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Biomedical subjects

J Zhu

Publications and source records attributed to J Zhu.

At least 343 records · Page 19Linked to original sources

Transcutaneous nitroglycerine in the treatment of erectile dysfunction: a placebo controlled clinical trial.

Transcutaneous nitroglycerine has previously been reported to be effective in the treatment of erectile dysfunction. We present our results with the drug in a randomised, placebo controlled, double-blind crossover study. The effect of the drug has been evaluated both under laboratory conditions and in a home study. Eighteen men were included in the study. No effect of nitroglycerine could be demonstrated under laboratory conditions by application of the Rigiscan Monitor. In the home study there was no statistical significant effect of transcutaneous nitroglycerine compared to placebo (P= 0.2813).

Administration, Cutaneous↗

Tissue factors on acute promyelocytic leukemia and endothelial cells are differently regulated by retinoic acid, arsenic trioxide and chemotherapeutic agents.

The aberrant expression of tissue factor (TF) in acute promyelocytic leukemia (APL) cells has been implicated in the pathogenesis of the APL coagulopathy. In this study, we found that in APL patients receiving ATRA or As2O3 treatment, the improvement in hypercoagulobility and hyperfibrinolysis paralleled the correction of plasma fibrinogen level and amelioration of bleeding symptoms. Notably, clinical improvement was also correlated to ATRA/As2O3-induced rapid decrease of membrane procoagulant activity (PCA) and TF contents of APL blasts. Consistent with the in vivo findings, the membrane PCA, TF antigen and its mRNA level within NB4 cells were rapidly down-regulated by 1 microM ATRA or As2O3, while 0.2 microg/ml DNR increased these TF parameters prior to its effect upon apoptosis induction. The down-regulation of TF mRNA by ATRA was partially de novo protein synthesis-dependent and at least partially attributed to a mechanism of destabilizing TF mRNA. On the other hand, in addition to its modulation on mRNA, As2O3 could also induce an accelerated TF protein turnover. These distinct effects were corroborated with the properties of these agents in causing the degradation of PML-RARalpha protein. All three therapeutic agents, however, enhanced the potential of NB4 cells to stimulate the expression of TF and PCA in endothelium. Taken together, our data suggest that the rapid and distinct regulation of TF on APL cells by these therapeutic agents might at least partially contribute to their effects on APL coagulopathy.

Adolescent↗

Linomide suppresses experimental autoimmune neuritis in Lewis rats by inhibiting myelin antigen-reactive T and B cell responses.

Linomide (quinoline-3-carboxamide) is a synthetic immunomodulator that suppresses several experimental autoimmune diseases. Here we report the effects of Linomide on experimental autoimmune neuritis (EAN), a CD4+ T cell-mediated animal model of acute Guillain-Barré syndrome (GBS) in humans. EAN induced in Lewis rats by inoculation with bovine peripheral nervous system (PNS) myelin and Freund's complete adjuvant was strongly suppressed by Linomide administered daily subcutaneously from the day of inoculation. Linomide dose-dependently delayed the interval between immunization and onset of clinical EAN, as well as the severity of EAN symptoms. These clinical effects were associated with dose-dependent down-modulation of PNS antigen-induced T and B cell responses and with suppression of the proinflammatory cytokines IL-12, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) mRNA. In PNS sections, Linomide suppressed IL-12 and TNF-alpha, and up-regulated IL-10 mRNA expression. These findings suggest that Linomide could be useful in certain T cell-dependent autoimmune diseases.

Adjuvants, Immunologic↗

Suppression of chronic experimental autoimmune neuritis by nasally administered recombinant rat interleukin-6.

Experimental autoimmune neuritis (EAN) is a CD4+ T-cell-mediated demyelinating disease of the peripheral nervous system (PNS) and serves as experimental model for human immune-demyelinating neurophathies, especially the Guillain-Barré syndrome. In this study, we examined the effect of recombinant rat interleukin-6 (rrIL-6) on chronic EAN in Lewis rats induced by immunization with P2 peptide 57-81 and Freund's complete adjuvant (FCA). Nasal administration of rat rIL-6 (1 microg/rat/day) beginning in the initial phase of EAN as a therapeutic agent, decreased the severity and the duration of clinical EAN. Low-grade inflammation and suppression of regional demyelination within the sciatic nerves were seen in rrIL-6-treated rats. Hyporesponsiveness of lymph node T cells, down-regulation of serum tumour necrosis factor-alpha (TNF-alpha) and increased levels of P2-specific immunoglobulin G1 (IgG1) antibodies document that nasal administration of rrIL-6 was effective systemically. However, because of the non-specific nature of the treatment and multiple effects of IL-6, more experience and great caution are needed, before nasal administration of IL-6 can be considered as a treatment of human autoimmune demyelinating neurophathies.

Administration, Intranasal↗

Local effects of recombinant rat interleukin-6 on the peripheral nervous system.

Interleukin-6 (IL-6) is a multifunctional cytokine with a broad range of activities and can affect a variety of target cells or systems in multiple ways. However, there is currently no consensus on how IL-6 directly affects the peripheral nervous tissue. We performed histopathological and immunohistochemical analyses to investigate the direct effects of recombinant rat IL-6 (rrIL-6) following its intraneural injection into the sciatic nerve of adult Lewis rats. One day after injection, a large number of macrophages, major histocompatibility complex (MHC) class II positive cells, and CD4+ and CD8+ T cells appeared within the perineurium and endoneurium. From day 4 to day 7 after injection, we observed a gradual increase of inflammation and demyelination. On day 7, demyelination affected more than 80% of nerve fibres. In contrast, in the sterile phosphate-buffered saline (PBS)-injected control group, lower inflammation and fewer demyelinating nerve fibres were observed on days 4 and 7. Thus, intraneural injection of rrIL-6 into the sciatic nerve induces high inflammation and severe demyelination. This study improves our understanding of the effector mechanisms underlying inflammation and demyelination and identifies IL-6 as an essential mediator of inflammation and demyelination in the peripheral nervous system after local administration.

Animals↗

The phenolic vir gene inducer ferulic acid is O-demethylated by the VirH2 protein of an Agrobacterium tumefaciens Ti plasmid.

Some or possibly all Ti plasmids of Agrobacterium tumefaciens encode a bicistronic operon designated virH, which encodes two proteins, VirH1 and VirH2, that resemble a family of cytochrome P450-type monooxygenases. Expression of this operon is induced by a family of phenolic compounds that induce all other operons within the vir regulon. We hypothesized that either or both of these proteins might metabolize some or all of these phenolic compounds. We therefore tested induction of a vir promoter by a variety of phenolic compounds in isogenic strains that express or lack virH1 and virH2. Although some compounds were equally effective inducers regardless of the virH status, other compounds induced vir expression far more effectively in the virH mutant than in the virH-proficient host. For all tested compounds, VirH2 appeared to be solely responsible for this effect. One such compound, ferulic acid, was chosen for biochemical analysis. Ferulic acid was degraded by a VirH-proficient host but not by a VirH mutant. The wild-type strain released large amounts of a more hydrophilic compound into the cell supernatant. This compound was tested by mass spectroscopy, nuclear magnetic resonance and UV spectroscopy and found to consist of caffeic acid. This indicates that wild-type strains convert virtually all added ferulic acid to caffeic acid, and that VirH2 is essential for this O-demethylation reaction. Ferulic acid was far more toxic than caffeic acid to the wild-type strain, although the wild-type strain was more resistant to ferulic acid than was the virH mutant. Caffeic acid was slowly removed from the broth, suggesting further metabolic reactions.

Agrobacterium tumefaciens↗

Inflammation and severe demyelination in the peripheral nervous system induced by the intraneural injection of recombinant mouse interleukin-12.

Inflammatory cytokines appear to be involved in damage to Schwann cells, myelin and axons, although the exact role of the different cytokines is uncertain. The direct injection model offers a new and simplified way of examining the mechanisms of early inflammation in the peripheral nervous system. The present study was performed to assess the direct effects of interleukin (IL)-12 on rat sciatic nerves injected with recombinant mouse IL-12. Histological and immunohistochemical examination 24 h after injection showed early inflammation as well as demyelination within the injected nerve fibres. By 4 days the inflammatory and demyelinating changes were significantly increased. Seven days after injection, the endoneurium still contained significant numbers of inflammatory cells and the demyelination was even more severe. Control rats injected with sterile phosphate-buffered saline exhibited no such inflammatory and demyelinating response. These changes are similar to those seen in inflammatory and demyelinating disorders of the peripheral nervous system and suggest that IL-12 could be relevant to the pathogenesis of demyelinating diseases such as Guillain-Barré syndrome.

Animals↗

Relationship of tacrolimus whole blood levels to efficacy and safety outcomes after unrelated donor marrow transplantation.

Tacrolimus has proved effective for preventing acute graft-vs.-host disease (GVHD) after unrelated donor marrow transplantation, but the therapeutic window is apparently narrow. Therapeutic drug monitoring could potentially be used to guide dose modifications, but the optimal target range of tacrolimus blood concentrations is unknown. We determined whether acute GVHD and renal dysfunction correlated with tacrolimus whole blood levels as measured by the IMx assay. Data were analyzed for 97 adults treated in a multicenter trial of tacrolimus and methotrexate or methylprednisolone as GVHD prophylaxis after unrelated donor marrow transplantation. The rate of grades II-IV GVHD was 49%; 81% of patients had a doubling of the serum creatinine; and 61% had a serum creatinine <2 mg/dL. The initial tacrolimus target range for the clinical trial was 10-60 ng/mL. Tacrolimus blood levels were averaged over a 14-day period, and Cox models were used with averaged blood levels as a time-dependent covariate. No significant change was observed in the risks of acute GVHD, doubling of creatinine, need for dialysis, or death over a tacrolimus blood level range of 5-40 ng/mL, but there was a direct correlation between risk of developing a creatinine <2 mg/dL and increasing tacrolimus blood levels (4.7% increased risk for each 1 ng/mL increase in blood concentration, p < 0.001). When the tacrolimus level exceeded 20 ng/mL, there was a 2.2-fold increase in the rate of renal toxicity (p < 0.001), a trend for an increase in mortality (relative risk 3.9, p=0.08), and no impact on the risk of GVHD. This analysis supports 10-20 ng/mL as the therapeutic range of tacrolimus whole blood steady state or trough levels for unrelated donor marrow transplantation.

Adolescent↗

Studies of hydroxypropyl methylcellulose donut-shaped tablets.

Simple uncoated compressed tablets with a central hole (donut shape) or multihole tablets were prepared. Theophylline and diltiazem hydrochloride were used as model drugs to investigate in vitro drug release from donut-shaped tablets. The effects of hole size, the number of holes, drug solubility, and stirring rate on release kinetics were investigated. As for the donut-shaped tablets, the duration of zero-order drug release could be up to 80-90%. When the hole size was increased, the release rate increased, and the duration of linear drug release was longer. The durations of linear drug release of two-hole and three-hole tablets were longer than that of the single-hole tablets. As the drug solubility increased, the duration of linear drug release was shortened. However, three stirring rates (50 rpm, 100 rpm, 150 rpm) had little effect on the drug release.

Diltiazem↗

A novel mechanism for cytokine regulation: screening, selection, and characterization of anticytokine monoclonal and polyclonal autoantibodies.

We have recently described an immunoregulatory mechanism involving release of neutralizing autoantibodies (Aab) to cytokines during bacterial infections. Intraperitoneal inoculation of Haemophilus influenzae type b (Hib) into Sprague-Dawley rats resulted in high levels of inflammatory mediators early after infection. Increased titers of cytokine Aab were observed, with a peak at day 7. We cloned Aab-producing B cells. Screening of the clones with five different cytokines resulted in detection of Aab-producing clones reactive with each cytokine. After repeated subcloning, monoclonal Aab (mAab) were selected and characterized for their specificity, isotypes, and affinities. To elucidate regulatory importance, mAab to interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) dose-dependently inhibited IFN-gamma-induced MHC expression by peritoneal macrophages and TNF-alpha-induced thymocyte proliferation, respectively. Fab fragments exhibited binding and neutralizing effects, confirming specificities. Cross-reactivity with other rat cytokines was excluded. Pools of clones containing several mAab to each cytokine were obtained and served as polyclonal Aab. The relative affinity of the Aab was determined and found to be of high index. The characterized Aab were tested in methodologic assays for cytokine detection, revealing that some Aab were useful in a cell release capturing (CRC) ELISA.

Animals↗

Rapacuronium for modified rapid sequence induction in elective caesarean section: neuromuscular blocking effects and safety compared with succinylcholine, and placental transfer.

We have compared rapacuronium 2.5 mg kg-1 (n = 20) with succinylcholine 1.5 mg kg-1 (n = 22) in a multicentre, blinded, randomized study in full-term parturients undergoing elective Caesarean section under general anaesthesia. Thiopental 5 mg kg-1 was given i.v. followed by the neuromuscular blocking agent. Sixty seconds later intubation was performed. Intubating conditions, evaluated as excellent, good or poor, were good to excellent in 95% and 91% in the intent-to-treat patients after rapacuronium and succinylcholine, respectively (ns). Mean onset times at the adductor pollicis muscle for rapacuronium and succinylcholine were 80.4 (SEM 14.4) s and 63.9 (5.6) s (ns) while maximum block was 96 (1.9)% and 99 (0.4)%, respectively (ns). Rate of recovery was significantly longer after rapacuronium; times for return of T1 to 25% were 16.9 (1.5) min and 9.6 (1.1) min for rapacuronium and succinylcholine, respectively (P = 0.0004). Maternal side effects included more tachycardia and skin erythema with rapacuronium; no maternal mortality or morbidity, including bronchospasm, occurred in either group. There were no neonatal adverse effects in either group based on: Apgar scores at 1 and 5 min; times to sustained respiration; neuroadaptive capacity scores at 15 min, 2 h and 24 h; and umbilical venous and arterial blood-gas values and acid-base status. At delivery (17.7 (3.2) min), mean maternal plasma concentrations of rapacuronium were 9041.4 (1259.1) ng ml-1 and 506.4 (24.9) ng ml-1 for Org 9488 (the main metabolite). Corresponding values for umbilical venous plasma were 808.0 (92.1) ng ml-1 and 59.1 (6.5) ng ml-1, and for umbilical arterial plasma, 361.4 (56.4) ng ml-1 and 29.7 (4.6) ng ml-1, respectively. Umbilical venous to maternal venous ratios for rapacuronium and Org 9488 were 8.8% (1.3)% and 10.2 (1.7)%, respectively.

Adolescent↗

Structural characterization of gangliosides isolated from mullet milt using electrospray ionization-tandem mass spectrometry.

Electrospray ionization (ESI) coupled with tandem mass spectrometry has been used in conjunction with microwave-mediated saponification, periodate oxidation, and clostridial sialidase hydrolysis to enable detailed structural characterization of gangliosides and their derivatives present in mullet milt. The gangliosides extracted from mullet milt were determined to be GM3, GM3 lactone, GM3 methyl ester, and 9-O-acetyl GM3. For the major ganglioside GM3 and all GM3 derivatives, the ceramide composition was revealed to be C18:1/C16:0. GM3 with a C18:0/C16:0 ceramide was also found as a minor ganglioside. Both the ganglioside intramolecular ester and the ganglioside methyl ester (lacking carboxylic acid groups) showed dominant chloride attachment peaks (M + Cl)- in negative ion ESI-MS in addition to low intensity peaks corresponding to (M-H)-. GM3 and O-acetyl GM3 bearing carboxylic acid functions showed only (M-H)-. In positive ion ESI, GM3 and O-acetyl GM3 revealed (M + 2Na-H)+ peaks in addition to (M + Na)+, indicating free exchange of the carboxylic acid proton with a sodium cation, while the ganglioside intramolecular ester and ganglioside methyl ester with no acidic protons yielded only (M + Na)+. The strategy of employing ESI-MS to detect products of established wet chemical reactions represents a general approach for elucidation of ganglioside structural details.

Animals↗

Stomata from npq1, a zeaxanthin-less Arabidopsis mutant, lack a specific response to blue light.

The Arabidopsis mutant npq1, which cannot accumulate zeaxanthin because of a defective violaxanthin deepoxidase, was used to investigate the role of zeaxanthin in the stomatal response to blue light. Neither dark-adapted nor light-treated guard cells or mesophyll cells of the npq1 mutant contained detectable zeaxanthin. In contrast, wild-type guard cells had a significant zeaxanthin content in the dark and accumulated large amounts of zeaxanthin when illuminated. The well-documented red light enhancement of blue light-stimulated stomatal opening, in which increasing fluence rates of background red light result in increased response to blue light, was used to probe the specific blue light response of Arabidopsis stomata. Stomata from the npq1 mutant did not have a specific blue light response under all fluence rates of background red light tested. On the other hand, stomata from leaves of hy4 (cry 1), an Arabidopsis mutant lacking blue light-dependent inhibition of hypocotyl elongation, had a typical enhancement of the blue light response by background red light. The lack of a specific blue light response in the zeaxanthinless npq1 mutant provides genetic evidence for the role of zeaxanthin as a blue light photoreceptor in guard cells.

Arabidopsis↗

Analysis of genetic polymorphisms in the major histocompatibility complex of Japanese quail.

The restriction fragment length polymorphisms (RFLP) of the Japanese quail MHC were assayed in seven lines using PvuII-digested DNA and a chicken Class II probe. The lines of Japanese quail surveyed included a randombred control population (R1) and sublines of R1 divergently selected for 4-wk body weight (HW and LW lines) or plasma yolk precursor as measured by total plasma phosphorus (TPP) (HP and LP lines). In addition, two sublines (HW-HP and HW-LP) of the HW line were included in the analysis. Males of both sublines were selected for increased 4-wk body weight whereas the females were selected for increased (HW-HP) or decreased (HW-LP) TPP. The number of birds surveyed per line ranged from 13 to 16. The chicken probe used produced discernible bands or fragments using Southern blot analysis. There were 16 different RFLP patterns as well as 7 different heterozygote patterns detected in the various Japanese quail lines. The band or fragment number of each pattern varied from 7 to 15. A total of 28 different bands or fragments were seen in the RFLP patterns and only 2 bands or fragments were common to all 16 patterns. The distribution of the RFLP patterns differed greatly among the Japanese quail lines. The R1 line differed in frequency of the patterns from all of the selected lines. The divergently selected lines (HW vs LW; HP vs LP; and HW-HP vs HW-LP) also differed in the frequency of the various RFLP patterns. In the comparison of the HW and LW lines, there were no RFLP patterns in common between the two lines. The results of the present study indicated that the Japanese quail MHC Class II genes were highly polymorphic.

Animals↗

Linear viscoelasticity of hard sphere colloidal crystals from resonance detected with dynamic light scattering.

We present measurements of the high-frequency shear modulus and dynamic viscosity for nonaqueous hard sphere colloidal crystals both in normal and microgravity environments. All experiments were performed on a multipurpose PHaSE instrument. For the rheological measurements, we detect the resonant response to oscillatory forcing with a dynamic light scattering scheme. The resonant response for colloidal crystals formed in normal and microgravity environments was similar, indicating that the bulk rheological properties are unaffected by differing crystal structure and crystallite size within the experimental error. Our high-frequency shear modulus seems reasonable, lying close to Frenkel and Ladd's predictions [Phys. Rev. Lett. 59, 1169 (1987)] for the static modulus of hard sphere crystals. Our high-frequency dynamic viscosity, on the other hand, seems high, exceeding Shikata and Pearson [J. Rheol. 38, 601 (1994)] and van der Werff et al.'s measurements [Phys. Rev. A 39, 795 (1989)] on the high-frequency dynamic viscosity for metastable fluids. The measurements are in the linear regime for the shear modulus but may not be for the dynamic viscosity as Frith et al. [Powder Technol. 51, 27 (1987)] report that the dynamic viscosity passes through a maximum with strain amplitude.

Colloids↗

Coarsening kinetics from a variable-mobility Cahn-Hilliard equation: application of a semi-implicit Fourier spectral method.

An efficient semi-implicit Fourier spectral method is implemented to solve the Cahn-Hilliard equation with a variable mobility. The method is orders of magnitude more efficient than the conventional forward Euler finite-difference method, thus allowing us to simulate large systems for longer times. We studied the coarsening kinetics of interconnected two-phase mixtures using a Cahn-Hilliard equation with its mobility depending on local compositions. In particular, we compared the kinetics of bulk-diffusion-dominated and interface-diffusion-dominated coarsening in two-phase systems. Results are compared with existing theories and previous computer simulations.

Journal Article↗

Neutralization of macrophage inflammatory protein 2 (MIP-2) and MIP-1alpha attenuates neutrophil recruitment in the central nervous system during experimental bacterial meningitis.

Chemokines are low-molecular-weight chemotactic cytokines that have been shown to play a central role in the perivascular transmigration and accumulation of specific subsets of leukocytes at sites of tissue damage. Using in situ hybridization (ISH), we investigated the mRNA induction of macrophage inflammatory protein 2 (MIP-2), MIP-1alpha, monocyte chemoattractant protein 1 (MCP-1), and RANTES. Challenge of infant rats' brains with Haemophilus influenzae type b intraperitoneally resulted in the time-dependent expression of MIP-2, MIP-1alpha, MCP-1, and RANTES, which was maximal 24 to 48 h postinoculation. Immunohistochemistry showed significant increases in neutrophils and macrophages infiltrating the meninges, the ventricular system, and the periventricular area. The kinetics of MIP-2, MIP-1alpha, MCP-1, and RANTES mRNA expression paralleled those of the recruitment of inflammatory cells and disease severity. Administration of anti-MIP-2 or anti-MIP-1alpha antibodies (Abs) resulted in significant reduction of neutrophils. Administration of anti-MCP-1 Abs significantly decreased macrophage infiltration. Combined studies of ISH and immunohistochemistry showed that MIP-2- and MIP-1alpha-positive cells were neutrophils and macrophages. MCP-1-positive cells were neutrophils, macrophages, and astrocytes. Expression of RANTES was localized predominantly to resident astrocytes and microglia. The present study indicates that blocking of MIP-2 or MIP-1alpha bioactivity in vivo results in decreased neutrophil influx. These data are also the first demonstration that the C-C chemokine MIP-1alpha is involved in neutrophil recruitment in vivo.

Animals↗

Secretory leukocyte protease inhibitor interferes with uptake of lipopolysaccharide by macrophages.

Macrophages are among the most sensitive targets of bacterial endotoxin (LPS), responding to minute amounts of LPS by releasing a battery of inflammatory mediators. Transfection of macrophages with secretory leukocyte protease inhibitor (SLPI) renders these cells refractory to LPS stimulation. Here we show that uptake of LPS from soluble CD14 (sCD14)-LPS complexes by SLPI-overexpressing cells was only 50% of that seen in control cells. SLPI transfectants and mock transfectants did not differ in the surface expression of CD14 or CD18. We show, in addition, that recombinant human SLPI can bind to purified endotoxin in vitro. SLPI caused a decrease in the binding of LPS to sCD14 as assessed both by fluorescence quenching of labeled LPS and by nondenaturing polyacrylamide gel electrophoresis. These results suggest that the inhibitory effect of SLPI on macrophage responses to LPS may, in part, be due to its blockade of LPS transfer to soluble CD14 and its interference with uptake of LPS from LPS-sCD14 complexes by macrophages.

CD18 Antigens↗