Search PubMed⌕ Search

Biomedical subjects

Z Qu

Publications and source records attributed to Z Qu.

At least 55 records · Page 3Linked to original sources
PubMed2000

Origins of spiral wave meander and breakup in a two-dimensional cardiac tissue model.

We studied the stability of spiral waves in homogeneous two-dimensional cardiac tissue using phase I of the Luo-Rudy ventricular action potential model. By changing the conductance and the relaxation time constants of the ion channels, various spiral wave phenotypes, including stable, quasiperiodically meandering, chaotically meandering, and breakup were observed. Stable and quasiperiodically meandering spiral waves occurred when the slope of action potential duration (APD) restitution was < 1 over all diastolic intervals visited during reentry; chaotic meander and spiral wave breakup occurred when the slope of APD restitution exceeded 1. Curvature of the wave changes both conduction velocity and APD, and their restitution properties, thereby modulating local stability in a spiral wave, resulting in distinct spiral wave phenotypes. In the LRI model, quasiperiodic meander is most sensitive to the Na+ current, whereas chaotic meander and breakup are more dependent on the Ca2+ and K+ currents.

Action Potentials↗
PubMed2000

[Clinical results of transmyocardial laser revascularization for 77 patients with coronary artery disease].

OBJECTIVE: To analyses the clinical results of transmyocardial laser revascularization (TMLR) for 77 patients with coronary artery diseases (CAD). METHODS: The mean age of the patients was (65 +/- 7) years. Previous medical record included CABG (6 patients), PTCA (9), AMI (66.2%), hypertension (70.1%), and diabetes mellitus (45.5%). TMLR was performed on the beating heart via a left anterolateral thoracotomy at the fifth intercostal space. Transesophageal echocardiography showed transmyocardial penetration of 23 +/- 6 channels. RESULTS: The hospital mortality was 3.8%, and postoperative complications were AMI (3.8%), left ventricular failure (2.6%), PVC (5.2%). After operation, the mean CCS angina class was improved from the baseline 3.5 +/- 0.7 to 2.1 +/- 0.3 at 3 months, 1.7 +/- 0.3 at 6 months, 1.7 +/- 0.3 at 12 months and 1.8 +/- 0.4 at 24 months. One patient died of AMI and two died not due to cardiac events during a follow-up of 3 to approximately 24 months. Echocardiography showed that the average of left ventricular ejection fractions was improved significantly at 6 months after operation compared with the preoperative value (P = 0.0457). (201)TI-SPECT showed a remarkable improvement in reversible ischemia in 70% patients followed up. Metabolic stress test for 20 patients followed up patients demonstrated an average increase in exercise tolerance from 7.1 +/- 3.2 min at the baseline to 9.6 +/- 1.3 min at 12 months (P = 0.021). Similarly the METs increased from 4.3 +/- 2.1 at the baseline to 5.4 +/- 2.0 at 12 months. CONCLUSIONS: TMLR is a safe and effective procedure for the treatment of end stage coronary artery diseases not amenable to PTCA or CABG. The effect of TMLR is associated with indication, correct evaluation of myocardial ischemia, and management for postoperative complications.

Aged↗
PubMed1999

Role of papillary muscle in the generation and maintenance of reentry during ventricular tachycardia and fibrillation in isolated swine right ventricle.

BACKGROUND: The role of papillary muscle (PM) in the generation and maintenance of reentry is unclear. METHODS AND RESULTS: Computerized mapping (477 bipolar electrodes, 1.6-mm resolution) was performed in fibrillating right ventricles (RVs) of swine in vitro. During ventricular fibrillation (VF), reentrant wave fronts often transiently anchored to the PM. Tissue mass reduction was then performed in 10 RVs until VF converted to ventricular tachycardia (VT). In an additional 6 RVs, procainamide infusion converted VF to VT. Maps showed that 77% (34 of 44) of all VT episodes were associated with a single reentrant wave front anchored to the PM. Purkinje fiber potentials preceded the local myocardial activation, and these potentials were recorded mostly around the PM. When PM was trimmed to the level of endocardium (n = 4), sustained VT was no longer inducible. Transmembrane potential recordings (n = 5) at the PM revealed full action potential during pacing, without evidence of ischemia. Computer simulation studies confirmed the role of PM as a spiral wave anchoring site that stabilized wave conduction. CONCLUSIONS: We conclude that PM is important in the generation and maintenance of reentry during VT and VF.

Animals↗
PubMed1999

Spatiotemporal heterogeneity in the induction of ventricular fibrillation by rapid pacing: importance of cardiac restitution properties.

The mechanism by which rapid pacing induces ventricular fibrillation (VF) is unclear. We performed computerized epicardial mapping studies in 10 dogs, using 19-beat pacing trains. The pacing interval (PI) of the first train was 300 ms and then was progressively shortened until VF was induced. For each PI, we constructed restitution curves for the effective refractory period (ERP). When the PI was long, the activation cycle length (CL) was constant throughout the mapped region. However, as the PI shortened, there was an increase in the spatiotemporal complexity of the CL variations and an increase in the slope of the ERP restitution curve. In 5 dogs, we documented the initiation of VF by wavebreak at the site of long-short CL variations. Computer simulation studies using the Luo-Rudy I ventricular action potential model in simulated 2-dimensional tissue reproduced the experimental results when normal ERP and conduction velocity (CV) restitution properties were intact. By altering CV and ERP restitutions in this model, we found that CV restitution creates spatial CL variations, whereas ERP restitution underlies temporal, beat-to-beat variations in refractoriness during rapid pacing. Together, the interaction of CV and ERP restitutions produces spatiotemporal oscillations in cardiac activation that increase in amplitude as the PI decreases, ultimately causing wavebreak at the site of intrinsic heterogeneity. This initial wavebreak then leads to the formation of spiral waves and VF. These findings support a key role for both CV and ERP restitutions in the initiation of VF by rapid pacing.

Action Potentials↗
PubMed1999

Chaos and the transition to ventricular fibrillation: a new approach to antiarrhythmic drug evaluation.

Sudden cardiac death resulting from ventricular fibrillation can be separated into 2 components: initiation of tachycardia and degeneration of tachycardia to fibrillation. Clinical drug studies such as CAST and SWORD demonstrated that focusing exclusively on the first component is inadequate as a therapeutic modality. The hope for developing effective pharmacological therapy rests on a comprehensive understanding of the second component, the transition from tachycardia to fibrillation. We summarize evidence that the transition from tachycardia to fibrillation is a transition to spatiotemporal chaos, with similarities to the quasiperiodic transition to chaos seen in fluid turbulence. In this scenario, chaos results from the interaction of multiple causally independent oscillatory motions. Simulations in 2-dimensional cardiac tissue suggest that the destabilizing oscillatory motions during spiral-wave reentry arise from restitution properties of action potential duration and conduction velocity. The process of spiral-wave breakup in simulated cardiac tissue predicts remarkably well the sequence by which tachycardia degenerates to fibrillation in real cardiac tissue. Modifying action potential duration and conduction velocity restitution characteristics can prevent spiral-wave breakup in simulated cardiac tissue, suggesting that drugs with similar effects in real cardiac tissue may have antifibrillatory efficacy (the Restitution Hypothesis). If valid for the real heart, the Restitution Hypothesis will support a new paradigm for antiarrhythmic drug classification, incorporating an antifibrillatory profile based on effects on cardiac restitution and the traditional antitachycardia profile (classes 1 through 4).

Anti-Arrhythmia Agents↗
PubMed1999

Identification of a critical motif responsible for gating of Kir2.3 channel by intracellular protons.

Protons are involved in gating Kir2.3. To identify the molecular motif in the Kir2.3 channel protein that is responsible for this process, experiments were performed using wild-type and mutated Kir2. 3 and Kir2.1. CO2 and low pHi strongly inhibited wild-type Kir2.3 but not Kir2.1 in whole cell voltage clamp and excised inside-out patches. This CO2/pH sensitivity was completely eliminated in a mutant Kir2.3 in which the N terminus was substituted with that in Kir2.1, whereas a similar replacement of its C terminus had no effect. Site-specific mutations of all titratable residues in the N terminus, however, did not change the CO2/pH sensitivity. Using several chimeras generated systematically in the N terminus, a 10-residue motif near the M1 region was identified in which only three amino acids are different between Kir2.3 and Kir2.1. Mutations of these residues, especially Thr53, dramatically reduced the pH sensitivity of Kir2.3. Introducing these residues or even a single threonine to the corresponding positions of Kir2.1 made the mutant channel pH-sensitive. Thus, a critical motif responsible for gating Kir2.3 by protons was identified in the N terminus, which contained about 10 residues centered by Thr53.

Amino Acid Sequence↗
PubMed1999

Suppression of Kir2.3 activity by protein kinase C phosphorylation of the channel protein at threonine 53.

Kir2.3 plays an important part in the maintenance of membrane potential in neurons and myocardium. Identification of intracellular signaling molecules controlling this channel thus may lead to an understanding of the regulation of membrane excitability. To determine whether Kir2.3 is modulated by direct phosphorylation of its channel protein and identify the phosphorylation site of protein kinase C (PKC), we performed experiments using several recombinant and mutant Kir2.3 channels. Whole-cell Kir2.3 currents were inhibited by phorbol 12-myristate 13-acetate (PMA) in Xenopus oocytes. When the N-terminal region of Kir2.3 was replaced with that of Kir2.1, another member in the Kir2 family that is insensitive to PMA, the chimerical channel lost its PMA sensitivity. However, substitution of the C terminus was ineffective. Four potential PKC phosphorylation sites in the N terminus were studied by comparing mutations of serine or threonine with their counterpart residues in Kir2.1. Whereas substitutions of serine residues at positions 5, 36, and 39 had no effect on the channel sensitivity to PMA, mutation of threonine 53 completely eliminated the channel response to PMA. Interestingly, creation of this threonine residue at the corresponding position (I79T) in Kir2.1 lent the mutant channel a PMA sensitivity almost identical to the wild-type Kir2.3. These results therefore indicate that Kir2.3 is directly modulated by PKC phosphorylation of its channel protein and threonine 53 is the PKC phosphorylation site in Kir2.3.

Animals↗
PubMed1999

[Long-term follow-up of combined therapy with large-dose zinc sulfate and low-dose penicillamine in children with hepatolenticular degeneration].

OBJECTIVE: To summarize the long-term effect of combined treatment with large-dose zinc sulfate and low-dose penicillamine in children with hepatolenticular degeneration (HLD). METHODS: The patients who had symptoms were treated with large-dose zinc sulfate (100-150mg, <6yr; 150-200mg, 6-8yr; 200-300mg, 9-10yr; 300mg,>10yr; 3 times a day) in addition to low-dose penicillamine(8-10mg/kg/d) at the beginning of treatment. Zinc sulfate alone was given to the presymptomatic patients and it was used as maintenance therapy when clinical improvement was obtained. 31 children were followed up for 4-11 years. RESULTS: In 3 presymptomatic patients, no clinical abnormalities were found. Among 28 patients with symptoms, 23 patients (82%) had their symptoms and signs subsided or much improved, 2 patients(7%) remained unchanged, and 3(11%) died. Blood concentrations of copper were persistently lower than normal. Urine copper excretion of 24 hours was significantly lower than that before the combined therapy in all patients, and it became normal in 5 cases(16%) after 6 months of treatment, and in 26 cases(84%) after 1-2 years of treatment. Higher blood concentrations of zinc were found in 20 cases(65%), and higher urine zinc excretion was noted in 25 cases(81%) once or more times during the therapy. CONCLUSION: Combined therapy of large-dose zinc sulfate and low-dose penicillamine is an effective, safe and cheap treatment for children with HLD.

Adolescent↗
PubMed1999

Mechanism of acceleration of functional reentry in the ventricle: effects of ATP-sensitive potassium channel opener.

BACKGROUND: The effect of effective refractory period (ERP) shortening on the vulnerability and characteristics of induced functional reentry in the ventricle remain poorly defined. We hypothesized that ERP shortening increases ventricular vulnerability to reentry and accelerates its rate, as is the case in the atrium. METHODS AND RESULTS: The epicardial surfaces of 19 isolated and superfused canine right ventricular slices (4x4 cm and <2 mm thick) were mapped with 480 bipolar electrodes 1.6 mm apart. Vulnerability was tested during pacing at a cycle length (CL) of 600 ms and with a single premature stimulus of 5-ms duration at increasing current strength of 1 to 100 mA. Cromakalim (10 micromol/L), an ATP-sensitive potassium channel opener, caused a significant (P<0. 001) shortening of the ERP but had no effect on conduction velocity. Cromakalim increased (P<0.01) the vulnerability (product of current and the stimulus coupling interval) for reentry induction. Reentry had a significantly shorter CL and lasted for a longer duration (P<0. 001). The central core around which the wave front rotated became smaller, which caused shortening of the CL of reentry. A significant (P<0.001) linear correlation was found between core size and reentry CL. These effects of cromakalim were reversible. Two-dimensional simulation studies using the modified Luo-Rudy I model of cardiac action potential, in which the refractory period was variably shortened by a progressive increase of the time-independent potassium conductance, reproduced the experimental findings. CONCLUSIONS: ERP shortening by an ATP-sensitive potassium channel opener increases ventricular vulnerability to reentry and accelerates its rate by decreasing the core size around which the wave front rotates.

Action Potentials↗
PubMed1999

Detection of PERIOD/PAS-binding proteins from rat brain nuclear extracts by affinity chromatography.

In Drosophila, period and timeless gene's products (dPER and dTIM) have been identified to act as circadian clock components in heterodimeric form. The formation of dPER-dTIM complex is based on the interaction between dPER's PAS domain and dTIM's PAS binding domain. As an initial step to understand the molecular mechanism of mammalian circadian clock, we screened His-tagged dPER/PAS binding proteins from rat brain nuclear extracts, using Ni2+-NTA affinity chromatography. As a result of screening, we identified two proteins (192 and 180 kDa), which specifically bound to His-dPER/PAS in rat brain extracts. Such proteins might be a candidate of rat timeless proteins.

Animals↗
PubMed1999

Mechanical properties of trabecular bone in the human mandible: implications for dental implant treatment planning and surgical placement.

PURPOSE: This study sought to establish the relationships between bone density, elastic modulus, and ultimate compressive strength of trabecular bone in the human mandible, and to determine the influence that the cortical plates have on these values. MATERIALS AND METHODS: Nine fresh-frozen human mandibles between the ages of 56 and 90 years were cut into anterior (incisors and canine), middle (premolars), and distal (molars) sections. Seventy-six cylindrical trabecular bone specimens with bone marrow in situ were then prepared and tested in compression in the vertical direction. These tests were performed at a constant strain rate of 0.01 s(-1) with and without the presence of the cortical plates. RESULT: The density of mandibular trabecular specimens with bone marrow in situ ranged from 0.85 to 1.53 g/cm3, with a mean value of 1.14 g/cm3 (SD = 0.15). With the cortical plates present, the elastic modulus ranged from 24.9 to 240.0 megapascals (MPa), with a mean value of 96.2 MPa (standard deviation (SD) = 40.6). Without the cortical plates present, the elastic modulus ranged from 3.5 to 125.6 MPa, with a mean value of 56.0 MPa (SD = 29.6). The ultimate compressive strength of the trabecular bone ranged from 0.22 to 10.44 MPa, with a mean value of 3.9 MPa (SD = 2.7). CONCLUSION: This study indicates that the trabecular bone in the human mandible possesses significantly higher density, elastic modulus, and ultimate compressive strength in the anterior region than in either the middle or distal regions. The absence of cortical plates decreases the bone elastic modulus. These findings quantitatively confirm the need for clinical awareness in altering implant treatment plans and/or design in relation to bone density and the presence of the cortical plates.

Adolescent↗
PubMed1999

Cardiac electrical restitution properties and stability of reentrant spiral waves: a simulation study.

Spiral wave breakup is a proposed mechanism underlying the transition from ventricular tachycardia to fibrillation. We examined the importance of the restitution of action potential duration (APD) and of conduction velocity (CV) to the stability of spiral wave reentry in a two-dimensional sheet of simulated cardiac tissue. The Luo-Rudy ventricular action potential model was modified to eliminate its restitution properties, which are caused by deactivation or recovery from inactivation of K+, Ca2+, and Na+ currents (IK, ICa, and INa, respectively). In this model, we find that 1) restitution of ICa and INa are the main determinants of the steepness of APD restitution; 2) for promoting spiral breakup, the range of diastolic intervals over which the APD restitution slope is steep is more important than the maximum steepness; 3) CV restitution promotes spiral wave breakup independently of APD restitution; and 4) "defibrillation" of multiple spiral wave reentry is most effectively achieved by combining an antifibrillatory intervention based on altering restitution with an antitachycardia intervention. These findings suggest a novel paradigm for developing effective antiarrhythmic drugs.

Action Potentials↗
PubMed1999

Humanization of Immu31, an alpha-fetoprotein-specific antibody.

Immu31 is a murine monoclonal antibody (Ab) specific for alpha-fetoprotein (AFP), a tumor-associated marker. The excellent tumor targeting ability of Immu31 has led to the development of a Immu31-based radioimmunodiagnostic agent, AFP-Scan, for hepatocellular carcinoma and other AFP-producing tumors. To enhance the capability of Immu31-based immunoconjugates being used in diagnostic and therapeutic procedures in humans, a humanized version of Immu31 (hImmu31) was constructed by grafting the complementarity determining regions (CDRs) of murine variable domains for the heavy (VH) and kappa (Vkappa) chain to the respective human VH and Vkappa framework regions (FRs). The cDNA encoding the VH and Vkappa of Immu31 was cloned by reverse transcription-PCR from hybridoma cells, and a chimeric Immu31 (cImmu31) composed of murine V and human C domains was constructed. Competitive ELISA assays showed identical AFP binding activity between the chimeric and murine Abs, confirming the authenticity of the cloned V genes. Based on sequence homology, the EU FR1, FR2, and FR3 and the NEWM FR4 were selected as the scaffold for grafting VH CDRs and REI FRs for Vkappa CDRs of Immu31. The amino acid residues in murine FRs that are considered to be in contact with the CDRs of the Ab were maintained in the humanized version. hImmu31, thus constructed and expressed, showed comparable immunoreactivity in a competitive binding ELISA assay to that of murine Immu31 and cImmu31. High-level production was achieved by expressing hImmu31 in a dhfr-based amplifiable system, and the productivity has exceeded 100 mg/liter in terminal cultures.

Amino Acid Sequence↗
PubMed1999

Generation and monitoring of cell lines producing humanized antibodies.

Antibody humanization has eliminated or reduced the human antimouse antibody response associated with the administration of murine antibodies. We have successfully humanized three different antibodies: (a) hMN-3 (granulocyte targeting); (b) hMu-9 (colorectal cancer targeting); and (c) hWI2 (anti-idiotype to the anti-carcinoembryonic antigen antibody MN-14). All humanized antibodies demonstrated immunoreactivities comparable to their parent counterparts. Previously, we reported the generation of high productivity cell lines for hMN-14 and hLL2 using the amplifiable vector pdHL2. Through amplification, selection, and cloning procedures, cell lines capable of large scale production were established, and further enhancement of production was achieved by a fed-perfusion bioreactor process. Using a similar and improved approach, we have enhanced the production of the above-mentioned humanized antibodies by gene amplification induced by a stepwise increase in the concentration of methotrexate in the culture media. A reliable IgG determination method is essential to monitor amplification, especially at the final cloning stage, for the selection of the subclones with the highest productivity. We found that measurement of humanized IgG concentration in culture media supplemented with more than 1 microM methotrexate by a standard ELISA assay could be unreliable and misleading. Whereas the determination of antibody by adsorption/elution on protein A from a 100-ml culture is accurate and reproducible, the method is time-consuming, tedious, and labor intensive. We have recently developed a Western blot assay that enables us to monitor the productivity of the cultures. The assay is simple and sensitive, and it makes simultaneous determinations of relative antibody production from individual clones at the 96-well stage feasible. With this method, amplification, cloning, and adaptation to serum-free conditions of multiple cell lines can be monitored in an efficient manner.

Animals↗
PubMed1999

The effects of domain deletion, glycosylation, and long IgG3 hinge on the biodistribution and serum stability properties of a humanized IgG1 immunoglobulin, hLL2, and its fragments.

Antibody (Ab) fragments are preferred agents for imaging applications because of their rapid clearance from the blood, thereby providing high tumor:blood ratios within a few hours. Several preclinical studies have also suggested that Ab fragments might be preferred for therapeutic applications over an intact IgG. The purpose of this project was to develop engineered Ab fragments using a humanized anti-carcinoembryonic antigen and anti-CD22 Ab as the parent. Three types of variants were prepared: a deltaCH2 (deletion mutant missing the CH2), a gamma3 F(ab')2 containing the human IgG3 hinge, and three glycosylated variants. The gamma3 F(ab')2 and glycosylated variants were developed because of the potential for site-specific linkage to the Ab in its divalent or monovalent fragment. The gamma3 F(ab')2 variant contains 10 cysteine residues that could be used for direct coupling using thiol chemistry, whereas the glycosylated variants have N-linked glycosylation sites engineered in the CH1 domain (two variants) as well as the VK domain (one variant). All of these variants were successfully prepared and shown to react with the target antigen. All Abs could be purified to a single peak by size-exclusion HPLC, but the deltaCH2 variant showed two distinct peaks, which were believed to be both the divalent and monovalent forms of this fragment. The two CH1 glycosylated variants showed differences in the extent of glycosylation. Modeling studies suggest that one variant would be better suited for site-specific coupling than the other because the carbohydrate chain is extended further away from the antigen-binding site. The Abs were radioiodinated to determine their pharmacokinetic behavior in mice. All of the humanized Ab divalent fragments cleared nearly 20 times faster from the blood than the murine parent F(ab')2 over a 24-h period. The glycosylated fragments showed some added stability compared to the other fragments over 4 h, but by 24 h, they had cleared to the same extent. Size-exclusion high-performance liquid chromatography of blood samples indicated that the humanized Ab fragments were quickly degraded in the blood. Thus, there is an inherent instability of the divalent fragments from these humanized IgG1 constructs that may affect their utility in imaging or therapy applications.

Animals↗
PubMed1999

In vivo production of type 1 cytokines in healthy sickle cell disease patients.

Interleukins (IL)-1, 2, 12, and interferon (IFN)-gamma, along with soluble IL-2 receptor (sIL-2R) were measured from sera obtained from healthy sickle cell disease (SCD) patients and comparable healthy control subjects. The cytokines were assessed by enzyme-linked immunosorbent assay (ELISA) in 60 SCD patients and 58 controls. No significant detectable levels of IL-1 or IL-12 were found in the sera of either group of patients. Significantly elevated levels of IFN-gamma were measured in 20 (33%) of 60 SCD patients and 21 (36%) of 58 controls. A large subset of 18 (41%) of 43 healthy controls and a smaller subset of 12 (21%) of 58 SCD demonstrated detectable levels of IL-2. The sIL-2R levels of the SCD group (4465 +/- 552 pg/mL) were significantly higher (P < .0001) than that of controls (3473 +/- 411 pg/mL). The results revealed comparable circulating levels of all type 1 cytokines in both healthy SCD and normal control subjects, with the exception of in vivo sIL-2R production. Elevated serum levels of both IL-6 and tumor necrosis factor (TNF)-alpha have been reported previously in a significant percentage of SCD steady-state subjects. These two cytokines are known to increase sIL-2R expression and may help explain the difference between the patient populations. Immune activation markers such as sIL-2R are produced by cells that mediate host responses to infection or inflammatory stimuli. The implication of higher levels of sIL-2R in SCD is not clear, but chronic parvovirus B19 infection, chronic polyclonal activation of B cells or defective regulation of antibodies are possible explanations for the elevated levels in SCD.

Adolescent↗
PubMed1999

[Cloning and sequencing analysis of rice stripe virus genome segment 4 of Chinese isolate Y].

The cDNA fragment covering full-length sequence of RStV RNA4 of Yunnan isolate in China was obtained by RT-PCR. The PCR-derived fragment was then cloned into vector pCRII. The cloned cDNA was sequenced. Comparison of the nucleotide and deduced amino acid sequences with those of the Japanese isolate T was made. The results showed that at the nucleotides level, vORF, vcORF and the intergenic region had 94.9%, 94.1% and 86.1% identity respectively, the 5'-untranslational region was exactly the same as that of Japanese isolate T, while the 3'-terminal sequence had 96.1% identity, differing by two nucleotides; at the amino acid level, vORF and vcORF had 99.4% and 98.3% identity respectively. Therefore, as well as being exactly the same size for the two isolates, the amino acid sequences of the coding regions and the 5'- and 3'-terminal sequences were well conserved. Our results indicated that the Chinese isolate is closely related to the Japanese isolate T.

Amino Acid Sequence↗