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Biomedical subjects

D D Joel

Publications and source records attributed to D D Joel.

At least 19 recordsLinked to original sources
PubMed1992

Control of intracerebral gliosarcomas in rats by boron neutron capture therapy with p-boronophenylalanine.

Boron neutron capture therapy (BNCT) of transplanted intracerebral GS-9L rat gliosarcomas was effected by irradiation at a nuclear reactor, primarily with thermal neutrons, after two intragastric doses of p-boronophenylalanine (BPA). At the time of BNCT, tumor 10B levels were approximately 40 micrograms 10B/g with tumor:blood and tumor:brain 10B concentration ratios of about 3.3:1 and 3.9:1, respectively. This resulted in calculated doses to tumor that were approximately 2.3-fold greater than those to normal brain parenchyma and brain vascular endothelium within the treatment volume. Approximately 75% of the tumor dose resulted from the 10B(n,alpha)7Li nuclear reaction. The median survival of untreated rats (n = 20) was 20 days after initiation of tumors. Reactor irradiation only (no BPA) increased the median survival to 25 days (n = 25). None of the rats in the untreated or irradiation-only groups survived longer than 34 days after initiation of tumors. Two BNCT dose levels were used: 8.9 Gy (19.3 Gy x relative biological effectiveness, or Gy-eq) and 13.4 Gy (29.0 Gy-eq). The median post-BNCT survivals of BPA-treated rats in the 8.9-Gy (n = 16) and 13.4-Gy (n = 12) groups were 60 and 120 days, respectively, including seven long-term (greater than 12 months) survivors at 8.9 Gy and six long-term (greater than 5 months) survivors at 13.4 Gy. Survival times following BPA-based BNCT (either 8.9 or 13.4 Gy) were significantly longer than those following 250-kVp X-ray doses of 15 Gy (n = 24), 22.5 Gy (n = 32) or 30 Gy (n = 26).

Animals↗
PubMed1990

Selective delivery of boron by the melanin precursor analogue p-boronophenylalanine to tumors other than melanoma.

The melanin precursor analogue p-boronophenylalanine (BPA) has been used to deliver 10B to melanoma tissue for boron neuron capture therapy. Uptake studies in tumor models other than melanoma now indicate that BPA is capable of delivering therapeutic amounts of boron to tumors other than melanoma. The KHJJ murine mammary tumor carried s.c. in BALB/c mice, the GS-9L rat glioma carried both s.c. and intracranially in F-344 rats, and the human U-87 MG glioma xenograft carried s.c. in nude mice have all shown significant accumulation of boron in tumor tissue following single p.o. (intragastric) doses of BPA. In this KHJJ mammary tumor, the L isomer of BPA was preferentially accumulated compared to the D isomer, indicative of a carrier-mediated transport process. Double-label, whole-body autoradiographic studies in a pigmented murine melanoma have shown that the boron distribution (from BPA) differs from the distribution of a tritiated melanin precursor (tyrosine). Boron accumulated only in the tumor; labeled tyrosine accumulated in tumor, liver, intestinal epithelium, bone-marrow, and secretory glands. Toxicity studies in mice and rabbits indicate that, even at very high doses, BPA p.o. caused no adverse effect in tissues, on blood chemistry, or on differential leukocyte counts. These data indicate that BPA may be generally useful as a boron delivery agent for boron neutron capture therapy of tumors.

Animals↗
PubMed1990

Uptake of a nido-carboranylporphyrin by human glioma xenografts in athymic nude mice and by syngeneic ovarian carcinomas in immunocompetent mice.

A tetraphenylporphyrin bearing four dicarbollide ([B9C2H11]-) cages linked to the o-phenyl ring positions by anilide bonds, known as boronated tetraphenylporphyrin (BTPP), has been synthesized in excellent yield from tetra-(o-aminophenyl) porphyrin and carborane carbonyl chloride followed by base-assisted cage opening and ion exchange to give the highly water-soluble potassium salt. Preliminary studies showed that BTPP accumulates in liver and in a syngeneic ovarian carcinoma, but not in normal brain parenchyma, of mice infused with BTPP subcutaneously for 6 or 7 days via surgically implanted osmotic minipumps. In this study, the uptake of boron was measured in human gliomas xenografted subcutaneously to athymic nude mice in which BTPP was infused intraperitoneally or subcutaneously or both for 3 or 7 days by using similar minipumps. Immunocompetent mice bearing a syngeneic ovarian carcinoma were similarly infused to provide comparative data. Bulk concentrations of boron up to 18 micrograms/g of glioma and up to 45 micrograms/g of carcinoma were observed when up to 102 micrograms/g of tissue was present in the liver after 7 days of BTPP infusion. Glioma boron concentrations were increased by approximately 80% on the average (up to 33 micrograms/g) when correspondingly greater amounts of BTPP were infused in only 3 days. Cell counts and chemical tests on blood samples from individual mice indicate that BTPP causes moderate hepatotoxicity and thrombocytopenia. This hepatohematic toxicity syndrome should be taken into account if BTPP or a similar agent is used for boron neutron-capture therapy (BNCT) of human malignancies.

Animals↗
PubMed1990

Boron neutron capture therapy of intracerebral rat gliosarcomas.

The efficacy of boron neutron capture therapy (BNCT) for the treatment of intracerebrally implanted rat gliosarcomas was tested. Preferential accumulation of 10B in tumors was achieved by continuous infusion of the sulfhydryl borane dimer, Na4(10)B24H22S2, at a rate of 45-50 micrograms of 10B per g of body weight per day from day 11 to day 14 after tumor initiation (day 0). This infusion schedule resulted in average blood 10B concentrations of 35 micrograms/ml in a group of 12 gliosarcoma-bearing rats and 45 micrograms/ml in a group of 10 similar gliosarcoma-bearing rats treated by BNCT. Estimated tumor 10B levels in these two groups were 26 and 34 micrograms/g, respectively. On day 14, boron-treated and non-boron-treated rats were exposed to 5.0 or 7.5 MW.min of radiation from the Brookhaven Medical Research Reactor that yielded thermal neutron fluences of approximately 2.0 x 10(12) or approximately 3.0 x 10(12) n/cm2, respectively, in the tumors. Untreated rats had a median postinitiation survival time of 21 days. Reactor radiation alone increased median postinitiation survival time to 26 (5.0 MW.min) or 28 (7.5 MW.min) days. The 12 rats that received 5 MW.min of BNCT had a median postinitiation survival time of 60 days. Two of these animals survived greater than 15 months. In the 7.5 MW.min group, the median survival time is not calculable since 6 of the 10 animals remain alive greater than 10 months after BNCT. The estimated radiation doses to tumors in the two BNCT groups were 14.2 and 25.6 Gy equivalents, respectively. Similar gliosarcoma-bearing rats treated with 15.0 or 22.5 Gy of 250-kilovolt peak x-rays had median survival times of only 26 or 31 days, respectively, after tumor initiation.

Animals↗
PubMed1989

Intestinal uptake of fluorescent microspheres in young and aged mice.

Rhodamine B-labeled synthetic latex particles (microspheres), 1.8 micron in diameter, were administered by gavage 5 days per week to young (24 days) and aged (18 months) mice. After 25 days (19 gavages), the particles were assayed in solubilized tissues by depositing them on filters and counting under fluorescence microscopy. Aged mice exhibited significantly more fluorescent particle accumulation in Peyer's patches but significantly less in lungs than young mice. Mesenteric lymph nodes and Peyer's patch-free intestinal segments contained measurable latex, but differences between young and aged animals were not significant. Liver contained only trace amounts of latex, and spleen and kidney were latex free in both young and aged animals. Nonquantitative observations on KOH-glycerol-cleared whole Peyer's patches and slices of liver, lung, and mesenteric lymph node were similar.

Aging↗
PubMed1989

Effect of PEEP on regional ventilation and perfusion in the mechanically ventilated preterm lamb.

Improvement of gas exchange through closer matching of regional ventilation (V) and lung perfusion (Q) with the application of positive end-expiratory pressure (PEEP) was evaluated in vivo in six mechanically ventilated preterm lambs (107-126 days/145 days gestation). Changes in V and Q were determined from in vivo scintigraphic measurements in four lung regions with inhaled radioactive 81mKr, and infused 81mKr/dextrose and/or [99mTc]MAA as PEEP was applied at 2, 4, and 6 cm H2O in each animal. Dynamic compliance varied between 0.02 and 0.40 ml/cm H2O, which was consistent with surfactant deficiency. As PEEP was increased, the regional distribution of Q shifted from the rostral to the caudal lung regions (p less than 0.02 to less than 0.05), while that of V remained unchanged. Regional V/Q matching improved together with a trend towards improvement of arterial blood gases as PEEP was increased from 2 to 4 cm H2O. Pulmonary scintigraphy offers a noninvasive methodology for the quantitative assessment of regional V and Q matching in preterm lambs and may be clinically applicable to ventilated neonates.

Animals↗
PubMed1987

Distribution of lung-associated lymphocytes from the caudal mediastinal lymph node: effect of antigen.

Lymphocytes from the efferent lymph of the caudal mediastinal lymph node (CMLN) were labelled in vitro with 125I-iododeoxyuridine [125I]UdR and Na2(51)CrO4. The labelled cells were re-infused i.v. and their distribution in organs/tissues was determined 20-24 hr later. As indicated by tissue 125I-activity, pulmonary lymphoblasts had a marked tendency to relocate in the lung, regional pulmonary lymph nodes and spleen. Localization of efferent CMLN lymphoblasts was greater in antigenically stimulated segments compared to unstimulated segments of the lung. Dual antigen experiments indicated that the increased localization was not specific for the antigen which stimulated production of lymphoblasts used for in vitro labelling and reinfusion. Intranodal labelling of blasts by the direct injection of [125I]UdR supported the results obtained from in vitro labelling. In these studies, comparisons were made with the localization of lymphocytes obtained from thoracic duct lymph.

Animals↗
PubMed1986

Fc receptor function on sheep alveolar macrophages.

We have examined the binding to sheep alveolar macrophages (AM) and peripheral blood polymorphonuclear leukocytes (PMN) of sheep immunoglobulin G subclasses or rabbit IgG immune complexes formed between rabbit anti-DNP IgG and DNP-bovine serum albumin. Binding studies using 125I-rabbit IgG immune complexes demonstrated 6.6 +/- 3.5 X 10(4) receptors per alveolar macrophage; these receptors bound immune complexes with an average association constant of 3.3 X 10(7) M-1. Saturation binding was achieved by 90 minutes at 4 degrees C with 6 X 10(-8) M IgG. Binding of subclasses of sheep IgG was examined by immunofluorescence. Only 10% of alveolar macrophages bound monomeric IgG1 and no binding of sheep IgG2 monomer could be demonstrated. In contrast, most peripheral blood PMN (93.0 +/- 9.5%) bound IgG2, but not IgG1. No binding to adult peripheral blood PMN of rabbit IgG immune complexes could be demonstrated. To study further the development of pulmonary host defense, we examined the expression of receptors for IgG immune complexes (Fc gamma R) on alveolar macrophages obtained from animals aged 8 through 180 days. At 8 and 21 days of age, the number of Fc gamma R varied considerably (75,000-192,000 sites per cell) and equalled or even exceeded that of adult sheep. Fc gamma R number declined by 42 and 90 days of age, where a nadir was reached (37,000 +/- 6,000 and 25,000 +/- 6,000 sites, respectively). By 180 days of age, the number of receptors had approached those of normal adult sheep (70,000 +/- 20,000 sites per cell). These studies parallel previous observations that revealed age-related differences in the phagocytic capacity of ovine alveolar macrophages.

Age Factors↗
PubMed1986

Contamination of lung lymph following standard and modified procedures in sheep.

The sheep lung lymph fistula preparation of Staub et al. is reported to be contaminated by systemic lymph. The published estimates of contamination range from 5% (awake sheep) to 60% (anesthetized sheep). In view of these conflicting estimates, we investigated the pre- and postoperative contaminating sources, morphological and functional consequences of the proposed contamination reducing modifications, and base-line lung lymph flow in awake sheep following standard and modified cannulation procedures. Our morphological observations are not compatible with the higher estimates of contamination (25-60%). Evidence of lymph leakage from cauterized lymphatics was found. The lymphatics that appear after diaphragmatic cautery and partial resection of caudal mediastinal lymph node were found to constitute "new" contaminating sources. The lymph flow data from base-line and increased vascular pressure conditions were consistent with the reported low estimates of contamination (5%). We propose simple modifications of the standard procedure of Staub et al. which may be nearly as effective in reducing contamination by extrapulmonary lymph as the more invasive and/or traumatic modifications.

Animals↗
PubMed1986

Postnatal maturation of pulmonary antimicrobial defense mechanisms in conventional and germ-free lambs.

The phagocytic and bactericidal capacities of ovine bronchoalveolar lavage (BAL) cells were investigated as a function of postnatal age. In addition, age-related changes in the elaboration by alveolar macrophages of chemotaxins for neutrophils, concentrations of BAL fluid and serum immunoglobulins, and serum opsonic capacity were determined. BAL cells exhibited major changes in morphology, composition, and in vitro proliferation during the 1st postnatal wk. Studies in germ-free lambs indicated that the antigenic burden of the ambient environment markedly influenced the concentration of BAL neutrophils but had no effect on the influx, phagocytic, and proliferative activities of alveolar macrophages. Phagocytic and bactericidal functions of BAL cells improved rapidly during the 1st postnatal wk, then declined, and did not reattain adult levels until day 180. The capacity of alveolar macrophages to elaborate chemotaxins for neutrophils was deficient at day 8, but not at subsequent ages. The concentration of BAL IgG1 increased until day 8, fell at day 21, and then continued to increase gradually. IgA was not detected in BAL until day 21 and increased rapidly thereafter. Serum opsonic capacity at days 1 and 4 was comparable to that of adult serum, but sera from days 8 to 42 showed a marked reduction in opsonic capacity. Pulmonary antimicrobial defenses in neonatal sheep were thus found to be deficient to some degree throughout the first 3 months of life. It was not until day 180 that the parameters investigated in this study approximated those of adult sheep.

Age Factors↗
PubMed1986

Distribution of label after intragastric administration of 7Be-labeled carbon to weanling and aged mice.

Single doses of 7Be-labeled carbon particles prepared by proton bombardment of carbon black were administered by gavage to weanling (4 weeks) and aged (18 months) mice. Body distribution of 7Be radioactivity was determined 4 hr and 1, 2, 5, and 14 days later. The results were compared with those obtained after administration of a solution of 7BeCl2. 7Be radioactivity in nonintestinal tissues was 17-58 times greater in mice gavaged with the soluble salt than in those gavaged with the particles, indicating that particle-bound 7Be was well confined to the gastrointestinal tract. Upper limits of the amount of labeled carbon remaining in intestinal Peyer's patches were as follows: 1 day: weanling, 1.8 X 10(-3)%, old, 5.5 X 10(-3)%; 15 days: weanling, 3.3 X 10(-5)%, old, 8.4 X 10(-5)%. The particles are potentially useful as models for diesel emissions or other particulate pollutants.

Age Factors↗
PubMed1986

Tracing the leukocyte marker protein in lung fluids and lung-draining lymph nodes during endotoxemia in sheep.

Infusion of Escherichia coli endotoxin into sheep produces a form of acute lung injury that resembles the adult respiratory distress syndrome (ARDS). A large portion of the physiologic derangements produced by E. coli endotoxin in this model is thought to be granulocyte-dependent. We measured the level of L1, a granulocyte and monocyte marker protein, in various tissues and fluids after infusion of E. coli endotoxin into sheep. In an acute study, sheep received saline or 1.25 microgram/kg E. coli endotoxin dissolved in saline, or endotoxin after hydroxyurea-induced granulocytopenia. L1 was measured by radioimmunoassay in efferent lymph from the caudal mediastinal lymph node collected between 5 and 6 h after infusion. In addition, L1 was visualized in both lung-draining and extrapulmonary lymph nodes by indirect immunofluorescence. In a chronic study, sheep were prepared with lung lymph fistulas, and L1 was measured in draining pulmonary lymph, plasma, and bronchoalveolar lavage (BAL) fluid, serially, over a 24-h period after infusion. Mean L1 level in pulmonary lymph in the acute study was 6 times higher by absolute concentration, and 19 times higher when lymph flow rates were taken into account, in the sheep that received endotoxin than in saline-infused sheep or endotoxin-infused, granulocytopenic sheep. Fluorescence was greater in the outer cortical region adjacent to subcapsular, afferent sinuses of lung draining-lymph nodes of endotoxin-treated sheep than in the comparable nodes of saline-infused sheep and endotoxin-infused granulocytopenic sheep. In endotoxin-treated sheep, extrapulmonary lymph nodes were less reactive than lung-draining nodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

The status of pulmonary host defense in the neonatal sheep: cellular and humoral aspects.

In consideration of the sheep neonate as a compromised host, we have examined the status of cellular and humoral pulmonary host defense components at selected developmental time points. The dynamic character of the early neonatal LFC population, reflected in changes in subpopulations and proliferative capacity, most probably contributed to the observed changes in in vitro cell function. While certain cell responses, e.g., blood and LFC PMN chemotaxis, appeared intact by day 1, others developed subsequently. The ability of AMs to elaborate a chemotactic factor(s) was first noted at day 21. Bacteria binding and killing presented a biphasic maturation pattern, with full competence not present until day 180. Although the in vitro binding and killing activity of day 8 LFCs was comparable to that of the adult, it may be a poor indicator of in vivo host defense capacity, given the relative paucity of endogenous opsonins at that age. In fact, the interdependence of mediators suggests that the sheep neonate may remain a compromised host during the first 3 months of life. Thereafter, cellular and humoral parameters begin to approximate those of adult sheep and by 180 days of life pulmonary defense, as assessed in this study, is fully developed.

Age Factors↗