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Biomedical subjects

M Moghaddam

Publications and source records attributed to M Moghaddam.

16 recordsLinked to original sources
PubMed2005

Prospective evaluation of a new platelet glycoprotein (GP)-specific assay (PakAuto) in the diagnosis of autoimmune thrombocytopenia (AITP).

Assays measuring platelet-associated immunoglobulin G (PAIgG), while highly sensitive, lack specificity in diagnosing autoimmune thrombocytopenia (AITP). We prospectively evaluated a new commercially available glycoprotein (GP)-specific assay, the PakAuto (GTI, Brookfield, WI), for its clinical usefulness in distinguishing immune from nonimmune thrombocytopenia (TP), in 216 patients with autoimmune TP (both primary "idiopathic" and "secondary") and 46 patients with TP due to other causes. This assay is designed to detect both platelet-associated (direct assay) and plasma (indirect assay) antiplatelet antibodies specific for GPs IIb/IIIa, Ib/IX, and Ia/IIa. The mean platelet counts of the immune (79 +/- 7 x 10(9)/L) and nonimmune groups (78 +/- 7 x 10(9)/L), were similar (P=0.95). The direct assay was positive in 114/216 patients with AITP (53%), and 13/46 with nonimmune TP (28%). Among the AITP group, the majority (61%) of patients with positive test results had autoantibodies reactive against all three GP targets. The sensitivity, specificity, positive, and negative predictive values for the direct PakAuto were 53%, 72%, 90%, and 24%, respectively, comparable to previously published experience of GP-specific assays. However, in some cases of TP due to nonimmune cause, the PakAuto was highly specific. Only 3 of 22 patients with gestational and 1 of 8 with familial/congenital TP had a positive direct assay, indicating that the test may be particularly useful for excluding an immune etiology for TP in certain patient subgroups.

Adolescent↗
PubMed2004

Preclinical evaluation of a prostate-targeted gene-directed enzyme prodrug therapy delivered by ovine atadenovirus.

Gene-directed enzyme prodrug therapy (GDEPT) based on the Escherichia coli enzyme, purine nucleoside phosphorylase (PNP), provides a novel strategy for treating slowly growing tumors like prostate cancer (CaP). PNP converts systemically administered prodrug, fludarabine phosphate, to a toxic metabolite, 2-fluoroadenine, that kills PNP-expressing and nearby cells by inhibiting DNA, RNA and protein synthesis. Reporter gene expression directed by a hybrid prostate-directed promoter and enhancer, PSMEPb, was assayed after plasmid transfection or viral transduction of prostate and non-CaP cell lines. Androgen-sensitive (AS) LNCaP-LN3 and androgen-independent (AI) PC3 human CaP xenografts in nude mice were injected intratumorally with an ovine atadenovirus vector, OAdV623, that carries the PNP gene under PSMEPb, formulated with cationic lipid for enhanced infectivity. Fludarabine phosphate was then given intraperitoneally for 5 days at 75 mg/m2/day. PNP expression was evaluated by enzymic conversion of its substrate using reverse phase HPLC. OAdV623 showed excellent in vitro transcriptional specificity for CaP cells. In vivo, expression of PNP persisted for > 6 days after OAdV623 injection and a single treatment provided 100% increase in tumor doubling time and > 50% inhibition of tumor growth for both LNCaP-LN3 and PC3 lines, with increased tumor necrosis and apoptosis and decreased tumor cell proliferation. OAdV623 significantly suppressed the growth of AS and AI human CaP xenografts in mice.

Adenine↗
PubMed2001

Identification and validation of P311 as a glioblastoma invasion gene using laser capture microdissection.

The mRNA expression profiles from glioblastoma cells residing at the tumor core and invasive rim of a human tumor resection were compared. From a single tumor specimen, 20,000 single cells from each region were collected by laser capture microdissection. Differential expression of 50-60 cDNA bands was detected. One of the sequences overexpressed by the invasive cells showed 99% homology to the P311 gene, the protein product of which is reported to localize at focal adhesions. Relative overexpression of P311 by invading glioblastoma cells compared with tumor core was confirmed by quantitative reverse transcription-PCR of six glioblastoma specimens after laser capture microdissection collection of rim and core cells. In vitro studies using antisense oligodeoxynucleotides and integrin activation confirmed the role of P311 in supporting migration of malignant glioma cells. Immunochemistry studies confirmed the presence of the P311 protein in tumor cells, particularly at the invasive edge of human glioblastoma specimens.

Amino Acid Sequence↗
PubMed2001

Heparin is not required for detection of antibodies associated with heparin-induced thrombocytopenia/thrombosis.

Heparin-induced thrombocytopenia (HIT), with or without thrombosis, is a common and often serious complication of heparin therapy. Platelet-activating, heparin-induced antibodies characteristic of HIT are thought to be specific for complexes formed between platelet factor 4 (PF4) and heparin, and such complexes are routinely used for antibody detection. We studied the binding of HIT antibodies to PF4 complexed with heparin fractions of uniform molecular size or linear polyanions other than heparin and found that many compounds other than heparin form complexes with PF4 that are suitable for antibody detection, provided they carry strong negative charges spaced about 0.5 nm apart along the molecular backbone and are of sufficient length to span about 40% of the circumference of the PF4 tetramer. Polyvinyl phosphonate was among the compounds that were equivalent to heparin. Thus neither a polysaccharide chain nor sulfate side groups--the hallmarks of heparin structure--are required for HIT antibody detection. The findings support the view that antibodies associated with HIT are specific for conformational changes that take place in the positively charged PF4 molecule when it reacts with a suitable, linear polyanion.

Antibody Specificity↗
PubMed2000

Tris lipidation: a chemically flexible technology for modifying the delivery of drugs and genes.

1. One of the major challenges in the development of pharmaceuticals is their formulation with other materials to give them the desired bioavailability profile when administered into the body. 2. We have developed a flexible platform technology (Tris lipidation) to simply and effectively alter the lipophilicity of drugs. As implied by the name, the technology uses the common buffer Tris as a linker between the drugs of interest and a domain of variable hydrophobicity. 3. We demonstrate, using a mouse melanoma model, that Tris-lipidated conjugates of the widely used cytotoxic and anti-inflammatory drug methotrexate (MTX) display enhanced potency in the local treatment of tumours and reduced systemic toxicity when compared with the unconjugated drug. 4. With genes now being predicted to be the pharmaceuticals of the future, we show that Tris-lipidated cationic peptides can efficiently deliver DNA into (transfect) cells in culture. Furthermore, by comparing the abilities of variants of these Tris-based cationic lipids to transfect cultured cells, we demonstrate that modifications made to variable regions of Tris-lipidated compounds can dramatically alter their delivery profiles.

Animals↗
PubMed1997

Rotation of water in the Morris water maze interferes with path integration mechanisms of place navigation.

The idea that place navigation in the Morris water maze is implemented by path integration between locations determined by landmark sighting was investigated in a 200-cm-diameter pool in which circular (7.2 degrees/s) motion of water could be induced by tangentially arranged water jets. The rats were trained at 8 trials per day to navigate to an erectable platform which was raised after the rat had spent a criterion time in the target annulus (30 cm in diameter) in the midpoint of the NW quadrant. Asymptotic escape latency of 7 s was reached after 9 days in moving water (n = 8) and after 6 days in stationary water (n = 8). The group overtrained for 13 days in stable water performed well even after it was transferred to moving water. Changing the sense of rotation of water from counterclockwise to clockwise did not affect the asymptotic performance. The above findings show that overtrained rats rely on landmark sighting rather than on path integration. The influence of water movement reappeared when place navigation to a new target (SW) was examined in alternating 2-s periods of light (L) and darkness (D). On the first day, the latencies were 15.2 +/- 1.2 and 22.8 +/- 1.9 s in stable and moving water, respectively, but dropped to 10 s on the following day. The tracks generated in the L period were more tortuous than those generated in the D period and this difference was more pronounced in moving than in stable water. It is concluded that path integration mechanisms supporting navigation during intervals of darkness are impaired in moving water but that this impairment disappears in overtrained animals.

Animals↗
PubMed1996

Novel metabolic pathways for linoleic and arachidonic acid metabolism.

Mouse liver microsomes oxidized linoleic acid to form 9,10- or 12,13-epoxyoctadecenoate. These monoepoxides were subsequently hydrolyzed to their corresponding diols in the absence of the microsomal epoxide hydrolase inhibitor, 1,2-epoxy-3,3,3-trichloropropane. Furthermore, both 9,10- and 12,13-epoxyoctadecenoates were oxidized to diepoxyoctadecanoate at apparently identical rates by mouse liver microsomal P-450 epoxidation. Both epoxyoctadecanoates and diepoxyoctadecanoates were converted to tetrahydrofuran-diols by microsomes. Tetrahydroxides of linoleate were produced as minor metabolites. Arachidonic acid was metabolized to epoxyeicosatrienoates, dihydroxyeicosatrienoates, and monohydroxyeicosatetraenoates by the microsomes. Microsomes prepared from clofibrate (but not phenobarbital) -treated mice exhibited much higher production rates for epoxyeicosatrienoates and vic-dihydroxyeicosatrienoates. This indicated an induction of P-450 epoxygenase(s) and microsomal epoxide hydrolase in mice by clofibrate and not by phenobarbital. Incubation of synthetic epoxyeicosatrienoates with microsomes led to the production of diepoxyeicosadienoates. Among chemically generated diepoxyeicosadienoate isomers, three of them possessing adjacent diepoxides were hydrolyzed to their diol epoxides which cyclized to the corresponding tetrahydrofuran-diols by microsomes as well as soluble epoxide hydrolase at a much higher rate. Larger cyclic products from non-adjacent diepoxides were not observed. The results of our in vitro experiments suggest that linoleic and arachidonic acid can be metabolized to their tetrahydrofuran-diols by two consecutive microsomal cytochrome P-450 epoxidations followed by microsomal or soluble epoxide hydrolase catalyzed hydrolysis of the epoxides. Incubation experiments with the S-9 fractions indicate that the soluble epoxide hydrolase is more important in this conversion. This manuscript is the first report of techniques for the separation and identification of regio and geometrical isomer of an interesting class of oxylipins and their metabolism by liver microsomes and S-9 fractions to THF-diols.

Animals↗
PubMed1996

Vestibular navigation directed by the slope of terrain.

Slope of terrain is an important orienting gradient affecting the goal-directed locomotion of animals. Its significance was assessed in experiment 1 by training rats to find in darkness a feeder on the top of a low cone (80-cm base, 0- to 4-cm high). A computerized infrared tracking system monitoring the rat's position in darkness showed that the path length on the cone surface was inversely proportional to cone height. A device allowing continuous generation of slope-guided locomotion was used in experiment 2. This device consists of a 1-m arena, the floor of which can be supported at a point corresponding to the position of one of three equidistant feeders located 17 cm from its center. The arena is inclined by the locomotion of the rat to a plane passing through the elevated (2- or 4-cm) feeder, the rat's center of gravity, and a point at the edge of the arena resting on the floor. The multitude of such planes generated by the rat's locomotion forms the surface of a virtual cone, the top of which is formed by the feeder. Additional path (difference between distance traveled and shortest distance of the animal from the goal at the onset of inclination) is inversely related to the incline of the arena and is a sensitive measure of performance in this type of vestibular navigation.

Animals↗
PubMed1996

Contribution of egocentric spatial memory to place navigation of rats in the Morris water maze.

Place navigation in the Morris water maze can be directed by memory of the target coordinates relative to remote landmarks (allocentric) or by the memory of the start-goal route (egocentric). When the start and goal positions remain constant and visual cues are eliminated by darkness, memory of the route may become decisive. This assumption was tested in 10 male hooded rats using an infrared television tracking system allowing navigation training in the dark. In Expt. 1, these animals were trained to swim in the dark from the start at the S rim of the pool to the goal position in the center of the NW quadrant of the pool. Mean escape latencies decreased from 47 s initially to 16 s during the 24 daily sessions. Another group of 10 male hooded rats learned the same task in the light. Mean escape latencies decreased from 20 s initially to 5 s during 4 daily sessions. In Expt. 2, possible allocentric location of the target was tested in the same rats by rotating both the start and goal positions by 90 degrees counterclockwise (i.e., to E-SW and later to N-SE). Mean escape latency during 5 days after the first rotation increased to 24 s, but returned back to the asymptotic level of 18 s after the second rotation. The same change of the start and goal position (from S-NW to E-SW) in the light only increased escape latency in the first session. In Expt. 3, both the goal position and route direction were changed to N-SW. Surprisingly, the animals rapidly acquired a new heading angle at the start and mean escape latencies were not significantly changed. It is concluded that overtrained place navigation in darkness can be easily changed to a new direction.

Animals↗
PubMed1996

Effects of lesions of the associative parietal cortex on the acquisition and use of spatial memory in egocentric and allocentric navigation tasks in the rat.

It has been hypothesized that the rat associative parietal cortex (APC) is involved in the association between visuospatial and locomotion-generated (kinesthetic) information. To study the kinesthetic component, APC-lesioned and control rats were trained in total darkness to reach a submerged platform in the Morris water maze. In the egocentric task, the relative position of the starting point and the platform was constant all over training. Parietal rats have been found impaired in acquisition and to a less extent in retention of this task. In the allocentric task, rats were then trained in the standard version of the navigation task. A mild deficit was observed in acquisition of this task because the APC-lesioned rats displayed longer escape latencies but control-like search patterns. These results suggest that the APC is involved in the coding of kinesthetic information that plays an important role in place navigation.

Animals↗
PubMed1993

Variable density linear acoustic inverse problem.

The linear acoustic inverse problem is solved simultaneously for density (rho) and compressibility (kappa) using the basic ideas of diffraction tomography (DT). The key to solving this problem is to utilize frequency diversity to obtain the required independent measurements. The receivers are assumed to be in the far field of the object, and plane wave incidence is also assumed. The Born approximation is used to arrive at a relationship between the measured pressure field and two terms related to the spatial Fourier transform of the two unknowns, rho and kappa. The term involving compressibility corresponds to monopole scattering and that for density to dipole scattering. Measurements at several frequencies are used and a least squares problem is solved to reconstruct rho and kappa at the same time. It is observed that the low spatial frequencies in the spectra of rho and kappa produce inaccuracies in the results. Hence, a regularization method is devised to remove this problem. Several results are shown. Low contrast objects for which the above analysis holds are used to show that good reconstructions are obtained for both density and compressibility after regularization is applied.

Acoustics↗
PubMed1991

Oxylipin metabolism in the red alga Gracilariopsis lemaneiformis: mechanism of formation of vicinal dihydroxy fatty acids.

Conversion of arachidonic acid into the vicinal diol fatty acid 12R,13S-dihydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid using an acetone powder of the marine red alga, Gracilariopsis lemaneiformis, occurred via intermediate formation of 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid. Incubations of the linoleic acid-derived 13S- and 13R-hydroperoxy-9Z,11E-octadecadienoic acids led to the formation of 13R,14S-dihydroxy-9Z,11E-octadecadienoic acid and 13S,14S-dihydroxy-9Z,11E-octadecadienoic acid, respectively, whereas incubation of 9S-hydroperoxy-10E,12Z-octadecadienoic acid resulted in the formation of 8S,9R-dihydroxy-10E,12Z-octadecadienoic acid. Experiments with 18O2-labeled 13S-hydroperoxyoctadecadienoic acid demonstrated that the oxygens of the two hydroxyl groups of 13R,14S-dihydroxy-9Z,11E-octadecadienoic acid originated in the hydroperoxy group of the substrate. Furthermore, experiments with mixtures of unlabeled and 18O2-labeled 13S-hydroperoxyoctadecadienoic acid showed that conversion into 13R,14S-dihydroxyoctadecadienoic acid occurred by a reaction involving an intramolecular hydroxylation at C-14 by the distal hydroperoxide oxygen. The existence of a hydroperoxide isomerase in G. lemaneiformis which catalyzes the conversion of fatty acid hydroperoxides into vicinal diol fatty acids is postulated.

Arachidonic Acids↗
PubMed1987

Mechanical slicing of frozen brain tissue: a reappraisal of catecholamine loss.

Catecholamine levels in mechanically sliced frozen bovine brain tissue were compared with those found in hand-cut, unfrozen tissue. Hemispheric content of catecholamines in small regions of cortex, caudate, nucleus accumbens, thalamus, and hippocampus in bovine brain was no different from that seen in the homologous area of the contralateral hemisphere, despite selective slicing of opposing hemispheres with the two techniques. Brodmann area 25 in human brain (previously suspected to be highly vulnerable to degradative loss of catecholamines by mechanical slicing) is shown to be a restricted area of dense catecholamine concentration when compared to surrounding cortical tissue. The usage of Brodmann area 25 for technique comparisons without precise control of cortical delineation is questioned.

Animals↗