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Biomedical subjects

M Lee

Publications and source records attributed to M Lee.

At least 55 records · Page 3Linked to original sources
PubMed2005

A randomised controlled trial of oral zinc on the immune response to tuberculosis in HIV-infected patients.

SETTING: The National HIV Unit, Singapore. OBJECTIVE: To test whether zinc supplementation improves the immune response to tuberculosis in HIV-positive patients. DESIGN: A double-blind, randomised, placebo-controlled trial of 28 days of oral zinc sulphate (50 mg of elemental zinc) or placebo in stable adult HIV-positive patients receiving antiretroviral therapy with a CD4 count <200 cells/microl. METHODS: IFN-gamma response to mycobacterial antigen stimulation, CD4/8 cell count, lymphocyte subsets, T-cell receptor excision circle (TREC) levels and viral load were measured at baseline and day 28. RESULTS: Thirty-two patients received zinc and 34 placebo. There was no significant change in the IFN-gamma response to human PPD stimulation in the zinc or placebo groups (placebo baseline: 0.42 +/- 1.03, day 28: 0.84 +/- 1.21 IU/ml, zinc baseline: 1.26 +/- 2.41, day 28: 1.39 +/- 1.88 IU/ml, P = 0.31 between groups), nor any of the other mycobacterial antigens tested. There were no changes in absolute CD4/8 cell levels or other lymphocyte subsets, TREC or viral load. Baseline zinc levels were normal in 62/66 (93.9%) patients. CONCLUSIONS: We found no evidence for recommending pharmacological supplementation with oral zinc in HIV-positive patients without zinc deficiency.

Administration, Oral↗
PubMed2004

The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine.

RATIONALE: Clozapine is a unique antipsychotic, with efficacy against positive symptoms in treatment-resistant schizophrenic patients, and the ability to improve cognition and treat the negative symptoms characteristic of this disease. Despite its unique clinical actions, no specific molecular mechanism responsible for these actions has yet been described. OBJECTIVES AND METHODS: To comprehensively profile a large library of neuropsychiatric drugs, including most antipsychotics, at human monoamine receptors using R-SAT, an in vitro functional assay. RESULTS: Profiling revealed that N-desmethylclozapine (NDMC), the principal metabolite of clozapine, but not clozapine itself, is a potent and efficacious muscarinic receptor agonist, a molecular property not shared by any other antipsychotic. To further explore the role of NDMC muscarinic receptor agonist properties in mediating the physiological actions of clozapine, systemically administered NDMC was found to stimulate the phosphorylation of mitogen-activated protein kinase (MAP kinase) in mouse CA1 hippocampal neurons, an effect that was blocked by scopolamine, confirming central M1 muscarinic receptor agonist activity in vivo. Lastly, an analysis of clozapine and NDMC serum levels in schizophrenic patients indicated that high NDMC/clozapine ratios better predicted improvement in cognitive functioning and quality of life than the levels of either compound alone. CONCLUSIONS: The muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.

Animals↗
PubMed2004

High resolution study of magnetic ordering at absolute zero.

High resolution pressure measurements in the zero-temperature limit provide a unique opportunity to study the behavior of strongly interacting, itinerant electrons with coupled spin and charge degrees of freedom. Approaching the precision that has become the hallmark of experiments on classical critical phenomena, we characterize the quantum critical behavior of the model, elemental antiferromagnet chromium, lightly doped with vanadium. We resolve the sharp doubling of the Hall coefficient at the quantum critical point and trace the dominating effects of quantum fluctuations up to surprisingly high temperatures.

Journal Article↗
PubMed2004

Molecular analysis of nicotinic receptor expression in autism.

Autism is a developmental disorder of unknown aetiopathology and lacking any specific pharmacological therapeutic intervention. Neurotransmitters such as serotonin, gamma-aminobutyric acid (GABA) and acetylcholine have been implicated. Abnormalities in nicotinic acetylcholine receptors have been identified including cortical loss of binding to the alpha4/beta2 subtype and increase in cerebellar alpha7 binding. Receptor expression (mRNA) has not so far been systematically examined. This study aims to further explore the role of nicotinic receptors in autism by analysing nicotinic receptor subunit mRNA in conjunction with protein levels and receptor binding in different brain areas. Quantitative RT-PCR for alpha4, alpha7 and beta2 subunit mRNA expression levels; alpha3, alpha4, alpha7 and beta2 subunit protein expression immunochemistry and specific radioligand receptor binding were performed in adult autism and control brain samples from cerebral cortex and cerebellum. Alpha4 and beta2 protein expression and receptor binding density as well as alpha4 mRNA levels were lower in parietal cortex in autism, while alpha7 did not change for any of these parameters. In cerebellum, alpha4 mRNA expression was increased, whereas subunit protein and receptor levels were decreased. Alpha7 receptor binding in cerebellum was increased alongside non-significant elevations in mRNA and protein expression levels. No significant changes were found for beta2 in cerebellum. The data obtained, using complementary measures of receptor expression, indicate that reduced gene expression of the alpha4beta2 nicotinic receptor in the cerebral cortex is a major feature of the neurochemical pathology of autism, whilst post-transcriptional abnormalities of both this and the alpha7 subtype are apparent in the cerebellum. The findings point to dendritic and/or synaptic nicotinic receptor abnormalities that may relate to disruptions in cerebral circuitry development.

Acetylcholine↗
PubMed2004

Aerobic production of alanine by Escherichia coli aceF ldhA mutants expressing the Bacillus sphaericus alaD gene.

Alanine was produced from glucose in an Escherichia coli aceF ldhA double mutant strain that contained the pTrc99A- alaD plasmid expressing Bacillus sphaericus alanine dehydrogenase. The aceF gene encodes one of the proteins of the pyruvate dehydrogenase complex, and therefore this strain required acetate as an additional carbon source. The ldhA gene encodes fermentative lactate dehydrogenase, a competitor of alanine dehydrogenase for the substrate pyruvate. Fermentations included an oxygenated growth phase followed by an oxygen-limited alanine production phase. The lowest value for the mass transfer coefficient ( k(L)a) studied during the production phase yielded the greatest alanine. With feeding of glucose and NH(4)Cl, 32 g/l alanine accumulated in 27 h with a yield of 0.63 g alanine generated per gram glucose consumed.

Aerobiosis↗
PubMed2004

Induction of neuropeptide gene expression and blockade of retrograde transport in facial motor neurons following local peripheral nerve inflammation in severe combined immunodeficiency and BALB/C mice.

Peripheral nerve inflammation is a common clinical problem that accompanies nerve injury and several diseases including Guillain-Barre syndrome and acute and chronic inflammatory demyelinating polyneuropathy. To determine if neuropeptides are induced in motor neurons after inflammation and to study the mechanisms involved, a nerve cuff soaked in complete Freund's adjuvant (CFA) was applied locally to the facial nerve of Balb/C mice. This procedure resulted in an influx of lymphocytes and macrophages to the affected area and a blockade of retrograde axonal transport distal, but not proximal, to the site of application. The same treatment resulted in a strong ipsilateral induction of pituitary adenylyl cyclase activating peptide (PACAP) gene expression in motor neurons in the facial motor nucleus. Because the changes could have occurred due to the loss of target-derived factors or to the production of new factors by immune cells, we studied the effect of the inflammatory stimulus on PACAP mRNA in mice with severe combined immunodeficiency (SCID). As expected, SCID mice showed a severely reduced influx of T-lymphocytes but not macrophages to the peripheral nerve. Moreover, although retrograde transport distal to the inflammation site was blocked similarly in control and SCID mice, the number of motor neurons expressing PACAP mRNA after CFA application was significantly reduced in SCID mice. The data indicate that the induction of PACAP mRNA during nerve inflammation requires the involvement of lymphocytes. However, because the induction of PACAP gene expression was only partially blocked in SCID mice, macrophages, loss of target-derived factors, or other mechanisms may also contribute to the upregulation of PACAP gene expression in motor neurons after nerve inflammation.

Animals↗
PubMed2004

Renal impairment and diabetes mellitus after liver transplant.

INTRODUCTION: One of the major concerns in liver transplant patients who survive past 1 year posttransplant is the development of chronic diseases. AIM: We studied two important clinical conditions that can have a chronic course-renal impairment and diabetes mellitus-among long-term liver transplant survivors. METHODS: All adult patients transplanted and followed for at least 1 year were evaluated for clinical status, blood tests, and imaging studies. The occurrence and development of renal impairment, defined as a serum creatinine above 125 micromol/L or creatinine clearance less than 75 mL/min, or diabetes mellitus were evaluated for contributing factors. RESULTS: The 35 evaluated patients of mean age at transplant of 50 years had a mean follow-up duration of 45 months. The incidence of posttransplant renal impairment was 22.8% at 1 year and 47.6% at 3 years. This disorder was associated with pretransplant renal impairment and with a diagnosis of diabetes. Posttransplant diabetes mellitus was observed in 48.6% with 41.1% resolving over time. CONCLUSION: Posttransplant renal impairment appears to be a potential long-term problem. Although this relates to pretransplant conditions, longer follow-up is required to examine whether posttransplant factors contribute to its progression.

Adolescent↗
PubMed2004

Functional neurosurgery in the MRI environment.

OBJECTIVE: The purpose of this study was to evaluate the feasibility of microelectrode recording, electrical stimulation, and electrode position checking during functional neurosurgical procedures (DBS, lesion) in the interventional magnetic resonance imaging (iMRI) environment. METHODS: Seventy-six surgical procedures for DBS implant or radiofrequency lesion were performed in an open 0.2 T MRI operating room. DBS implants were performed in 54 patients (72 surgical procedures) and unilateral radiofrequency lesions in three for a total of 76 surgeries in 57 patients. Electrophysiological studies including macrostimulation and microelectrode recordings for localization were obtained in the 0.5 to 10 mT fringes of the magnetic field in 51 surgeries. MRI confirmation of the electrode position during the procedure was performed after electrophysiological localization. RESULTS: The magnetic field associated with the MRI scanner did not contribute significant noise to microelectrode recordings. Anatomical confirmation of electrode position was possible within the MRI artifact from the DBS hardware. Symptomatic hemorrhage was detected in two (2.6 %) patients during the operation. Image quality of the 0.2 T MRI scan was sub-optimal for anatomical localization. However, image fusion with pre-operative scans permitted excellent visualization of the DBS electrode tip in relation to the higher quality 1.5 T MRI anatomical scans. CONCLUSION: This study shows that conventional stereotactic localization, microelectrode recordings, electrical stimulation, implant of DBS hardware, and radiofrequency lesion placement are possible in the open 0.2 T iMRI environment. The convenience of having an imaging modality that can visualize the brain during the operation is ideal for stereotactic procedures.

Adolescent↗
PubMed2004

Expression and function of peroxisome proliferator-activated receptors in human melanocytes.

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) belong to the superfamily of nuclear receptors that heterodimerize with the retinoic X receptor. Agonists of PPAR have been known to play an important role in cellular responses including proliferation and differentiation. The expression and function of PPARs have not been investigated in human melanocytes, although they have been widely demonstrated in keratinocytes of the skin. OBJECTIVES: To investigate the expression of PPARs in human melanocytes and the effects of PPAR activators on melanocyte growth and melanogenesis. METHODS: We used immunocytochemistry and Western blot analysis to determine whether PPARs are expressed in melanocytes. To investigate further expression of PPAR subtypes, reverse transcriptase-polymerase chain reaction analysis was performed using PPAR subtype-specific oligonucleotides. The cell proliferation was measured using the Coulter counter. The effects on pigmentation were investigated with measurement of melanin contents, tyrosinase activity and its expression. RESULTS: The mRNA of all three PPAR subtypes, PPAR-alpha, PPAR-beta/delta and PPAR-gamma, were expressed in melanocytes. Activators for PPAR-alpha (WY-14643) and PPAR-gamma (ciglitazone) inhibited proliferation of melanocytes in a dose-dependent manner, whereas bezafibrate, a preferential activator for PPAR-beta/delta, had no effect. This growth inhibition was accompanied by the morphological change of the melanocytes to an activated form with an increased number of dendrites and enlarged cell area compared with the control. The WY-14643 and ciglitazone also appeared to stimulate the melanin synthesis of melanocytes. This increase in pigmentation was due to stimulation of the tyrosinase activity without an increase in the expression of tyrosinase. CONCLUSIONS: PPARs are expressed in human melanocytes and PPAR-alpha and PPAR-gamma activators inhibit melanocyte growth and stimulate melanogenesis.

Blotting, Western↗
PubMed2004

MAO-B knockout mice exhibit deficient habituation of locomotor activity but normal nicotine intake.

Low levels of monoamine oxidase-B (MAO-B) activity, such as those observed in smokers, are also associated with behavioral traits such as a heightened responsiveness to novelty. However, the exact mechanism by which low MAO-B activity influences smoking and heightened responsiveness to novelty is still poorly understood. We used MAO-B knockout (KO) mice to test the hypothesis that MAO-B concomitantly affects locomotor responses in a novel inescapable open field and nicotine intake. Male wild-type (WT) and MAO-B KO mice were placed in an inescapable open field and their horizontal locomotor activity was measured for 30 min per day for 5 days. MAO-B KO mice exhibited impaired within-session habituation of locomotor activity, as compared to WT mice. Separate groups of male WT and MAO-B KO mice were individually housed in their home cages with two water bottles. One of the bottles contained tap water and the other contained nicotine (0, 3.125, 6.25, 12.5, 25, 50 or 100 micro g/ml). The total amount of water and nicotine solution consumed was measured every three days for 16 days. MAO-B KO mice and WT mice consumed equal amounts of nicotine and exhibited comparable concentration-dependent nicotine preference and aversion over a period of 16 days. The data suggest that the absence of MAO-B impairs the ability of mice to habituate in the inescapable environment, but does not alter their nicotine intake.

Administration, Oral↗
PubMed2004

The Seoul Metropolitan Preschool Vision Screening Programme: results from South Korea.

AIM: To report on a new model of preschool vision screening that was performed in metropolitan Seoul and to investigate the distribution of various ocular disorders in this metropolitan preschool population. METHODS: Vision screening was conducted on 36 973 kindergarten children aged 3-5 years in a stepwise manner. The first step was home screening using a set of five picture cards and a questionnaire. The children who did not pass the first step (VA <0.5 in at least one eye or any abnormal responses on the questionnaire) were retested with regular vision charts at the regional public healthcare centres. After this retest, some children were referred to ophthalmologists. The referral criteria for visual acuity were <0.5 at 3 years and <0.63 at 4 or 5 years in at least one eye. RESULTS: Of those screened, 7116 (19.2%) children did not pass the home screening tests and 2058 (28.9%) out of the 7116 were referred. The results of the ophthalmological examination in eye clinics were only available for 894 children (43.4%) of those who were referred. The rest of the children did not visit ophthalmologists because they had been checked at an eye clinic, were currently under treatment, or for personal reasons. Refractive errors were found in 608 (1.6%) children. Astigmatism was associated in 78.2% of ametropes. Amblyopia was discovered in 149 (0.4%) children and refractive error was the major aetiology with a predominant rate (82.5%). Manifest strabismus was detected in 52 children. The positive predictive value of vision screening for any ophthalmological disorder was 0.77, and 0.49 for significant disorders requiring treatment. CONCLUSIONS: This preschool vision screening model was highly accessible to the children and their parents, easy to administer, and effective to detect a variety of ocular disorders. However, the participation rate of the referred children in the examinations by ophthalmologists was quite low. The performance and efficiency of this screening programme need to be optimised with further revision.

Amblyopia↗
PubMed2004

Screening for lung cancer using low dose CT scanning.

BACKGROUND: Lung cancer is the most common cause of cancer related death in Ireland. The majority of lung cancers are inoperable at the time of diagnosis and consequently the overall 5 year survival is less than 10%. The objective of the ProActive Lung Cancer Detection (PALCAD) study was to evaluate whether low dose chest computed tomographic scanning (LDCCT) can detect early stage asymptomatic lung cancer in a high risk urban population. METHODS: Four hundred and forty nine subjects of median age 55 years (range 50-74) with a median pack year smoking history of 45 years (range 10-160), with no previous cancer history and medically fit to undergo thoracic surgery were recruited. After informed consent, LDCCT was performed on all subjects. Non-calcified nodules (NCNs) of >/=10 mm in diameter were referred for biopsy. Follow up with interval LDCCT at 6, 12 and 24 months to exclude growth was recommended for NCNs <10 mm in diameter. RESULTS: Six (1.3%) NCNs of >/=10 mm were detected of which one (0.23%) had non-small cell lung cancer stage 1; 145 NCNs of <10 mm were detected in 87 (19.4%) subjects. Mediastinal masses were detected in three subjects (0.7%)-one small cell lung cancer and two benign duplication cysts. Incidental pathology was noted in 276 patients (61.5%), most commonly emphysema and coronary artery calcification. CONCLUSION: The prevalence of resectable lung cancer detected by LDCCT at baseline screening was low at 0.23%, but there was a high rate of significant incidental pathology.

Aged↗
PubMed2003

Genetic mapping and analysis of quantitative trait loci affecting fiber and lignin content in maize.

Plant cell walls of forage provide a major source of energy for ruminant animals. Digestion of cell walls is limited by the presence of lignin, therefore the improving the digestibility of forages by reducing lignin content is a major goal in forage crop breeding programs. A recombinant inbred line maize population was used to map quantitative trait loci (QTL) for neutral detergent fiber (NDF), acid detergent fiber (ADF), and acid detergent lignin (ADL) of leaf-sheath and stalk tissues. All traits were positively genetically correlated. The larger genetic correlations were between NDF and ADF in sheaths (r = 0.84), NDF and ADF (r = 0.96), ADF and ADL (r = 0.83), and NDF and ADL (r = 0.76) in stalks. Twelve QTL were detected for NDF and 11 QTL for ADF in leaf-sheaths. Eight QTL detected for both traits were defined by the same or linked marker loci. Eight QTL were associated with leaf-sheath ADL. Eleven QTL were detected for NDF and ADF, and 12 QTL for ADL in stalks. Nine of eleven QTL detected for both NDF and ADF in stalks coincided in their genomic position. A high proportion of QTL detected for these traits had the same parental effects and genomic locations, suggesting that it is only necessary to select on one fiber component (NDF or ADF) to improve digestibility. Favorable correlated responses of unselected fiber components are expected due to coincident genomic locations of QTL and the high genetic correlation between fiber components. Several QTL detected in this study coincided in their positions with putative cellulose synthase genes from maize.

Cell Wall↗
PubMed2003

Systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease: analysis of clinicopathologic features and activating c-kit mutations.

The majority of patients with systemic mastocytosis with associated clonal, hematological non-mast cell lineage disease (SM-AHNMD) have a myeloid stem cell malignancy including myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative disorders, acute myeloid leukemia (AML), or chronic myeloproliferative disease. The clinicopathologic features of SM-AHNMD have not been fully characterized. We describe seven cases of this entity: 3 with MDS, 3 with AML, and 1 with chronic myelomonocytic leukemia. In the majority of cases, SM was diagnosed concurrently with the myeloid malignancy and aberrant mast cell morphology was observed. The commonly described c-kit enzymatic site mutation Asp816Val was detected only in 2 cases, while 3 patients carried the Asp816His mutation. Among the 3 cases with AML, 2 patients carried the translocation t(8;21). On the basis of our results and other reported cases, there appears to be a specific association between SM and AML with t(8;21). Concurrent occurrence of SM may define a subset of patients with de novo AML and other myeloid malignancies who have an adverse prognosis. As clinically effective tyrosine kinase inhibitors that inhibit enzymatic-type c-kit mutations are being developed, detection of mast cell proliferation associated with myeloid malignancy may have important therapeutic implications.

Adult↗
PubMed2003

Profiling genes expressed in human fetal cartilage using 13,155 expressed sequence tags.

OBJECTIVE: To analyze the gene expression profile of human fetal cartilage by expressed sequence tags (ESTs). METHODS: A human fetal cartilage (8-12 weeks) cDNA library was constructed using the lambda ZAP Express vector. ESTs were obtained by partial sequencing of cDNA clones. The basic local alignment search tool algorithm was used to compare all generated ESTs to known sequences. RESULTS: A total of 13,155 ESTs were analyzed, of which 8696 ESTs (66.1%) matched known genes, 53 ESTs (0.4%) were putatively novel (with no match) and the rest matched other ESTs, genomic DNA and repetitive sequences. Importantly, we identified 2448 unique known genes through non-redundancy analysis of the known gene matches, which were then functionally categorized. The tissue specificity of this library was reflected by its EST profile of the extracellular matrix (ECM) proteins. Collagens were the major transcripts, representing 68.5% of the ECM proteins. Proteoglycans were the second most abundant, constituting 9.5%. Collagen type II was the most abundant gene of all. Glypican 3, decorin and aggrecan were the major transcripts of proteoglycans. Many genes involved in cartilage development were identified, such as insulin-like growth factor-II, its receptor and binding proteins, connective tissue growth factor and fibroblast growth factors. Proteases and their regulatory factors were also identified, including matrix metalloprotease 2 and tissue inhibitor of metalloproteinase 1. CONCLUSIONS: The EST approach is an effective way of characterizing the genes expressed in cartilage. These data represent the most extensive molecular information on human fetal cartilage to date. The availability of this information will serve as a basis for further research to identify genes that are essential in cartilage development.

Cartilage, Articular↗
PubMed2003

Water-soluble lipopolymer as an efficient carrier for gene delivery to myocardium.

Water-soluble lipopolymer (WSLP), which consisted of polyethylenimine (PEI, 1800 Da) and cholesterol, was characterized as a gene carrier to smooth muscle cells and myocardium. Acid-base titration showed that WSLP had a proton-buffering effect. The size of WSLP/plasmid DNA (pDNA) complex was around 70 nm. WSLP/pDNA complex was transfected to A7R5 cells, a smooth muscle cell line. WSLP showed the highest transfection at a 40/1 N/P ratio. WSLP has higher transfection efficiency than PEI (1800 and 25 000 Da), SuperFect, and lipofectamine. In addition, WSLP has less cytotoxicity than PEI (25 000 Da), SuperFect, and lipofectamine. Since WSLP has cholesterol moiety, it may utilize cellular cholesterol uptake pathway, in which low-density lipoprotein (LDL) is involved. An inhibition study with free cholesterol or low-density lipoprotein (LDL) showed that transfection was inhibited by cholesterol or LDL, suggesting that WSLP/pDNA complex is transfected to the cells through the cholesterol uptake pathway. To evaluate the transfection efficiency to myocardium, WSLP/pDNA complex was injected into the rabbit myocardium. WSLP showed higher transfection than PEI and naked pDNA. WSLP expressed the transgene for more than 2 weeks. In conclusion, WSLP is an efficient carrier for local gene transfection to myocardium, and useful in in vivo gene therapy.

Animals↗
PubMed2003

Hypoxia-inducible VEGF gene delivery to ischemic myocardium using water-soluble lipopolymer.

Therapeutic angiogenesis with gene encoding vascular endothelial growth factor (VEGF) is a new potential treatment in cardiovascular disease. However, unregulated VEGF-mediated angiogenesis has the potential to promote tumor growth, accelerate diabetic proliferative retinopathy, and promote rupture of atherosclerotic plaque. To be safe and effective, gene therapy with VEGF must be regulated. To limit the risk of pathological angiogenesis, we developed a hypoxia-inducible VEGF gene therapy system using the erythropoietin (Epo) enhancer and water-soluble lipopolymer (WSLP). pEpo-SV-VEGF or pSV-VEGF-Epo was constructed by insertion of the Epo enhancer upstream of the Simian Virus 40 (SV40) promoter or downstream of the poly(A) signal of pSV-VEGF. In vitro transfection showed that pEpo-SV-VEGF, not pSV-VEGF-Epo, induced the VEGF expression in hypoxic cells. In addition, the VEGF protein, which was produced from the Epo-SV-VEGF-transfected and hypoxia-incubated cells, was able to enhance the proliferation of the endothelial cells. Injection of the pEpo-SV-VEGF/WSLP complex showed that the expression of VEGF was induced in ischemic myocardium, compared to normal myo-cardium. Therefore, with the localized induction of VEGF and the low cytotoxicity of WSLP, the pEpo-SV-VEGF/WSLP system may be helpful to eventually treat ischemic heart disease.

Animals↗