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Biomedical subjects

J H Chan

Publications and source records attributed to J H Chan.

At least 19 recordsLinked to original sources
PubMed2001

X-Ray crystal structures of Candida albicans dihydrofolate reductase: high resolution ternary complexes in which the dihydronicotinamide moiety of NADPH is displaced by an inhibitor.

X-ray crystallographic analysis of 5-(4'-substituted phenyl)sulfanyl-2,4-diaminoquinazoline inhibitors in ternary complex with Candida albicans dihydrofolate reductase (DHFR) and NADPH revealed two distinct modes of binding. The two compounds with small 4'-substituents (H and CH3) were found to bind with the phenyl group oriented in the plane of the quinazoline ring system and positioned adjacent to the C-helix. In contrast, the more selective inhibitors with larger 4'-substituents (tert-butyl and N-morpholino) were bound to the enzyme with the phenyl group perpendicular to the quinazoline ring and positioned in the region of the active site that typically binds the dihydronicotinamide moiety of NADPH. The cofactor appeared bound to DHFR but with the disordered dihydronicotinamide swung away from the protein surface and into solution. This unusual inhibitor binding mode may play an important role in the high DHFR selectivity of these compounds and also may provide new ideas for inhibitor design.

Candida albicans↗
PubMed2001

2-Amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1.

A series of 2-amino-5-arylthiobenzonitriles (1) was found to be active against HIV-1. Structural modifications led to the sulfoxides (2) and sulfones (3). The sulfoxides generally showed antiviral activity against HIV-1 similar to that of 1. The sulfones, however, were the most potent series of analogues, a number having activity against HIV-1 in the nanomolar range. Structural-activity relationship (SAR) studies suggested that a meta substituent, particularly a meta methyl substituent, invariably increased antiviral activities. However, optimal antiviral activities were manifested by compounds where both meta groups in the arylsulfonyl moiety were substituted and one of the substituents was a methyl group. Such a disubstitution led to compounds 3v, 3w, 3x, and 3y having IC50 values against HIV-1 in the low nanomolar range. When gauged for their broad-spectrum antiviral activity against key non-nucleoside reverse transcriptase inhibitor (NNRTI) related mutants, all the di-meta-substituted sulfones 3u-z and the 2-naphthyl analogue 3ee generally showed single-digit nanomolar activity against the V106A and P236L strains and submicromolar to low nanomolar activity against strains E138K, V108I, and Y188C. However, they showed a lack of activity against the K103N and Y181C mutant viruses. The elucidation of the X-ray crystal structure of the complex of 3v (739W94) in HIV-1 reverse transcriptase showed an overlap in the binding domain when compared with the complex of nevirapine in HIV-1 reverse transcriptase. The X-ray structure allowed for the rationalization of SAR data and potencies of the compounds against the mutants.

Anti-HIV Agents↗
PubMed2001

Artifacts in musculoskeletal magnetic resonance imaging: identification and correction.

A large number of artifacts occur in magnetic resonance (MR) imaging of the musculoskeletal system. These artifacts may potentially affect the quality of MR images, and may also simulate pathologic conditions and produce pitfalls in interpretation. Motion artifacts may be periodic or random. Protocol-error artifacts include saturation, wraparound, radiofrequency (RF) interference, shading, and partial volume averaging artifacts. Truncation artifacts occur when the number of phase-encoding steps of high spatial frequencies is insufficient (or under-sampled) for faithful reproduction of the true anatomic detail of the original image. Chemical shift artifacts are due to the protons in fat being mismapped relative to water protons. Susceptibility artifacts occur at the interfaces of structures with different magnetic susceptibilities. Artifacts special to the musculoskeletal system include the magnic angle phenomenon and spurious signal induced at very short echo times, both of which affect anisotropic structures such as tendon, ligament, and cartilage. Recognition and, if possible, correction of these artifacts are an important aspect of practical musculoskeletal MR imaging.

Artifacts↗
PubMed2001

Late temporal lobe necrosis in patients with nasopharyngeal carcinoma: evaluation with combined multi-section diffusion weighted and perfusion weighted MR imaging.

Late temporal lobe necrosis is a well-known and serious complication in patients with nasopharyngeal carcinoma (NPC) following radiotherapy. Owing to the close proximity to the skull base, the medial temporal lobes are inevitably included in the target volume of irradiation. Patients with NPC provide a unique opportunity in study of delay radiation effect in normal human brain. The objective of this study was to evaluate late temporal lobe radiation injury by combined multi-section diffusion weighted and perfusion weighted MR imaging. We prospectively studied 16 patients with typical clinical symptoms of late temporal lobe necrosis or other abnormalities in the temporal lobes incidentally detected by conventional MR imaging. All patients had a previous history of radiotherapy for histologically proven NPC. Conventional T1- and T2-weighted images, fast gradient echo with echo-planar diffusion-weighted and perfusion-weighted MR imaging were performed. Apparent diffusion coefficient (ADC) map and relative cerebral blood volume (rCBV) map were computed via commercially available software. MR diffusion and perfusion images were then analyzed and graded by two independent observers with focusing on the diffusion and perfusion mismatch. The temporal lobe lesions displayed marked high diffusion on the ADC map. The rCBV map also revealed marked hypoperfusion in these temporal lobe lesions in all patients. The areas of abnormality on the rCBV map were significantly larger than the lesions on the ADC map in 14 patients (observer 1) and 13 patients (observer 2). Since late temporal lobe necrosis is probably caused by damage of the endothelium of vessels and ischemia, perfusion and diffusion mismatch might imply injured tissue but potentially salvageable brain tissue. A mismatch may be potentially used to predict the response to treatment in-patients with late temporal lobe necrosis.

Adult↗
PubMed2001

Galpha(14) links a variety of G(i)- and G(s)-coupled receptors to the stimulation of phospholipase C.

1. The bovine Galpha(14) is a member of the G(q) subfamily of G proteins that can regulate phospholipase Cbeta isoforms but the extent to which Galpha(14) recognizes different receptor classes is not known. 2. Galpha(14) was cotransfected with a variety of receptors in COS-7 cells, and agonist-induced stimulation of phospholipase C was then measured. 3. Activation of the type 2 but not type 1 somatostatin receptor in cells coexpressing Galpha(14) stimulated the accumulation of inositol phosphates; functional expression of both subtypes of somatostatin receptors was determined by the ability of somatostatin to inhibit cyclic AMP accumulation. 4. Among the three opioid receptors (mu, delta, and kappa), only the delta receptor was capable of stimulating IP formation when coexpressed with Galpha(14) in COS-7 cells. 5. A panel of G(i)- and G(s)-linked receptors was screened for their ability to stimulate IP accumulation via Galpha(14). The adenosine A(1), complement C5a, dopamine D(1), D(2) and D(5), formyl peptide, luteinizing hormone, secretin, and the three subtypes of melatonin (mt1, MT2, and Xenopus) receptors were all incapable of activating Galpha(14), while the alpha(2)- and beta(2)-adrenoceptors were able to do so. 6. Galpha(14)-mediated stimulation of phospholipase Cbeta was agonist dose-dependent. These data demonstrate that although Galpha(14) can interact with different classes of receptors, it is much less promiscuous than Galpha(15) or Galpha(16).

Animals↗
PubMed2001

Effect of ABO blood group mismatching on corneal epithelial cells: an in vitro study.

AIM: To determine, in vitro, the effects of blood group ABO mismatching on corneal epithelial cells. METHODS: Corneal epithelial cell cultures were established from 32 human cadaver donor eyes. Epithelial cells (100 microl of 4 x 10(2) cells per microl) were incubated for 4 hours with antibodies against blood group antigens A, B, and AB, with and without complement. Cell lysis was assayed by a chemiluminescent assay using Cytolite reagent. Live cells, remaining after incubation, were counted in a scintillation counter. The blood group of the donors was determined retrospectively, in a blinded manner. RESULTS: Retrospective tracing of donor blood groups was possible for 20 donors. In all cases the blood group corresponded with that suggested by the cell lysis assay. Significant cell lysis was observed when known A group cells were incubated with anti-A and anti-AB antibody, B group cells were incubated with anti-B and AB antibody, and AB group cells were incubated with anti-AB antibody. Lysis occurred only in the presence of complement. No lysis of O group cells was observed with any of the antibodies. In all cases, lysis was observed only with neat (serum) antibody concentrations. CONCLUSIONS: Blood group ABO mismatching results in significant lysis of corneal epithelial cells. The antibody concentration required for lysis equals that found in serum. Such levels of antibody are unlikely to be achieved in tears and/or aqueous. This may offer an explanation for the conflicting reports of the studies on the effect of blood group matching on corneal grafts. The variability in the outcome may reflect the levels of antibodies gaining access to the corneal cells and not the mismatching alone.

ABO Blood-Group System↗
PubMed2000

Cognitive function of patients with nasopharyngeal carcinoma with and without temporal lobe radionecrosis.

BACKGROUND: Radiotherapy is the primary treatment for nasopharyngeal carcinoma, and temporal lobe necrosis is observed in about 7% of patients after radiotherapy. Although some studies reported that these patients demonstrated cognitive impairment after radiotherapy, it is still unclear if the cognitive deficits are related to the radiation exposure or the radiation-induced necrosis. OBJECTIVE: To compare the cognitive function of patients with and without temporal lobe necrosis after radiotherapy for nasopharyngeal carcinoma. METHODS: A comprehensive neuropsychological battery was administered to 53 patients with nasopharyngeal carcinoma who had completed their radiotherapy at least 1 year previously. As evidenced by magnetic resonance imaging, 31 patients developed necrosis after treatment. Thirty-one age- and education-matched individuals were recruited as normal control subjects. RESULTS: Whereas the performance of patients without temporal lobe necrosis was similar to that of normal control subjects, patients with temporal lobe necrosis demonstrated significant impairment on tests of verbal (P<.001) and visual memory (range, P<.001 to P =.03), language (range, P<.001 to P =.01), motor ability (P =.02), planning (P =.02), cognitive ability (P =.007), and abstract thinking (range, P =.009 to P =.04). However, the performance of patients with necrosis on tests of general intelligence (range, P =.08 to P =.15), attention (range, P =.06 to P =.55), and visual abilities (range, P =.06 to P =.47) was not significantly different from that of normal control subjects and patients without necrosis. CONCLUSIONS: Radiotherapy for nasopharyngeal carcinoma seemed to have adverse but insignificant effects on the cognitive functions of the patients. However, for patients who developed temporal lobe necrosis after radiotherapy, memory, language, motor ability, and executive functions were significantly impaired, although their general intelligence remained relatively intact.

Cognition Disorders↗
PubMed2000

Radionecrosis of the temporal lobe: dynamic susceptibility contrast MRI.

We examined nine patients with histologically proven nasopharyngeal carcinoma (NPC), treated with radiotherapy, using dynamic susceptibility contrast MRI (DSC-MRI). In eight there was clinical evidence of radionecrosis of the temporal lobe, and one was examined for local recurrence in the nasopharynx. All patients had either high-signal finger-like or cystic lesions in the temporal lobes on T2-weighted images. Heterogeneous contrast enhancement occurred in all patients. Relative regional cerebral blood volume (rrCBV) mapping revealed marked hypoperfusion in all patients. One underwent bilateral temporal lobectomy and radionecrosis was confirmed histologically.

Adult↗
PubMed2000

Rapid spontaneous resolution and redistribution of acute subdural hematoma in a patient with chronic alcoholism: a case report.

We report a case of a 54-year-old man who had documented traumatic acute subdural hematoma. He suffered from a transient episode of confusion and a follow-up CT scan of brain 6 h after the initial scan showed resolution and redistribution of the subdural hematoma. In this case report, we review the literature for the underlying pathophysiology of this uncommon phenomenon.

Accidental Falls↗
PubMed1999

Microfabricated polymer devices for automated sample delivery of peptides for analysis by electrospray ionization tandem mass spectrometry.

Delivery of proteins and peptides to electrospray ionization mass spectrometers (ESI-MS) has been demonstrated using glass and quartz microfabricated devices. This paper reports the construction and use of poly(dimethylsiloxane) (PDMS) microfabricated soft polymer devices with mass spectrometry for protein analysis. The PDMS devices were fabricated using replica molding against a patterned photoresist generated by photolithographic techniques. The PDMS devices were connected to the mass spectrometer via a derivatized transfer capillary and samples were transferred by electroosmotic pumping. The formulation of PDMS was optimized for compatibility with ESI, and the devices were tested for performance. The practical application of PDMS devices was demonstrated by the identification of rat serum albumin separated by 2-D gel electrophoresis. Extended contact of the sample with the surface of the PDMS device did not significantly affect the sample analysis, and the limit of detection for samples run on a PDMS device was comparable to the limit of detection achieved on glass devices. This study suggests that PDMS devices fabricated using replica molding are compatible with ESI-MS. This will potentially lead to the construction of inexpensive microfabricated devices with complex designs and advanced functionalities.

Amino Acid Sequence↗
PubMed1999

Determining the lumbar vertebral segments on magnetic resonance imaging.

STUDY DESIGN: A study to test the ability of an additional cervicothoracic localizer scan to decrease interobserver discrepancy in the identification of vertebral segments in magnetic resonance imaging of the lumbar spine. OBJECTIVES: To investigate whether lumbar vertebral segments can be identified correctly from lumbosacral magnetic resonance localizer scans, the degree of interobserver discrepancy, and the value of an additional cervicothoracic localizer scan. SUMMARY OF BACKGROUND DATA: In magnetic resonance imaging of the lumbar spine, it may be difficult to identify transitional lumbosacral vertebral segments. METHODS: The sagittal and coronal lumbosacral localizer scans of 141 consecutive patients referred for magnetic resonance imaging of the lumbosacral spine were reviewed independently by two radiologists with the aim of locating the L5 vertebra. An additional sagittal cervicothoracic localizer scan also was performed in each case. The final study group consisted of 129 patients. The L5 vertebra was identified by counting caudally from C2 using the sagittal cervicothoracic and lumbosacral localizer scans. In the 54 most recently studied patients, cod liver oil capsule surface markers were placed near the thoracolumbar junction to quantify any marker shift between the two sagittal localizer scans. RESULTS: The lumbar segments could be identified consistently by counting caudally using cervicothoracic and lumbosacral localizer scans. Using sagittal lumbosacral localizer scans alone, the lumbar vertebral segments could be identified correctly in only 80.2% of patients. Coronal lumbosacral localizer scans produced similar results (82.2%). The accuracy fell to 77.9% when using a combination of both sagittal and coronal lumbosacral localizer scans. There was a 11.6% interobserver discordance in assessment of these levels. Lumbosacral transitional vertebrae were identified in 17 patients (13.2%), including 8 sacralized L5 and 9 lumbarized S1 vertebrae. Apparent surface-marker shift between cervicothoracic and lumbosacral localizer scans was insignificant, averaging only 1.9 mm (range, 0.0-5.6 mm). CONCLUSIONS: The addition of a cervicothoracic localizer scan in magnetic resonance imaging of the lumbosacral spine is highly recommended.

Humans↗
PubMed1999

Breath-hold 3D gadolinium-enhanced subtraction MRA in the detection of transplant renal artery stenosis.

AIMS: The purpose of this study was to assess the value of breath-hold 3D gadolinium-enhanced subtraction magnetic resonance angiography (GD-MRA) in the detection of transplant renal artery stenosis (TRAS). PATIENTS AND METHODS: Seven patients with suspected post-transplant renal artery stenosis were studied. GD-MRA was performed at 1.5T with a 3D fast spoiled gradient recalled echo (FSPGR) pulse sequence. Before injection of contrast medium, the 3D pulse sequence was performed to obtain a set of non-contrast images for subtraction purposes. Dynamic 3D imaging was performed simultaneously with the bolus injection of 40 ml of gadopentetate dimeglumine. Angiographic images were reconstructed using the Advantage Window workstation (version 2.0 GE Medical Systems) and subtraction was made with the pre-contrast image data. Any signal intensity cut-off or narrowing of more than 50% was regarded as significant stenosis. Ultrasound Doppler (USD) study was performed with both colour and spectral studies. Peak systolic velocity (PSV) of greater than 2.0 m/s and acceleration time (AT) greater than 120ms was regarded as positive for TRAS. These were then compared with the digital subtraction angiography (DSA) as the gold standard. RESULTS: A total of nine examinations performed in seven patients were included in the analysis. MRA correlated with the DSA findings in eight examinations, with one false negative. USG correlated with DSA in six examinations, with two false negative and one false positive case. CONCLUSION: In our opinion, GD-MRA is a promising and non-invasive technique in the detection of TRAS.

Adult↗
PubMed1999

The effect of using shorter echo times in MR imaging of knee menisci: a study using a porcine model.

OBJECTIVE: Increasingly shorter TEs are being used for T1-weighted and proton density-weighted sequences in MR imaging of the knee. This study aims to evaluate the effect of a short TE on meniscal signal intensity. MATERIALS AND METHODS: Thirty porcine knees were imaged with a 1.5-T MR scanner using spin-echo T1-weighted and proton density-weighted sequences. TR was kept constant at 700 msec for T1-weighted and 2200 msec for proton density-weighted sequences. For each set of sequences, sagittal images were obtained using these TE values: 9, 12, 16, 20, and 25 msec. Imaging parameters, such as slice thickness and interslice gap, number of excitations, matrix size, and field of view, were identical for each set of sequences. Using a fixed window level and width, we assessed the anterior and posterior horns of the medial meniscus for signal hyperintensity at each TE value. Signal intensity was also measured in eight knees. The menisci were then dissected and examined grossly and histopathologically. RESULTS: Intrameniscal signal intensity increased progressively with shorter TEs. At a TE of 9 msec, signal hyperintensity was present in 100% of T1-weighted and 96.7% of proton density-weighted images. At a TE of 12 msec, signal hyperintensity was seen in 86.7% of T1-weighted and 80% of proton density-weighted images. At a TE of 16 msec, increased signal intensity was seen in only 3.3% of T1-weighted and 6.6% of proton density-weighted images. At TEs of 20 and 25 msec, increased signal intensity was seen in none of the T1-weighted and proton density-weighted images. Meniscal signal intensity increased exponentially at very short TE values. All menisci were found to be normal on gross and histopathological examination. CONCLUSION: Spurious signal hyperintensity appears in normal menisci at short TE values. Images acquired with short TEs should be interpreted with caution, and a TE of 16 msec or more is recommended.

Animals↗