Biomedical subjects

J Bao

Publications and source records attributed to J Bao.

At least 37 records · Page 2Linked to original sources

PubMed1999

Correolide and derivatives are novel immunosuppressants blocking the lymphocyte Kv1.3 potassium channels.

The voltage-gated potassium channel, Kv1.3, is specifically expressed on human lymphocytes, where it controls membrane potential and calcium influx. Blockade of Kv1.3 channels by margatoxin was previously shown to prevent T cell activation and attenuate immune responses in vivo. In the present study, a triterpene natural product, correolide, was found to block Kv1.3 channels in human and miniswine T cells by electrophysiological characterization. T cell activation events, such as anti-CD3-induced calcium elevation, IL-2 production, and proliferation were inhibited by correolide in a dose-dependent manner. More potent analogs were evaluated for pharmacokinetic profiles and subsequently tested in a delayed-type hypersensitivity (DTH) response to tuberculin in the miniswine. Two compounds were dosed orally, iv, or im, and both compounds suppressed DTH responses, demonstrating that small molecule blockers of Kv1.3 channels can act as immunosuppressive agents in vivo. These studies establish correolide and its derivatives as novel immunosuppressants.

Animals↗

PubMed1998

Differences in Ca2+ channels governing generation of miniature and evoked excitatory synaptic currents in spinal laminae I and II.

Many neurons of spinal laminae I and II, a region concerned with pain and other somatosensory mechanisms, display frequent miniature "spontaneous" EPSCs (mEPSCs). In a number of instances, mEPSCs occur often enough to influence neuronal excitability. To compare generation of mEPSCs to EPSCs evoked by dorsal root stimulation (DR-EPSCs), various agents affecting neuronal activity and Ca2+ channels were applied to in vitro slice preparations of rodent spinal cord during tight-seal, whole-cell, voltage-clamp recordings from laminae I and II neurons. The AMPA/kainate glutamate receptor antagonist CNQX (10-20 microM) regularly abolished DR-EPSCs. In many neurons CNQX also eliminated mEPSCs; however, in a number of cases a proportion of the mEPSCs were resistant to CNQX suggesting that in these instances different mediators or receptors were also involved. Cd2+ (10-50 microM) blocked evoked EPSCs without suppressing mEPSC occurrence. In contrast, Ni2+ (</=100 microM), a low-threshold Ca2+ channel antagonist, markedly decreased mEPSC frequency while leaving evoked monosynaptic EPSCs little changed. Selective organic antagonists of high-threshold (HVA) Ca2+ channels, nimodipine, omega-Conotoxin GVIA, and Agatoxin IVA partially suppressed DR-EPSCs, however, they had little or no effect on mEPSC frequency. La3+ and mibefradil, agents interfering with low-threshold Ca2+ channels, regularly decreased mEPSC frequency with little effect on fast-evoked EPSCs. Increased [K+]o (5-10 mM) in the superfusion, producing modest depolarizations, consistently increased mEPSC frequency; an increase suppressed by mibefradil but not by HVA Ca2+ channel antagonists. Together these observations indicate that different Ca2+ channels are important for evoked EPSCs and mEPSCs in spinal laminae I and II and implicate a low-threshold type of Ca2+ channel in generation of mEPSCs.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1998

Pathogenic poxviruses reveal viral strategies to exploit the ErbB signaling network.

Virulence of poxviruses, the causative agents of smallpox, depends on virus-encoded growth factors related to the mammalian epidermal growth factor (EGF). Here we report that the growth factors of Shope fibroma virus, Myxoma virus and vaccinia virus (SFGF, MGF and VGF) display unique patterns of specificity to ErbB receptor tyrosine kinases; whereas SFGF is a broad-specificity ligand, VGF binds primarily to ErbB-1 homodimers, and the exclusive receptor for MGF is a heterodimer comprised of ErbB-2 and ErbB-3. In spite of 10- to 1000-fold lower binding affinity to their respective receptors, the viral ligands are mitogenically equivalent or even more potent than their mammalian counterparts. This remarkable enhancement of cell growth is due to attenuation of receptor degradation and ubiquitination, which leads to sustained signal transduction. Our results imply that signal potentiation and precise targeting to specific receptor combinations contribute to cell transformation at sites of poxvirus infection, and they underscore the importance of the often ignored low-affinity ligand-receptor interactions.

Animals↗

PubMed1998

Frequent coexpression of MRP/GS-X pump and gamma-glutamylcysteine synthetase mRNA in drug-resistant cells, untreated tumor cells, and normal mouse tissues.

Expression of the multidrug-resistance protein gene MRP, which confers non-P-glycoprotein-mediated multidrug resistance, has been found in many drug-resistant variants and tumor samples. Recent studies have demonstrated that MRP functions as an ATP-dependent transporter functionally related to the previously described glutathione-conjugate (GS-X) pump. We have shown recently that the MRP and gamma-glutamylcysteine synthetase (gamma-GCS) heavy subunit mRNA levels are coordinately overexpressed in cisplatin (CP)-resistant human leukemia cells (Ishikawa et al., J Biol Chem 271: 14981-14988, 1996) and frequently co-elevated in human colorectal tumors (Kuo et al., Cancer Res 56: 3642-3644, 1996). In the present study, we showed the coexpression patterns of thirteen additional human drug-resistant cell lines representing different tumor cell origins selected with different agents, except for one doxorubicin-selected line which demonstrated minor elevation in MRP mRNA with no detectable increase in gamma-GCS mRNA, suggesting that the increase of MRP mRNA preceded the increase in gamma-GCS mRNA. Furthermore, in seventeen randomly selected untreated tumor cell lines, the overall correlation coefficient between MRP and gamma-GCS mRNA levels was 0.861. In normal mice, the correlation coefficient of mrp and gamma-gcs mRNA was 0.662 in fourteen tissues (kidney and liver were not included) analyzed. Kidney and liver expressed low levels of mrp relative to gamma-gcs; however, these two tissues expressed high levels of a functionally related mrp homologue, mrp2 (cMoat or cMrp), which may have compensated for the underexpressed mrp in maintaining the total GS-X pump activities. Altogether, these results demonstrated the frequent coexpression of these two genes in various cell settings.

ATP-Binding Cassette Transporters↗

PubMed1998

Comparison of biodegradable and metallic tension-band fixation for patella fractures. 38 patients followed for 2 years.

We compared the outcome of patella fractures fixed by biodegradable tension-band (B) with self-reinforced polyglycolide or self-reinforced poly-L-lactide plugs and polyester ligaments or by metallic tension-band (M) with Kirschner wires and metallic cerclage wire in a randomized study. 38 fractures (18 with B and 20 with M) were treated. The follow-up time was 24 (14-32) months. The fractures healed in all patients after a medium of 8 weeks. In the B group, the clinical outcome was good in 13, fair in 4, and poor in 1 patient. In the M group, the corresponding figures were 15, 3 and 2. There were no clinical or radiographic differences between the two methods. Patella fractures can be treated, successfully using biodegradable tension-band fixation with no need for a second operation to remove the implants after bone union.

Absorption↗

PubMed1998

[Clinical study of gentamycin-loaded chitosan drug delivery system].

An clinical and pharmacokinetic study for a drug delivery system (DDS) of gentamycin-loaded chitosan bar were carried out with the purpose to evaluate its efficacy and giving further data for its clinical applications. Eighteen cases of chronic osteomyelitis were treated by surgical necrectomy with implantation of gentamycin-load chitosan bar in the prepared bone cavity. After operation, the concentration of gentamycin in serum and wound drainage fluid were examined at different times and blood urea nitrogen (BUN) and serum creatinine (Cr) as well. The clinical results were evaluated by the conditions of wound healing and clinical and roentgenographic manifestations. The results showed that the serum gentamycin concentration reached its peak level (0.86 microgram/ml) at 24 hours after operation and lasted for 4 days. No increase in the concentrations of BUN and Cr were observed after implantation. The gentamycin concentration in wound drainage fluid was several hundred times higher than the minimum inhibitory concentration (MIC) for staphylococcus aureus. All of the 18 cases were followed up for 24.8 months (in an range of 6-34 months) 16 patients received initial cure and without any recurrence. So, it could be concluded that the gentamycin-loaded chitosan DDS was a simple and effective method for the treatment of chronic osteomylitis without the necessity to carry out a second operation to remove the drug carrier, and it was sound to popularize its clinical application.

Administration, Topical↗

PubMed1998

TCM differential treatment of child hood persisting pneumonia--a report of 52 cases.

According to TCM differentiation of the symptoms and signs, 52 children with presisting pneumonia were divided into the following four types: 1) deficiency of body fluid due to accumulation of heat in the lung, 2) earth failing to generate metal, 3) deficiency of the Ying and Wei systems, and 4) excessiveness of pathogens due to qi deficiency. After treatment for 2-3 weeks, 40-cases were cured, 8 improved, and 4 ineffective.

Adolescent↗

PubMed1998

[Tail-suspended rats with inguinal canal ligation and their myocardial function].

To examine the effect of testosterone level on myocardial contractility and to prevent the testis from sliding into abdominal cavity when subjected to tail-suspension, a new tail-suspended model of rat with its inguinal canal ligated was made. Rats suspended for 4 w without inguinal canal ligation (SUS) exhibited significant reduction in weight of testis (CON 1.70 +/- 0.19 g; SUS 0.60 +/- 0.16 g) and in serum testosterone level (CON 99.5 +/- 32.7 ng/dl; SUS 23.0 +/- 13.2 ng/dl) (P<0.01). Unexpectedly, 4 w tail-suspension of rats with inguinal canal ligation (ST) also showed significant changes in testis weight (1.21 +/-0.30 g) and serum testosterone level (40.7 +/- 32.6 ng/dl). A significant decrease of the developed tension of the papillary muscle of the left cardiac ventricle was observed in SUS and ST group as compared with controls (CON: 3.93 +/- 0.42 g/mm2, SUS: 2.54 +/- 0.85 g/mm2, ST: 2.60 +/- 0.73 g/mm2). There was no relationship between the developed tension and serum testosterone level. It suggests that the decrease of blood supply of the testis may result in an atrophy of the testis in ST group.

Animals↗

PubMed1998

[Endovascular exclusion of abdominal aortic aneurysm].

OBJECTIVE: To explore the indications, methods, manipulations, and problems of endovascular exclusion of abdominal aortic aneurysm (AAA). METHOD: Under general anesthesia and dynamic supervision of DSA, an endovascular exclusion with a stent-graft complex of 11.0 cm x 2.6 cm was successfully performed on a 70-year-old man contraindicated for major open surgery with AAA of 10.0 cm x 6.0 cm and an AAA neck of 2.5 cm x 1.6 cm. RESULT: The patient was up and about on the first postoperative day. Duplex scan (by the end of the first postoperative week) and CT (on the postoperative 20th day) revealed a completely excluded AAA by the stent-graft that was patent and had an inner diameter of 2.2-2.4 cm, without migration and torsion. The primary AAA sac was full of thrombi and no patent lumbar and inferior mesenteric arteries were observed. The external diameter of AAA was unchanged, renal and iliac arteries were all patent, but a micro-crevice between the proximal end of the stent-graft and the anterior wall of the AAA neck was revealed. Six months postoperative follow-up showed that the patient's abdominal pulsatile mass and the left lower extremity's claudication disappeared. CONCLUSION: Endovascular exclusion of AAA is of great practical value.

Aged↗

PubMed1998

[The effects of graded spinal cord injuries on transcranial electric stimulation motor evoked potentials in the rat].

OBJECTIVE: To study the effects of graded spinal cord injury (SCI) on the motor evoked potentials (MEP) characteristics and the prognostic value of MEP for the motor function. METHOD: Modified Allen's method was used by weight drop force of 30 gcf, 50 gcf, 80 gcf and 100 gcf on the T(8 - 9) spinal cord of 40 SD rats in order to make SCI models. MEP was recorded continuously at L(1 - 2) epidurally and bilateral gastrocnemius muscles before and after the spinal cord lesion was produced (followed up for 1 month). The inclined plane and Tarlov technique were used to assess clinical neurological function. RESULT: The amplitude of rat's MEP changed significantly with graded SCI, the more sever the lesion, the lower the potentials. mMEP was more sensitive than scMEP, though the abolishment of mMEP soon after SCI didn't indicate that the animals could not regain ambulation. Changes in amplitude of scMEP recorded early after SCI were collaborate significantly with inclined plane (gamma = 0.9665, P < 0.01) and Tarlov scale (gamma = 0.8893, P < 0.01) assessed 1 month later, and can be used as a chronic measure parameter of motor function prognosis. scMEP still existed 1 month after SCI in 3 of 11 rats (27.3%) without any voluntary movement in bilateral hindlimbs, suggesting that some parts of conductive function still existed in the spinal cord. So it should be called "discomplete SCI". CONCLUSIONS: scMEP can be used as a reliable parameter for motor function prognosis, because it reflects objectively and sensitively the severity of central motor neurol fiber injury.

Animals↗

PubMed1998

Metabolic and dispositional fate of 1,2-dibromo-2,4-dicyanobutane in the male fischer 344 Rat.

Studies were conducted to characterize the absorption, disposition, metabolism, and excretion of 1,2-dibromo-2,4-dicyanobutane (BCB; methyldibromoglutaronitrile) following iv, oral, and topical administration to male Fischer 344 rats. Following iv administration of [14C]BCB (8 mg/kg, 120 microCi/kg), no parent compound was detected in the blood; however, its debrominated metabolite, 2-methyleneglutaronitrile (2-MGN; Cmax 7.3 micrograms/ml), was observed up to 1 hr. Within 72 hr, greater than 60% of the dose was excreted in the urine and 4.1% in the feces, and 6.6% was exhaled as 14CO2. Although less than 5% of the dose was retained in tissues, approximately 12% was bound to the erythrocyte fraction of the blood. Following oral administration of [14C]BCB (80 mg/kg, 100 microgramsCi/kg), approximately 85% of the dose was absorbed, whereas 72% of the dosed radioactivity was recovered in the urine and 9.7% in the feces, 7.5% was exhaled as 14CO2, 3.5% bound to tissues, and 2. 6% bound to blood. Although parent compound could not be detected in the blood following oral administration, 2-MGN was detected (Cmax 0. 32 micrograms/ml). Following topical application of [14C]BCB (25 mg/kg, 50 microgramsCi/kg), less than 12% of the dose was absorbed, with the major route of excretion being the urine (6.6% of dose). Urinary metabolite profiles were nearly identical for each route of administration, and the primary urinary metabolite was a mercapturate conjugate of 2-MGN that was identified as N-acetyl-S-(2, 4-dicyanobutane)-L-cysteine. BCB was found to be extremely labile in whole blood, plasma, and glutathione containing solutions, and in each case the formation of 2-MGN could be reduced by the alkylation of free-sulfhydryls with N-ethylmaleimide. These results suggest that BCB is totally debrominated prior to systemic distribution, and tissue exposure to intact BCB seems to be exceedingly low regardless of route of administration.

Animals↗

PubMed1998

Sulfhydryl-dependent biotransformation and macromolecular binding of 1,2-dibromo-2,4-dicyanobutane in blood.

1,2-Dibromo-2,4-dicyanobutane (BCB) is a broad-spectrum microbicide used commercially in consumer products. The objectives of this study were to elucidate the biotransformation of BCB, characterize its ability to covalently bind macromolecules, and predict the possible toxicological ramifications of such events. After iv administration of [14C]BCB to male Fischer 344 rats, 14C-equivalents were observed to bind gradually to blood constituents. By 48 hr, approximately 12% of the total dose was covalently bound. At no time was parent compound detected in the blood. However, the debrominated BCB metabolite 2-methyleneglutaronitrile (MGN) was observed. In vitro experiments revealed that BCB was extremely labile and was readily debrominated in fresh whole blood, erythrocyte preparations, and buffered glutathione (GSH) solutions. In each case, the formation of MGN was inhibited by the alkylation of free sulfhydryls with N-ethylmaleimide (NEM). For every 1 mol of BCB converted to MGN, 2 mol of GSH were oxidized to glutathione disulfide (GSSG) (BCB + 2 GSH --> MGN + GSSG + 2 HBr). The oxidation of free sulfhydryls during the conversion of BCB to MGN caused erythrocyte hemolysis (EC50 approximately 1 mM) in isolated preparations. Hemolysis was increased by coincubation of BCB with NEM (EC50 approximately 0.3 mM) and was decreased by coincubation with GSH (EC50 > 3 mM). However, MGN did not cause hemolysis of erythrocytes, even at concentrations 10-fold higher than the EC50 of BCB. In vitro experiments also demonstrated that incubation with either BCB or MGN resulted in significant macromolecular binding to the erythrocyte fraction of the blood (approximately 80%). Incubation with NEM resulted in a significant decrease in binding for both BCB (11.3% bound) and MGN (29.5% bound). Because BCB is rapidly debrominated in whole blood, it appears that MGN is the reactive species responsible for macromolecular binding. From these studies, we conclude that the conversion of BCB to MGN is mediated by a free sulfhydryl-dependent biotransformation pathway. Furthermore, BCB biotransformation is required for erythrocyte binding, and the consumption of free sulfhydryls associated with the biotransformation of BCB is responsible for hemolysis.

Animals↗

PubMed1997

Microelectrode arrays for stimulation of neural slice preparations.

A planar 6 x 6 array of iridium electrodes with four reference electrodes has been developed for use with neural tissue preparations. Precise knowledge of the relative locations of the array elements allows for spatial neurophysiological analyses. The 10 microns diameter platinized iridium electrodes on a 100 microns pitch have been used to stimulate acutely prepared slices of spinal cord from free-ranging rodents. An intracellular recording from a single neuron in the substantia gelatinosa (SG) using the whole-cell, tight-seal technique allowed low noise, high resolution studies of excitatory or inhibitory electrical responses of a given neuron to inputs from the primary afferent fibers or from stimulation by individual electrodes of the array. The resulting maps of responses provide an indication of the interconnectivity of neural processes. The pattern emerging is that of limited interconnectivity in the SG from areas surrounding a recorded neuron but with strong excitatory or inhibitory effects from those oriented in a longitudinal (rostral-caudal) direction relative to the neuron. The observations to date suggest the neurons of the SG are arranged in sets of independent networks, possibly related to sensory modality and input from particular body regions.

Animals↗

PubMed1997

Simultaneous determination of cyclohexene oxide and its metabolites in rat plasma and urine by gas chromatography.

An assay was developed for the simultaneous measurement of cyclohexene oxide and its metabolites (cyclohexanol, trans-cyclohexane-1,2-diol, cyclohexane-1,2-diol-O-glucuronide, and N-acetyl-S-(2-hydroxycyclohexyl)-L-cysteine) in rat urine and plasma using gas chromatography. A mixture of ethyl acetate-acetonitrile (70:30) was used as the extracting solvent for both matrices. This liquid-liquid extraction procedure was followed by the separation of cyclohexene oxide and its metabolites on an HP-FFAP fused-silica capillary column. In order to determine the amount of cyclohexane-1,2-diol-O-glucuronide, samples were incubated at 37 degrees C with beta-glucuronidase and the amount of cyclohexane-1,2-diol formed from the reaction determined. The extraction efficiencies of cyclohexene oxide and cyclohexanol were greater than 90% both in urine and plasma. However, recovery from the plasma and urine for trans-cyclohexane-1,2-diol (60-68%) and N-acetyl-S-(2-hydroxycyclohexyl)-L-cysteine (approximately 76%) were considerably less. Long term stability studies showed that urine samples spiked with cyclohexene oxide and trans-cyclohexane-1,2-diol are stable at -20 degrees C for up to 9 weeks. However, plasma samples are only stable for up to 2 weeks under the same conditions. The calibration curves for all analytes were linear over the range of 12.5 to 400 micrograms/ml and correlation coefficients (r2) were greater than 0.990. The limit of detection for cyclohexene oxide, cyclohexanol, and N-acetyl-S-(2-hydroxycyclohexyl)-L-cysteine is 1.56 micrograms/ml, while the limit of detection for trans-cyclohexane-1,2-diol is 3.12 micrograms/ml. This method has been used for the determination of the disposition and metabolism of cyclohexene oxide, and may be applied in environmental monitoring, as well as in microbiological studies for other epoxide materials.

Administration, Oral↗

PubMed1997

Effect of age and gender on azimilide pharmacokinetics after a single oral dose of azimilide dihydrochloride.

Azimilide is a new class III antiarrhythmic drug that blocks K+ channels. To determine the effects of age and gender on azimilide pharmacokinetics, a single 150-mg oral dose was administered to 66 healthy volunteers in a 3 x 2 factorial design (age groups of 18-40, 41-64, and > or = 65 years). Blood and urine were analyzed for azimilide and metabolites. The single dose was well-tolerated. Azimilide was 94% plasma protein-bound, and binding was not affected by age or gender. Age does not affect azimilide pharmacokinetics. The renal clearance of azimilide was significantly higher in women than in men (19%), but oral clearance did not differ between genders. Although the maximum azimilide concentration (Cmax) was 27% higher in women, time to maximum concentration or area under the azimilide concentration-time curve were not different from those for men. Body weight-adjusted Cmax did not differ between genders. Dosing adjustments based on either age or gender are not required.

Administration, Oral↗

PubMed1997

Nerve growth factor attenuates cholinergic deficits following traumatic brain injury in rats.

Traumatic brain injury (TBI) results in chronic derangements in central cholinergic neurotransmission that may contribute to posttraumatic memory deficits. Intraventricular cannula (IVC) nerve growth factor (NGF) infusion can reduce axotomy-induced spatial memory deficits and morphologic changes observed in medial septal cholinergic neurons immunostained for choline acetyltransferase (ChAT). We examined the efficacy of NGF to (1) ameliorate reduced posttraumatic spatial memory performance, (2) release of hippocampal acetylcholine (ACh), and (3) ChAT immunoreactivity in the rat medial septum. Rats (n = 36) were trained prior to TBI on the functional tasks and retested on Days 1-5 (motor) and on Day 7 (memory retention). Immediately following injury, an IVC and osmotic pump were implanted, and NGF or vehicle was infused for 7 days. While there were no differences in motor performance, the NGF-treated group had significantly better spatial memory retention (P < 0.05) than the vehicle-treated group. The IVC cannula was then removed on Day 7, and a microdialysis probe was placed into the dorsal hippocampus. After a 22-h equilibration period, samples were collected prior to and after administration of scopolamine (1 mg/kg), which evoked ACh release by blocking autoreceptors. The posttraumatic reduction in scopolamine-evoked ACh release was completely reversed with NGF. Injury produced a bilateral reduction in the number and cross-sectional area of ChAT immunopositive medial septal neurons that was reversed by NGF treatment. These data suggest that cognitive but not motor deficits following TBI are, in part, mediated by chronic deficits in cholinergic systems that can be modulated by neurotrophic factors such as NGF.

Acetylcholine↗

PubMed1997

Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia.

Nitric oxide (NO) and peroxynitrite, formed from NO and superoxide anion, have been implicated as mediators of neuronal damage following focal ischemia, but their molecular targets have not been defined. One candidate pathway is DNA damage leading to activation of the nuclear enzyme, poly(ADP-ribose) polymerase (PARP), which catalyzes attachment of ADP ribose units from NAD to nuclear proteins following DNA damage. Excessive activation of PARP can deplete NAD and ATP, which is consumed in regeneration of NAD, leading to cell death by energy depletion. We show that genetic disruption of PARP provides profound protection against glutamate-NO-mediated ischemic insults in vitro and major decreases in infarct volume after reversible middle cerebral artery occlusion. These results provide compelling evidence for a primary involvement of PARP activation in neuronal damage following focal ischemia and suggest that therapies designed towards inhibiting PARP may provide benefit in the treatment of cerebrovascular disease.

Adenosine Triphosphate↗

PubMed1997

[Laser assisted uvulopalptoplasty treatment for obstructive sleep apnea syndrome].

71 patients of obstructive sleep apnea symdrome (OSAS) were treated by Nd:YAG laser assisted uvulopalptoplasty (LAUP). According to the atonamic features of every patient, and type of operation which should be selected, the success rate of surgery would increase, and complications would be reduced. The effect rate is 97.2% by clinic, 90.0% by polysimnograph (PSG).

Adult↗