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Biomedical subjects

J Power

Publications and source records attributed to J Power.

At least 37 records · Page 2Linked to original sources
PubMed1995

Iodine-123 N-methyl-4-iododexetimide: a new radioligand for single-photon emission tomographic imaging of myocardial muscarinic receptors.

Cardiac muscarinic receptor ligands suitable for positron emission tomography have previously been characterised. Attempts to develop radioligands of these receptors suitable for single-photon emission tomographic (SPET) imaging have not been successful due to high lung retention and high non-specific binding of previously investigated potential tracers. The purpose of this study was to evaluate the biodistribution and in vivo imaging characteristics of a new radiopharmaceutical, [123I]N-methyl-4-iododexetimide. Biodistribution studies performed in rats showed high cardiac uptake (2.4% ID/g) 10 min after injection with a heart to lung activity ratio of 5:1. Specificity and stereoselectivity of cardiac binding were demonstrated using blocking experiments in rats. Dynamic imaging studies in anaesthetised greyhounds demonstrated rapid and high myocardial uptake and low lung binding with stable heart to lung activity ratios of > 2.5:1 between 10 and 30 min, making SPECT imaging feasible. Administration of an excess of an unlabelled muscarinic antagonist, methyl-quinuclidinyl benzylate rapidly displaced myocardial activity to background levels and the pharmacologically inactive enantiomer, [123I]N-methyl-4-iodolevetimide, had no detectable cardiac uptake, indicating specific and stereoselective muscarinic receptor binding. SPET revealed higher activity in the inferior than in the anterior wall, this being consistent with previously described regional variation of cardiac parasympathetic innervation. [123I]N-methyl-4-iododexetimide shows promise as an imaging agent for muscarinic receptor distribution in the heart and may be helpful in evaluating diverse cardiac diseases associated with altered muscarinic receptor function, including heart failure and diabetic heart disease.

Animals↗
PubMed1995

An outbreak of hepatitis A among Irish haemophiliacs.

BACKGROUND: An outbreak of hepatitis A (HAV) occurred in 1992 in Irish haemophilia A patients treated with high purity solvent-detergent (SD) treated factor VIII. Similar outbreaks were reported in Italy, Germany and Belgium. The aim of this study was to investigate the outbreak, and to test the hypothesis that it was caused by exposure to SD-treated factor VIII. METHODS: A case-control study was started in early 1993. Haemophilia A cases with acute HAV (n = 29) were compared with haemophilia A controls for exposure to SD-treated factor VIII and other environmental factors. Details of factor VIII usage were obtained from the National Haemophilia Register and environmental data were obtained by a telephone-administered questionnaire. The response rate was approximately 90%. RESULTS: The incidence of acute HAV infection among haemophilia A patients exceeded the notified national incidence of HAV by a factor of approximately 300. The incidence was higher in younger patients and those with more severe bleeding disorders. Contact with hepatitis, with children, and exposure to factor VIII were associated with increased risk. The association with factor VIII was the strongest risk factor after controlling for other factors (odds ratio = 27.6, 95% confidence interval [CI] 6.5-117.3). A dose-response effect was demonstrated. CONCLUSIONS: Although person-to-person transmission is likely to have caused a few of the cases, the results of our investigation suggest that the major contributing factor was exposure to certain batches of SD-treated factor VIII.

Adolescent↗
PubMed1995

A congenital heart defect in Drosophila caused by an action-potential mutation.

The mutation no action potential (nap) induces arrhythmia in the heartbeat of Drosophila melanogaster larvae at temperatures above 20 degrees C; heartbeat becomes normally rhythmic again after a shift back to 20 degrees C. For this phenotype, napa is almost completely recessive to the wild type, napa also reduces the temperature-sensitivity of heart rate over a wide range of temperature, for this phenotype, napa is dominant over the wild type, napa causes reversible paralysis in adults by epistatic effects on the expression of paralyrica, a gene encoding a voltage-dependent sodium channel. However, the paramutation, which induces paralysis in adults at 29 degrees C, has no effect on larval heartbeat at temperatures between 20 degrees and 37.5 degrees C. The period gene, contra earlier reports, has no effect on heartbeat.

Action Potentials↗
PubMed1995

The role of light in the initiation of circadian activity rhythms of adult Drosophila melanogaster.

Rearing Drosophila melanogaster in constant darkness (DD) for multiple generations disrupts the circadian activity rhythm of adults. In order to determine under what conditions normal rhythms can be initiated, DD-reared Drosophila (either the wild type or the periodshort [pers] mutant) were exposed to light either as embryos, third-instar larvae, or adults. Exposing DD-reared flies to light as embryos or larvae had no effect, while exposing them as adults fully restored normal rhythms in pers and partially restored normal rhythms in the wild type. The percentage of adults with normal rhythms was not significantly different between animals given a 1-h pulse of light as adults and animals given two LD cycles as adults. LD-reared and DD-reared animals given 2 LD cycles were synchronous. In the latter, offset of activity followed the LD transition (CT 12) by 2-6 subjective hours in pers and 2-3 subjective hours in per+. Circadian rhythms did not exhibit phase coherence in the other treatments.

Activity Cycles↗
PubMed1994

Effect of antibody valency on interaction with cell-surface expressed HIV-1 and viral neutralization.

F(ab) and F(ab')2 fragments of the human mAb, F105, were compared to intact IgG1 for binding to the CD4 binding site of HIV-1/gp120 on the surface of infected cells and viral neutralization. F105 IgG1 and F(ab')2 bound to IIIB, MN, and RF infected cells and neutralized these strains in an identical fashion, whereas strain-specific differences were observed in F(ab) activity. Although F105 F(ab) bound with equivalent affinity to IIIB-infected cells, there was a 4- to 10-fold decrease in the neutralization of IIIB by monovalent F(ab) compared to the bivalent molecules. F105 F(ab) demonstrated both diminished binding and neutralization of the MN strain and failed to bind or neutralize the RF strain. When cooperativity of V3 loop antibody (V3ab) with F105 IgG and fragments was examined, the binding of F105 IgG and F(ab')2 to IIIB-, MN-, or RF-infected cells was modestly enhanced by V3ab; viral neutralization was substantially enhanced by the combination of V3ab and F105 IgG and F(ab')2. The combination of F105 F(ab) with V3ab also resulted in significant cooperative neutralization of IIIB and MN, but the lack of F105 F(ab) binding and neutralization of RF was unaltered by V3ab. These results suggest that bivalent interaction may be important in binding and neutralization of virus, and support the notion that this interaction may depend on conformational changes in oligomeric gp120 on intact virions and cell surface rather than on affinity or steric effects.

Antibodies, Monoclonal↗
PubMed1994

The bop2-1 mutation reveals radial asymmetry in the inner dynein arm region of Chlamydomonas reinhardtii.

Strains of Chlamydomonas reinhardtii with a mutant allele at the BOP2 locus swim slowly and have an abnormal flagellar waveform similar to previously identified strains with defects in the inner arm region. Double mutant strains with the bop2-1 allele and any of 17 different mutations that affect the dynein arm region swim more slowly than either parent, which suggests that the bop2-1 mutation does not affect solely the outer dynein arms, the I1 or ida4 inner dynein arms, or the dynein regulatory complex. Flagellar axonemes isolated from bop2-1 cells are missing a phosphorylated polypeptide of 152 kD. Electron microscopic analysis shows that bop2-1 axonemes are missing density in the inner dynein arm region. Surprisingly, two populations of images were observed in longitudinal sections of axonemes from the bop2-1 strain. In the 10 longitudinal axonemes examined, a portion of the dynein regulatory complex and a newly identified structure, the projection, are affected. In five of these 10 longitudinal axonemes examined, two lobes of the ida4 inner arm are also missing. By examining the cross-sectional images of wild-type and bop2-1 axonemes at each outer doublet position around the axoneme, we have determined that the bop2-1 mutation affects the assembly of inner arm region components in a doublet specific manner. Doublets 5, 6, and 8 have the most severe deficiency, doublet 9 has an intermediate phenotype, and doublets 2, 3, 4, and 7 have the least severe phenotype. The bop2-1 mutation provides the first evidence of radial asymmetry in the inner dynein arm region.

Animals↗
PubMed1994

Phase I study of adozelesin (U-73,975) in patients with solid tumors.

During a phase I clinical and pharmacologic trial, 26 patients with refractory solid tumors were treated with increasing doses of adozelesin by brief intravenous infusion every 3 weeks. Overall, adozelesin was well tolerated. The dose-limiting toxicity was myelosuppression, mainly thrombocytopenia and leukopenia. Nonhematologic toxicity was generally mild, with fatigue (36%), local reaction at the infusion site (24%), nausea or vomiting (20%) and hypersensitivity reaction (16%) being the most common adverse effects. There were no objective clinical responses. The maximally tolerated dose on this schedule was 188 micrograms/m2 with the recommended phase II starting dose being 150 micrograms/m2 on an every 3 week schedule. Adozelesin merits broad investigation at the phase II level.

Adult↗
PubMed1994

Plasma pharmacokinetics and biological activity of a human immunodeficiency virus type 1 neutralizing human monoclonal antibody, F105, in cynomolgus monkeys.

The IgG1 kappa human monoclonal antibody (HMab), F105 reacts with a discontinuous epitope on the CD4 binding site (CD4BS) of human immunodeficiency virus type 1 (HIV-1)/gp120 and has broad neutralizing activity. F105 HMab (60 mg/kg bolus) was administered intravenously to four monkeys and serum was collected at intervals to determine pharmacokinetics in a primate model. Average serum F105 concentrations, as determined by enzyme-linked immunosorbent assay, were analyzed with MINSQ software using a two-compartment, first-order model. The half-life for the alpha phase of the distribution curve is 6.7 h and for the beta elimination phase, 9.6 days. The volume of distribution is 0.65 L/kg and the rate of clearance 2 ml/kg/h. Serum levels of 1.3-1.6 mg/ml of F105 were maintained for 24 h. When monkey serum from day 15 postdose was tested, total serum F105 was 230 +/- 79 micrograms/ml and was immunoreactive with cells infected with the MN and IIIB strains of HIV-1 as determined by flow cytometry. Binding activity was identical to that obtained with stock F105 HMab. Identical neutralizing activity between the injected and uninjected antibody was also observed. Thus, serum neutralizing titers (90%) of 1:2000 at peak and 1:30 at day 15 postdose for MN virus were observed. These data indicate that high in vivo levels of HMab F105 can be attained by single bolus administration with full retention of biological activity. Of importance, levels of antibody necessary for effective neutralization can be achieved and maintained.

Animals↗
PubMed1994

A mathematical model of sinus node function: validation by recording of sinus node electrograms.

We have applied a mathematical function to model sinus node recovery after atrial pacing at different cycle lengths in 13 autonomically denervated, anesthetized canines. This model provides "pure" indexes of sinoatrial conduction and of suppression of automaticity. We compared sinoatrial conduction computed from the model (SACTc) with sinoatrial conduction measured directly utilizing a catheter recording the sinus node electrogram (SACTd) to test the validity of the model. We used both the model and the sinus node electrogram to further define events after pacing. There was close agreement between SACTc and SACTd with correlation coefficients at pacing cycle lengths of 20 and 50% below resting of 0.86 (P < 0.0001) and 0.78 (P < 0.0001), respectively. We verified that the conventional sinus node recovery time is due both to suppression of automaticity and prolongation of sinoatrial conduction. Sinoatrial conduction time returned rapidly to normal over 1-3 beats, whereas automaticity recovered exponentially over 20-40 postpacing intervals. The model accurately describes postpacing phenomena and has the potential to provide a useful adjunct to the measurement of the sinus node electrogram for assessment of sinus node function in the experimental laboratory.

Animals↗
PubMed1993

Pharmacokinetics and protein binding of 3-ketodesogestrel and gestodene in the serum of women during 6 cycles of treatment with two low dose oral contraceptives.

The serum concentrations of 3-ketodesogestrel (KDG) and gestodene have been measured in 30 and 31 women respectively who took low dose oral contraceptives containing 30 micrograms ethinylestradiol together with either 150 micrograms desogestrel or 75 micrograms gestodene for 6 months. On days 1, 10 and 21 of the first third and sixth treatment cycles blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4 and 24 h. KDG and gestodene levels were measured by radioimmunoassays and were evaluated for Cmax (peak serum concentration), tmax (time to Cmax), and AUC (area under the curve) to 4 and 24 h. The overall total gestodene concentrations were higher and the accumulation of the steroid throughout a cycle greater than that of KDG. For example, the AUC0-4 of gestodene increased in cycle 1 by a factor of 2.8 (day 10 vs. day 1) and 3.6 (day 21 vs. day 1) compared to 2.3 and 2.6 for KDG. The higher concentration of gestodene reflects a lower volume of distribution than KDG, and is consistent with gestodene binding to sex hormone binding globulin (SHBG) with a higher affinity than KDG. Concentrations of KDG and gestodene were higher on day 1 of cycles 3 and 6 than on day 1 of cycle 1. The serum concentrations of KDG and gestodene during multiple dosing cannot be predicted on the basis of single dose pharmacokinetics.

Adolescent↗
PubMed1993

Loss of serum antibodies to a conformational epitope of HIV-1/gp120 identified by a human monoclonal antibody is associated with disease progression.

Serum antibody reactive with epitopes within the CD4 binding site (CD4BS) of HIV-1/gp120 on infected cells was measured by inhibition of binding of a human monoclonal antibody, F105, which recognizes a conformational epitope within this region. Serum samples from 27% of ARC/AIDS patients blocked binding of F105 to this epitope, while samples from 100% of asymptomatic seropositive patients blocked binding. F105 blocking activity increased in 87% of asymptomatic donors who maintained stable disease over a 3-6 year period and decreased in 50% of asymptomatic patients with progressive disease. Moreover, serum samples from patients with stable disease exhibited higher titers of F105 blocking activity. The presence of F105 blocking activity also correlated with serum neutralization of virus. When diluted 1:640, serum with low F105 blocking activity neutralized only 20-30% of viral cytopathic effect (CPE), while serum with high F105 blocking activity neutralized > 80%. Serum neutralization was enhanced by the addition of F105. Seroreactivity to infected cells was detectable within 6 months of seroconversion, but F105 blocking activity was delayed by an additional 6-12 months, as was the development of high titers of neutralizing antibody. These data support the notion that the humoral response to the CD4BS on gp120 may be important in the maintenance of health.

AIDS-Related Complex↗
PubMed1993

Neutralization of HIV-1 by F105, a human monoclonal antibody to the CD4 binding site of gp120.

The functional ability of the human monoclonal antibody (HMab) F105 to neutralize commonly available laboratory strains and a selection of primary isolates of human immunodeficiency virus (HIV)-1 was studied. F105 is representative of a class of human antibodies that react with conformational epitopes within the discontinuous CD4 binding site on HIV-1 envelope glycoprotein gp120. F105 binds with relatively similar affinities to native antigen expressed on the surfaces of cells infected with each of five laboratory isolates tested (IIIB, SF2, MN, RF, and CC) and neutralizes SF2, IIIB, and MN with concentrations of antibody ranging from 140 ng to 10 micrograms/ml. Nonetheless, neutralization by F105 alone of RF and CC is poor at modest antibody concentrations despite high affinity binding to surface gp120 on infected cells. Neutralization of HIV-1 strains by F105 is unaffected by normal sera and cooperativity is observed with serum samples from HIV-1 infected patients. Of significance, neutralization of RF and MN by F105 is enhanced by some HIV-seropositive sera at low concentrations. F105 also neutralized 30% of HIV-1 primary isolates in lymphocyte cultures. Although it is unclear how relevant in vitro studies will be to in vivo events, these data allow comparison of F105 with other HMabs to the CD4 binding site and V3 loop and provide an in vitro reference for in vivo activity. These studies demonstrate that antibody interactions among different classes of antibodies may be important in in vivo neutralization of HIV-1.

Antibodies, Monoclonal↗
PubMed1993

Human monoclonal antibodies to the V3 loop of HIV-1 gp120 mediate variable and distinct effects on binding and viral neutralization by a human monoclonal antibody to the CD4 binding site.

Interactive effects between human monoclonal antibodies specific for the V3 loop (257-D and 447-D) and an epitope within the CD4 binding site (F105) of HIV-1 gp120 were evaluated for neutralization of viral cytopathogenicity and binding to HIV-infected cells. Regardless of antibody pair, only additive effects were observed in neutralization of MN and SF2 virus though each antibody alone had potent neutralizing activity on these strains. Significant cooperativity was observed between F105 and 447-D in neutralization of RF. Relatively high concentrations (> 100 micrograms/ml) of each individual antibody are required for partial neutralization (25--40%) of RF. Coincubation with 10 micrograms/ml of each antibody increased neutralization activity 3--4-fold more than predicted for additive effects alone. No enhancement was seen upon coincubation of F105 with 257-D which does not neutralize RF. Antibody interactions with native antigen on HIV-infected cells was measured by flow cytometry. Results were consistent with neutralization results in the majority of flow cytometry experiments; however, enhanced binding did not necessarily predict enhanced neutralization. These data support the notion that either a conformational change occurs with binding of V3 loop antibodies which enhances the binding and neutralizing activity of antibodies directed to the CD4 binding site of gp120 or vice versa, or new antigenic sites are exposed by the V3 loop antibodies on cell surfaces and virions. Of importance, cooperativity is observed even at very low antibody concentrations.

Animals↗
PubMed1992

Modelling the growth and protein production by insect cells following infection by a recombinant baculovirus in suspension culture.

A mathematical model has been developed to describe the growth and infection of insect cells by recombinant baculoviruses. The model parameters were determined from a series of independent experiments involving batch suspension culture. The profiles generated by the model for cell growth, virus production and protein production agree with those observed in experiments. Presently, the model simulates only systems where cells are not growth-limited. The model is useful in aiding the design and optimization of large-scale systems for production of biological insecticides as well as recombinant proteins and in delineating those areas which are limiting the process and require further, more fundamental, investigation.

Animals↗
PubMed1992

Extragenic suppressors of paralyzed flagellar mutations in Chlamydomonas reinhardtii identify loci that alter the inner dynein arms.

We have analyzed extragenic suppressors of paralyzed flagella mutations in Chlamydomonas reinhardtii in an effort to identify new dynein mutations. A temperature-sensitive allele of the PF16 locus was mutagenized and then screened for revertants that could swim at the restrictive temperature (Dutcher et al. 1984. J. Cell Biol. 98:229-236). In backcrosses of one of the revertant strains to wild-type, we recovered both the original pf16 mutation and a second, unlinked suppressor mutation with its own flagellar phenotype. This mutation has been identified by both recombination and complementation tests as a new allele of the previously uncharacterized PF9 locus on linkage group XII/XIII. SDS-PAGE analysis of isolated flagellar axonemes and dynein extracts has demonstrated that the pf9 strains are missing four polypeptides that form the I1 inner arm dynein subunit. The primary effect of the loss of the I1 subunit is a decrease in the forward swimming velocity due to a change in the flagellar waveform. Both the flagellar beat frequency and the axonemal ATPase activity are nearly wild-type. Examination of axonemes by thin section electron microscopy and image averaging methods reveals that a specific domain of the inner arm complex is missing in the pf9 mutant strains (see accompanying paper by Mastronarde et al.). When combined with other flagellar defects, the loss of the I1 subunit has synergistic effects on both flagellar assembly and flagellar motility. These synthetic phenotypes provide a screen for new suppressor mutations in other loci. Using this approach, we have identified the first interactive suppressors of a dynein arm mutation and an unusual bypass suppressor mutation.

Animals↗