MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice.

Large-scale consortia mapping the genomic risk architectures of schizophrenia provide vast amounts of molecular information, with largely unexplored therapeutic potential. We harnessed publically available information from the Psychiatric Genomics Consortium, and report myocyte enhancer factor 2C (MEF2C) motif enrichment in sequences surrounding the top scoring single-nucleotide polymorphisms within risk loci contributing by individual small effect to disease heritability. Chromatin profiling at base-pair resolution in neuronal nucleosomes extracted from prefrontal cortex of 34 subjects, including 17 cases diagnosed with schizophrenia, revealed MEF2C motif enrichment within cis-regulatory sequences, including neuron-specific promoters and superenhancers, affected by histone H3K4 hypermethylation in disease cases. Vector-induced short- and long-term Mef2c upregulation in mouse prefrontal projection neurons consistently resulted in enhanced cognitive performance in working memory and object recognition paradigms at baseline and after psychotogenic drug challenge, in conjunction with remodeling of local connectivity. Neuronal genome tagging in vivo by Mef2c-Dam adenine methyltransferase fusion protein confirmed the link between cognitive enhancement and MEF2C occupancy at promoters harboring canonical and variant MEF2C motifs. The multilayered integrative approaches presented here provide a roadmap to uncover the therapeutic potential of transcriptional regulators for schizophrenia and related disorders.

Comparative usefulness of C-reactive protein and erythrocyte sedimentation rate in juvenile rheumatoid arthritis.

OBJECTIVE: To compare serial C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels in juvenile rheumatoid arthritis (JRA) patients and investigate their application as diagnostic parameters and prognostic predictive factors. METHODS: We carried out retrospective chart review among JRA patients who were followed-up at the National Taiwan University Hospital (NTUH) between 1994 and 2005. RESULTS: Thirty-nine girls and 68 boys were included in this study. At the time of diagnosis, the prevalence of ESR was significantly greater than that of CRP (86.8% vs. 47.2%, p < 0.05). ESR revealed more responsiveness to treatment compared to CRP (SRMs were -0.69 and -0.31, respectively). At the time of diagnosis, high CRP levels (>or= 5mg/dL) correlated with poor therapeutic response, as do positive CRP (> 0.8 mg/dL) and high ESR levels (> 40 mm/h) after treatment for six months. Overall, initial high CRP levels (>or= 5mg/dL) demonstrated the strongest predictive role of failure of the first remission. CONCLUSION: For disease diagnosis, ESR can be a better parameter than CRP but a high initial CRP level can strongly predict treatment failure of the first remission.

Galloway-Mowat syndrome: a glomerular basement membrane disorder?

We report a female infant with Galloway-Mowat syndrome. In addition to the characteristic dysmorphic appearance, neurological anomalies and early-onset nephrotic syndrome, she had arachnodactyly, an observation thus far reported uniquely in Taiwan. Also, her elder sister had the same condition. Renal pathology on light microscopy showed cystic dilatation of the renal tubules. Electron microscopy showed an irregular glomerular basement membrane and effacement of foot processes. This observation suggests that malformation of the glomerular basement membrane may cause the glomerulopathy in Galloway-Mowat syndrome.

Ataxia telangiectasia: report of two cases.

Ataxia telangiectasia (A-T) is a rare autosomal recessive multisystem disease. The diagnosis of A-T is based on the typical clinical picture: ataxia and telangiectasia. However, an increase in (alpha-fetoprotein (AFP) level and the identification of the A-T mutated gene (ATM) assist in an early diagnosis. Here we report two cases of A-T diagnosed in our hospital (case 1: a 7-year-old boy; case 2: an 8-year-old girl). Both of these patients had typical clinical pictures of ataxia and telangiectasia, AFP was also increased (case 1:471.2 ng/dL; case 2: 196 ng/dL). T-cell dysfunction was noted in both patients. Case 1 had IgG2 deficiency and case 2 had IgA, IgG2 and IgG3 deficiency. Case 2 developed malignant lymphoma at 9 years of age and died of pneumonia with respiratory failure at 10 years of age. Because of rhe rarity of A-T in Taiwan, we report two cases to help pediatricians make an early diagnosis of A-T if they have a patient with progressive ataxia and oculocutaneous telangiectasia.

Effects of ascorbate in microdialysis perfusion medium on the extracellular basal concentration of glutamate in rat's striatum.

There are many evidences suggest that ascorbate in the extracellular space can affect glutamate concentration in the rat's brain. In this report, we studied how ascorbate in microdialysis perfusion medium affected glutamate level at the striatum in freely-moving rats. Three perfusion mediums were used: 0, 250, and 400 microM of ascorbate in perfusion medium. The extracellular basal concentrations of glutamate were determined to be 1.29+/-0.52 microM for the no ascorbate group, 0.86+/-0.35 microM for the low ascorbate group and 4.76+/-1.48 microM for the high ascorbate group. By using 400 microM of ascorbate in a perfusion medium, we found that the extracellular basal concentration of glutamate significantly increased and its in vivo recovery significantly decreased. This indicated that ascorbate concentration in a perfusion medium was important and must be carefully considered while using microdialysis technique to monitor glutamate concentration in vivo.

Association of allergy with Tourette's syndrome.

In our clinical practice, we often encounter signs and symptoms of allergy, such as rhinitis and asthma, in patients with Tourette's syndrome (TS). Some of the allergic manifestations are similar to the oral tics or motor tics found in TS patients. To clarify the association between TS and allergy, we evaluated 72 consecutive patients with TS from 1 September 1996 through 31 August 1997. The diagnosis of TS was based on the Diagnostic and Statistical Manual of Mental Disorders diagnostic criteria. Sixty-five boys and 7 girls, 4 to 17 years old (9.4 +/- 3.1 yr) were evaluated using the Multiple Allergens Simultaneous Tests (MAST) for the detection of total and specific immunoglobulin. Forty-five patients had positive results, of whom 41 (56.9%) had clinical evidence of allergy. The prevalence of allergy in the local population as reported by The International Study of Asthma and Allergy in Childhood Taiwan Group (1994) was 44.3% (33.5% with allergic rhinitis and 10.8% with asthma). These subjects served as controls. Comparing the number of patients with clinical evidence of allergy in the MAST positive group (56.9%) of TS patients with the control group (44.3%), the difference was significant++ (p < 0.05). The prevalence of allergy in TS patients in our study was significantly higher than in the general population. TS had an association with allergy.

Gastro-intestinal bleeding caused by leiomyoma of the small intestine in a child with neurofibromatosis.

UNLABELLED: Gastro-intestinal bleeding is an uncommon presentation in children with neurofibromatosis. Gastro-intestinal involvement caused by jejunal leiomyoma has only been described in adults. To the best of our knowledge, this is the first paediatric case of jejunal leiomyoma associated with neurofibromatosis. We present a 10-year-old girl with a 9-month history of anaemia and low gastro-intestinal bleeding. Abdominal sonography and small bowel series showed a submucosal mass in the proximal jejunum. On surgery, a submucosal tumour was excised and histological examination suggested a diagnosis of "smooth muscle tumour of undetermined malignant potential". There were no recurrence of symptoms for 4 years after the operation. CONCLUSION: Jejunal leiomyoma should be considered in a child with neurofibromatosis presenting with gastro-intestinal bleeding.

Tuberous sclerosis with visceral organ involvement.

This study is to determine the incidence of visceral organ involvement in tuberous sclerosis (TS). We reviewed 30 cases of TS diagnosed between 1987 to 1997. There were 17 males and 13 females, ages ranged from one day old to 17 years old. Among the 30 cases, 25 patients had seizures and skin manifestations; 24 had cerebral tubercles; 10 had heart involvement (9 rhabdomyoma, 1 dilated cardiomyopathy); 4 had kidney involvement (3 polycystic kidney disease, 1 renal hamartoma); and 3 had retinal astrocytic hamartoma. Based on our study, the most common visceral organs involved were the heart and kidney. Among the ten patients with cardiac rhabdomyoma, six were less than 1 year old (mean age 1.6 +/- 2.2 years old). One newborn presented with a cardiac mass diagnosed by prenatal sonography and another newborn, noted to have tachycardia after birth, underwent surgical intervention due to impending heart failure. Four patients had kidney abnormalities; three were less than 5 years old (mean age 5.2 +/- 5.2 years). During this 10 year period, there was no mortality seen among patients with visceral organ involvement. We suggest that clinicians treating patients with TS should not overlook the visceral organs, especially heart and kidney, which, if involved can have significant morbidity.

Excitatory and inhibitory amino acid levels in the cerebrospinal fluids of children with neurological disorders.

Measurement of amino acid levels in the cerebrospinal fluid (CSF) of children with various neurological disorders was performed with high performance liquid chromatography (HPLC). Glutamate increased in patients with bacterial meningitis, aseptic meningitis and encephalitis. Aspartate increased in bacterial meningitis and seizure disorders. Glycine increased in both bacterial and aseptic meningitis. Taurine increased in bacterial meningitis and encephalitis. GABA, the main inhibitory amino acid, increased in encephalitis. Excitatory and inhibitory amino acids are richly distributed in brain tissue and are related to neuron activity. Changes in amino acid levels in the CSF may reflect the pathologic state and severity of brain insults, and may be useful in monitoring disease processes. Further study is necessary to determine whether CSF aminos acid levels have a role in practical clinical application.

Cerebral perfusion in children with Alice in Wonderland syndrome.

Alice in Wonderland syndrome (AIWS) is characterized by visual hallucinations and bizarre perceptual distortions. Technetium-99m hexamethylpropyleneamine tomography (SPECT) brain scans were performed in four patients during the acute stage of AIWS. Two patients were demonstrated to have Epstein-Barr virus infections. One had abnormal (EEG) findings. The visual-evoked potential, cranial CT, and MRI findings were negative. The decreased cerebral perfusion areas in all patients were near the visual tract and visual cortex. All involved some regions of the temporal lobe. In most patients with AIWS, the EEG, CT, and MRI are unable to determine the precise pathologic areas. However, a SPECT brain scan may demonstrate abnormal perfusion areas and explain the clinical presentations.

Prospective neurosonographic study in infantile purulent meningitis.

Fourteen infants or neonates with purulent meningitis underwent prospective brain sonography follow-up for early detection of intracranial complications. Most patients had 12 scans during a 6 month period. The children's ages ranged from 5 days to 11 months. Early surgical intervention is suggested in progressive ventricular dilatation or severe subdural fluid collection. One patient with hydrocephalus had ventriculoperitoneal shunting. Three patients developed subdural empyema. One had subdural external drainage; and repeat subdural tappings were done in the other two. All these patients recovered without obvious neurologic sequelae. Two other patients developed ventricular dilatation one month after the onset of meningitis. Hydrocephalus ex vacuo was suspected and there were no indications for shunt surgery. These latter two cases had developed mild psychomotor retardation on their last follow-up. This primitive observation suggests that early detection with prospective, sequential sonography follow-up and appropriate surgical intervention for hydrocephalus or subdural fluid collection may lessen the neurologic sequelae in infantile and neonatal purulent meningitis.

Solitary maxillary central incisor and congenital nasal pyriform aperture stenosis.

UNLABELLED: Solitary maxillary central incisor (SMCI) and congenital nasal pyriform aperture stenosis (CNPAS) have been reported as an isolated morphogenic defect or associated with pituitary deficiency, holoprosencephaly, ocular coloboma, or chromosomal abnormalities. We report two cases and analyse 40 cases of SMCI and 24 cases of CNPAS, including 15 cases of combined SMCI and CNPAS, obtained from the literature. Of the patients with SMCI, 69% had short stature, 48% growth hormone deficiency or hypopituitarism, 23% pituitary absence or hypoplasia, and 17% had del (18p-) or r(18). Of the patients with CNPAS, 63% had SMCI, 75% were short, 43% had hypopituitarism or growth hormone deficiency, 36% had pituitary or CNS anomaly, and 33% had del (18p), r(18), or del (13q). CONCLUSIONS: Solitary maxillary central incisor and congenital nasal pyriform aperture stenosis can be a diagnostic clue to pituitary hypofunction, CNS, ophthalmological and cytogenic anomalies.

Neurosonographic findings in high risk neonates with hypoglycemia.

In a prospective study, 28 neonates with hypoglycemia underwent a series of neurosonographic follow-ups. Most of the patients completed a total of 12 scans beginning on the first day of admission and finishing at age of 6 months. One patient died of intracranial hemorrhage, 5 cases had severe neurological sequelae and 22 cases developed normally. The main sonographic findings during early the neonatal stage included: (1) diffuse increase of echogenecity; (2) compressed ventricles; (3) increased periventricular echogenecity and (4) hemorrhage. In late neonatal stage, the abnormal findings were (1) increased periventricular echogenecity; (2) ventricular dilatation and (3) increased gyral pattern. Periventricular cystic leukomalacia and brain atrophy were observed on the late follow-up sonography in those cases with neurological sequelae. Hypoglycemia per se may not account for all the damage in the brain. Treatment of the underlying causes should start as soon as possible. However, early sonographic finding may provide critical information for vigorous treatment of hypoglycemia, while the late scans enable early prediction of poor neurological outcome.

Neurogenic diabetes insipidus in children with hypoxic encephalopathy: six new cases and a review of the literature.

UNLABELLED: Hypoxic encephalopathy is rarely mentioned as a cause of neurogenic diabetes insipidus (DI) in children. We here report six cases of DI which occurred after severe hypoxic/ischaemic brain damage and include a review of the literature on 28 paediatric cases of neurogenic DI due solely to severe hypoxia/ischaemia. Airway obstruction, haemorrhagic shock and sudden infant death syndrome are the three major causes of hypoxia/ischaemia. The ages (25/28) ranged from 0.03 to 18 years (mean 7.27 years, median 5 years). The intervals between the hypoxic insult and the onset of DI (23/28) ranged from 0.08 days (2 h) to 13 days (mean 4.07 days, median 3.5 days). Linear regression analysis revealed no significant correlation between the age and the interval. Nineteen cases (82.6%) developed DI within 6 days after the hypoxic/ischaemic insult. Only two neonates survived with developmental delay. The remaining 26 cases died. CONCLUSION: Neurogenic DI can be caused by hypoxia/ischaemia and is an ominous sign of severe brain damage in children with hypoxic encephalopathy. It is important to recognize this potential sequel by regularly monitoring intake and output, plasma sodium level, and urine specific gravity.

Cleft lip and palate associated with malformation of the central nervous system: a prospective neurosonographic study.

A prospective neurosonographic study was undertaken on 190 patients with non-syndrome cleft lip and/or palate. Among them, six cases (3.2%) demonstrated malformations of the central nervous system. Included were four cases of midline cleft lip and palate showing holoprosencephaly; one case of bilateral cleft lip and midline cleft palate showing dysplasia of the septum pallicidum and one case of bilateral cleft lip and palate showing dysgenesis of corpus callosum. The patients with midline clefts were not obligatory associated with malformation of the brain, but their incidence was higher (four of nine case or 44.4%). The neurosonogram provides a portable, low cost, non-invasive and efficient technique in the diagnosis of gross anomaly of the neonatal brain, and can thus serve as a screening test in those patients with clefts.

Continuous infusion of vasopressin in comatose children with neurogenic diabetes insipidus.

Three comatose children with neurogenic diabetes insipidus were treated with intravenous infusion of vasopressin. The infusion of vasopressin was started at a dose of 1.3 to 2.7 mU/kg/h as soon as diabetes insipidus was diagnosed. The effect (urine flow < 2 ml/kg/h with increased specific gravity) was noted in 1 to 6 hours. The infusion rate of vasopressin was adjusted according to urine flow rate which was usually kept around 65 ml/100 kcal metabolized/day. Hypernatremia was corrected 17 to 53 hours after the initiation of infusion of vasopressin. The levels of sodium stayed between 127 and 151 mmol/l during a period of 2.5 to 22 days until the patients' death due to the termination of respiratory support or cardiac decompensation. A continuous infusion of vasopressin offered the advantage of rapid onset and termination of effect and therefore could be easily titrated. It seems a rational therapy for comatose children with neurogenic diabetes insipidus.

Enamel pitting in childhood tuberous sclerosis.

Dental enamel pitting was studied as a diagnostic sign of pediatric tuberous sclerosis (TSC). Thirteen patients aged 2.5 to 18 years with varying degrees of TSC were evaluated. They were checked for the presence of enamel pitting by the use of two to three drops of dental plaque disclosing stain which was applied to the labial surfaces of dry teeth. This technique provides a remarkable color contrast allowing for the detection of many small and subtle enamel pits. A control group of 39 unrelated patients without TSC were also examined. A total of 77% of TSC patients (10/13) revealed enamel pitting, compared with 13% of controls. The distribution of enamel pitting among TSC patients and normal controls of each sex was statistically significant. The total number of enamel pits in each patient varied from 1 to 26 and increased with age; 90% of the teeth with enamel pitting displayed one to two pits per tooth. The youngest patient with enamel pitting was 5 years old. The simplicity of this test and the high probability of pitting in TSC make the examination useful in the assessment of patients in whom the diagnosis of this serious genetic disease is being considered.

Epilepsy as the sole manifestation of brain tumor--report of two cases.

Epilepsy may be the earliest and the sole clinical manifestation of a brain tumor. The existence and the character of the brain tumor cannot be predicted based solely on the severity and pattern of seizure. Epilepsy is common in patients with brain tumors, however, it is less common to find brain tumors in patients with epilepsy. Due to the slow progression of brain tumors and limitations in the use of brain computed tomography (CT), it often takes a long time to diagnose brain tumors in an epileptic child. Relief of epilepsy by surgical removal of the etiologic brain tumor appears to be promising. We report two cases of brain tumors presenting as intractable epilepsy with a discordant neuroimage. Therefore for those children taking long-term anticonvulsants with frequent recurrence, it appears reasonable to perform magnetic resonance imaging (MRI) to enable discovering of any organic lesions.