Biomedical subjects

L Ma

Publications and source records attributed to L Ma.

At least 19 recordsLinked to original sources

PubMed2006

One-stage correction for blepharophimosis syndrome.

PURPOSE: To classify the severity of blepharophimosis, describe associated features and their effects on the incidence of amblyopia and to recommend guidelines for surgical treatment and management of surgical complications. METHODS: The case records of 23 patients with blepharophimosis syndrome were examined retrospectively. Patients' photographs and measurements were reviewed to analyse the severity of blepharophimosis, surgical techniques undertaken, surgical outcomes, and complications. Statistical analyses were performed using paired-sample t-tests to evaluate the surgical outcome and Spearman correlation to examine the influence of blepharophimosis on the interpalpebral fissure height (PFH). RESULTS: Eighteen out of 23 (78%) patients underwent one-stage surgery before the age of 5 years. About 31% of these patients had amblyopia. Only two patients had a blepharophimosis ratio greater than 1.5 as poor result. Two out of 18 (11%) patients with PFHs more than 2 mm needed a repeat operation, but all five (100%) patients with s less than 2 mm (very severe ptosis) needed repeat operations. CONCLUSIONS: The one-stage corrective procedure provided acceptable results both in function and cosmesis. However, patients with very severe ptosis required multiple stages of reconstruction for ptosis correction at an earlier age, after which correction of telecanthus and small horizontal palpebral fissure length followed at an older age.

Adolescent↗

PubMed2006

c-Jun N-terminal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells.

c-Jun N-terminal kinase (JNK) has been reported to either potentiate or inhibit oncogenesis, depending upon the cellular context, but its role in lung neoplasia is unclear. Here we sought to define the role of JNK in lung neoplasia by examining evidence of JNK phosphorylation in non-small-cell lung cancer (NSCLC) biopsy samples and by using genetic and pharmacologic approaches to modulate JNK expression and activity in cultured cells. Immunohistochemical staining for JNK phosphorylation was detected in 114 (45%) of 252 NSCLC biopsy samples and was predominantly nuclear, providing evidence of JNK activation in a subset of NSCLC cases. Introduction of a doxycycline-inducible, constitutively active, mutant mitogen-activated protein kinase kinase 4 (MKK4) into the human bronchial epithelial cell lines BEAS-2B and HB56B increased the cells' proliferation, migration, invasion and clonogenicity. Depletion of JNK in MKK4 mutant-transformed BEAS-2B cells by introduction of JNK1/2 short hairpin RNA reversed the transformed phenotype, indicating that JNK activation is oncogenic and MKK4 confers neoplastic properties in these cells. The proliferation of NSCLC cell lines HCC827 and H2009, in which JNK and its substrate c-Jun are constitutively phosphorylated, was inhibited by SP600125, a JNK kinase inhibitor. We conclude that JNK is activated in a subset of NSCLC biopsy samples and promotes oncogenesis in the bronchial epithelium, suggesting that strategies to inhibit the JNK pathway should be considered for the prevention and treatment of NSCLC.

Bronchi↗

PubMed2006

Efficacy and safety of adeno-associated viral vectors based on serotype 8 and 9 vs. lentiviral vectors for hemophilia B gene therapy.

BACKGROUND: Adeno-associated viral (AAV) and lentiviral vectors are promising vectors for gene therapy for hemophilia because they are devoid of viral genes and have the potential for long-term gene expression. OBJECTIVES: To compare the performance of different AAV serotypes (AAV8 and AAV9) vs. lentiviral vectors expressing factor (F) IX. METHODS AND RESULTS: AAV-based and lentiviral vectors were generated that express FIX from the same hepatocyte-specific expression cassette. AAV9 transduced the liver as efficiently as AAV8 and resulted in supra-physiological FIX levels (3000-6000% of normal) stably correcting the bleeding diathesis. Surprisingly, AAV9 resulted in unprecedented and widespread cardiac gene transfer, which was more efficient than with AAV8. AAV8 and AAV9 were not associated with any proinflammatory cytokine induction, in accordance with their minimal interactions with innate immune effectors. In contrast, lentiviral transduction resulted in modest and stable FIX levels near the therapeutic threshold (1%) and triggered a rapid self-limiting proinflammatory response (interleukin-6), which probably reflected their ability to efficiently interact with the innate immune system. CONCLUSIONS: AAV8 and 9 result in significantly higher FIX expression levels and have a reduced proinflammatory risk in comparison with lentiviral vectors. The unexpected cardiotropic properties of AAV9 have implications for gene therapy for heart disease.

Animals↗

PubMed2006

Differential expression of group I metabotropic glutamate receptors in human motoneurons at low and high risk of degeneration in amyotrophic lateral sclerosis.

Glutamate excitotoxicity has been suggested to play a role in amyotrophic lateral sclerosis, since overstimulation of post-synaptic glutamate receptors by accumulated extracellular glutamate leads to motoneuron cell death. It is however unclear as to why some groups of motoneurons degenerate in this disease while other groups remain relatively intact even during terminal stages of the disease. Our previous studies in the rat showed differential expression of group I metabotropic glutamate receptors in motoneurons at low and high risk of degeneration in amyotrophic lateral sclerosis. Here we have extended this study to normal human brains. In situ hybridization showed that transcripts of both metabotropic glutamate receptor (mGluR) 1 and mGluR5 were expressed in motoneurons in both the resistant motor nucleus III and the vulnerable motor nucleus XII. Immunolabeling of mGluR1alpha and mGluR5 was found in both motoneurons and glia-like cells in all the motor nuclei and the ventral horn of the cervical spinal cord studied. Quantitative analysis of optical density measurements showed higher levels of mGluR1alpha protein expression but lower levels of mGluR5 protein expression in the vulnerable motoneuron pool (VII, XII and spinal cord) than in the resistant motoneuron pool (III, IV and VI). This differential expression of group I metabotropic glutamate receptor proteins within vulnerable motoneuron pools may predispose these neurons to degeneration as seen in amyotrophic lateral sclerosis.

Central Nervous System↗

PubMed2006

Sex-specific effect of the Val1483Ile polymorphism in the fatty acid synthase gene (FAS) on body mass index and lipid profile in Caucasian children.

OBJECTIVE: A Val1483Ile polymorphism in the human fatty acid sythase gene (FAS) has recently been shown to be associated with lower percentage of body fat and substrate oxidation rates in Pima Indians, but its role in other populations has not been described. Here, we investigate the effect of this variant on obesity in Caucasian children and adolescents. SUBJECTS AND METHODS: In total, 738 Caucasian children and adolescents aged 6-17 years of the Leipzig Schoolchildren cohort, which constitutes an unselected representative German population and 205 obese children (body mass index (BMI) 2.71+/-0.04 SDS) were genotyped for genotype-phenotype associations. RESULTS: The frequency of the Ile-allele was lower in German Caucasians compared with Pima Indians (0.03 compared to 0.10). Using generalized linear regression models, there was no effect of the polymorphism on BMI in the whole normal population. However, we identified a significant interaction effect between sex and genotype (P=0.004). Subsequent sex stratified analyses revealed a lower BMI SDS in boys with Ile/Val genotype compared to Val/Val (-0.36+/-0.29 vs 0.09+/-0.05, P<0.05), while an opposite effect was observed in girls (0.48+/-0.19 vs 0.09+/-0.05, P<0.05). In genotype-phenotype associations in obese children, the polymorphism did not affect parameters of insulin, glucose, or lipid metabolism in the whole population. Again, however, obese boys with Ile/Val genotype had significantly higher high-density lipoprotein (HDL) cholesterol levels (1.46+/-0.07 vs 1.23+/-0.03 mmol/l, P<0.05). CONCLUSION: In conclusion, our findings suggest a sex-specific protective effect of the Val1483Ile polymorphism in FAS for obesity in Caucasian boys. In addition, the polymorphism may be associated with a beneficial lipid profile in obese boys.

Adolescent↗

PubMed2006

Livin promotes Smac/DIABLO degradation by ubiquitin-proteasome pathway.

Livin, a member of the inhibitor of apoptosis protein (IAP) family, encodes a protein containing a single baculoviral IAP repeat (BIR) domain and a COOH-terminal RING finger domain. It has been reported that Livin directly interacts with caspase-3 and -7 in vitro and caspase-9 in vivo via its BIR domain and is negatively regulated by Smac/DIABLO. Nonetheless, the detailed mechanism underlying its antiapoptotic function has not yet been fully characterized. In this report, we provide, for the first time, the evidence that Livin can act as an E3 ubiquitin ligase for targeting the degradation of Smac/DIABLO. Both BIR domain and RING finger domain of Livin are required for this degradation in vitro and in vivo. We also demonstrate that Livin is an unstable protein with a half-life of less than 4 h in living cells. The RING domain of Livin promotes its auto-ubiquitination, whereas the BIR domain is likely to display degradation-inhibitory activity. Mutation in the Livin BIR domain greatly enhances its instability and nullifies its binding to Smac/DIABLO, resulting in a reduced antiapoptosis inhibition. Our findings provide a novel function of Livin: it exhibits E3 ubiquitin ligase activity to degrade the pivotal apoptotic regulator Smac/DIABLO through the ubiquitin-proteasome pathway.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Quasi-monochromatic fiber depolarizer and its application to polarization-dependent loss measurement.

We theoretically derive the relationship between the degrees of polarization (DOPs) of input and output for an optical component with polarization-dependent loss (PDL) and birefringence. Based on the theoretical result, we propose a novel depolarizer for quasi-monochromatic light that can depolarize a fully polarized light with a 50 MHz linewidth to less than 0.2% in the DOP The depolarized light is then used to measure PDL in a single-mode optical fiber link. To the best of our knowledge, our new PDL measurement method is significantly faster than all known methods. Experimental results show excellent agreement with other methods.

Journal Article↗

PubMed2006

Robustness analysis of biochemical network models.

Biological systems that have been experimentally verified to be robust to significant changes in their environments require mathematical models that are themselves robust. In this context, a necessary condition for model robustness is that the model dynamics should not be sensitive to small variations in the model's parameters. Robustness analysis problems of this type have been extensively studied in the field of robust control theory and have been found to be very difficult to solve in general. The authors describe how some tools from robust control theory and nonlinear optimisation can be used to analyse the robustness of a recently proposed model of the molecular network underlying adenosine 3',5'-cyclic monophosphate (cAMP) oscillations observed in fields of chemotactic Dictyostelium cells. The network model, which consists of a system of seven coupled nonlinear differential equations, accurately reproduces the spontaneous oscillations in cAMP observed during the early development of D. discoideum. The analysis by the authors reveals, however, that very small variations in the model parameters can effectively destroy the required oscillatory dynamics. A biological interpretation of the analysis results is that correct functioning of a particular positive feedback loop in the proposed model is crucial to maintaining the required oscillatory dynamics.

Animals↗

PubMed2006

Topiramate: a new agent for patients with alternating hemiplegia of childhood.

Alternating hemiplegia of childhood is a rare syndrome characterized by the onset, before 18 months of age, of frequent attacks of alternating paralysis. Here we report the efficacy of topiramate in four patients with alternating hemiplegia of childhood (AHC) that did not respond to flunarizine, as well as in two newly diagnosed patients. Following treatment with topiramate, the frequency and duration of hemiplegic attacks significantly improved in all patients. Additional symptoms such as seizures, migraine, involuntary movements, autonomic symptoms, and impaired mental development also improved. Topiramate is worth trying when treating patients with AHC as a first trial, or a substitute for flunarizine once the latter agent loses effect.

Anticonvulsants↗

PubMed2006

Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis in 2 patients with end-stage renal disease on hemodialysis.

Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis (NFD/NSF) is a newly recognized disorder occurring in patients with renal failure. It is manifested by progressive cutaneous and systemic fibrosis involving the extremities and the trunk with usual sparing of the face and internal organs. NFD/NSF can lead to joint contractures and painful disability. The etiology is unknown and there are no proven effective treatments. NFD/NSF must be distinguished from other clinically similar disorders such as scleroderma, scleromyxedema, and eosinophilic fasciitis among a myriad of others. NFD/NSF can pose many diagnostic challenges to physicians; however, a team of experienced rheumatologists, nephrologists, dermatologists, and dermatopathologists is essential in identifying this disorder. We report 2 new cases of NFD/NSF in patients on hemodialysis.

Adult↗

PubMed2006

Co-immunoprecipitation of putative proteins that interact with mosquito proliferating cell nuclear antigen.

We have sequenced cDNAs encoding proliferating cell nuclear antigen (PCNA) from Aedes albopictus cells and from Aedes aegypti mosquitoes. The mosquito cDNAs contained an open reading frame encoding a 260 amino acid protein with a calculated mass of 29.0 kDa and a pI of 4.46. There was a single amino acid difference between PCNA proteins from Ae. albopictus and Ae. aegypti. In An. gambiae, the PCNA homolog contained 260 residues, and the pcna gene was interrupted by a single 67 nucleotide intron in the betaC2 region of the protein. A phylogenetic comparison grouped known Dipteran PCNA sequences into two clusters, representing the Nematocera and the Cyclorrhapha. PCNA transcripts measured 1.1 kb, and were stable, as was PCNA protein. Mosquito PCNA was efficiently recognized by a commercially available mouse anti-PCNA monoclonal antibody, which coprecipitated 29 kDa and 35 kDa proteins from mosquito cells representing different growth states. These results support the feasibility of recovering mosquito cell cycle inhibitory proteins by virtue of their interaction with PCNA.

Aedes↗

PubMed2006

Design and analysis of genetic association studies to finely map a locus identified by linkage analysis: sample size and power calculations.

Association (e.g. case-control) studies are often used to finely map loci identified by linkage analysis. We investigated the influence of various parameters on power and sample size requirements for such a study. Calculations were performed for various values of a high-risk functional allele (fA), frequency of a marker allele associated with the high risk allele (f1), degree of linkage disquilibrium between functional and marker alleles (D') and trait heritability attributable to the functional locus (h2). The calculations show that if cases and controls are selected from equal but opposite extreme quantiles of a quantitative trait, the primary determinants of power are h2 and the specific quantiles selected. For a dichotomous trait, power also depends on population prevalence. Power is optimal if functional alleles are studied (fA= f1 and D'= 1.0) and can decrease substantially as D' diverges from 1.0 or as f(1) diverges from fA. These analyses suggest that association studies to finely map loci are most powerful if potential functional polymorphisms are identified a priori or if markers are typed to maximize haplotypic diversity. In the absence of such information, expected minimum power at a given location for a given sample size can be calculated by specifying a range of potential frequencies for fA (e.g. 0.1-0.9) and determining power for all markers within the region with specification of the expected D' between the markers and the functional locus. This method is illustrated for a fine-mapping project with 662 single nucleotide polymorphisms in 24 Mb. Regions differed by marker density and allele frequencies. Thus, in some, power was near its theoretical maximum and little additional information is expected from additional markers, while in others, additional markers appear to be necessary. These methods may be useful in the analysis and interpretation of fine-mapping studies.

Alleles↗

PubMed2006

Dietary factors and smoking as risk factors for PD in a rural population in China: a nested case-control study.

BACKGROUND: Dietary factors and history of smoking remain elusive in the pathogenesis of Parkinson's disease (PD). OBJECTIVE: We investigated the association of environmental factors with PD in a rural population in China. METHODS: Subjects were participants of a past nutritional intervention trial. Information on their characteristics was collected during the baseline interview of the trial. Control subjects were randomly selected from the same cohort and frequency matched for sex, age and residential area. RESULTS AND CONCLUSION: Among 16,488 subjects surveyed, we diagnosed 464 subjects with PD. Then, four sex- and age-matched controls were paired with each definite PD case. A total of 85 cases and 340 controls were analyzed. Meat consumption and the body mass index (BMI) were inversely associated with PD. The PD risk declined with the increment of BMI. A history of gastric ulcer was associated with an increased risk of PD. As to smoking, there seemed an increased risk of PD among individuals who smoked regularly, non-significantly. However, a significantly increased risk of PD was found among those who smoked more than 30 pack-years.

Adult↗

PubMed2006

Liver ischemia contributes to early islet failure following intraportal transplantation: benefits of liver ischemic-preconditioning.

Early graft failure following intraportal islet transplantation (IPIT) represents a major obstacle for successful islet transplantation. Here, we examined the role of islet emboli in the induction of early graft failure and utilized a strategy of ischemic-preconditioning (IP) to prevent early islet destruction in a model of syngeneic IPIT in STZ-induced diabetic mice. Numerous focal areas of liver necrosis associated with the islet emboli were observed within 24 h post-IPIT. Pro-inflammatory cytokines, IL-1beta and IL-6, were significantly increased 3 h after IPIT, while TNF-alpha was elevated for up to 5 days post-IPIT. Caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive cells were observed in the transplanted islets trapped in areas of necrotic liver at 3 h and 1 day post-IPIT. Hyperglycemia was corrected immediately following IPIT of 200 islets, but recurrence of hyperglycemia was observed within 14 days associated with a poor response to glucose challenge. IP, a procedure of pre-exposure of the liver to transient ischemia and reperfusion, protected the liver from embolism-induced ischemic injury and prevented early islet graft failure. These data suggest that islet embolism in the portal vein is a major cause of functional loss following IPIT that can be prevented by liver IP.

Animals↗

PubMed2006

TLR engagement prevents transplantation tolerance.

In many experimental models, heart, pancreas and kidney allografts are accepted long-term following costimulation-targeting therapies, whereas skin, lung and intestine resist the induction of tolerance under the same regimens. We noted that a common feature of the resistant organs is their constant exposure to commensal microbes and hypothesized that these microorganisms may stimulate Toll-like receptors (TLRs), promote alloresponses and prevent tolerance induction. This hypothesis prompts the predictions that TLR engagement at the time of transplantation should avert tolerance to heart allografts in animals treated with costimulation-targeting therapies, whereas inhibition of TLR signaling should promote tolerance to skin allografts under the same conditions. Indeed, engagement of a single TLR was sufficient to prevent anti-CD154-mediated long-term cardiac allograft acceptance and correlated with abolished intragraft recruitment of CD4+/FoxP3+ regulatory T cells and the development of linked-suppression. Conversely, a lack of donor and recipient MyD88-dependent signaling led to successful skin allograft acceptance in anti-CD154-treated animals. Thus, the status of TLR signaling contributes to the resistance versus susceptibility of organs to transplantation tolerance.

Animals↗

PubMed2006

Comparative pharmacokinetics and pharmacodynamic target attainment of ertapenem in normal-weight, obese, and extremely obese adults.

Little is known of the effects of obesity on ertapenem drug disposition and pharmacodynamics. Thirty healthy volunteers in three body mass index (BMI) groups (10 per group), normal weight (BMI, 18.5 to 24.9 kg/m2), class I-II obesity (BMI, 30 to 39.9 kg/m2), and class III obesity (BMI, >or=40 kg/m2), were administered a 1-g dose of ertapenem. Serum concentrations were obtained over 24 h. Population pharmacokinetic data were obtained using a nonparametric adaptive grid followed by Monte Carlo simulation to determine the probability of obtaining the free drug exposure targets of the time that the free drug concentration remains above the MIC (fT>MIC) of 20% and 40% for bacteriostatic and maximal bactericidal activity, respectively. Compared to the subjects in the obese groups, area under the concentration-time curve from 0 h to infinity was significantly higher in the normal-weight subjects, whereas the total central compartment volume was higher in the class III obese subjects (P MIC of 20% with a 90% probability was attained at MICs of MIC, 40%), no group attained the target at the 90% probability level at any tested MIC. The results suggest that the standard 1-g ertapenem dose may not provide adequate drug exposure for any body mass index classification for MICs in excess of 0.25 to 0.5 microg/ml.

Adult↗

PubMed2006

Oncogenic osteomalacia associated with an occult phosphaturic mesenchymal tumour: clinico-radiologico-pathological correlation and ultrastructural studies.

A middle-aged man presented with bone pain at multiple sites due to tumour-induced osteomalacia. The underlying occult phosphaturic mesenchymal tumour was identified by octreotide scan 5 years after presentation and confirmed by computed tomography. Tumour resection resulted in normalisation of blood chemistry and bone densitometry. Clinico-radiologico-pathological correlation and ultrastructural studies of the tumour threw light on the pathogenesis and pathophysiology of this rare disease.

Fibroblast Growth Factor-23↗

PubMed2005

Comparative analyses of linac and Gamma Knife radiosurgery for trigeminal neuralgia treatments.

Dedicated linac-based radiosurgery has been reported for trigeminal neuralgia treatments. In this study, we investigated the dose fall-off characteristics and setup error tolerance of linac-based radiosurgery as compared with standard Gamma Knife radiosurgery. In order to minimize the errors from different treatment planning calculations, consistent imaging registration, dose calculation and dose volume analysis methods were developed and implemented for both Gamma Knife and linac-based treatments. Intra-arc setup errors were incorporated into the treatment planning process of linac-based deliveries. The effects of intra-arc setup errors with increasing number of arcs were studied and benchmarked against Gamma Knife deliveries with and without plugging patterns. Our studies found equivalent dose fall-off properties between Gamma Knife and linac-based radiosurgery given a sufficient number of arcs (>7) and small intra-arc errors (<0.5 mm) were satisfied for linac-based deliveries. Increasing the number of arcs significantly decreased the variations in the dose fall-off curve at the low isodose region (e.g. from 40% to 10%) and also improved dose uniformity at the high isodose region (e.g. from 70% to 90%). As the number of arcs increased, the effects of intra-arc setup errors on the dose fall-off curves decreased. Increasing the number of arcs also reduced the integral dose to the distal normal brain tissues. In conclusion, linac-based radiosurgery produces equivalent dose fall-off characteristics to Gamma Knife radiosurgery with a high number of arcs. However, one must note the increased treatment time for a large number of arcs and isocentre accuracies.

Dose-Response Relationship, Radiation↗