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Biomedical subjects

J R Williams

Publications and source records attributed to J R Williams.

At least 127 records · Page 7Linked to original sources
PubMed1993

Preclinical evaluation of intravenously administered 111In- and 90Y-labeled B72.3 immunoconjugate (GYK-DTPA) in beagle dogs.

B72.3, a monoclonal antibody with reactivity against human adenocarcinomas was obtained from the Cytogen Corporation in the form of an immunoconjugate coupled with linker-chelator GYK-DTPA by using proprietary carbohydrate directed site specific chemistry. The immunoconjugate was radiolabeled with indium-111 or yttrium-90. A preclinical analysis was performed in 10 normal beagle dogs. The pharmacokinetics of intravenously administered indium- and yttrium-labeled immunoconjugates were compared serially in blood, bone marrow and urine samples. Compared to 90Y less of the 111In label ended up in urine and more was found in blood and bone marrow. Indium-labeled B72.3 GYK-DTPA had relatively higher uptake in most glandular tissues than 111In-labeled antiferritin immunoconjugate. Bone marrow toxicity was the dose limiting side effect after intravenous infusion of 90Y-labeled B72.3 GYK-DTPA. Toxicity was also observed in the liver but not in other organ systems. Recently other investigators obtained similar results with these immunoconjugates in human patients. A preclinical pharmacokinetic analysis of radioimmunoconjugates in beagle dogs provided useful information regarding bone marrow toxicity, liver toxicity and in vivo instability of the immunoconjugate. Data suggest that for future trials in human patients, a more stable chelated immunoconjugate for yttrium is needed to achieve less liver uptake and a better correlation with the 111In-labeled product than the 90Y-labeled B72.3 GYK-DTPA used in this investigation.

Animals↗
PubMed1993

Fractionated intravenous administration of 90Y-labeled B72.3 GYK-DTPA immunoconjugate in beagle dogs.

B72.3, a monoclonal antibody with reactivity against human adenocarcinomas, was coupled with linker-chelator GYK-DTPA using carbohydrate mediated conjugation chemistry and radiolabeled with yttrium-90. Single and double intravenous injections of radioimmunoconjugate were compared for acute and late normal tissue toxicity in 15 beagle dogs. The second injection was given 4 or 8 days after the first. Pharmacokinetics of the radioimmunoconjugate in blood, bone marrow and urine were similar for first and second injections. Only bone marrow (acute) and liver (late) toxicity were observed. Both liver and bone marrow toxicity were decreased by fractionation of the injections. After double injections, the total equitoxic dose was 15 and 60% higher for bone marrow and liver toxicity, respectively. The mechanisms of normal tissue protection offered by fractionated radioimmunoglobulin therapy (RIT) remain to be defined. Fractionated RIT will have a better therapeutic ratio than single injection RIT, if antitumor effects appear to be less susceptible to fractionation than normal tissues.

Animals↗
PubMed1993

Characterization of a New York ovine lentivirus isolate.

A lentivirus has been isolated from a Finnish ewe with ovine progressive pneumonia in a closed upstate New York flock. We demonstrated that the virus, designated ovine lentivirus strain CU1 (OLV-CU1), is biologically, biochemically and molecularly related to, but distinct from, previously described sheep and goat lentiviruses. Nine of 32 ewes (from the affected flock) with precipitating antibodies for ovine lentivirus also produced antibodies that were able to neutralize the infectivity of OLV-CU1. The virus replicated in cultured sheep fibroblasts and caused the formation of large multi-nucleated cells. OLV-CU1-specific RNA transcripts found in infected cells and virion antigenic proteins were similar to those of other small ruminant lentiviruses. However, the virus was distinguished from other isolates at the DNA level by nucleic acid hybridization, restriction endonuclease mapping and partial sequencing of the virus genome.

Amino Acid Sequence↗
PubMed1993

Copper-resistant enteric bacteria from United Kingdom and Australian piggeries.

Thirty-three enteric isolates from Australian (Escherichia coli only) and United Kingdom (U.K.) (Salmonella sp., Citrobacter spp., and E. coli) piggeries were characterized with respect to their copper resistance. The copper resistance phenotypes of four new Australian E. coli isolates were comparable with that of the previously studied E. coli K-12 strain ED8739(pRJ1004), in that the resistance level in rich media was high (up to 18 mM CuSO4) and resistance was inducible. Copper resistance was transferable by conjugation from the new Australian isolates to E. coli K-12 recipients. DNA similarity between the new Australian isolates and the pco copper resistance determinant located on plasmid pRJ1004 was strong as measured by DNA-DNA hybridization; however, the copper resistance plasmids were nonidentical as indicated by the presence of restriction fragment length polymorphisms between the plasmids. DNA-DNA hybridization and polymerase chain reaction analysis demonstrated DNA homology between the pco determinant and DNA from the U.K.E. coli, Salmonella sp., and Citrobacter freundii isolates. However, the copper resistance level and inducibility were variable among the U.K. strains. Of the U.K. E. coli isolates, 1 demonstrated a high level of copper resistance, 4 exhibited intermediate resistance, and 16 showed a low level of copper resistance; all of these resistances were expressed constitutively. A single U.K. C. freundii isolate, had a high level of copper resistance, inducible by subtoxic levels of copper. Transconjugants from one E. coli and one C. freundii donor, with E. coli K-12 strain UB1637 as a recipient, showed copper resistance levels and inducibility of resistance which differed from that expressed from plasmid pRJ1004.(ABSTRACT TRUNCATED AT 250 WORDS)

Animal Husbandry↗
PubMed1993

The impact of preconception counseling on pregnancy outcomes. The experience of the Maine Diabetes in Pregnancy Program.

OBJECTIVE: To determine if a noncentralized, statewide program could be established to educate health-care providers and women with pregestational diabetes on available strategies to prevent adverse outcomes in pregnancies complicated by diabetes. Characteristics of women who participated in the program and the outcomes of their pregnancies are evaluated. RESEARCH DESIGN AND METHODS: A network of regional providers caring for pregnant women with diabetes was developed. Continuing education sessions were delivered to both providers and women with existing diabetes on the importance of preconception counseling. RESULTS: Maine health-care providers collaborated on the development and adoption of three patient-care guidelines that address preconception counseling, prenatal care, and contraception for women with established diabetes. A total of 185 pregnancies among 160 women with pregestational diabetes reporting estimated delivery dates between 1 January 1987 and 31 December 1990 were identified. Of the total pregnancies, 62 (34%) occurred in women who received preconception counseling: among these 62 pregnancies were one major congenital defect (1.6%) and four fetal or neonatal deaths (6.4%). Among the 123 (66%) pregnancies occurring in women that had not received preconception counseling, 8 (6.5%) infants were born with congenital abnormalities, and 26 (21.1%) fetal or neonatal deaths were documented. CONCLUSIONS: A program promoting preconception counseling can be implemented on a statewide basis by using various health-care providers to deliver the program. Participation in such a program appears to be related to improved pregnancy outcomes among women with pregestational diabetes.

Adult↗
PubMed1993

Assessment of radiolabeled stabilized F(ab')2 fragments of monoclonal antiferritin in nude mouse model.

The biodistribution of 111In-labeled stabilized fragments of monoclonal antiferritin was studied in nude mice bearing a human hepatoma tumor xenograft. Pharmacokinetics and tumor targeting of fragment Fab'-linker-Fab' fragment molecules (stabilized F(ab')2) were compared to unmodified F(ab')2 fragment molecules and immunoglobulin G (IgG). Significant differences were observed in tumor and normal organ uptake at 12, 24, 48 and 72 hr. Tumor retention of stabilized F(ab')2 fragments was approximately 2.5-fold higher than of unmodified F(ab')2 at 48 hr. Blood clearance for stabilized F(ab')2 was relatively faster than intact IgG, while unmodified F(ab')2 cleared more rapidly from the circulation. Kidney radioactivity of unmodified F(ab')2 was at least two times higher than kidney radioactivity of stabilized F(ab')2 at all time points. Stabilized F(ab')2 demonstrated 40% less liver uptake than intact IgG. In these studies with nude mice, substantial retention of stabilized F(ab')2 in tumor and significant reduction in liver and kidney uptake of these fragments indicated that they could also have a higher therapeutic ratio than IgG or unmodified F(ab')2 in human patients.

Animals↗
PubMed1993

Evaluation of indium-111- and yttrium-90-labeled linker-immunoconjugates in nude mice and dogs.

Rapid uptake and slow transit of radioactivity from normal organs are detrimental to any clinical utilized radioimmunoconjugate because they lower the target-to-nontarget ratio and deliver undesirable radiation to normal organs. To mitigate this problem, two labile chemical linkages (EGS and DST) were introduced between a monoclonal antiferritin antibody (QCI) and a chelating agent (DTPA). The biodistribution of labile-linker immunoconjugates (EGS and DST) and stable linker immunoconjugates (DSS and ITCB) were compared. In a nude mouse model, all of the four immunoconjugates labeled with 111In targeted subcutaneously-implanted human tumor cells. Tumor-to-normal organ ratios were enhanced for the EGS linkage in comparison to the two stable linkages. Serial whole-body immunoscintigraphy confirmed the biodistribution study. The EGS and ITCB 90Y-labeled immunoconjugates had biodistributions similar to their respective 111In-labeled immunoconjugates. As the mouse model is not representative of the high uptake of monoclonal antibodies in the human liver, beagle dogs were used to further explore the retention of radiolabel in normal liver. The EGS-linked immunoconjugate significantly reduced the dog liver activity when compared to the ITCB immunoconjugate. The combination of the animal models (mouse and dog) appears to allow for a more compete and optimal preclinical analysis of chelated radiolabeled monoclonal antibodies for diagnosis or treatment and illustrates the potential clinical improvements possible with labile chemical linkages in radioimmunoconjugates.

Animals↗
PubMed1992

Oxytocin and social bonding.

The prairie vole is an excellent model for examining the neurobiology of social attachment, and in particular of pair-bond formation. In female prairie voles either sexual interactions or oxytocin infusions can hasten the formation of a partner preference. These results implicate oxytocin in the formation of adult heterosexual social bonds. In conjunction with work on other social systems described in this volume, these findings also support the suggestions of Klopfer and Newton that oxytocin may be important in coordinating mammalian social interactions with other critical reproductive events such as birth, lactation, and sexual behavior.

Aggression↗
PubMed1992

Partner preference development in female prairie voles is facilitated by mating or the central infusion of oxytocin.

Results of these experiments indicate that females given at least 24 hours of cohabitation with a male develop a social preference for the familiar partner versus a stranger. Mating is not essential for the development of partner preferences, but clearly facilitates the onset of preferences. Females given six hours of cohabitation showed partner preferences only if they mated with the partner during cohabitation (Experiment 2) or if they received oxytocin (Experiment 3). Females that continued to mate during preference tests (Experiment 2, n = 4) mated exclusively with the partner. Oxytocin infusions, even in the absence of mating or estrogen priming, facilitated the development of partner preferences.

Animals↗
PubMed1992

Prehospital thrombolysis in a rural community: short- and long-term survival.

In order to assess the feasibility and outcome of using prehospital thrombolysis in acute myocardial infarction in a rural community, we performed an open randomized study of patients with symptoms of acute myocardial infarction of less than 6 hours. One hundred and forty-five patients with acute myocardial infarction were allocated to receive IV streptokinase prehospital by means of a mobile coronary care unit (MCCU) (n = 43) or to receive IV streptokinase in hospital (n = 102). The mean delay time to treatment was 138 minutes (MCCU group) and 172 minutes (hospital group) (p less than 0.02). Reperfusion time was 88 minutes for the MCCU group and 92 minutes for the hospital group. Mortality at 14 days was 2.3% for the MCCU group and 11.7% for the hospital group (p less than 0.05). Six month mortality was 4.9% for the MCCU group and 17.3% for the hospital group (p = 0.03). Mortality at 1 year was 6.1% for the MCCU group and 20.0% for the hospital group (p = 0.04). There were no significant adverse events in either treatment group. Thus, prehospital thrombolysis by streptokinase is feasible and allows significant reduction in the delay time to treatment initiation. There are encouraging improvements in both short- and long-term survival with no apparent reduction in safety profile.

Adult↗
PubMed1992

Development of partner preferences in female prairie voles (Microtus ochrogaster): the role of social and sexual experience.

Prairie voles (Microtus ochrogaster) exhibit a monogamous mating system characterized by long-term pair bonds between mates. The purpose of this study was to examine the effect of cohabitation time and sexual experience on the development of pair bond formation in female prairie voles. Females that were allowed to cohabit for 24 hr or more, with or without mating, exhibited a strong social preference for a familiar partner versus a strange male. Females that cohabited and mated for 6 hr showed strong preferences for a familiar partner, while cohabitation for less than 24 hr, without mating, did not result in preferences for the familiar male. These results indicate that mating was not essential for partner preference formation; however, preferences developed more rapidly when mating occurred.

Aggression↗
PubMed1992

Olfactory bulb removal affects partner preference development and estrus induction in female prairie voles.

In female prairie voles (Microtus ochrogaster) bilateral olfactory bulbectomy reduced affiliative behavior, as measured by social contact, and prevented the formation of partner preferences. Unilateral olfactory bulb removal did not significantly influence affiliative behavior, but did inhibit partner preferences. Bilateral, but not unilateral, bulbectomy significantly reduced the proportion of females exhibiting behavioral estrus following male exposure. In contrast to affiliative and sexual behavior, parental behavior was not significantly affected by either bilateral or unilateral olfactory bulbectomy. These results suggest that divergent sensory-neural pathways underlie social, sexual, and parental behaviors in this species.

Aggression↗
PubMed1992

Receptors for 1,25-dihydroxyvitamin D3 in gynecologic neoplasms.

To determine if gynecologic malignancies are candidates for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) therapy we measured vitamin D receptor (VDR) levels in 11 tumor specimens using a radiolabeled ligand-binding assay. VDR was demonstrated in 3 of 6 ovarian tumors and 1 of 1 uterine sarcomas, but not in endometrial tumors (2), cervical tumors (1), or Krukenberg tumors (1). Scatchard plots revealed that [3H]1,25(OH)2D3 was bound to a single class of high-affinity (Kd = 0.3 to 0.6 nM), saturable sites characteristic of authentic 1,25(OH)2D3 receptors. Specificity of binding activity for 1,25(OH)2D3, the active vitamin D3 metabolite, was demonstrated by failure of 25-hydroxy- and 24,25-dihydroxyvitamin D3 to compete effectively against 1,25(OH)2D3 binding in total cellular tumor extracts. The ovarian carcinoma cell line NIH:OVCAR3 was shown to possess VDR (binding capacity = 137 fmol/mg protein, Kd = 0.48 nM). A 3-day incubation of NIH:OVCAR3 cells with 100 nM 1,25(OH)2D3 resulted in 49% inhibition of cell growth. The growth inhibition of an ovarian carcinoma line and the observation that 36% of gynecologic tumors assayed were shown to be VDR-positive suggest that further study is warranted to delineate the mechanism and possible therapeutic aspects of 1,25(OH)2D3 action in gynecologic tumors.

Calcitriol↗
PubMed1992

Sensitization processes in human tumor cells during protracted irradiation: possible exploitation in the clinic.

Recent studies documenting the response of several human tumor cell lines to protracted, continuous irradiation and to acutely delivered radiation, suggest that tumor control may be enhanced with a tumor therapy combining external beam fractionated therapy and protracted irradiation from radiolabeled antibodies. We have evaluated the cytotoxic effect of continuous, protracted irradiation (0.005 Gy/hr to 0.50 Gy/hr) and acutely delivered high-dose-rate irradiation (1.0 Gy/min) on monolayer cultures of human tumor cell lines. Colony formation in these studies was analyzed by the seven-parameter simulation model of Dillehay. Additionally, for some cell lines, cultures were challenged during irradiation with an acute dose of 2.5, 5.0, 7.5 or 10.0 Gy at high-dose-rate. Results from these various studies indicate an altered cellular radiosensitivity occurs for some cell lines during protracted irradiation. At least two mechanisms have been identified that underlie this altered radiosensitivity. One mechanism, G2B, associated with redistribution within the cell cycle, has been previously described by Mitchell and others, and is associated with the phenomenon termed "the inverse dose-rate effect". The other mechanism is only observable following a challenge by acute high-dose-rate irradiation. We have termed this phenomenon "protracted-exposure-sensitization." The characteristics of these two mechanisms are discussed from the perspective of clinical therapeutic exploitation of combined external beam fractionated therapy and radiolabeled immunoglobulin therapy.

Cell Cycle↗
PubMed1992

Selection of reagents for human radioimmunotherapy.

Promising response rates are noted in patients with refractory Hodgkin's disease after radioimmunoglobulin therapy (RIT) with Yttrium-90 labeled polyclonal antiferritin. To explore the most efficacious selection of RIT reagents for use in humans, experimental animal data are reviewed for radiolabeled antiferritin and B72.3. Nude mice with subcutaneously implanted human malignancies provide an excellent primary screen for radiolabeled antibodies under consideration for use in humans. They provide information on the potential of a new reagent to target a human malignancy in vivo. The other determinant of the therapeutic ratio of RIT reagents--normal tissue toxicity--is best analyzed in large animals, such as dogs. Hematologic toxicity is dose limiting in all species and best predicted by a prescription of radiolabeled antibodies in mCi per kilogram body weight and the presence or absence of bone marrow targeting. Per cGy, RIT is more effective in causing BM damage in dogs than in rats. In dogs, bone marrow transplantation with autologous cryopreserved bone marrow cells or G-CSF treatment can accelerate hemopoietic recovery and granulopoiesis, respectively, after RIT. When dose escalation beyond bone marrow toxicity is performed, the liver (dog) or the intestinal tract (rat) become the next dose limiting tissue in dose escalation studies. Significant improvement in RIT results will be achieved when the normal liver uptake of chelated monoclonal antibody in dogs and in human patients can be prevented. The described animal models and continued investigations of RIT in patients with endstage Hodgkin's disease will allow for further improvement in the therapeutic ratio of RIT and the applicability of RIT in humans.

Animals↗
PubMed1992

The influence of the site of sampling and assay medium upon the measurement and interpretation of blood lactate responses to exercise.

UNLABELLED: This paper reports the findings of two investigations into methodological problems associated with the interpretation of blood lactate (BLa) in the sports sciences. In Experiment 1, brachial artery (A), antecubital venous (V) and fingertip capillary (C) blood samples were drawn simultaneously from nine subjects (mean age 21.1 +/- 1.3 years) during an incremental treadmill protocol and immediately assayed for BLa concentration. Experiment 2 investigated the extent of lactate concentration differences in whole blood (WB), lysed blood (LB) and plasma (P) measured using a YSI 23 AM analyser. In Experiment 1, a comparison of the mean BLa concentrations obtained from the three sites revealed no significant differences (P greater than 0.05). Correlations between BLa samples from different sites were very high, with r values ranging from 0.858 to 0.983. In Experiment 2, the mean lactate concentrations were: WB, 4.7 +/- 2.7 mM; LB, 5.0 +/- 3.0 mM; P, 7.0 +/- 3.8 mM. Plasma (P) values were significantly higher than WB and LB. Values from all sites were highly correlated with coefficients ranging from 0.963 to 0.987. IN CONCLUSION: (1) Significant arterial and venous BLa concentration differences do not exist during incremental treadmill exercise. (2) As capillary BLa concentrations reflect arterial values, their use in laboratory and field settings is recommended. (3) Lactate concentration differences in whole blood, lysed blood and plasma will influence the assessment of performance at fixed lactate reference values. (4) If the inter-laboratory test procedures are to be standardized and results compared, precise reporting of lactate sampling and assay techniques is critical.

Adult↗
PubMed1992

A dosimetric intercomparison of megavoltage photon beams in UK radiotherapy centres.

A dosimetry intercomparison has been carried out for all 64 radiotherapy centres in the UK. Doses were measured with an ionization chamber in an epoxy resin water-substitute phantom of relatively simple geometry. Reference-point measurements were made for all MV photon beams. For 61 Co-60 beams, a mean ratio of measured-to-stated dose of 1.002 was observed with a standard deviation of 0.014, whilst for 100 MV x-ray beams, the corresponding figures were 1.003 and 0.015. 97% of beams lay within a +/- 3% deviation. One measurement was instrumental in discovering a large discrepancy. Doses were also investigated in two planned three-field distributions at one beam quality in each centre. One of these was in a homogeneous phantom, whilst the second included a lung-equivalent insert. Doses were measured at the central point and at four other points in the high dose volume. In both situations, the mean ratio of measured-to-calculated doses for all points was 1.008, with standard deviations of 0.027 and 0.035 for the uniform and non-uniform phantoms, respectively. Discrepancies over 5% were followed up. The work must be viewed in the context of other international intercomparisons and is an essential part of wider radiotherapy audit processes.

Humans↗