Biomedical subjects
Publications and source records attributed to G G Long.
Ultra-small-angle X-ray scattering data were obtained from deformed single-crystal aluminium samples. These data are consistent with recent theoretical predictions of scattering from dislocation walls, allowing quantitative microstructural parameters to be extracted.
The performance of the p53-/- transgenic (knockout) mouse model was evaluated through review of the data from 31 short-term carcinogenicity studies with 21 compounds tested as part of the International Life Sciences Institute's (ILSI) Alternatives to Carcinogenicity Testing (ACT) project, together with data from other studies which used comparable protocols. As expected based on the hypothesis for the model, a significant number (12/16 or 75%) of the genotoxic human and/or rodent carcinogens tested were positive and the positive control, p-cresidine, gave reproducible responses across laboratories (18/19 studies positive in bladder). An immunosuppressive human carcinogen, cyclosporin A, was positive for lymphomas but produced a similar response in wild type mice. Two hormones that are human tumorigens, diethylstilbestrol and 17beta-estradiol, gave positive and equivocal results, respectively, in the pituitary with p53-deficient mice showing a greater incidence of proliferative lesions than wild type. None of the 22 nongenotoxic rodent carcinogens that have been tested produced a positive response but 2 compounds in this category, chloroform and diethylhexylphthalate, were judged equivocal based on effects in liver and kidney respectively. Four genotoxic noncarcinogens and 6 nongenotoxic, noncarcinogens were also negative. In total (excluding compounds with equivocal results), 42 of 48 compounds or 88% gave results that were concordant with expectations. The technical lessons learned from the ILSI ACT-sponsored testing in the p53+/- model are discussed.
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MK(+)801 (dizocilpine maleate) is a noncompetitive antagonist at the N-methyl-D-aspartate (NMDA) receptor, the major glutamate receptor at excitatory synapses in the central nervous system. Since NMDA antagonists are neuroprotective, there is interest in their development for treatment of cerebral ischemia. Unfortunately, many of these compounds also induce vacuole formation in neurons of the rat retrosplenial cortex (Olney et al., Science 244: 1360-1362, 1989). Although vacuolization was initially reported to be reversible with MK(+)801, preliminary data later suggested that higher doses might produce neuronal necrosis. To explore this issue, young male Sprague-Dawley rats were given a single subcutaneous dose of vehicle or 1, 5, or 10 mg/kg MK(+)801. At 4 h and 1, 2, 3, 4, 7, and 14 days postdose (DPD), the retrosplenial cortex was examined by light and electron microscopy. At 4 h, vacuoles occurred in neurons of retrosplenial cortical layers 3 and 4 in all rats given MK(+)801. Mitochondria and endoplasmic reticulum contributed to vacuole formation. At 1 DPD, vacuoles or necrotic neurons were rarely observed. At all subsequent time points, necrotic neurons were readily evident in rats given 5 or 10 mg/kg MK(+)801, but only rarely evident in rats given 1 mg/kg. Necrotic neurons were associated with reactive microglial cells that contained electron-dense debris ultrastructurally. If similar dose-dependent neuronal necrosis proves to be a feature of other NMDA antagonists, such effects might raise concerns for the development and use of these compounds in human cerebrovascular diseases.
First litter sows in naturally occurring post-weaning estrus were hand mated to proven boars and were fed a diet supplemented with zearalenone, an estrogenic mycotoxin (1 mg zearalenone/kg body weight), or a control diet on days 7 through 10 after mating. Embryos (blastocysts) and endometrial biopsies were collected from control and treated sows on days 9, 11, and 13 after mating. All blastocysts harvested on day 9 were spherical; treatment of sows with zearalenone had no effect on blastocyst development. Blastocysts collected from treated sows on day 11 were in stages of elongation comparable to those of blastocysts from control sows but had mild degenerative changes in the embryonic disks, characterized by slightly retarded development and an increase in the number of necrotic cells. Blastocysts collected from treated sows on day 13 were in an advanced stage of degeneration, characterized by circumferential constrictive division, fragmentation, and degeneration and disorganization of the embryonic disk. Feeding zearalenone to pregnant sows had no effect on the normal decrease in height of the endometrial luminal epithelium on days 9 through 13 after mating and no effect on morphologic appearance of secretory vesicles in the endometrial glandular epithelium. The dosage scheme of zearalenone used in this study did not cause any morphologic changes in the endometrium that could be associated with hyperestrogenism.
It has been shown that zearalenone disrupts early pregnancy in swine without altering intrauterine content of estradiol 17 beta or progesterone, embryo migration, or estradiol-17 beta synthesis by blastocysts. However, serum concentrations of progesterone were reduced 2 to 3 weeks after mating in gilts that ingested zearalenone. Therefore, progesterone was administered to gilts during early pregnancy to determine whether it could counteract the detrimental actions of zearalenone on embryonic development. Thirty-two crossbred gilts (Hampshire x Chester White x Yorkshire x Duroc) were assigned randomly to a 2 x 2 factorial arrangement of treatments: zearalenone (Z); zearalenone plus progesterone (ZP); progesterone (P); or control (C). From postmating days 4 to 15, Z- and ZP-treated gilts were fed 1 mg of Z/kg of body weight, and P-treated and C gilts were fed ethanol as vehicle in a corn-soybean diet. On postmating days 3 to 15, P- and ZP-treated gilts were injected IM with 100 mg of progesterone, and C and Z-treated gilts were injected with progesterone carrier (15% ethanol, 15% benzyl alcohol, 70% propylene glycol). Blood was collected from gilts by puncture of the jugular vein daily from days 3 to 15, on alternate days from days 17 to 31, and then twice weekly until the end of the experiment. Fetal development was assessed in Z- and ZP-treated gilts on postmating day 47.6 +/- 2.9 by cesarean section and in P-treated and C gilts at slaughter on postmating days 51.2 +/- 3.2. Serum concentrations of progesterone in P-treated gilts were greater on days 7 to 8, 10 to 15, 17, and 19 than in C gilts. Serum concentrations of progesterone were greater on days 8, 10, and 12 in ZP-treated than in C gilts. However, serum concentrations of progesterone were lower in ZP-treated gilts than in C gilts on postmating days 19 to 31.(ABSTRACT TRUNCATED AT 250 WORDS)
Forty-eight prepubertal gilts (178.7 +/- 4.1 d; 94.2 +/- 4.1 kg), 16 in each of three trials, were assigned randomly to receive 0 (C) or 10 ppm zearalenone (Z) daily in 2.5 kg of a 14% protein finishing ration for 2 wk. Blood samples were collected at 20-min intervals for 4 h 1 wk after the start of the experiment and 1 wk after Z was withdrawn. Two weeks after Z was withdrawn, gilts were exposed to mature boars 15 min per day for 3 wk. Gilts in estrus were mated to two different boars 12 h apart. Twice each week, blood was sampled and analyzed for progesterone to establish age of puberty. Age at puberty differed (P = .008) among replicates but was similar (P = .13) between Z and C gilts within each replicate. Mean serum concentrations of LH were suppressed (P = .025) during consumption of Z (.25 vs .42 ng/ml) but were similar (P = .16) to concentrations in C gilts 1 wk after Z was withdrawn (.35 vs .45 ng/ml). Frequency and amplitude of LH secretory spikes did not differ (P greater than .50) between Z and C gilts during either sampling period. Mean serum concentrations of FSH were similar (P = .25) between Z and C gilts. Number of corpora lutea and live fetuses were similar (P = .29 and P = .94, respectively) between Z and C gilts. Fetal weights were greater (P = .025) and crown to rump length tended to be greater (P = .10) in fetuses from Z gilts.(ABSTRACT TRUNCATED AT 250 WORDS)
Embryos were harvested at the blastocyst stage from nontreated outbred mice and were grown in vitro for 4 days. Embryos cultured in control medium hatched and grew to the egg cylinder stage. Purified zearalenone (ZEN) added to the culture medium at concentrations of 8.5 to 68 micrograms/ml decreased the number of embryos growing, with a 50% decrease in the number growing in 32 micrograms of ZEN/ml of medium. Embryos growing in ZEN had decreased numbers of cells derived from the inner cell mass, normal growth of the trophoblast, less cellular differentiation than was seen in control embryos, and increased numbers of phagosomes. Undifferentiated cells of the inner cell mass of control and treated embryos were of the same size, as determined by morphometric analysis. Addition of 25 micrograms of estradiol/ml of culture medium caused no decrease in number of embryos growing or in embryonic size. Saturation of culture medium with ZEN (68 micrograms/ml) did not inhibit the growth of a tissue culture line of goat synovial cells. Seemingly, ZEN at concentrations near saturation inhibited the growth of mouse embryos in vitro. This effect was not duplicated with similar concentrations of estradiol and was not manifested in culture-adapted cells.
Female guinea pigs were tested to determine whether they could serve as a model of zearalenone (ZEN) toxicosis during early pregnancy, as observed in domestic swine. Only 1 of 4 female guinea pigs that were given 21 mg of ZEN/kg of body weight orally during the first 8 days after mating was pregnant when examined 22 days after mating. Guinea pigs that were given 7 or 14 mg of ZEN/kg had normal fetal development. Serum concentrations of progesterone were less than 12 ng/ml in all guinea pigs 8 and 15 days after mating. Serum concentrations of progesterone were greater than 100 ng/ml in pregnant guinea pigs on day 22, but remained less than 12 ng/ml in nonpregnant guinea pigs. Three of 5 guinea pigs treated with 20 mg of ZEN/kg and only 1 of 4 guinea pigs given 30 mg of ZEN/kg on days 1 to 3 after mating were pregnant 22 days after mating. Female guinea pigs treated with 20 or 30 mg of ZEN/kg on days 4 to 5 or 6 to 8 after mating and female guinea pigs treated with 60 or 90 mg of ZEN/kg on days 4 and 5 after mating had normal pregnancies. Serum concentrations of progesterone were less than 10 ng/ml in all guinea pigs on day 15 and remained low on day 22 only in nonpregnant guinea pigs.(ABSTRACT TRUNCATED AT 250 WORDS)
Sixteen primiparous sows were bred and fed either a control ration (n = 8) or a diet containing purified zearalenone (n = 8; 1 mg/kg of body weight) from days 7 to 10 after breeding. On day 7 after breeding, the jugular vein of each sow was cannulated and blood was collected at 20-minute intervals for 4 hours before feeding and 4 hours after feeding. On day 10 after breeding, blood samples were collected from 4 control sows and 4 zearalenone-fed sows at 20-minute intervals for 4 hours before collection of blastocysts. A similar blood sampling schedule was followed for the remaining 4 control and 4 zearalenone sows on day 14 after breeding. On day 10 after breeding, spherical blastocysts were recovered from all control sows and from 3 of 4 zearalenone-treated sows. Average diameter of blastocysts from zearalenone-treated sows were similar to that of control sows. On day 14 after breeding, blastocysts were recovered from all control sows and 3 of 4 zearalenone-treated sows. Blastocysts from the control sows were filamentous, whereas blastocysts from zearalenone-treated sows were fragmented and contained foci of necrosis. Incidence of luteinizing hormone (LH) secretory spikes per sow was less (P less than 0.01) in zearalenone-treated sows (0.25 +/- 0.25/4 h) than control sows (1.75 +/- 0.25/4 h) on day 10 after breeding. Incidence of follicle-stimulating hormone (FSH) secretory spikes was similar (P = 0.45) among treatments on days 7, 10, and 14 after breeding.(ABSTRACT TRUNCATED AT 250 WORDS)
On d 7 to 10 postmating, first-litter sows were fed either a control diet or a diet containing zearalenone (ZEN; 1 mg/kg body weight). Surgery was performed on either d 9, 11 or 13 postmating to collect blastocysts and uterine flushings. The rostral and caudal portion of each uterine horn was flushed with phosphate buffered saline, and the blastocysts were separated from the recovered solution. Uterine flushings were analyzed for total Ca, Mg, Zn, estradiol-17 beta (E2 17 beta) and progesterone (P4). Administration of ZEN did not affect the number of blastocysts recovered or the position of embryos within the uterus on d 9 or 11. Blastocysts recovered on d 13 were filamentous and could not be enumerated. Total Ca in uterine flushings of control sows was higher (P less than .001) on d 11 than on d 9 or 13, but intrauterine Ca of ZEN-treated sows did not vary by sampling day (P greater than .05) and was lower (P = .01) than that of controls on d 11. Total intrauterine Mg of ZEN sows was greater (P = .002) than of control sows on d 11 and 13, and total intrauterine Zn of ZEN sows was greater than that in control sows on d 13. There were no differences in total intrauterine P4 or E2 17 beta among ZEN-treated and control sows on d 9, 11 or 13 postmating. Serum concentrations of 13, 14-dihydro-15-ketoprostaglandin F2 alpha (PGFM) increased from d 9 to 13 in control and ZEN-treated sows, but there were no differences between treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Weakness, lethargy, ataxia, lateral recumbency, limb paddling, tremors, salivation, and diarrhea were observed in newborn pigs on a commercial swine farm. Many pigs became moribund and died. All had been treated with an aerosol wound spray containing 2.5% chlorpyrifos. A controlled study was undertaken to determine whether the aerosol spray was the cause of these clinical signs. Pigs exposed to aerosol spray containing 2.5% chlorpyrifos at 3 hours (n = 4) and 6 hours (n = 3) after birth developed clinical signs similar to those on the farm; none survived. Pigs exposed at 24 hours (n = 5) after birth developed clinical signs consistent with those that had developed in pigs on the farm; 3 died and 2 survived. Of 3 pigs exposed to the same spray at 36 hours after birth, 1 developed tremors 7.5 hours later and diarrhea 9 hours later, then returned to normal.
To determine whether manure gases can influence onset of puberty in gilts, 42 crossbred gilts were reared from 10 to 40 wk of age on concrete slats over a 1.22-m deep pit that was drained and refilled with clean water biweekly (clean group). Forty-one gilts were reared over a similar type pit where manure was allowed to accumulate (control group). Treatments were in two separate rooms of the same building with similar feeding, water, floor space, lighting and room temperature. Ventilation fans with timer controls in each room were set so fans in the clean environment ran twice as long as fans in the control environment. Aerial concentrations of ammonia in the control room were fourfold higher than in the clean room (21 vs 5 ppm), while aerial concentrations of hydrogen sulfide were similar. Average daily gain and feed efficiency were similar for both groups [.69 vs .72 kg/d (P = .31) and 1.61 vs 1.54 kg feed/kg gain (P = .52)]. From 20 to 40 wk of age, all gilts were exposed to a mature boar three times weekly, utilizing four boars in rotation. Blood samples were collected weekly from each gilt by venipuncture and analyzed for progesterone to establish time of first ovulation. A greater proportion of gilts in the clean group attained puberty by 24 to 26 wk (P less than .05) and 27 to 29 wk of age (P less than .10) compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)
The primary purpose of necropsy of the porcine fetus is the collection of tissues to be submitted to the laboratory to assist in identification of the causative agent(s). Proper collection and handling of tissues are critical for optimum identification of infectious agents. Gross examination is an aid in differentiating stillbirth and neonatal death, determining relative time of fetal death, and identifying congenital defects.
An aerosol preparation containing 2.5% chlorpyrifos was applied to the tail and umbilicus of newborn pigs. Mortality was 7/7 pigs treated 0-3 hr after birth, 3/5 pigs treated at 24-30 hr, and 0/3 pigs treated 30-36 hr after birth. Clinical signs consistent with organophosphate (OP) toxicosis were demonstrated by pigs that subsequently died or were euthanatized in extremis. Blood and brain cholinesterase (ChE) activities were depressed in affected pigs compared to controls. Only 1/3 pigs treated 30-36 hr after birth had a diagnostically significant depression in blood ChE. These results indicate that piglets one day or less of age are susceptible to OP toxicosis by cutaneous absorption of chlorpyrifos.
Mature gilts (n = 16) were hand mated and randomly assigned to 1 of 4 groups of 4 gilts each. Treated gilts had 108 mg of purified zearalenone added to their diet on postmating days (PMD) 2 to 6, 7 to 10, or 11 to 15. Control gilts were given the same diet without added zearalenone. On PMD 6, 10, and 15, control gilts had venous cannulas placed in the jugular vein, and blood samples were taken at 20-minute intervals for 4 hours before feeding and 4 hours after feeding. Samples were collected from treated gilts on the last day that zearalenone was consumed. Samples were analyzed for follicle stimulating hormone, luteinizing hormone (LH), and prolactin. Single blood samples were taken by venipuncture on PMD 8, 12, 16, 20, 24, and 28 and at euthanasia and were analyzed for serum concentration of progesterone and estradiol-17 beta. All gilts were euthanatized 30 to 32 days after mating, and fetal development was assessed. Three gilts that were given zearalenone on PMD 7 to 10 were not pregnant and had regressing corpora lutea on the ovaries at euthanasia. All other treated and control gilts were pregnant. Serum samples from treated gilts on PMD 10 and 15 had lower mean prolactin concentrations than did those from controls. The number of LH spikes were fewer (P less than 0.05) in gilts that were given zearalenone on PMD 15 compared with those in controls on PMD 15. Serum progesterone concentrations indicated that corpora lutea regressed between PMD 20 and 28 in nonpregnant gilts.(ABSTRACT TRUNCATED AT 250 WORDS)
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