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Biomedical subjects

B Chong

Publications and source records attributed to B Chong.

At least 19 recordsLinked to original sources
PubMed2004

Use of the newborn screening card to define cause of death in a 12-year-old diagnosed with epilepsy.

Post-mortem investigation of sudden death in young people frequently reveals no overt cause for the death. Full investigation is hampered if tissue or blood is not retained for DNA analysis. We report a post mortem molecular diagnosis of long QT syndrome in a 12-year-old boy diagnosed with epilepsy who died suddenly playing sport. The DNA was extracted from an archived blood spot on his newborn screening ('Guthrie') card, which had been taken from him at 6 days of age. A missense mutation was detected in exon 5 of the KCNQ1 gene; R243C (835C > T), associated with long QT type 1. The same mutation was found in the mother (who now takes effective preventative therapy), but not in the sib who has now been reassured that she is not at risk of sudden death.

Arginine↗
PubMed2002

Treatment with the novel anti-angiogenic agent PI-88 is associated with immune-mediated thrombocytopenia.

BACKGROUND: The novel molecule PI-88 is a highly sulfonated oligosaccharide which inhibits heparanase activity and competes with heparan sulfate binding of growth factors such as FGF and VEGF. Preclinical data demonstrates that PI-88 inhibits angiogenesis and has anti-metastatic effects. The aim of this phase I study was to determine the recommended dose and toxicity profile of PI-88. PATIENTS AND METHODS: PI-88 was given intravenously in increasing duration of administration (0.57 mg/kg for 2 h, 0.57 mg/kg/day for 1 day, 4, 7 and 14 consecutive days) and then increasing dose for 14 consecutive days (1.14 mg/kg/day and 2.28 mg/kg/day) in patients with advanced malignancies until dose-limiting toxicity (DLT) was observed. Fourteen assessable patients with advanced malignancies received PI-88 intravenously. RESULTS: DLT was thrombocytopenia. The thrombocytopenia appeared to be immunologically mediated with the development of anti-heparin platelet factor 4 complex antibodies. There were no other significant toxicities. At the final dose and schedule (2.28 mg/kg/day for 14 days), there was limited evidence of biological activity as measured by the surrogate marker activated partial thromboplastin time (APTT), although two patients had stabilisation of disease. CONCLUSIONS: In conclusion, PI-88 at a dose of 2.28 mg/kg/day for 14 days resulted in dose-limiting thrombocytopenia which appeared to be immune related. Limited evidence of biological activity was noted. Alternate scheduling and routes of administration are now being explored.

Adult↗
PubMed2002

Molecular and cultural analysis of the microflora associated with endodontic infections.

Cultural studies have indicated that a subset of the oral microflora is responsible for endodontic infections. Approximately 50% of oral bacteria are unculturable, so it is likely that currently unknown bacteria are present in such infections. In this study, cultural and molecular analyses were performed on the microflora in aspirate samples collected from 5 infected root canals. 16S rDNA sequences from 261 isolates and 624 clones were identified by comparison with database sequences. Sixty-five taxa were identified, of which 26 were found by the molecular method alone. A mean of 20.2 taxa was found in each sample. A new species of Dialister was the only organism present in all 5 samples. Twenty-seven novel taxa were detected, 18 of which belonged to the phylum Firmicutes and 8 to Bacteroidetes. Culture-independent, molecular analysis has revealed a more diverse microflora associated with endodontic infections than that revealed by cultural methods alone.

Adult↗
PubMed2001

Compound heterozygosity at the FMR1 gene.

Individuals affected with Fragile X syndrome are usually characterized at the DNA level by the presence of at least 200 CGG repeats in the 5' untranslated region of the FMR1 gene; this number of repeats is defined as a full mutation. Repeats that number 50-200 usually define those with premutations and are termed unaffected carriers. We report here a compound heterozygous female who carried CGG repeats in the FMR1 gene that fall within the premutation and full mutation ranges. The former appears to have been inherited from the father, whereas the latter is an expansion of the premutation carried by the proband's mother. Therefore, the offspring of the proband will carry a significant risk of being affected with Fragile X syndrome, and the paternal uncle and any cousins should be counselled for being at risk for this syndrome.

DNA Mutational Analysis↗
PubMed2001

Detection of sequence variations in the adenomatous polyposis coli (APC) gene using denaturing high-performance liquid chromatography.

We have evaluated the usefulness of denaturing high performance liquid chromatography (dHPLC) for scanning the adenomatous polyposis coli (APC) gene for point mutations, small deletions, and insertions. Our assay consists of 28 sets of primers to amplify the 15 exons of the APC gene. All PCR reactions were amplified simultaneously using the same reaction conditions in a 96-well format and then analyzed by dHPLC, using empirically determined optimum temperatures for partial fragment denaturation. Previously studied DNA specimens from 47 familial adenomatous polyposis (FAP) patients were analyzed by dHPLC and all mutations were correctly identified and confirmed by sequence analysis. This approach identified a single-base substitution in exon 6 and a 2-bp insertion in exon 15 that initially had not been detected by single-strand conformational polymorphism (SSCP) analysis. A novel mutation in exon 15 of the APC gene, 2065delG (codon 689) that had previously been undetected by the protein truncation test (PTT) was also identified by dHPLC. We present our validation studies of dHPLC technology for APC gene analysis in terms of sensitivity and specificity and compare it to current standard scanning technologies including PTT, SSCP, and conformational sensitive gel electrophoresis (CSGE).

Adenomatous Polyposis Coli↗
PubMed2001

Clinical & genetic analysis of four patients with distal upper limb spinal muscular atrophy.

BACKGROUND & OBJECTIVES: Distal upper limb spinal muscular atrophy (SMA) is an uncommon segmental variant of SMA. The condition is usually sporadic, affects males more often than females, and manifests late in the second decade of life, remaining confined to the upper limbs. We examined four patients with this form of SMA in order to determine if they carried homozygous deletion mutations in the survival motor neuron (SMN) or neuronal apoptosis inhibitory protein (NAIP) genes that underlie proximal SMA. METHODS: The four patients with distal upper limb SMA were analysed clinically, electrophysiologically and biochemically. Genomic DNA from each of the patients was analysed by restriction enzyme digestion of polymerase chain reaction (PCR) amplification products, as well single stranded conformation polymorphism (SSCP), to detect deletion events of selected exons of the SMN and NAIP genes. RESULTS: The clinical phenotype of the four patients, together with the biochemical and electrophysiological studies, confirmed a diagnosis of distal upper limb SMA. The molecular studies excluded homozygous deletion mutations in these patients as causative of their phenotype. INTERPRETATION & CONCLUSION: The genetic component underlying distal upper limb SMA appears not to involve mutations that are common in proximal SMA patients. It is possible that genes other than SMN and NAIP may be involved, while somatic mosaicism of SMN gene mutations could be implicated in the segmental nature of distal upper limb SMA.

Adolescent↗
PubMed2000

Eos and pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities.

Members of the Ikaros family of transcription factors, Ikaros, Aiolos, and Helios, are expressed in lymphocytes and have been implicated in controlling lymphoid development. These proteins contain two characteristic clusters of zinc fingers, an N-terminal domain important for DNA recognition, and a C-terminal domain that mediates homo- and heterotypic associations between family members. The conservation of these domains is such that all three proteins recognize related DNA sequences, and all are capable of dimerizing with other family members. Here we describe two additional Ikaros family proteins, Eos and Pegasus. Eos is most highly related to Helios and shares its DNA binding and protein association properties. Pegasus is related to other Ikaros proteins in its C-terminal dimerization domain but contains a divergent N-terminal zinc finger domain. Pegasus self-associates and binds to other family members but recognizes distinct DNA-binding sites. Eos and Pegasus repress the expression of reporter genes containing their recognition elements. Our results suggest that these proteins may associate with previously described Ikaros family proteins in lymphoid cells and play additional roles in other tissues.

3T3 Cells↗
PubMed2000

Hierarchical mutation screening protocol for the BRCA1 gene.

The identification of mutations in the BRCA1 gene poses difficulties in achieving a screening outcome that satisfies the twin needs of speed and accuracy. These needs must also take into account the patient's family history and the statistical evaluation of the probability of detecting a mutation. Given the above, we present here a hierarchical mutation screening strategy that comprises two tiers: first, multiplex heteroduplex and exon 13 duplication analysis; second, exon amplification and direct sequencing using a 96-well tray format. The advantages of this strategy are two-fold: first, the division of analytical tools in order to achieve low and high-resolution mutation screening, respectively; second, a streamlined sequencing approach that leads to a sensitive and rapid assay that reduces labor costs and handling errors. The success of this approach is shown by the identification of a novel deletion mutation in exon 14 of the BRCA1 gene, which was not detected by the more conventional protein truncation assay due to the small size of the predicted truncated protein.

Adult↗
PubMed1999

hFOG-2, a novel zinc finger protein, binds the co-repressor mCtBP2 and modulates GATA-mediated activation.

We have identified a novel human zinc finger protein, hFOG-2, which is related to but distinct from the murine transcription factor Friend-of-GATA-1 (mFOG-1). The hFOG-2 gene was initially detected in K562 cells using a polymerase chain reaction approach with degenerate primers corresponding to zinc finger regions of mFOG-1. A murine homologue of hFOG-2 was also identified in the mouse expressed sequence tag data banks, indicating that a family of FOG genes exists in mammals. hFOG-2 appears to be widely expressed, while mFOG-1 is expressed primarily in erythroid and megakaryocytic cells and plays a fundamental role in the development of these lineages. Sequencing of the full-length hFOG-2 cDNA indicates that the interaction domains for transcription factors GATA-1 and mCtBP2 are both conserved and we have shown that this new FOG protein also physically interacts with these factors. We have demonstrated that hFOG-2, like mFOG-1, can act in concert with GATA-1 to activate gene expression from the p45 NF-E2 promoter region, but that it can also act to repress GATA-mediated activation of additional reporter constructs. Finally, we have identified a repression domain in hFOG-2 and show that repression is dependent upon the integrity of the mCtBP2 interaction motif Pro-Ile-Asp-Leu-Ser.

Alcohol Oxidoreductases↗
PubMed1999

Cord blood is better than bone marrow for generating megakaryocytic progenitor cells.

Thrombocytopenia remains an important problem for patients post high-dose chemotherapy and hematopoietic stem cell transplantation. The study of megakaryocytes, the direct precursors of platelets, has been hampered by their relatively low frequency in hematopoietic tissues. In an attempt to obtain a large number of functional megakaryocytic cells, we established a serum-free culture system to grow megakaryocytic progenitor cells derived from normal human bone marrow (BM) and cord blood (CB). Highly purified (purity >95%) CD34+ cells were obtained using magnetic cell sorting (MACS) followed by fluorescence activated cell sorting (FACS). The cells were cultured in a serum-free culture system for 3 weeks in the presence of a single dose of MGDF (50 ng/mL). On days 0, 5, 8, 12, 14, 18, and 21 of culture, the cellularity and morphology were examined. Megakaryocytic cells were monitored by detecting the expression of GPIIIa (CD61), GPIIb/IIIa (CD41) and GPIb (CD42b), and the distribution of megakaryocyte (MK) ploidy was analyzed by two-color flow cytometry. MGDF alone induced maximal nucleated cell expansion at day 14, resulting in a 38.20+/-10.47-fold increase in cell number for CB and a 5.08+/-1.30-fold increase in cell number for BM. On day 14 of the culture, the percentage of CD41-/CD14- cells derived from CB reached 73.54%+/-6.01% giving an absolute number of CD41+/CD14- cells of 27.25+/-2.23 x 10(4)/mL (27,250-fold increase), whilst the percentage of CD41+/CD14- cells derived from BM was only 29.21%+/-5.63% with an absolute number of 1.36+/-0.26 x 10(4)/mL (680-fold increase). Increased expression of GPIIIa occurred the earliest in culture, followed by GPIIb/IIIa, and then GPIb. The majority (81.6%-92.6%) of megakaryocytes (CD41+ cells) on day 14 of culture were 2N, although we did detect some 4N, 8N and greater ploidy cells. In conclusion, CD34+ cells stimulated by MGDF alone generated highly enriched MK progenitor cells at day 14 of serum-free culture. CB stem and progenitor cells have a greater proliferative response to MGDF alone than those derived from BM and may, therefore, prove to be a better source of cells for MK expansion.

Cell Differentiation↗
PubMed1999

The relationship of magnetic source imaging to ictal electrocorticography in a neuronavigational workspace.

Magnetic source imaging (MSI) registers magnetoencephalographic (MEG) activity to a three-dimensional MRI volume. State-of-the-art MSI allows concurrent whole head coverage, but is practically restricted to interictal recording. However, the purpose of the presurgical evaluation of epileptic patients, in which MSI is playing an increasing role, is the elucidation of the ictal epileptogenic focus. The manner in which interictal MSI activity relates to the ictal focus has not yet been adequately examined. To facilitate this analysis, we are developing techniques to precisely coregister MSI to the ictal onset zone as defined by extraoperative intracranial grid/strip monitoring. The neuronavigational workspace is a convenient area in which to precisely coregister these (and other) imaging and physiological data sets.

Cerebral Cortex↗
PubMed1999

Magnetoencephalographic patterns of epileptiform activity in children with regressive autism spectrum disorders.

BACKGROUND: One-third of children diagnosed with autism spectrum disorders (ASDs) are reported to have had normal early development followed by an autistic regression between the ages of 2 and 3 years. This clinical profile partly parallels that seen in Landau-Kleffner syndrome (LKS), an acquired language disorder (aphasia) believed to be caused by epileptiform activity. Given the additional observation that one-third of autistic children experience one or more seizures by adolescence, epileptiform activity may play a causal role in some cases of autism. OBJECTIVE: To compare and contrast patterns of epileptiform activity in children with autistic regressions versus classic LKS to determine if there is neurobiological overlap between these conditions. It was hypothesized that many children with regressive ASDs would show epileptiform activity in a multifocal pattern that includes the same brain regions implicated in LKS. DESIGN: Magnetoencephalography (MEG), a noninvasive method for identifying zones of abnormal brain electrophysiology, was used to evaluate patterns of epileptiform activity during stage III sleep in 6 children with classic LKS and 50 children with regressive ASDs with onset between 20 and 36 months of age (16 with autism and 34 with pervasive developmental disorder-not otherwise specified). Whereas 5 of the 6 children with LKS had been previously diagnosed with complex-partial seizures, a clinical seizure disorder had been diagnosed for only 15 of the 50 ASD children. However, all the children in this study had been reported to occasionally demonstrate unusual behaviors (eg, rapid blinking, holding of the hands to the ears, unprovoked crying episodes, and/or brief staring spells) which, if exhibited by a normal child, might be interpreted as indicative of a subclinical epileptiform condition. MEG data were compared with simultaneously recorded electroencephalography (EEG) data, and with data from previous 1-hour and/or 24-hour clinical EEG, when available. Multiple-dipole, spatiotemporal modeling was used to identify sites of origin and propagation for epileptiform transients. RESULTS: The MEG of all children with LKS showed primary or secondary epileptiform involvement of the left intra/perisylvian region, with all but 1 child showing additional involvement of the right sylvian region. In all cases of LKS, independent epileptiform activity beyond the sylvian region was absent, although propagation of activity to frontal or parietal regions was seen occasionally. MEG identified epileptiform activity in 41 of the 50 (82%) children with ASDs. In contrast, simultaneous EEG revealed epileptiform activity in only 68%. When epileptiform activity was present in the ASDs, the same intra/perisylvian regions seen to be epileptiform in LKS were active in 85% of the cases. Whereas primary activity outside of the sylvian regions was not seen for any of the children with LKS, 75% of the ASD children with epileptiform activity demonstrated additional nonsylvian zones of independent epileptiform activity. Despite the multifocal nature of the epileptiform activity in the ASDs, neurosurgical intervention aimed at control has lead to a reduction of autistic features and improvement in language skills in 12 of 18 cases. CONCLUSIONS: This study demonstrates that there is a subset of children with ASDs who demonstrate clinically relevant epileptiform activity during slow-wave sleep, and that this activity may be present even in the absence of a clinical seizure disorder. MEG showed significantly greater sensitivity to this epileptiform activity than simultaneous EEG, 1-hour clinical EEG, and 24-hour clinical EEG. The multifocal epileptiform pattern identified by MEG in the ASDs typically includes the same perisylvian brain regions identified as abnormal in LKS. When epileptiform activity is present in the ASDs, therapeutic strategies (antiepileptic drugs, steroids, and even neurosurgery) aimed at its control can lead to a significa

Autistic Disorder↗
PubMed1996

Expansion and shrinkage of central nervous system tumor coinciding with human growth hormone therapy: case report.

OBJECTIVE AND IMPORTANCE: The influence of human growth hormone (hGH) therapy on the recurrence rates of childhood central nervous system tumors is controversial. Because growth hormone has the ability to increase cell proliferation, it is recommended that hGH therapy wait until central nervous system lesions are inactive and antitumor therapy complete, usually 1 to 2 years. CLINICAL PRESENTATION: We report the enlargement and decrease in size of a hypothalamic pilocytic astrocytoma in a 12-year-old boy after two trials of hGH. Partial resection and radiation of the tumor were performed at 3 years of age, with no change noted over the next 9 years. His height was less than the 5th centile with midparental height at the 90th to 95th centiles. Growth velocity was 3.3 cm/yr. Bone age was normal and there were no signs of puberty. There was no GH response to clonidine and L-dopa testing. INTERVENTION: Volume measurements were performed on gadolinium enhanced tumor images. Growth rate increased to 11.7 cm and the tumor volume increased 230% over the 12 months of hGH therapy. Significant tumor shrinkage (42%) and growth deceleration occurred within the 3 month interval of stopping hGH. Tumor volume again increased (134%) and decreased (22%) after restarting and then stopping hGH. No evidence of tumor necrosis or alteration in ventricular size was found. The patient was asymptomatic. CONCLUSION: These observations indicate that tumor size change is associated with the metabolic response to hGH therapy. It is unclear whether the volume increase represents altered blood-brain or selective blood-tumor barrier permeability, growth factor receptors, and/or tumor cell growth.

Astrocytoma↗
PubMed1994

Iron(II)/reductant(DH2)-induced activation of dioxygen for the hydroxylation and ketonization of hydrocarbons; mimics for the cytochrome P-450 hydroxylase/reductase system.

Several metal complexes [(FeII(DPAH)2 (DPAH2 = 2,6-dicarboxyl pyridine), FeII(PA)2 (PAH = picolinic acid), FeII(bpy)2(2+), FeII(OPPh3)4(2+), (Cl8TPP)FeIIIX (X = Cl, OH, SCH2Ph) [Cl8TPP = tetrakis (2,6-dichlorophenyl)porphyrin], (TPP) FeIIICl (TPP = tetraphenylporphyrin), and CuI(tpy)2+ (typ = 2,2'-6,2"-terpyridine)] in combination with one of several reductants [DH2; PhNHNHPh (mimic of dihydroflavin), PhNHNH2, ascorbic acid (H2asc), and PhCH2SH (model ligand for cysteine residue)] catalytically activate O2 (1 atm) for the hydroxylation of saturated hydrocarbons (e.g. c-C6H12-->c-C6H11OH). This chemistry closely parallels that of cytochrome P-450 proteins, and both appear to involve a Fenton-like reactive intermediate), [LxFeOOH(DH)]. With cyclohexane as the substrate the dominant product is its ketone (as well as significant amounts of its hydroperoxide). 1,4-Cyclohexadiene (with two double-allylic carbon centers) undergoes dehydrogenation to give benzene, but also yields substantial amounts of phenol via ketonization of an allylic carbon. The 1:1 FeII(bpy)2(2+)/(PhNHNH2 or H2asc), FeII(PA)2/H2asc, and (Cl8TPP)FeIIICl/PhNHNH2 combinations initiate the autoxidation of 1,4-cyclohexadiene with turnover numbers (moles of product per mole of reductant) from 71 to 26, respectively (alpha-tocophenol reduces the turnover numbers by 20-80%). With respect to aerobic biology, the present results indicate that dysfunctional transition metals (degradation products of metalloproteins) in combination with biological reductants activate O2 for reaction with organic substrates. The level of activation is similar to that for Fenton reagents and cytochrome P-450 hydroxylases. Hence, dysfunctional transition metals, reductants, and O2 are a hazardous combination within a biological matrix.

Cytochrome P-450 Enzyme System↗
PubMed1994

MR of the spine in Guillain-Barré syndrome.

MR examination of the spine after injection of gadopentetate dimeglumine showed enhancement of the cauda equina in a case of Guillain-Barré syndrome. These MR observations may help confirm the diagnosis of Guillain-Barré syndrome.

Cauda Equina↗
PubMed1981

Amrinone--a new inotropic agent in chronic resistant congestive cardiac failure.

A patient with severe cardiac failure due to idiopathic congestive cardiomyopathy resistant to conventional therapy, responded to amrinone, a new non-glycosidic non-catecholamine positive inotropic agent. Amrinone produced significant haemodynamic improvement during both intravenous and oral administration. Thrombocytopaenia, however, was induced, necessitating cessation of the drug. Amrinone is a promising, orally effective inotropic agent for patients with refractory congestive cardiac failure, but is limited to its tendency to cause thrombocytopaenia.

Administration, Oral↗