For this reason the true incidence of Hib meningitis in Malaysia remains unknown. These findings are consistent with previous studies in Malaysia.

Stress experienced by mothers of Malaysian children with mental retardation.

OBJECTIVE: To compare parenting stress among Malaysian mothers of children with mental retardation and a control group, and to determine factors associated with stress. METHODOLOGY: Seventy-five mothers of children with mental retardation aged 4-12 years and 75 controls (those without disabilities who attended the walk-in paediatric clinic) participated in the Parenting Stress Index (PSI). Intelligence quotient (IQ) and Child Behaviour Checklist (CBCL) scores, together with sociodemographic data, were entered into a multiple stepwise regression analysis, using the PSI as the criterion. RESULTS: Mothers of children with mental retardation scored significantly higher than control subjects in both the child-related domain (difference between means 26.1, 95% confidence interval 19.6-32.5) and parent-related domain (difference between means 15.0, 95% confidence interval 7.9-22.1) of the PSI. The total child behaviour scores from the CBCL (P < 0.01), IQ scores (P < 0.01) and sibship size (P < 0.01) were associated with child-related domain scores. For the parent-related domain, CBCL (P < 0.01) and IQ scores (P = 0.01) remained important factors but Chinese ethnicity (P < 0.01) and maternal unemployment (P < 0.01) were also significant predictors of stress. CONCLUSION: A large proportion of mothers of children with mental retardation experienced substantial parenting stress, especially Chinese and unemployed mothers, and this warrants appropriate intervention.

Congenital talipes in Malaysian neonates: incidence, pattern and associated factors.

A study was carried out on 8,369 neonates delivered in the Maternity Hospital, Kuala Lumpur over a period of four months. Forty-nine neonates (5.6 per 1000 livebirths) had congenital talipes. The incidence of congenital talipes equinovarus (CTEV) was 4.5 per 1000 livebirths while that of congenital talipes calcaneovalgus (CTCV) was 1.3 per 1000 livebirths. 6/11 (54.5%) of the CTCV was unilateral, the ratio of right to left feet involvement being 1:1. Only 12/38 (31.5%) of the CTEV were unilateral, the ratio of right to left feet involvement being 1:2. Congenital talipes was significantly more common in the low birthweight neonates (p less than 0.001). However, the condition was not significantly more common in neonates with breech presentation nor in those born to primigravida mothers. Our data suggested that multifactorial genetic background as the most likely underlying cause of congenital talipes in Malaysian neonates.

Malaysian children with spina bifida: relationship between functional outcome and level of lesion.

PURPOSE: To determine the relationship between spinal lesion level and functional outcome in children with spina bifida. METHODS: Prospective observational study of 66 children who attended the Spina Bifida Clinic from 1994-1997. Data were obtained from serial physical examination and parent interview to determine mobility status, neurosensory deficits, continence and school placement. RESULTS: Eighteen (27.3%) had high-level (thoracic and thoracolumbar), 27 (40.9%) intermediate (low lumbar) and 21 (31.8%) low-level (sacral) lesions. Children with high-level lesions experienced more mobility problems (independent ambulation, balance and use of appliances), than those with intermediate or low-level lesions (p<0.001). 58.8% of children with low-level lesions used diapers, compared with those with high (90%) or intermediate (100%) level lesions (p = 0.005), but there were no significant differences in the incidence of soiling or urinary incontinence among all three groups. There were no significant differences among the three groups in terms of school placement, skin breakdown, epilepsy or visual defect. CONCLUSION: Although there is good correlation between the level of the lesion and mobility in children with spina bifida, other measures of functional outcome like continence and school placement are more difficult to predict. These data are important for realistic counselling of families with newborns with spina and planning long term rehabilitation resources.

Intrauterine growth of liveborn Malaysian infants between gestation of 28 to 42 weeks.

A cross-sectional study was carried out on 8,478 consecutive normal singleton Malaysian neonates born in the Maternity Hospital, Kuala Lumpur. The objectives were to compare the mean birth-weights, crown-heel lengths and head circumferences of Malay, Chinese and Indian infants at gestation age from 28 to 42 weeks, and to construct the Malaysian growth charts. Above the gestation age of 34 weeks, the birthweights were significantly influenced by maternal gravida status (p < 0.03), ethnic origin (p < 0.001) and/or sex of the neonates (p < 0.026). Above this gestation age, neonates of multigravida mothers were significantly heavier than those of primigravida mothers; Indians were significantly lighter than Malays and Chinese; and males were significantly heavier than females. The head circumferences and body lengths of neonates were significantly influenced by ethnic origin, sex and/or maternal gravida status at gestation above 35 and 36 weeks respectively (p < 0.05). It was most likely due to the small sample size which explained our inability to detect statistically significant difference in all measurements (birthweight, length and head circumference) by sex, ethnicity and maternal gravida status at gestation below 35 weeks. Based on the measurements obtained in this study, percentile charts for the Malaysian population were constructed and made available for the first time. These charts will be useful for the assessment of Malaysian neonates during the perinatal period.

Computed tomography findings in maple syrup urine disease.

Maple syrup urine disease (MSUD) is an inherited metabolic disorder characterised by a severe, usually lethal, neonatal course unless dietary intake of branched chain amino acids is restricted. We describe a patient with MSUD who had computed tomography (CT) changes of diffuse white matter hypodensity, particularly in the deep white cerebellar matter, brain stem, cerebral peduncles, thalamus and posterior limb of the internal capsule. With dietary treatment, there was neurological improvement with simultaneous disappearance of the oedema. These CT changes are typical of MSUD, hence are relevant findings in the neuroradiologic differential diagnosis of a possible metabolic disorder.

Neurodevelopmental outcome of Malaysian very low birth weight infants: predictive value of cranial ultrasound appearances.

The aim of the study was to determine the predictive value of cranial ultrasound scans done in the neonatal period for neurodevelopmental outcome of the Malaysian very low birthweight (VLBW, < 1500 grams) infants assessed at 12 months of corrected age. Of the 101 infants studied, 68 (67.3%) were neurodevelopmentally normal at one year of age, 18 (17.8%) had major and 15 (14.9%) had minor neurodevelopmental impairment. Neurodevelopmental outcome was normal in 66/88 (75.0%) infants who did not have severe intraventricular haemorrhage (IVH) or periventricular intraparenchymal echo densities (PVE) in the first week of life, and in 57/73 (78.1%) with uncomplicated scans at discharge. In contrast, 11/13 (84.6%) with parenchymal echo densities or severe intraventricular bleed in the early neonatal period and 17/28 (60.7%) with complicated scans at discharge had adverse sequelae. There was a significant association between lesions seen on cranial ultrasound in the neonatal period and subsequent neurodevelopmental impairment. Late neonatal ultrasound scans appear to be a better predictor of short-term neurodevelopmental outcome than early scans.

Epidemiology of head injury in Malaysian children: a hospital-based study.

A prospective observational study was carried out at the Emergency Department, Hospital Kuala Lumpur to determine the proportion of accidental head injury among children and the circumstances of injury. The study was carried out from November 1993 to January 1994 on all children below 14 years who presented to the Emergency Department with accidental head injury. Accidental head injury made up (4.75%) of all cases seen at the Casualty Department. The ratio of boys to girls was 2:1. The mean age of head injured children was 5.2 (S.D. 3.63) years. The leading cause of head injury was fall (63%) followed by road traffic accidents (RTA) in (30.7%) while the rest were due to 'impact' (injury caused by flying object or missiles) injuries. More than half (54.4%) of those injured in RTA were pedestrians. Pedestrian injury was particularly important in the 5-< 14 years age group, where adult supervision was lacking in two thirds of the children. None of the patients who were involved in vehicle-related injuries had used a suitable protective or restraining device. All three patients who died were from this group. This study emphasises the need for stricter enforcement of laws related to the use of protective devices and measures to decrease child pedestrian injury. The issues of lack of adult supervision, both in and outside the home need to be addressed.

Dopa responsive dystonia with diurnal fluctuation (Segawa's syndrome).

A 10-year-old girl presented with progressive dystonia with diurnal fluctuation. Response to low dose L-Dopa was dramatic and sustained with no complications. Recurrence of symptoms was observed on attempted withdrawal. Because of the dramatic response to therapy, dopa-responsive dystonia must be considered in the differential diagnosis of disorders presenting as gait disorders in childhood.

A clinical audit on the practice of platelet transfusions at a tertiary paediatric referral centre.

Platelet transfusions are indicated in a wide variety of clinical conditions especially those with thrombocytopenia. However, without proper clinical practice guidelines, inappropriate transfusions are bound to happen. To ascertain the provision of a quality and appropriate practice of platelet transfusions, an audit study was carried out over a period of one month at the Paediatric Institute, Kuala Lumpur Hospital. A prospective audit was performed during that period whilst a retrospective collection of data was carried out for the previous month for comparison. Based on a set of criteria agreed upon by the audit committee, it was found that in 18.5% (22 of 119) of the cases, the indications for platelet transfusions were inappropriate. The audit committee concluded that there is a need for a more detailed clinical practice guideline for local use to reduce or lower the incidence of inappropriate transfusions of platelets.

The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML.

Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2(V617F) mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2(V617F) mutation, and the MOLM-13 model of FLT3-ITD-driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations.

TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties.

TG02 is a novel pyrimidine-based multi-kinase inhibitor that inhibits CDKs 1, 2, 7 and 9 together with JAK2 and FLT3. It dose-dependently inhibits signaling pathways downstream of CDKs, JAK2 and FLT3 in cancer cells with the main targets being CDKs. TG02 is anti-proliferative in a broad range of tumor cell lines, inducing G1 cell cycle arrest and apoptosis. Primary cultures of progenitor cells derived from acute myeloid leukemia (AML) and polycythemia vera patients are very sensitive to TG02. Comparison with reference inhibitors that block only one of the main targets of TG02 demonstrate the benefit of combined CDK and JAK2/FLT3 inhibition in cell lines as well as primary cells. In vivo, TG02 exhibits favorable pharmacokinetics after oral dosing in xenograft models and accumulates in tumor tissues, inducing an effective blockade of both CDK and STAT signaling. TG02 induces tumor regression after oral dosing on both daily and intermittent schedules in a murine model of mutant-FLT3 leukemia (MV4-11) and prolongs survival in a disseminated AML model with wild-type FLT3 and JAK2 (HL-60). These data demonstrate that TG02 is active in various models of leukemia and provide a rationale for the ongoing clinical evaluation of TG02 in patients with advanced leukemias.

Refractive status of children under the age of three years born premature without retinopathy of prematurity.

OBJECTIVES: A cross-sectional study was undertaken to determine and compare the refractive status of premature children without retinopathy of prematurity (ROP) and full term children below the age of three years. MATERIALS AND METHODS: Seventy children were examined. One group comprised of 40 children born premature without ROP and another group consisted of 30 children born full term and normal. Refractive error was determined using the Mohindra technique. RESULTS: Children below the age of three years born premature without ROP were significantly less hyperopic compared to children born full term and normal (t = 3.76, p = 0.0003). Our results show that children born premature without ROP are emmetropic when compared to children born full term. CONCLUSION: It is appears that emmetropization does occur in children born premature and full term. RESULTS: Need to be written in a new paragraph and in italics

Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia.

FMS-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene found in acute myeloid leukemia (AML) patients and its activating mutations have been proven to be a negative prognostic marker for clinical outcome. Pacritinib (SB1518) is a tyrosine kinase inhibitor (TKI) with equipotent activity against FLT3 (IC(50)=22 n) and Janus kinase 2 (JAK2, IC(50)=23 n). Pacritinib inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3 K signaling in FLT3-internal-tandem duplication (ITD), FLT3-wt cells and primary AML blast cells. Oral administration of pacritinib in murine models of FLT3-ITD-driven AML led to significant inhibition of primary tumor growth and lung metastasis. Upregulation of JAK2 in FLT3-TKI-resistant AML cells was identified as a potential mechanism of resistance to selective FLT3 inhibition. This resistance could be overcome by the combined FLT3 and JAK2 activities of pacritinib in this cellular model. Our findings provide a rationale for the clinical evaluation of pacritinib in AML including patients resistant to FLT3-TKI therapy.