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Biomedical subjects

Lin Lu

Publications and source records attributed to Lin Lu.

At least 37 records · Page 2Linked to original sources
PubMed2005

Lack of evidence for Nocardia asteroides in brain specimens from Lewy body-containing disorders.

Previous studies have suggested that Nocardia asteroides may play a role in the pathogenesis of Parkinson's disease (PD), including the production of Lewy bodies, the inclusion bodies present in this disorder. This study explored the possible connection between Nocardia and two Lewy body-containing disorders, PD and dementia with Lewy bodies (DLB). Substantia nigra specimens from individuals with PD, DLB, other neurodegenerative disorders, and normal subjects were evaluated for nocardial infection by in situ hybridization, PCR, and Gram staining. Brain specimens from a cynomolgus monkey experimentally infected with N. asteroides for 48 h served as the controls for in situ hybridization and Gram staining, and a nocardial pellet was the PCR control. The organism was detected by in situ hybridization and Gram stain in the experimentally infected monkey brain, and by PCR from the nocardial pellet. However, in situ hybridization reactivity was detected in only three of the 125 human brain specimens (2.4%; one case each of PD, DLB, and Alzheimer's disease), and none of the specimens was positive for Nocardia by PCR or Gram staining. These findings do not support an association of Nocardia with Lewy body-containing disorders.

Adult↗
PubMed2005

Role of withdrawal in reinstatement of morphine-conditioned place preference.

RATIONALE: Relapse is a major characteristic of drug addiction and the primary problem in treating drug abuse. Based on the negative reinforcement view of addiction, in which the motivation to take drugs is thought to result from the desire to avoid the aversive effect of drug withdrawal, it has been theorized that withdrawal symptoms play a major role in the maintenance of and relapse to drug taking. However, the role of withdrawal in relapse has not yet been systemically investigated in the reinstatement model. OBJECTIVES: Using a conditioned place preference (CPP) paradigm, we examined the role of different morphine withdrawal states (spontaneous withdrawal, naloxone-precipitated withdrawal, and conditioned withdrawal) in relapse to drug seeking. METHODS: Rats alternately received morphine (10 mg/kg, s.c.) and saline for 8 days to acquire the CPP. The morphine CPP disappeared after a 2-week extinction phase of saline-paired training. Rats were then chronically administered morphine to induce physical dependence. The different withdrawal states were induced and their roles in the reinstatement of extinguished CPP were assessed. During conditioned withdrawal, trunk blood samples were taken and the corticosterone level was measured by radioimmunoassay. To examine the role of corticotropin-releasing factor (CRF) receptor antagonist on conditioned-withdrawal-induced reinstatement of CPP, different doses of alpha-helical CRF (0.1 and 1 mug, i.c.v.) were administered 30 min prior to the CPP testing. RESULTS: The results show that morphine spontaneous withdrawal and naloxone-precipitated morphine withdrawal were ineffective in reinstatement morphine CPP. However, the withdrawal cues significantly elicited the reinstatement of CPP and increased corticosterone level. Moreover, pretreatment with the CRF receptor antagonist alpha-helical CRF (1 mug, i.c.v.) significantly attenuated the effects of withdrawal cues on reinstatement of CPP and corticosterone levels. CONCLUSION: These findings demonstrate that the cues associated with previous drug withdrawal play a major role in drug relapse and that activation of the CRF receptor is involved in conditioned-withdrawal-induced reinstatement. The present study suggests that CRF receptor antagonists might be of value in the treatment and prevention of relapse to drug seeking after long-term abstinence.

Animals↗
PubMed2005

Anti-angiogenesis effects of meisoindigo on chronic myelogenous leukemia in vitro.

Meisoindigo, an active compound of a Chinese anti-leukemia medicine, has been effectively used in the treatment of chronic myelogenous leukemia (CML). Increasing evidences have demonstrated that angiogenesis is an important pathobiologic feature of CML. The anti-angiogenesis effect of meisoindigo on CML is unknown. In this study, we determined the effects of meisoindigo on the apoptosis, adherence and differentiation of endothelial cells as well as the secretion of vascular endothelial growth factor (VEGF) by CML cells. We found that VEGF level, measured by enzyme-linked immunosorbent assay (ELISA), was higher in bone marrow plasma from CML patients compared with the healthy controls (334.83+/-23.09 ng/L versus 102.36+/-38.76 ng/L, P<0.01). CML cell VEGF production was decreased after CML cells were treated with 10 micromol/L meisoindigo compared with the controls (212.10+/-46.13 ng/L versus 293.75+/-64.79 ng/L, P<0.05). Ten micromole per liter of meisoindigo could induce time-dependent apoptosis of ECV304 cells determined by annexin-V. Treatment of ECV304 cells with meisoindigo for 48 h reduced the number of adherent cells and the expression of VCAM-1 compared with the control cells (43.78+/-9.09% versus 73.51+/-3.21%, P<0.05). Meisoindigo also inhibited tubule formation of HUVECs in an in vitro Matrigel after HUVECs were incubated with meisoindigo for 6 h. Our findings suggest that meisoindigo could inhibit angiogeneic process through decreasing the VEGF secretion in leukemic cells and also through inhibiting the proliferation, adhesion and differentiation of endothelial cells, causing the interruption of a reciprocal stimulatory loop between leukemic and endothelial cells. This effect may contribute to the anti-leukemic effect of this drug.

Angiogenesis Inhibitors↗
PubMed2005

Central amygdala ERK signaling pathway is critical to incubation of cocaine craving.

Using a rat model of craving and relapse, we have previously found time-dependent increases in cue-induced cocaine seeking over the first months of withdrawal from cocaine, suggesting that drug craving incubates over time. Here, we explored the role of the amygdala extracellular signal-regulated kinase (ERK) signaling pathway in this incubation. Cocaine seeking induced by exposure to cocaine cues was substantially higher after 30 withdrawal days than after 1 withdrawal day. Exposure to these cues increased ERK phosphorylation in the central, but not the basolateral, amygdala after 30 d, but not 1 d, of withdrawal. After 30 d of withdrawal from cocaine, inhibition of central, but not basolateral, amygdala ERK phosphorylation decreased cocaine seeking. After 1 d of withdrawal, stimulation of central amygdala ERK phosphorylation increased cocaine seeking. Results suggest that the incubation of cocaine craving is mediated by time-dependent increases in the responsiveness of the central amygdala ERK pathway to cocaine cues.

Amygdala↗
PubMed2005

eBLOCKs: enumerating conserved protein blocks to achieve maximal sensitivity and specificity.

Classifying proteins into families and superfamilies allows identification of functionally important conserved domains. The motifs and scoring matrices derived from such conserved regions provide computational tools that recognize similar patterns in novel sequences, and thus enable the prediction of protein function for genomes. The eBLOCKs database enumerates a cascade of protein blocks with varied conservation levels for each functional domain. A biologically important region is most stringently conserved among a smaller family of highly similar proteins. The same region is often found in a larger group of more remotely related proteins with a reduced stringency. Through enumeration, highly specific signatures can be generated from blocks with more columns and fewer family members, while highly sensitive signatures can be derived from blocks with fewer columns and more members as in a superfamily. By applying PSI-BLAST and a modified K-means clustering algorithm, eBLOCKs automatically groups protein sequences according to different levels of similarity. Multiple sequence alignments are made and trimmed into a series of ungapped blocks. Motifs and position-specific scoring matrices were derived from eBLOCKs and made available for sequence search and annotation. The eBLOCKs database provides a tool for high-throughput genome annotation with maximal specificity and sensitivity. The eBLOCKs database is freely available on the World Wide Web at http://motif.stanford.edu/eblocks/ to all users for online usage. Academic and not-for-profit institutions wishing copies of the program may contact Douglas L. Brutlag (brutlag@stanford.edu). Commercial firms wishing copies of the program for internal installation may contact Jacqueline Tay at the Stanford Office of Technology Licensing (jacqueline.tay@stanford.edu; http://otl.stanford.edu/).

Algorithms↗
PubMed2005

The relationship between soft-bottom macrobenthic communities and environmental variables in Singaporean waters.

Univariate and multivariate methods were used to study soft-bottom macrobenthos collected in December 2002 from the coastal waters of Singapore. The univariate parameters and community structure of benthic communities were related to environmental variables. Three samples were taken with a 0.1 m2 Van Veen grab (33 x 30 x 15 cm) at each station from 12 sampling stations of two different geographical areas. The water depth ranged from 6.5 m to 34.0 m. The mean values of species number, abundance and species diversity (H') were 24 species/grab, 77 animals/grab and 3.35/grab, respectively. A total of 172 species was recorded. Total petroleum hydrocarbons were strongly negatively related to species number, abundance and species diversity, suggesting that petroleum hydrocarbons have harmful effects on macrobenthic communities. The BIO-ENV analyses for all stations identified median particle size, silt-clay content, salinity and Zn as the major environmental variables influencing the infaunal patterns. However, separate analyses for two areas produced stronger correlations and different best-correlated environmental variable combinations. Total petroleum hydrocarbons were the only common factor in both areas, showing the importance of petroleum contamination in determining the community structure of benthic infauna in Singaporean waters.

Animals↗
PubMed2005

Differential long-term neuroadaptations of glutamate receptors in the basolateral and central amygdala after withdrawal from cocaine self-administration in rats.

Humans and laboratory animals remain highly vulnerable to relapse to cocaine-seeking after prolonged periods of withdrawal from the drug. It has been hypothesized that this persistent cocaine relapse vulnerability involves drug-induced alterations in glutamatergic synapses within the mesolimbic dopamine reward system. Previous studies have shown that cocaine self-administration induces long-lasting neuroadaptations in glutamate neurons of the ventral tegmental area and nucleus accumbens. Here, we determined the effect of cocaine self-administration and subsequent withdrawal on glutamate receptor expression in the amygdala, a component of the mesolimbic dopamine system that is involved in cocaine seeking and craving induced by drug-associated cues. Rats were trained for 10 days to self-administer intravenous cocaine (6 h/day) or saline (a control condition) and were killed after one or 30 withdrawal days. Basolateral and central amygdala tissues were assayed for protein expression of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunits (GluR1 and GluR2) and the NMDA receptor subunits (NR1, NR2A and NR2B). In the basolateral amygdala, GluR1 but not GluR2 levels were increased on days 1 and 30, NR2A levels were increased on day 1, and NR2B levels were decreased on day 30 of withdrawal from cocaine. In the central amygdala, GluR2 but not GluR1 levels were increased on days 1 and 30, NR1 levels were increased on day 30 and NR2A or NR2B levels were not altered after withdrawal from cocaine. These results indicate that cocaine self-administration and subsequent withdrawal induces long-lasting and differential neuroadaptations in basolateral and central amygdala glutamate receptors.

Adaptation, Physiological↗
PubMed2005

[Number of circulating endothelial progenitor cells inversely correlate with the severity of coronary artery disease in patients with stable coronary artery disease].

OBJECTIVE: To investigate whether the number of circulating endothelial progenitor cells (EPCs) correlate with the severity of coronary stenosis in patients with stable coronary artery disease (CAD). METHODS: 80 consecutive patients who underwent coronary angiography (exclusion of acute coronary syndrome and myocardial infarction) were enrolled. Physical examination and blood tests were performed to assess the disease severity and cardiovascular risk factors. Circulating EPCs as measured by the number of CD133/KDR double positive cells were detected by FACS. RESULTS: The number of EPCs inversely correlated with age, creatinine clearance (Ccr) and left ventricular mass index (LVMI) (P = 0.004, 0.015, 0.014 respectively). Patients with hypertension showed significant reduction in number of EPCs compared to those without hypertension (P = 0.004). Moreover, the number of EPCs in patients with coronary artery disease was significantly lower than that of those with normal coronary artery (P < 0.01). EPCs also inversely correlated with angiographic Gensini score (n = 49, r = -0.305, P = 0.039). CONCLUSIONS: In patients with stable CAD, the numbers of circulating EPCs correlate with the severity of CAD as well as cardiovascular risk factors.

AC133 Antigen↗
PubMed2005

[Clinical features and prognostic factors in primary myelofibrosis patients under 45 years old].

OBJECTIVE: To investigate the clinical and hematological features and identify the prognostic factors associated with short-term survival in primary myelofibrosis (PMF) patients under 45 years old. METHODS: The clinical manifestations, laboratory parameters, and survival were retrospectively analyzed in 56 PMF patients under 45 years old. Univariate analysis of prognostic factors was performed using Logrank test and multivariate analysis using COX model. RESULTS: Of the 56 patients, 27 were males and 29 females. The range of age was from 20 to 45 years (median 38 years). 84% of the patients were anemic and 66% Hb < 100 g/L. 32% of the patients had constitutional symptoms including fever, night sweats and weight loss. The median survival was 69 months (95% CI 11-127). By univariate analysis, Hb < 100 g/L, platelet count < 100 x 10(9)/L, WBC < 10 x 10(9)/L, constitutional symptoms and the duration from first signs to diagnosis < or = 6 months were associated with poor prognosis. By multivariate analysis, only Hb < 100 g/L and constitutional symptoms were independently associated with short survival. With these two adverse prognostic factors, the patients could be separated into a high risk and a low risk groups, and the median survivals were 16 and 88 months, respectively (P < 0.001). Using these two factors to predict the less than 3-years survival for individual patient, the sensitivity, specificity and positive predictive value were 67%, 100% and 100%, respectively. CONCLUSION: Hb < 100 g/L and constitutional symptoms in PMF patients under 45 years old were significantly associated with short survival and poor prognosis. These two prognostic factors enabled to separate patients into a high and a low risk groups. The survival of high-risk patients was less than three years.

Adult↗
PubMed2005

[Gene clone and sequence analysis of retinal specific rho promoter].

PURPOSE: To obtain the gene encoding retinal specific Rho promoter therefore to prepare for exogenous gene transcription and expression in retina. METHODS: Extract the genomic DNA of a BLAB/c mice . The Rho promoter DNA were then amplified by PCR, the product of which was subcloned into PcDNA3.1 +vector. After identification by restriction enzymes, the recombinant PcDNA3.1+vectors were subjected to sequence analysis. RESULTS: The fragments of the promoter as amplified by PCR were of predicted length. Digestion with HindIII and NheI proved correct insertion of the target fragments with expected length into the recombinant PcDNA3.1+vectors. As indicated by homology analysis the Rho promoter was highly conservative, and the Rho promoter we got had hole homology as reported by Boulanger A etc. CONCLUSION: Retinal specific Rho promoter has been successfully cloned, thus making possible the subsequent research as the mechanism and gene therapy of retina.

Acute-Phase Proteins↗
PubMed2004

A role of ventral tegmental area glutamate in contextual cue-induced relapse to heroin seeking.

The environmental context previously associated with opiate use plays an important role in human relapse, but the neuronal mechanisms involved in context-induced drug relapse are not known. Using a rat relapse model, we determined the effect of a group II metabotropic glutamate receptor agonist [LY379268 ((-)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid)] on contextual cue-induced reinstatement of heroin seeking. LY379268, which acts centrally to reduce evoked glutamate release, was injected systemically or directly into the ventral tegmental area (VTA), a brain area involved in opiate reward and conditioned drug effects. Rats were trained to self-administer intravenous heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Subsequently, lever pressing was extinguished in the presence of the discrete cue in a context that differed from the drug self-administration context in terms of visual, auditory, tactile, and circadian cues. After extinction of lever responding, LY379268 was injected systemically or into the VTA, and nonreinforced responding was determined in the extinction context or the drug context. Exposure to the heroin-associated context induced robust reinstatement of drug seeking, and this effect was attenuated by systemic or intra-VTA injections of LY379268. Results indicate that glutamate transmission in the VTA plays an important role in contextual cue-induced relapse to heroin seeking.

Amino Acids↗
PubMed2004

Cocaine seeking over extended withdrawal periods in rats: different time courses of responding induced by cocaine cues versus cocaine priming over the first 6 months.

RATIONALE AND OBJECTIVES: We previously found time dependent increases, or incubation, of cocaine seeking induced by re-exposure to cocaine cues over withdrawal periods of up to 3 months. Here, we studied cocaine seeking induced by re-exposure to cocaine cues or cocaine itself over an extended withdrawal period of 6 months. METHODS: Rats were trained to self-administer intravenous cocaine for 6 h/day for 10 days. Cocaine seeking induced by re-exposure to cocaine cues or cocaine itself, as measured in extinction or drug-induced reinstatement tests, respectively, was then assessed 1 day, or 1, 3 or 6 months after withdrawal. Rats were first given six 1-h extinction sessions wherein lever presses resulted in contingent presentations of cues previously paired with cocaine infusions. Subsequently, reinstatement of drug seeking induced by cocaine injections (expt 1: 0, 5, and 15 mg/kg, i.p.; expt 2: 0, 2.5, and 5 mg/kg) was assessed during three 1-h sessions. RESULTS: Profound time dependent changes in responsiveness to cocaine cues in the extinction tests were observed, with low responding after 1 day, high responding after 1 and 3 months, and intermediate responding after 6 months of withdrawal. In contrast, no significant time dependent changes in cocaine-induced drug seeking were found; acute re-exposure to cocaine effectively reinstated responding at all withdrawal periods. CONCLUSIONS: Results indicate that the withdrawal period is a critical modulator of drug seeking provoked by re-exposure to cocaine cues, but not cocaine itself. Results also indicate that while the incubation of responsiveness to cocaine cues is a long lasting phenomenon, it is not permanent.

Animals↗
PubMed2004

Cocaine seeking over extended withdrawal periods in rats: time dependent increases of responding induced by heroin priming over the first 3 months.

RATIONALE: Using a rat relapse model, recent studies reported time dependent increases in cocaine seeking induced by re-exposure to cocaine cues, but not cocaine itself, over withdrawal periods of up to 3 months. OBJECTIVES: In the present study, we explored the time course of cocaine seeking induced by priming injections of heroin over the first 3 months of withdrawal from cocaine. METHODS: Rats were trained to self-administer intravenous cocaine for 6 h/day over a period of 10 days. Cocaine seeking induced by heroin priming was then assessed in different groups of rats after 1 day, and 1 and 3 months of withdrawal from cocaine. During the test day, rats were first given six 1-h extinction sessions. Subsequently, reinstatement of cocaine seeking induced by non-contingent saline and heroin injections (0.125 and 0.25 mg/kg, s.c.) was assessed during three 1-h sessions. RESULTS: As in previous studies, extinction responding was substantially greater after 1 and 3 months of withdrawal than after 1 day. More importantly, we also found that the effect of heroin priming on reinstatement of cocaine seeking is time dependent, with higher responding occurring after 1 and 3 months than after 1 day. CONCLUSION: The present results replicate previous findings on the time dependent increases in resistance to extinction after withdrawal from cocaine, and further indicate that the duration of the drug withdrawal period is a critical modulator of the effect of heroin priming on cocaine seeking. These data may have implications for the treatment of cocaine relapse induced by other drugs.

Animals↗
PubMed2004

A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting potentiation of cocaine seeking after withdrawal.

Cocaine addiction in humans is associated with long-term propensity to relapse. Using a rat relapse model, we found that cocaine seeking induced by exposure to cocaine-associated cues progressively increases after withdrawal. This progressive increase is associated with increases in brain-derived nerve growth factor (BDNF) levels within the mesolimbic dopamine system. Based on these findings, we studied whether BDNF infusions into the ventral tegmental area (VTA), the cell body region of mesolimbic dopamine neurons, would potentiate cocaine seeking after withdrawal. Rats were trained to self-administer cocaine for 10 d, and cocaine seeking was measured in extinction tests 3, 10, or 30 d after withdrawal. During testing, rats were exposed to contextual cues that had predicted cocaine availability during training, and lever presses resulted in contingent presentations of a discrete tone-light cue that was previously temporally paired with cocaine infusions. BDNF (0-0.75 microg/site) or nerve growth factor (NGF; 0-0.75 microg/site) was infused into the VTA 1-2 hr after the last self-administration session. To examine the role of the mitogen-activated protein kinase (MAPK) pathway in BDNF effects, U0126 (1 microg/site), an MEK inhibitor, was used. A single intra-VTA infusion of BDNF, but not NGF, induced long-lasting enhancement of cocaine seeking for up to 30 d, an effect reversed by U0126. In contrast, neither BDNF infusions into the substantia nigra, nor acute intra-VTA BDNF infusions 2 hr before testing on day 3 of withdrawal, were effective. These data suggest that BDNF-mediated neuroadaptations in mesolimbic areas are involved in the persistent cocaine seeking induced by exposure to drug cues after withdrawal.

Animals↗
PubMed2004

Incubation of cocaine craving after withdrawal: a review of preclinical data.

Using a rat model of drug craving and relapse, we recently found that cocaine seeking induced by re-exposure to drug-associated cues progressively increases over the first 2 months after withdrawal from cocaine self-administration, suggesting that drug craving incubates over time [Nature 412 (2001) 141]. Here, we summarize data from studies that further characterized this incubation phenomenon and briefly discuss its implications for drug addiction. The main findings of our ongoing research are: 1. Incubation of cocaine craving is long-lasting, but not permanent: cocaine seeking induced by exposure to cocaine cues remains elevated for up to 3 months of withdrawal, but decreases after 6 months. 2. Incubation of reward craving is not drug specific: sucrose seeking induced by re-exposure to the reward cues also increases after withdrawal, but for a time period that is shorter than that of cocaine. 3. Incubation of cocaine craving is not evident after acute re-exposure to cocaine itself: cocaine seeking induced by cocaine priming injections remains essentially unchanged over the first 6 months of withdrawal. 4. Incubation of cocaine craving after withdrawal is associated with increases in the levels of brain-derived neurotrophic factor (BDNF) in mesolimbic dopamine areas.

Amphetamine-Related Disorders↗
PubMed2004

The cystine-glutamate transporter in the accumbens: a novel role in cocaine relapse.

Baker et al. have recently studied the potential role of cocaine-induced alterations in accumbens cystine-glutamate transporter activity (which controls basal extracellular glutamate levels) during cocaine-induced relapse to drug seeking in rats. Their data provide new evidence that neuroadaptations induced by repeated exposure to cocaine and subsequent withdrawal can play a causal role in drug relapse. These data also suggest the cystine-glutamate transporter as a novel target for medication that could prevent cocaine relapse.

Adaptation, Physiological↗
PubMed2004

Identification of tyrosine hydroxylase as a physiological substrate for Cdk5.

Cyclin-dependent kinase 5 (Cdk5) is emerging as a neuronal protein kinase involved in multiple aspects of neurotransmission in both post- and presynaptic compartments. Within the reward/motor circuitry of the basal ganglia, Cdk5 regulates dopamine neurotransmission via phosphorylation of the postsynaptic signal transduction pathway integrator, DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein, M(r) 32,000). Cdk5 has also been implicated in regulating various steps in the presynaptic vesicle cycle. Here we report that Cdk5 phosphorylates tyrosine hydroxylase (TH), the key enzyme for synthesis of dopamine. Using phosphopeptide mapping, site-directed mutagenesis, and phosphorylation state-specific antibodies, the site was identified as Ser31, a previously defined extracellular signal-regulated kinases 1/2 (ERK1/2) site. The phosphorylation of Ser31 by Cdk5 versus ERK1/2 was investigated in intact mouse striatal tissue using a pharmacological approach. The results indicated that Cdk5 phosphorylates TH directly and also regulates ERK1/2-dependent phosphorylation of TH through the phosphorylation of mitogen-activated protein kinase kinase 1 (MEK1). Finally, phospho-Ser31 TH levels were increased in dopaminergic neurons of rats trained to chronically self-administer cocaine. These results demonstrate direct and indirect regulation of the phosphorylation state of a Cdk5/ERK1/2 site on TH and suggest a role for these pathways in the neuroadaptive changes associated with chronic cocaine exposure.

Animals↗