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Biomedical subjects

D Dixon

Publications and source records attributed to D Dixon.

At least 73 records · Page 4Linked to original sources
PubMed1989

Implanted coil MR microscopy of renal pathology.

Inductively coupled implanted coils have been shown to provide up to a 10-fold increase in signal-to-noise ratio when compared to whole-body imaging of small animals. The current study was designed to extend the implanted coil imaging technique to a rodent model of renal pathology. Resonant radiofrequency (RF) coils were implanted around the left kidney of four rats and inductively coupled from within a birdcage body coil. All images were acquired at 2 T using a T1-weighted spin-echo sequence with TR = 500 ms and TE = 20 ms. In vivo MR microscopy with voxels of 117 x 117 x 2000 microns demonstrated cortex, inner and outer medulla, and major vascular structures on baseline images. Mercuric chloride-induced nephrotoxic acute tubular necrosis (ATN) diminished cortico-medullary contrast at 24 h after dosing with pathologic evaluation demonstrating nephrotoxic changes in the inner cortex. The kidney regained a baseline MR appearance 360 h after dosing and resolution of the damage was confirmed with histology. T1 data were gathered on excised kidneys as an adjunct to the images to help correlate the loss and return of cortico-medullary contrast with the pathology and pathophysiology of nephrotoxic ATN. With implanted RF coils we were able to demonstrate renal pathology and follow its subsequent resolution. Specifically, loss and return of cortico-medullary contrast as a result of nephrotoxic ATN were serially documented in four rats. Such serial in vivo studies performed on single animals should further the use of MR microscopy by minimizing the number of animals required for adequate biostatistics.

Animals↗
PubMed1989

Rapid introduction of long-lasting synaptic changes at crustacean neuromuscular junctions.

In this review we present recent evidence implicating second-messenger systems in two forms of long-lasting synaptic change seen at crustacean neuromuscular junctions. Crustacean motor axons are endowed with numerous terminals, each possessing many individual synapses. Some synapses appear to be quiescent or impotent, but can be recruited in response to imposed functional demands. Supernormal impulse activity leads to long-term facilitation (LTF) which persists for many hours. During the persistent phase, additional synapses are physiologically effective, and morphological changes in synapses are seen at the ultrastructural level. Pulsatile application of serotonin, a neuromodulator, also enhances synaptic transmission, but this enhancement declines more rapidly than LTF. Elevation of intraterminal Ca2+ is neither necessary nor sufficient for long-lasting enhancement of transmission, but activation of A-kinase is necessary. LTF is set in motion by an unknown depolarization-dependent mechanism leading to A-kinase activation, whereas serotonin facilitation depends for its initiation on the phosphatidylinositol system. The initial phase of serotonin facilitation may be accounted for by production of inositol triphosphate, whereas the secondary long-lasting phase appears to require participation of both C kinase and A kinase. Neither LTF nor serotonin facilitation requires an intact neuron; both are presynaptic phenomena expressed by the nerve terminals. Brief comparison is made with long-lasting synaptic changes in other systems.

Animals↗
PubMed1989

Gallbladder function is altered in sickle hemoglobinopathy.

Despite comparable rates of hemolysis, only 50% of patients with sickle hemoglobinopathy (SH) develop pigment gallstones by age 20 yr. Thus, pathogenetic factors, other than hemolysis, may contribute to gallstone formation. In the present study we determined whether gallbladder function, measured by real-time ultrasonography or bile acid metabolism, determined by isotope dilution-mass spectrometry, were altered in adolescents and young adults with SH. Compared with healthy controls, SH subjects had larger fasting (27 +/- 16 vs. 15 +/- 5 ml, p less than 0.02), and residual (8 +/- 6 vs. 4 +/- 2 ml, p less than 0.03) volumes of the gallbladder, but similar rates of emptying (0.029 +/- 0.016 vs. 0.034 +/- 0.029 min-1) and percentage of fasting volume emptied (71% +/- 13% vs. 72% +/- 14%). In SH subjects, the volume and emptying of the gallbladder were similar between those with and without gallstones. Some SH subjects had stasis of bile within the gallbladder, as demonstrated by isotopic disequilibrium between the circulating bile acid pool and bile stored in the gallbladder. Subjects with SH with gallstones tended to have smaller bile acid pools than SH subjects without gallstones (81 +/- 11 vs 163 +/- 91 mumol/kg, p = 0.051). We conclude that adolescents and young adults with SH have enlarged gallbladders that retain an increased postprandial volume of bile. Bile retention within the gallbladder may lead to stasis and contribute to the pathogenesis of pigment gallstones.

Adolescent↗
PubMed1989

Phosphatidylinositol system's role in serotonin-induced facilitation at the crayfish neuromuscular junction.

1. In a crustacean neuromuscular preparation, the walking leg opener muscle of the freshwater crayfish Procambarus clarkii, application of serotonin (1 microM) produces presynaptic depolarization and long-lasting facilitation of excitatory postsynaptic potentials (EPSPs). The frequency of spontaneously released transmitter quanta also increases. Facilitation of evoked EPSPs declines after serotonin application in two phases. 2. Serotonin-induced facilitation was examined using simultaneous pre- and postsynaptic intracellular microelectrode recording. A presynaptic microelectrode recorded action potentials and membrane potential of a presynaptic axonal branch, and one or more postsynaptic microelectrodes recorded EPSPs in muscle fibers innervated by the excitatory motor axon. Components of the phosphatidylinositol second messenger system and pharmacologic agents affecting this system were injected through the presynaptic electrode, and changes in synaptic transmission were measured. 3. Presynaptic injection of inositol 1,4,5-triphosphate (IP3) causes presynaptic depolarization, increases the frequency of spontaneously released transmitter quanta, and promotes a relatively short-lasting facilitation of evoked EPSPs. These actions are consistent with elevation of intracellular Ca2+ and resemble the early phase of serotonin-induced facilitation. 4. Application of a phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), that activates protein kinase C (C-kinase), produces a long-lasting, low-level facilitation of evoked EPSPs. Application of another phorbol ester, phorbol-12-monoacetate (PTMA), which does not activate C-kinase has no effect. 5. Presynaptic injection of RA 233, a phospholipase C (PLP-C) inhibitor, blocks all aspects of serotonin-induced facilitation. This compound was found to have no general deleterious effects on synaptic transmission and does not block other forms of synaptic facilitation in this preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Conjoint action of phosphatidylinositol and adenylate cyclase systems in serotonin-induced facilitation at the crayfish neuromuscular junction.

1. Pulsatile application of serotonin (5-HT) leads to facilitation of excitatory postsynaptic potentials (EPSPs) in crayfish "opener" neuromuscular preparations. The facilitation resulting from a single application of serotonin shows two phases: an early, rapidly decaying phase, and a less intense, long-lasting phase of 1- to 2-h duration. A previous study implicated the phosphatidylinositol system as an essential component in serotonin-induced facilitation, especially the early phase. The present study was conducted to determine the roles of the adenylate cyclase and phosphatidylinositol systems in both phases of serotonin-induced facilitation. 2. Relatively brief applications of agents known to affect the intracellular concentration of cAMP (forskolin, 1 microM; and IBMX, 100 microM) cause an increase in EPSP amplitude, which persists for 1-2 h. 3. The duration of the less intense, long-lasting phase of serotonin-induced facilitation is prolonged in the presence of 1 microM IBMX. This concentration of IBMX does not affect EPSP amplitude by itself. A membrane-permeant analog of cAMP (applied in concentrations less than or equal to 1 mM) is also not effective in altering EPSP amplitude. However, when dibutyryl cAMP is applied in the presence of 1 microM IBMX, EPSP amplitude is increased (60-80%). 4. Localized presynaptic injection of the "Walsh Inhibitor" (PKI), which inhibits cAMP-activated protein kinase, blocks the less intense, long-lasting phase of serotonin-induced facilitation at synapses near the site of injection. Normal facilitation develops at synapses within the same preparation remote from the site of injection. Distribution of the injected inhibitor within the axon can be visualized by tagging PKI with a fluorescent marker.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1989

Adenylate cyclase system is essential for long-term facilitation at the crayfish neuromuscular junction.

Long-term facilitation (LTF), a form of synaptic plasticity demonstrated at the crayfish neuromuscular junction, is induced by tetanic stimulation and persists for hours. LTF can be divided into 2 phases: a tetanic phase, which occurs during stimulation, and a long-lasting phase, which persists after stimulation. Activators and potentiators of cAMP (forskolin and 3-isobutyl-methyl-xanthine) produce facilitation of excitatory postsynaptic potentials, which attain approximately the amplitude of the long-lasting phase of LTF but last for a shorter time. Localized presynaptic injection of a protein inhibitor ("Walsh inhibitor") specific for the cAMP-dependent protein kinase blocks the long-lasting phase of LTF at synapses near the injection site with no apparent effect on the tetanic phase. Normal LTF develops and persists at synapses of the same axon distant from the injection site. Localization of the injected inhibitor was confirmed by fluorescent tagging. Localized injection of SQ22,536, an adenylate cyclase inhibitor, also blocks the second phase of LTF near the injection site, but not at distant synapses. These experiments establish a role for adenylate cyclase activation in the long-lasting phase of LTF. The phosphatidylinositol second-messenger system is not important in LTF as inhibition of phospholipase C by injection of RA233, which blocks facilitatory effects of serotonin, does not affect any aspect of LTF.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Cerebrospinal nematodiasis in prairie dogs from a research facility.

Baylisascaris spp larvae were determined to cause CNS disease in 3 prairie dogs maintained at a research facility. Clinical signs consisted of ataxia, stumbling, and head tilt, which progressed to severe torticollis, paddling in lateral recumbency, and loss of the righting reflex. Gross lesions were not found at necropsy. Microscopically, the cerebellar white matter and medulla oblongata were most severely affected and had numerous sections of large ascarid larvae. Our findings indicated that natural infections of Baylisacaris spp larvae can cause CNS disease in prairie dogs. Also, Baylisascaris spp larval infection should be considered in differential diagnoses of CNS disease in prairie dogs.

Animals↗
PubMed1988

Characteristics of accelerated disease in chronic myelogenous leukemia.

Determination of the characteristics of accelerated disease in chronic myelogenous leukemia (CML) helps in individual prognostication, and in the introduction and analysis of investigative approaches based on risk-benefit ratios. The outcome of 357 patients with Philadelphia chromosome-positive CML was analysed from the time of development of suspected features of accelerated disease. Median survivals shorter than 18 months were associated with the appearance of any of the following: cytogenetic clonal evolution; extramedullary disease; peripheral blasts greater than or equal to 15%, peripheral blasts and promyelocytes greater than or equal to 30%, or peripheral basophils greater than or equal to 20%; platelet count less than 1.0 X 10(5)/microliters; marrow blasts greater than or equal to 15%, marrow blasts and promyelocytes greater than or equal to 30%, or marrow basophils greater than or equal to 20%. Relative hazard ratios, or risk of death per unit time, were calculated based on the relative survivals of patients who did or did not develop the particular feature of accelerated disease, after accounting for the time to development of the characteristic. Further analysis identified five features that have additive independent prognostic importance: cytogenetic clonal evolution; peripheral blasts greater than or equal to 15%; peripheral basophils greater than or equal to 20%; peripheral blasts and promyelocytes greater than or equal to 30%; and thrombocytopenia. By providing an objective estimate of prognosis in accelerated disease, the model identifies patients in need of different therapeutic interventions before the development of blastic crisis.

Follow-Up Studies↗
PubMed1988

Magnetic resonance imaging (MRI): a new tool in experimental toxicologic pathology.

Magnetic Resonance Imaging (MRI) is a noninvasive imaging technique that provides multidimensional images of the soft tissues of the body. This imaging technique has proven to be an excellent diagnostic and experimental tool for the detection of pathologic alterations in soft tissues, as well as an adjunct screening method for following the genesis, progression, or regression of chemically induced lesions in the same live animal. Future applications of MRI technology in small animals include MRI microscopy, mapping of vascular or circulatory alterations, measurement of perfusion and diffusion rates of body fluids, and acquisition of cell metabolic states in combination with Nuclear Magnetic Resonance (NMR) spectroscopy, all of which will contribute immensely to the advancement of toxicologic and biomolecular research.

Animals↗
PubMed1988

A comparison of marrow transplantation with chemotherapy for adults with acute leukemia of poor prognosis in first complete remission.

From July 1980 to November 1985, 109 patients with acute myelogenous and lymphoblastic leukemia who had reached a complete remission (CR) following induction treatment were assigned to a study comparing marrow transplantation with chemotherapy as a postremission treatment. Sixty-nine patients did not have a human leukocyte antigen (HLA)-identical donor, and therefore served as chemotherapy controls; 40 patients had HLA-identical donors, and therefore were assigned to the transplant arm. Of these, 23 were transplanted in first remission and 17 were not. Ten of these 17 were subsequently transplanted in relapse. Initially, only patients with poor prognosis determined by a predictive model were entered into the study. Subsequently, patients with moderately poor prognosis were admitted. Comparing the chemotherapy group with the patients transplanted in first CR, significant control of leukemia relapse in transplanted patients was seen in the subgroup with acute myelogenous leukemia (AML) (P less than .1), and acute lymphoblastic leukemia (ALL) (P less than .01), in the poor (P = .01) and intermediate subgroup (P = .01), and in the good-prognostic groups (P = .05). The survival was affected significantly in only the poor and intermediate subgroups. The use of predictive models might help to select patients for whom bone marrow transplantation is appropriate in first remission and those for whom bone marrow transplantation can be left as the initial treatment of relapse. Predictive models could further be helpful in comparing studies performed at different transplant centers.

Adolescent↗
PubMed1988

Prognosis of asymptomatic multiple myeloma.

Prognostic factors were assessed in 35 consecutive, asymptomatic patients with multiple myeloma. The presence of any lytic bone lesion or a serum myeloma protein concentration of at least 3.0 g/dL was followed by early disease progression and the need for chemotherapy within two years. Such patients require frequent monitoring of electrophoretic data. In patients without these features, the myeloma did not progress for a median of three years and the subsequent median survival time was seven years, identifying those likely to live for ten years after diagnosis. Because the treatment of myeloma remains palliative, chemotherapy should be withheld until symptoms develop or complications are imminent.

Actuarial Analysis↗
PubMed1988

Prognostic factors with high-dose melphalan for refractory multiple myeloma.

High doses of melphalan (HDM) and dexamethasone were administered to 43 patients with advanced multiple myeloma, 36 of whom were refractory to both standard melphalan-prednisone and vincristine-adriamycin-dexamethasone (VAD). Forty-four percent responded with greater than 75% reduction in calculated tumor mass, including three patients who achieved a complete remission. The response rate to HDM was 56% in 18 relapsing patients and 50% in 12 patients with less than 12 months of primary drug resistance, but it was only 23% among the remaining 13 unresponsive patients. A high early mortality rate of 30% was confined to 26 patients with either poor performance (Zubrod greater than 1) or impaired renal function (creatinine greater than 1.4 mg%). When this toxic treatment was given to the 21 patients with good performance (Zubrod less than 2) whose disease lacked high serum lactic dehydrogenase (less than or equal to 500 U/L) as a recently recognized feature of high-grade myeloma, a superior median survival of 18 months was obtained as opposed to only 3 months for the 22 remaining patients (P less than .001). Thus, when employed in a timely fashion, HDM overcomes resistance to standard chemotherapy and VAD and benefits selected patients with advanced myeloma.

Aged↗
PubMed1987

DNA aneuploidy in adult acute leukemia.

Using flow cytometric techniques, we determined DNA ploidy levels in the bone marrow of 318 successive adult patients with newly diagnosed acute leukemia. Overall, 26% exhibited DNA stem line abnormalities, usually with a 10%-15% DNA excess, regardless of morphologic diagnosis. DNA aneuploidy was seen most frequently in patients with a hyperdiploid chromosome number and karyotype instability (50%), but was also present in a third of patients with chromosomal translocations and in 20% of patients with a normal diploid karyotype. Thus, among 73 patients with DNA aneuploidy, quantitatively concordant karyotype abnormalities were observed in almost 40% of patients; the discrepancy between DNA content and chromosome number in the remaining patients may reflect differences in the cell cycle position of target cells in G1/0 phase or mitosis, respectively. Cytogenetics affected treatment outcome in acute myelogenous leukemia (AML) with more favorable short- and long-term prognosis among patients with translocations compared with those with numeric abnormalities. The presence of an abnormal DNA stem line, among AML patients with translocations, identified a favorable subgroup with significantly longer remission duration and survival (25 and 26 months versus 18 and 13 months, respectively). In addition, the prognostic implications of DNA aneuploidy in AML were age-dependent, in that favorable effects among patients with translocations and unfavorable effects among those with numeric abnormalities or diploid karyotypes were most obvious in young and not in older patients (greater than or equal to 40 years). In adults with ALL, DNA aneuploidy was associated with shorter survival (15 versus 39 months in the diploid group), an observation that is distinctly at variance with recent findings in childhood ALL. Our results indicated that DNA flow cytometry was complementary to standard cytogenetics for the detection of genomic abnormalities; and DNA aneuploidy emerged, like in children but not in adults with ALL, as a new favorable prognostic feature in a subgroup of adults with AML, the biologic basis of which remains to be determined.

Adult↗
PubMed1987

Activation of transforming potential of the human insulin receptor gene.

A retrovirus containing part of the human insulin receptor (hIR) gene was constructed by replacing ros sequences in the avian sarcoma virus UR2 with hIR cDNA sequences coding for 46 amino acids of the extracellular domain and the entire transmembrane and cytoplasmic domains of the beta subunit of hIR. The resulting virus, named UIR, contains the hIR sequence fused to the 5' portion of the UR2 gag gene coding for p19. UIR is capable of transforming chicken embryo fibroblasts and promoting formation of colonies in soft agar; however, it does not form tumors in vivo. A variant that arose from the parental UIR is capable of efficiently inducing sarcomas in vivo. UIR-transformed cells exhibit higher rates of glucose uptake and growth than normal cells. The 4-kilobase UIR genome codes for a membrane-associated, glycosylated gag-hIR fusion protein of 75 kDa designated P75gag-hir. P75gag-hir contains a protein tyrosine kinase activity that is capable of undergoing autophosphorylation and of phosphorylating foreign substrates in vitro; it is phosphorylated at both serine and tyrosine residues in vivo.

Animals↗
PubMed1987

Molecular cloning and chemical synthesis of a region of platelet glycoprotein IIb involved in adhesive function.

Membrane glycoprotein (GP) IIb-IIIa is a component of a platelet adhesive protein receptor. A region of the heavy chain of GPIIb, defined by the monoclonal antibody PMI-1, is involved in adhesion receptor function. We have localized and chemically synthesized this region of GPIIb. A cDNA clone that directs the synthesis of a fusion protein reactive with the PMI-1 antibody was isolated from a phage lambda gt11 expression library constructed with mRNA from an erythroleukemia (HEL) cell line. The deduced amino acid sequence of this clone indicates that it spans the light-heavy chain junction of GPIIb and contains a portion of the carboxyl terminus of the heavy chain and the amino terminus of the light chain. The PMI-1 epitope was found to be contained within a 9-kDa staphylococcal V8 protease fragment of GPIIb, and such a fragment was predicted within the putative heavy-chain sequence. A computerized antigen prediction program identified a single sequence with a high probability of containing a continuous epitope. A synthetic 17-residue peptide containing this sequence binds PMI-1 and inhibits PMI-1 binding to GPIIb-IIIa. The peptide-antibody complex has an approximate Kd of 1.2 microM, which compares to a Kd of 0.95 microM for PMI-1 binding to GPIIb. The region containing the PMI-1 epitope shows no similarity to corresponding regions of two other adhesion receptors, indicating that this portion of GPIIb may function in activities unique to the platelet receptor.

Amino Acid Sequence↗
PubMed1987

Short-term oral administration of polybrominated biphenyls enhances the development of hepatic enzyme-altered foci in initiated rats.

FireMaster BP-6 (FM), a commercial mixture of polybrominated biphenyls (PBB), has been shown to act as a tumor promoter in hepatocarcinogenesis assays in rats. Most hepatic tumor promoters must be administered for many weeks or months. Because FM is highly persistent in animal tissues, it was hypothesized that very short-term administration of FM would result in tumor promotion. Female Sprague-Dawley rats weighing 185-215 g were initiated by a two-thirds partial hepatectomy followed by 10 mg diethylnitrosamine/kg body weight (BW) 24 h later. Thirty days later, rats were gavaged with FM in corn oil, at total doses of 0, 13, or 130 mg FM/kg BW. Half the dose was given on d 30, and the remaining half was given 24 h later. At 120 d after gavage the rats were killed and necropsied. Five liver sections from each animal were histochemically stained for gamma-glutamyl transpeptidase-positive enzyme-altered foci (EAF). EAF were significantly increased over control values in initiated rats given 130 mg FM/kg. In animals given 13 mg FM/kg, EAF were increased to a lesser extent but not significantly above controls. Enhancement of these EAF in initiated rats reflects tumor-promoting activity. In this study, 24-h administration of FM in initiated rats was sufficient to enhance hepatic EAF measured 120 d later in an rats was sufficient to enhance hepatic EAF measured 120 d later in an initiation-promotion protocol, and a dose of 13 mg FM/kg was apparently close to a possible no-effect threshold level for enhancement of EAF.

Administration, Oral↗