Biomedical subjects
Publications and source records attributed to S Lu.
Montelukast, a new leukotriene modifier, has several benefits in the treatment of asthma in adults and children including improved relief of asthma symptoms, rapid onset, a safety profile comparable with placebo, and oral, once-daily dosing means excellent adherence.
Rat models are useful for studies of the pathogenesis of rheumatoid arthritis (RA) since rats are extraordinarily sensitive to induction of arthritis with adjuvants. Injection of not only the classical complete Freund's adjuvant but also mineral oil without mycobacteria and pure adjuvants such as pristane and squalene, induce severe arthritis in many rat strains. Models like pristane-induced arthritis in rats are optimal models for RA since they fulfill the RA criteria including a chronic relapsing disease course. Arthritogenic adjuvants like pristane, avridine, squalene and mineral oil are not immunogenic since they do not contain major histocompatibility complex (MHC) binding peptides. Nevertheless, the diseases are MHC-associated and dependent on the activation of alphabetaTCR (T-cell receptor)-expressing T cells. However, it has not been possible to link the immune response to joint antigens or other endogenous components although immunization with various cartilage proteins induce arthritis but with different pathogeneses. To unravel the mechanisms behind adjuvant-induced arthritis, a disease-oriented genetic approach is optimal. Several loci that control onset of arthritis, severity and chronicity of the disease have been identified in genetic crosses and most of these have been confirmed in congenic strains. In addition, many of these loci are found in other autoimmune models in the rat as well as associated with arthritis in mice and humans.
The ability to gain entry and resist the antimicrobial intracellular environment of mammalian cells is an essential virulence property of Mycobacterium tuberculosis. A purified recombinant protein expressed by a 1362 bp locus (mce1) in the M. tuberculosis genome promoted uptake into HeLa cells of polystyrene latex microspheres coated with the protein. N-terminus deletion constructs of Mce1 identified a domain located between amino acid positions 106 and 163 that was needed for this cell uptake activity. Mce1 contained hydrophobic stretches at the N-terminus predictive of a signal sequence, and colloidal gold immunoelectron microscopy indicated that the corresponding native protein is expressed on the surface of the M. tuberculosis organism. The complete M. tuberculosis genome sequence revealed that it contained four homologues of mce (mce1, mce2, mce3, mce4) and that they were all located within operons composed of genes arranged similarly at different locations in the chromosome. Recombinant Mce2, which had the highest level of identity (67%) to Mce1, was unable to promote the association of microspheres with HeLa cells. Although the exact function of Mce1 is still unknown, it appears to serve as an effector molecule expressed on the surface of M. tuberculosis that is capable of eliciting plasma membrane perturbations in non-phagocytic mammalian cells.
We studied the regulation of the expression of vascular endothelial growth factor (VEGF) by TSH in monolayer cultures of rat thyroid FRTL-5 cell lines. The VEGF mRNA synthesis was significantly inhibited by TSH as well as dibutyryl cyclic adenosine monophosphate (cAMP) in a dose-dependent manner in FRTL-5 cells. This observation is contrary to previously published results using the thyroid follicular culture system. Our results suggest that the direct effect of TSH/cAMP is to inhibit the VEGF synthesis in monolayer cells.
The objective of this research was to compare the demographics, acquired immune deficiency syndrome (AIDS) progression, and survival in persons with AIDS with pulmonary tuberculosis (PTB) versus extrapulmonary tuberculosis (EPTB), because there are limited population-based data on this topic. A population-based longitudinal study with 3 years of follow-up was performed. Data were collected every 6 months from medical records of persons with AIDS and TB treated at private and public medical facilities throughout Los Angeles County (LAC). Participants included a population-based sample of 216 persons with AIDS and PTB and 166 persons with AIDS and EPTB (including 113 persons with both PTB and EPTB), with an AIDS diagnosis reported in 1993. Compared to persons with AIDS with PTB, persons with AIDS and EPTB were 2.2 times more likely to be Latino than white (95% confidence intervals [CIs]: 1.2, 4.0) and 1.7 times more likely to be foreign-born (95% CIs: 1.1, 2.5). Compared to persons with AIDS with PTB, persons with AIDS and EPTB had similar antiretroviral and PCP prophylaxis use; lower CD4 counts at time of AIDS diagnosis (p = 0.0004); no differences in CD4 counts over the total follow-up period (p = 0.4); higher rates of total opportunistic infections (OIs) (incidence density ratio [IDR] = 2.0; 95% CIs: 1.6, 2.4); and comparable survival curves (p = 0.07). Persons with AIDS and EPTB had a more complicated medical course with lower CD4 counts at time of AIDS diagnosis and more OIs over the follow-up period than persons with AIDS and PTB, however the survival profiles for the two groups were comparable.
The three-dimensional structure of the amaranth alpha-amylase inhibitor (AAI) adopts a knottin fold of abcabc topology. Upon binding to alpha-amylase, it adopts a more compact conformation characterized by an increased number of intramolecular hydrogen bonds, a decreased volume and in addition a trans to cis isomerization of Pro20. A systematic analysis of the 3-D structural databanks revealed that similar proteins and domains share with AAI the characteristic presence of proline residues, many of which are in a cis backbone conformation. As these proteins fulfil a variety of functional roles and are expressed in very different organisms, we conclude that the structure of the knottin fold, including the propensity of the cis bond, are the result of convergent evolution.
A linear and nonlinear autoregressive (AR) moving average (MA) (ARMA) identification algorithm is developed for modeling time series data. The new algorithm is based on the concepts of affine geometry in which the salient feature of the algorithm is to remove the linearly dependent ARMA vectors from the pool of candidate ARMA vectors. For noiseless time series data with a priori incorrect model-order selection, computer simulations show that accurate linear and nonlinear ARMA model parameters can be obtained with the new algorithm. Many algorithms, including the fast orthogonal search (FOS) algorithm, are not able to obtain correct parameter estimates in every case, even with noiseless time series data, because their model-order search criteria are suboptimal. For data contaminated with noise, computer simulations show that the new algorithm performs better than the FOS algorithm for MA processes, and similarly to the FOS algorithm for ARMA processes. However, the computational time to obtain the parameter estimates with the new algorithm is faster than with FOS. Application of the new algorithm to experimentally obtained renal blood flow and pressure data show that the new algorithm is reliable in obtaining physiologically understandable transfer function relations between blood pressure and flow signals.
A new algorithm for autoregresive moving average (ARMA) parameter estimation is introduced. The algorithm is based on the group method of data handling (GMDH) first introduced by the Russian cyberneticist, A. G. Ivakhnenko, for solving high-order regression polynomials. The GMDH is heuristic in nature and self-organizes into a model of optimal complexity without any a priori knowledge about the system's inner workings. We modified the GMDH algorithm to solve for ARMA model parameters. Computer simulations have been performed to examine the efficacy of the GMDH and comparison of the GMDH is made to one of the most accurate and one of the most widely used algorithms, the fast orthogonal search (FOS) and the least-squares methods, respectively. The results show that in some cases with noise contamination and incorrect model order assumptions, the GMDH performs better than either the FOS or the least-squares methods in providing only the parameters that are associated with the true model terms.
Partial deletion of the second hypervariable region from the envelope of the primary-like SF162 virus increases the exposure of certain neutralization epitopes and renders the virus, SF162DeltaV2, highly susceptible to neutralization by clade B and non-clade B human immunodeficiency virus (HIV-positive) sera (L. Stamatatos and C. Cheng-Mayer, J. Virol. 78:7840-7845, 1998). This observation led us to propose that the modified, SF162DeltaV2-derived envelope may elicit higher titers of cross-reactive neutralizing antibodies than the unmodified SF162-derived envelope. To test this hypothesis, we immunized rabbits and rhesus macaques with the gp140 form of these two envelopes. In rabbits, both immunogens elicited similar titers of binding antibodies but the modified immunogen was more effective in eliciting neutralizing antibodies, not only against the SF162DeltaV2 and SF162 viruses but also against several heterologous primary HIV type 1 (HIV-1) isolates. In rhesus macaques both immunogens elicited potent binding antibodies, but again the modified immunogen was more effective in eliciting the generation of neutralizing antibodies against the SF162DeltaV2 and SF162 viruses. Antibodies capable of neutralizing several, but not all, heterologous primary HIV-1 isolates tested were elicited only in macaques immunized with the modified immunogen. The efficiency of neutralization of these heterologous isolates was lower than that recorded against the SF162 isolate. Our results strongly suggest that although soluble oligomeric envelope subunit vaccines may elicit neutralizing antibody responses against heterologous primary HIV-1 isolates, these responses will not be broad and potent unless specific modifications are introduced to increase the exposure of conserved neutralization epitopes.
Long-chain polyunsaturated fatty acids (LC-PUFA) are important in the development of the immature nervous system, and adding these fatty acids to infant formula has been proposed. To determine the effect of n-3 LC-PUFA on apolipoprotein secretion and lipid synthesis in newborn swine enterocytes, differentiated IPEC-1 cells were incubated for 24 h with docosahexaenoic acid (DHA; 22:6) or eicosapentaenoic acid (EPA; 20:5) complexed with albumin at a fatty acid concentration of 0.8 mM or albumin alone (control) added to the apical medium. Oleic acid (OA; 18:1) was used a control for lipid-labeling studies. Both DHA and EPA reduced apolipoprotein (apo) B secretion by one-half, whereas EPA increased apo A-I secretion. The increased apo A-I secretion occurred primarily in the high-density lipoprotein fraction. These changes in apoprotein secretion were not accompanied by significant changes in synthesis. Modest decreases in apo B mRNA levels were observed for DHA and EPA, whereas there were no changes in apo A-I mRNA abundance. EPA reduced cellular triacylglycerol labeling by one-half, and DHA and EPA decreased cellular phospholipid labeling compared with OA. Labeled triacylglycerol secretion was decreased 75% by EPA, and DHA doubled labeled phospholipid secretion. If present in vivo, these effects should be considered before supplementing infant formula with these fatty acids.
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Myelinated axons of the human vagus nerve were analyzed morphometrically on 30 cadavers (16 males and 14 females). The result showed that the transverse area and perimeter of myelinated axons decreased with age, although the total number of their axons did not change.
We analysed numbers and sizes of the human tibial nerve branch innervating the soleus muscle. The material was taken from 13 cadavers aged from 67 to 98 years. A linear regression analysis disclosed a significant age-related decrease in the mean number per unit area and the mean transverse area of axons. Such decreases with age may indicate atrophy and loss of motoneurons. Our results could help in understanding the correlation between morphology and function during the ageing process.
The development of the human gracilis nucleus was studied on serial sections of the brain of 9 fetuses and neonates at 18-40 weeks of gestation, a two-month-old infant and a 63-year-old adult using a microscope with a drawing tube and an image-analyzing computer system. A morphometric evaluation revealed that the human gracilis nucleus, whose neurons were distinguished from glia from 18 weeks of gestation onward, showed a gradual development in terms of the columnar volume, neuronal size and number, and revealed two kinds of phenomenon: a normal process which occur in the development of the fetus, viz. natural cell death (also called apoptosis), and a phenomenon due to yet unknown causes regarding a discrepancy between the number of neurons and the neuropil index.
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The chemokine signaling system, which coordinates the basal and emergency trafficking of leukocytes, presumably coevolved with the hematopoietic system. To study its phylogenetic origins, we used the open reading frame (ORF) of the human chemokine receptor CXCR4 as a genomic probe, since in mammals it is the most highly conserved chemokine receptor known. CXCR4 cross-hybridized to genomic DNA from mouse and chicken, but not zebrafish, Drosophila, or Caenorhabditis elegans. Accordingly, we cloned the corresponding chicken cDNA. The ORF is 359 codons long versus 352 for human CXCR4, and encodes a protein 82% identical to human CXCR4. In a calcium flux assay of receptor function, CHO-K1 cells stably transfected with the chicken cDNA responded specifically to human SDF-1, the specific ligand for CXCR4, but not to a panel of other chemokines tested at 100 nM. SDF-1 activated the cells in a dose-dependent manner (EC50 approximately 5 nM), whereas parental CHO-K1 cells did not respond. The CHO-K1 cell transfectants also bound 125I-SDF-1 specifically. Leukocytes from chicken peripheral blood expressed chCXCR4 mRNA and responded to human SDF-1 in a calcium flux assay with an EC50 similar to that for chCXCR4-transfected CHO cells, suggesting that this response is mediated by native chCXCR4. Analysis of chicken genomic DNA with the chicken cDNA as probe revealed a pattern consistent with a single copy gene, and the absence of any closely related genes. mRNA was detected in brain, bursa, liver, small and large intestine, embryonal fibroblasts, and blood leukocytes, but not in stomach or pancreas. These results, which identify the first functional non-viral, non-mammalian chemokine receptor, suggest that the origins of a functional chemokine system extend at least to birds and suggest that, as in mammals, CXCR4 functions in many avian tissues.
OBJECTIVE: To investigate if low dose total body irradiation (TBI, 6.0-9.0 Gy) combined with intensified chemotherapy followed by autologous peripheral blood stem cell transplantation results in better survival in children with refractory leukemia or solid tumors. METHODS: Twenty-one children with malignant tumors were included in this study. There were 14 males and 7 females aged 3.5-12 years. Underlying disease included high-risk acute lymphoblastic leukemia (ALL, CR1 in 3 children and CR2 in 5 children), acute myeloblastic leukemia (AML, 9 children), non-Hodgkin's lymphoma stage IV (2 children), and neuroblastoma stage IV (2 children). The peripheral hematopoietic stem cells were collected six to eleven months after complete response, mobilized with high dose chemotherapy alone or combined with GM-CSF or G-CSF. The conditioning regimen consisted of chemotherapy with two to three combinations of the following drugs: cyclophosphamide, arabinosylcytosine, McNU, etopside, and ldarubicin on the basis of TBI (6.0-9.0 Gy). A mean of (1.8 +/- 0.5) x 10(8)/kg autologous mononuclear cells were transplanted. The patients were followed up after transplantation. RESULTS: Severe bone marrow suppression occurred in all patients around day +7. Peripheral white blood cell count decreased to 0 in all patients at day +4.8 +/- 2.9, and platelet count decreased to less than 20 x 10(9)/L at day +9.0 +/- 2.6. Successful engraftment was achieved in 21 patients, but four died of infection at day +17, +20, +31 and +67, respectively. Recovery of white blood cell (WBC) to 10 x 10(9)/L, absolute neutrophil count to 0.5 x 10(9)/L, platelet count to 20 x 10(9)/L occurred on 21 +/- 12, 26 +/- 13, and 27 +/- 10 days, respectively. During the follow up period, three patients relapsed at months, +1.5 years, and +2 years 10 months, respectively. One patient died of intracranial hemorrhage at +8 months. Thirteen patients had event-free survival for 2-12 years, with a mean of 6.7 +/- 3.4 years. CONCLUSION: Our preliminary data suggest that myeloablative therapy with low dose TBI (6.0-9.0 Gy) combined with intensified chemotherapy followed by autologous peripheral blood stem cell transplantation might be associated with favorable results in children with refractory leukemia or solid tumors.
OBJECTIVE: To study the changes and significance of MMP-2 and MT1-MMP mRNA expressions in fibroblasts and macrophages of rat pulmonary fibrosis model. METHODS: Fifty pathogen-free Sprague-Dawley rats were randomly divided into ten groups. Five groups were instillated with bleomycin A5 (BLM A5) intratracheally, while 5 control groups with normal saline instead. Pulmonary interstitial fibroblasts and alveolar macrophages were isolated at day 1,3,7,14,28th after BLM exposure. The mRNA expression of MMP-2 and MT1-MMP was evaluated by RT-PCR quantitative analysis. RESULTS: (1) The MMP-2 gene expression of fibroblasts increased 2.05 times(t = 10.667, P < 0.01) higher than that of control in 24 hours after bleomycin instillation and remained at the high level until the 28th day after exposure. It was only slightly increased in macrophages at the first day (t = 3.27, P < 0.05) and dropped down to the level of control during pulmonary fibrosis. (2) The mRNA expressions of MT1-MMP were enhanced both in fibroblasts and macrophages of fibrosis groups. They were 2.1 times(t = 4.823, P < 0.01) higher than that of control at the 14th day and 1.8 times(t = 4.016, P < 0.01) at the 28th day, respectively, in fibroblasts, while it was 2.4 times(t = 5.851, P < 0.01) higher than that of control at the 28th day in macrophages. CONCLUSIONS: (1) Fibroblasts not only were the target cells but also involved in the damage of the pulmonary basement membrane and in the initiation of pulmonary fibrosis mediated by up-regulation of the mRNA expression of MMP-2. (2) The highly expressed MT1-MMP of fibroblasts and macrophages in the late stage of pulmonary fibrosis participated in the activation of pro-MMP-2 to promote the progression of pulmonary fibrosis.