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Biomedical subjects

W E Wilson

Publications and source records attributed to W E Wilson.

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

Randomized phase II comparison of standard CHOP with weekly CHOP in elderly patients with non-Hodgkin's lymphoma.

PURPOSE: To determine whether modifying the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) from full doses given every 3 weeks to one-third doses given weekly (chop) increases the received chemotherapy dose-intensity in elderly patients with advanced-stage intermediate-grade lymphoma. PATIENTS AND METHODS: Consenting patients, age > or = 65 years who had acceptable cardiac, renal, and liver function and an Eastern Cooperative Oncology Group (ECOG) performance status less than 4, were stratified by bone marrow and performance status and randomized to receive standard CHOP or weekly chop. Drug doses were attenuated or escalated according to a defined dose-modification schedule. The primary outcome was average relative received dose-intensity. Secondary outcomes included response, progression-free and overall survival, toxicity, and performance status. RESULTS: Nineteen patients were allocated to each group. No difference in received dose-intensity was seen. When dose-intensity was calculated for the first six cycles of therapy, average relative received dose-intensity was .92 with CHOP versus .89 with weekly chop (P = .5); when calculated for the first 18 weeks of therapy, values were .88 with CHOP versus .89 with weekly chop (P = .8). The complete response rate was 68% with CHOP versus 74% with weekly chop (P = .9). At 2 years, the progression-free survival rate was 57% with CHOP versus 46% with weekly chop (P = .16) and the survival rate was 74% with CHOP versus 51% with weekly chop (p = .05). More myelotoxicity was seen with CHOP. CONCLUSION: We conclude that CHOP can be given in sufficient doses to elderly patients and that weekly chop does not increase received dose-intensity. Progression-free and overall survival are unlikely to be superior with weekly chop, and may be worse. CHOP should remain the standard against which new therapies for elderly patients with intermediate-grade lymphoma are compared.

Aged↗
PubMed1994

Direct ionization of DNA in solution.

Most of the energy absorbed in the cell nucleus from a radiation field goes into the aqueous medium that surrounds macromolecules, like DNA, which are critical to the normal function of cells. This part of the energy deposition produces numerous reactive species that can diffuse to DNA sequences and induce chemical changes. The average diffusion distance of the free radicals that mediate this indirect mode of DNA damage is only a few nanometers because the cellular medium contains a high concentration of molecules that rapidly scavenge the radiation-induced species. Under these conditions, direct interaction of the radiation field with the DNA can not be neglected as a potential mode of damage induction. Two aspects of the direct effect will be discussed in this paper: (1) screening of the interaction between DNA and charged particles by the dielectric response of the aqueous medium and (2) the impact-parameter dependence of these interactions.

Cell Nucleus↗
PubMed1994

The stochastics of the positive ion penumbra.

Statistical analysis of Monte Carlo simulations of positive ion track structure is presented for 1 MeV protons passing outside an absorbing region of interest. Energy deposition and production of ionization within the region occur only by delta-ray transport from the ion's path. Depositions in spherical absorber regions of 2 to 100 nm diameter in unit density tissue were scored. It is shown that production of delta rays sufficiently energetic to reach the region is infrequent and the delta rays are therefore relatively far apart along the ion path compared to their average range. The probability for any delta-ray energy deposition in a distant site is small and proportional to the solid angle intercepted by the site. The functional dependence of the frequency density distributions in energy imparted and in ionization number, conditional on there being some interaction, is approximately exponential, and the first and second moments of the distributions are largely independent of distance from the ion path. These findings confirm similar conclusions from experimental measurements on the track structure of germanium, iron and uranium ions.

Monte Carlo Method↗
PubMed1993

Acute lung injury at Baragwanath ICU. An eight-month audit and call for consensus for other organ failure in the adult respiratory distress syndrome.

To test the expanded definition of acute lung injury (ALI), we prospectively, over a period of 8 months, studied all adult ICU admissions who fitted the definition. Our study consisted of 83 patients with the adult respiratory distress syndrome (ARDS) and 60 with mild to moderate ALI. Sepsis and trauma were the most common diagnoses on admission. The overall mortality rate was 45 percent for ARDS and 38 percent in the other group. Mortality rose significantly with associated other organ failure, the incidence of which was as follows: hepatic, 39 percent; cardiac, 38 percent; hematologic, 22 percent; renal, 21 percent; neurologic, 5 percent. Sepsis syndrome eventually occurred in 73 percent and septic shock in 38 percent of all cases of ALI. We found the expanded definition a useful grading system and consider this definition of ARDS to be currently the best. There are, however, problems with the determination of lung compliance, the effect of inverse ratio ventilation, and the lack of consensus in defining other organ failure.

Adult↗
PubMed1992

Stereospecificity of amino acid side chains in deltorphin defines binding to opioid receptors.

A series of individual D-amino acid replacement analogues of deltorphin A, several of which were in combination with a His4 deletion, were used to probe alterations of side-chain orientation on peptide binding parameters with rat brain opioid receptors. Peptides with D-amino acids in residues 1, 3, and 5 exhibited diminished affinities primarily for delta receptors (88-1200-fold) with selectivity decreasing by factors of 13-64-fold relative to deltorphin A (Ki delta = 0.45 nM; Ki mu/Ki delta = 764): the aromatic side chains Tyr1 and Phe3, which lie in the N-terminal "message" domain and the aryl side chain of Leu5 in the C-terminal "address" domain, appear to play essential roles in conferring high delta affinity and selectivity. Although D-His4 only decreased delta affinity by 6-fold and selectivity by a factor of 4, His appears to be involved as an integral component of both domains: [des-His4]deltorphin A and [des-His4] analogues containing consecutive D-amino acid replacements in the remaining residues exhibited weak binding to delta receptors and poor delta selectivity. Substitution of D-Met2 in deltorphin A by D-Ala or D-Nle decreased delta selectivities 3-6-fold through an elevation in mu affinities; however, the converse replacement, D-Met for D-Ala2 in deltorphin B, diminished beta selectivity by an order of magnitude only through the loss in delta affinity. The data show that the high delta affinity and selectivity of deltorphins correlate with and require a strict stereospecificity of the amino acid residue side chains.

Amino Acids↗
PubMed1992

A pilot study of carboplatin augmentation therapy for patients with poor risk acute non-lymphocytic leukemia.

Eleven patients with acute non-lymphocytic leukemia and persistent leukemia on a bone marrow done 6 days after the start of standard induction chemotherapy with daunorubicin and cytosine arabinoside were given augmentation chemotherapy with carboplatin as a continuous intravenous infusion over 3 days. Nine of the 11 patients (82%) entered complete remission. The hematologic and non-hematologic toxicities encountered by these patients were similar to those seen after conventional therapy alone with the exception of peripheral neuropathy in one patient. Of the two induction failures, one patient died of treatment-related toxicity and one patient had resistant leukemia.

Adolescent↗
PubMed1992

Microdosimetric measurements of heavy ion tracks.

The biological effectiveness of radiations depends on the spatial pattern of ionizations and excitations produced by the charged particle tracks involved. Ionizations produced by both the primary ion and by energetic delta rays may contribute to the production of biologically relevant damage and to the concentration of damage which may effect the probability of repair. Although average energy concentration (dose) can be calculated using homogeneous track models, the energy is actually concentrated in small volumes containing segments of the ion and delta ray tracks. These local concentrations are studied experimentally using low pressure proportional counters, and theoretically, using Monte Carlo methods. Small volumes near an ion track may be traversed by a delta ray. If they are, the energy deposited will be similar to that produced by a single electron track in a low-energy x-ray irradiation. The probability of a delta ray interaction occurring decreases with the square of the radial distance from the track. The average energy deposited is the product of this probability and the energy deposited in an interaction. Average energy deposited calculated from measured interaction probability is in good agreement with the results of homogeneous track models.

Computer Simulation↗
PubMed1991

Opioid receptor selectivity reversal in deltorphin tetrapeptide analogues.

Deltorphin N-terminal tetrapeptides [DEL A: H-Tyr-D-Met-Phe-His-R, where R = -NH2, -NH-NH2, -OCH3, -OH, -NH-NH-CO-R' (R' = -CH3 or adamantane); DEL C: H-Tyr-D-Ala-Asp-R (R = -OH, -NHCH3)], were used in a receptor binding assay with [3H]DADLE and [3H]DPDPE for delta sites, and [3H]DAGO for mu sites; tetrapeptide Ki delta values were similar with either [3H]-delta ligand. DEL A tetrapeptides C-terminally substituted with -NH2, -NH-NH2, -OCH3, and -OH had 10 to greater than 1,000-fold decreased Ki delta values, while Ki mu increased 5 to 100-fold to yield mu selectivity. C-Terminal substitution with -NH-NH2 and -OCH3 conferred highest mu selectivities; adamantyl and acetyl hydrazide derivatives were non-selective. DEL-(1-4)-OH peptides had decreased delta and mu affinities: DEL A-[Asp4]-(1-4)-OH and DEL C-(1-4)-OH had low affinities (greater than 1 microM), however, the Ki delta of the former was 5-fold greater than the latter, and the Ki mu was less by 15-fold. The data suggest that the "message" domain of DEL exhibits receptor selectivity different from that of the heptapeptide.

Animals↗
PubMed1991

Function of negative charge in the "address domain" of deltorphins.

Deltorphins A, B, and C exhibit high delta-affinities (Ki = 0.12-0.31 nM) and very high delta-receptor binding selectivities (Ki mu/Ki delta = 1800-4100). A study of the delta-receptor binding properties of 15 deltorphin analogues focused primarily on the influence of the anionic group in the C-terminal tetrapeptide. Amidation of the beta-carboxyl groups of [Asp7], [Glu4], or [Asp4] in deltorphins A, B, and C, respectively, yielded peptides with enhanced mu-receptor affinities and minor changes in delta-affinities (Ki delta = 0.20-0.65 nM), but 5-8-fold diminished delta-selectivities. A free C-terminal carboxyl group markedly reduced delta-affinities and decreased delta-selectivities 6-11-fold; thus, the C-terminal amide group critically facilitates delta-affinity. Modifications in the anionic charged group or hydrophobic residues in the C-terminal tetrapeptide address domain of deltorphin A altered spatial distributions critical for delta-affinity and selectivity; e.g., [Nle6]deltorphin A enhanced mu-affinity and lowered delta-selectivity by two-thirds; the progressive, step-wise repositioning of Asp in deltorphin C (from position 4 to 7) was accompanied by linear decreases in delta-affinities and -selectivities, and increased mu-affinities of these peptides; enhancement of the charge density to -2, in [Asp6, Asp-OH7]deltorphin A, decreased delta-affinity and -selectivity, while [Asp4,5,His7]deltorphin A bound to neither mu- nor delta-sites. These results demonstrate that while an anionic group may occasionally facilitate high delta-receptor affinity, it represents an absolute requirement for the high delta-binding selectivity of these peptides. The locations of the charged groups relative to hydrophobic residues in the address domain of the peptide are also critical determinants for both delta-affinity and -selectivity.

Animals↗
PubMed1990

Dermorphin interaction with rat brain opioid receptors: involvement of hydrophobic sites in the binding domain.

Dermorphin structural analogues were utilized to determine the nature of opioid receptor subsite specificity, affinity, and selectivity in rat brain membranes. The data suggest that these parameters are influenced by the amino acid composition and sequence and the known solution conformation of dermorphin, in addition to the conformation of the membrane receptor. Two hydrophobic components of dermorphin are required for optimal binding. One component encompasses the stacked phenol groups in Tyr1 and Tyr5; the second involves the phenyl group of Phe3. Evidence to support this proposal includes the following results: (a) removal of aromaticity, as occurs in [des-Tyr5]- and [Gly5]dermorphin, drastically reduced binding to both mu and delta sites; (b) inversion of the Phe3-Gly4 sequence in dermorphin to the Gly3-Phe4 in enkephalin enhanced binding to delta receptor sites, yet the peptide remained mu-selective; (c) substitution of Pro4 for Gly4 disrupted the solution conformation of dermorphin and decreased affinities at both receptor subsites, substantiating the requirement for the Phe3-Gly4-Tyr5 sequence in dermorphin to interact with mu sites; and (d) modification of the serine residue, as occurs in [Ser(Bzl7)] dermorphin and [Ser-NHNHZ7]dermorphin, enhanced interaction with delta opioid receptors; the apparent delta affinity increased over 50-fold with [Ser(Bzl7)]dermorphin, although it retained a weak mu-selectivity. However, both [Ser(Bzl7)]- and [Ser-NHNHZ7]dermorphin exhibited high affinity for mu receptor sites. Furthermore, the D-configuration about the alpha-carbon of residue 2 and the alpha-amine function and hydroxyl group on Tyr1 are essential for receptor binding. We conclude that mu-opioid receptors contain distinct regions that accomodate the stacked phenol groups of Tyr1 and Tyr5 residues and the phenyl group of Phe3.

Amino Acid Sequence↗
PubMed1989

Bradykinin and kininogens in bovine milk.

Two peptides exhibiting kinin activity in an isolated rat uterus assay were purified from pasteurized skim bovine milk. The amino acid sequence of the more prominent peptide was found to be that of bradykinin. Partially purified kinin preparations were also obtained from N-tosyl-L-phenylalanyl chloromethyl ketone-treated trypsin digests of non-fat dry milk and insoluble lactalbumin. The application of fast atom bombardment/mass spectrometry permitted detection of the bradykinin protonated molecular ion in each of these samples. Collision-activated decomposition of the ion of m/z 1061 confirmed it to be the protonated molecular ion of bradykinin. Fast atom bombardment/mass spectrometry analysis further confirmed the occurrence of bradykinin in a pancreatic kallikrein digest of a partially purified bovine milk kininogen preparation. In apparent contrast with bovine plasma kininogens, the forms of kininogen which occur in milk include a high Mr kininogen (Mr greater than 68,000) and a low Mr kininogen (Mr 16,000-17,000). Kinin formation from the high Mr kininogen is catalyzed by porcine pancreatic kallikrein or trypsin.

Animals↗
PubMed1989

Dermorphin gene sequence peptide with high affinity and selectivity for delta-opioid receptors.

Skin of the frog Phyllomedusa sauvagei contains a cDNA sequence that codes for the selective mu-receptor peptide dermorphin and a new heptapeptide we have designated as dermorphin gene-associated peptide (DGAP). Investigation of the opioid receptor binding characteristics of synthetic DGAP and [D-Met2]DGAP revealed that the latter peptide had high affinity and selectivity for delta-type opioid receptors in rat brain synaptosomes. The IC50 values for DGAP on mu- and delta-receptors were only 28 microM and 670 nM, respectively, while that for [D-Met2]DGAP was 0.80 nM for delta-receptors and greater than 1 microM for mu-receptors yielding a very high delta selectivity ratio (SR) of 1345. In comparison, the SR values for [D-Ala2,D-Leu5]enkephalin, [D-Ser2,Leu5,Thr6]enkephalin, and [D-Pen2,5]enkephalin, ligands which are considered to be specific for delta-receptors, were 20, 42, and 301, respectively. Dermorphin, which contains a D-Ala2 residue and is a selective mu-receptor ligand (Lazarus, L.H., Guglietta, A., Wilson, W.E., Irons, B.J., and de Castiglione, R. (1989) J. Biol. Chem. 264, 354-362), exhibits a SR of 0.0055 similar to that for the conventional mu-agonist [D-Ala2,NMePhe4,Gly-ol]enkephalin (0.0040). This finding that frog skin cDNA contains the information to code for dermorphin and DGAP, or the presumed [D-Met2]DGAP molecule, which are among the most selective high affinity opioid ligands described for mu- and delta-receptors, may permit new insight into the design of future opioid receptor agonists and antagonists.

Analgesics, Opioid↗
PubMed1989

Dimeric dermorphin analogues as mu-receptor probes on rat brain membranes. Correlation between central mu-receptor potency and suppression of gastric acid secretion.

The opioid receptor preference for dermorphin and several dimerized structural analogues was investigated using rat brain synaptosomes and correlated with the potencies of intracerebroventricularly administered dimeric dermorphin peptides to inhibit gastric acid secretion. The carboxyl terminus of dermorphin or amino-terminal dermorphin analogues was bridged by dihydrazide or (poly)ethylenediamine structures. Synaptosomal membranes were prepared for radioligand binding assay in the presence of soybean trypsin inhibitor and preincubated to remove endogenously bound opioid peptides before storage at -70 degrees C. Specific radiolabeled agonists used in the radioligand binding assays were [D-Ala2,N-methyl-Phe4,Gly-ol5] [3H] enkephalin for mu-receptors and [D-Ala2,D-Leu5] [3H]enkephalin for delta-receptors. delta-Receptor binding assays were conducted in the presence of 2.6 microM [N-Me-Phe3,D-Pro4]morphiceptin to suppress peptide binding to mu-receptors. [D-Ala2,N-methyl-Phe4,Gly-ol5]enkephalin and dermorphin had affinities of 1.39 and 1.22 nM for mu-receptors and 355.8 and 178.6 nM for delta-receptors, respectively. Affinities of dimeric-dermorphin0 for mu- and delta-receptors, and the mu-selectivity ratio, exceeded values characteristic of dermorphin. The dimerized amino-terminal dermorphin analogues are peptides whose receptor binding differed from the parent molecule; e.g. the affinity of dimeric tetrapeptides toward mu-receptors was reduced but was increased for delta-receptors relative to monomeric dermorphin-(1-4)-amide. Dimeric tetradermorphin linked by a bridge containing 12 methylene units (di-tetra-dermorphin12), exhibited a dramatic loss in the mu-selectivity ratio as a result of diminished mu-affinity. On the other hand, substitution of Gly4 by Sar in di-tetra-dermorphin2 enhanced binding to mu-receptors: substitution of D-Arg2 for D-Ala resulted in an increased binding to mu-receptors while decreasing binding to delta-receptors, yielding a peptide with the highest mu-selectivity ratio. These substitutions of D-Arg2 and Sar4 in dimeric amino-terminal dermorphin pentapeptides enhanced binding to both mu- and delta-receptors relative to dermorphin-(1-5)-amide, but led to a decrease in its mu-selectivity ratio. Several dimeric dermorphin analogues exhibited an enhanced mu-selectivity ratio relative to their monomeric analogues. Dimeric peptides, which had a relatively high affinity for mu-receptors, were effective in the suppression of gastric acid secretion.

Analgesics, Opioid↗
PubMed1989

Recognition, purification, and structural elucidation of mammalian physalaemin-related molecules.

Although the PHLIPs are able to enhance gastrointestinal contractility to a very modest extent, the actual physiological significance of the PHLIPs is not completely understood at the present time. Should the high Mr PHLIM be the precursor molecule(s), the PHLIPs may represent partial enzymatic hydrolysis products of the amino-terminal region of the precursor(s). In this regard, it is interesting to note that immunohistochemical staining of rat duodenum indicates the presence of PHY antiserum cross-reacting material in Brunner's glands, which appear to be involved in secretion of mucin. The amphibian peptide, bombesin, has also been detected in amphibian skin mucous glands by immunochemistry; other investigators have indicated that cerulein, an amphibian analog of the carboxy-terminal region of cholecystokinin, is discharged along with mucin from cutaneous glands in Xenopus after the injection of adrenalin.

Amino Acid Sequence↗
PubMed1989

Modeling the biological effectiveness of high-LET radiation.

Reevaluation of neutron exposures to atomic bomb survivors has greatly reduced the significance of that data base for estimating the relative biological effectiveness of radiations with high linear energy transfer (LET). Consequently, greater emphasis is being given to animal data and mechanistic studies at the cellular and molecular level in assessing the role of radiation quality in the health effects of low-level radiation exposure. We are investigating the spatial patterns of energy deposited in DNA by ionizing radiation and their influence on cell killing and mutation induction. Our basic hypothesis is that high ionization density increases the probability that radiation-induced DNA damage will be unrepairable or misrepaired. This paper discusses the use of computer simulation to investigate damage induced in DNA by the decay of incorporated 125I.

Computer Simulation↗
PubMed1988

Assessment of neuromedin B polyclonal antibodies as molecular probes in neural tissue.

Five unique, high affinity rabbit polyclonal antibodies against neuromedin B were characterized in a radioimmunoassay in terms of the following parameters: pH and type of buffer, ionic strength, and non-ionic detergents in order to optimize immunoglobulin-peptide interaction; specificity using peptides of the bombesin family, in addition to the tachykinin substance P; and affinity to neuromedin B. Optimum conditions included acidic pH (5.25), high ionic strength (greater than 0.1 M) and absence of non-ionic detergents, which inhibited the assay. Affinities for the 5 antibodies ranged from 10 to 48 fmol neuromedin B with titers from 1:1,000 to 1:10,000 and the sequence-specificity covered the entire peptide; cross-reactivity towards substance P was negligible. As a model tissue, rat spinal cord was homogenized with 5 different extraction solvents, including acetone, methanol, acid and alkaline conditions, and assayed by each polyclonal antiserum; neuromedin B immunoreactivity levels were highest in acid and alkaline extracts and reflected the specificity of the antibody used. Applying these antisera to rat brain extracts, the posterior pituitary gland contained the highest concentration of immunoreactive equivalents of neuromedin B followed by the anterior pituitary, hypothalamus, and hippocampus. The immunoreactive content in the pituitary and hypothalamus, however, depended on the particular antisera used with significant (P less than 0.01) differences existing between them. Further application of these polyclonal antibodies to a spinal cord extract analyzed by isocratic reverse-phase HPLC conditions also revealed differences in their cross-reactivity with the immunoreactive peptides. These antisera may now be used as molecular probes for the determination of extractable immunoreactive neuromedin B from neural tissue and in situ localization by immunohistochemical techniques.

Amino Acid Sequence↗
PubMed1988

Stochastic model of free radical yields in oriented DNA exposed to densely ionizing radiation at 77K.

Monte Carlo simulation techniques were used to calculate the probability that thymine radical anions (T.-), formed by the slowing-down of high-energy protons in oriented DNA, will undergo a secondary protonation reaction. By assuming a large asymmetry in the thermal conductivity of oriented DNA fibres we predict a significant enhancement of protonation of T.- when the proton flux is incident on the sample parallel to the orientation of the DNA. These results are in qualitative agreement with experimental data on the production of TH. radicals when oriented DNA is exposed to fast neutrons.

DNA↗