Alteration of Kupffer cell function and morphology by low melt point paraffin wax in female Fischer-344 but not Sprague-Dawley rats

This study was conducted to compare the effects of 60-day dietary exposure (2%) to low melt point paraffin wax (LMPW) on both general liver morphology and Kupffer cell (KC) function and morphology in female F-344 and Sprague-Dawley (SD) rats. Livers from only F-344 rats fed LMPW had granuloma formation/lymphoid cell aggregates with small areas of necrosis. Significant increases in serum alanine and aspartate aminotransferase as well as gamma-glutamyltransferase activities were detected only in treated F-344 rats. Additionally, detectable amounts of LMPW were present only in livers of treated F-344 rats. Because KC can be involved in granuloma formation, their morphology and function were examined. Electron microscopy revealed the presence of large, irregularly shaped, membrane-associated vacuoles in cells isolated from F-344 rats exposed to LMPW. These vacuoles were not seen in KC from control rats and rarely detected in KC isolated from LMPW-exposed SD rats. Moreover, indices of KC function including phagocytic activity and nitric oxide and superoxide anion production were significantly increased by KC isolated from F-344 rats exposed to LMPW (1.6-, 36-, and 2.2-fold increases, respectively) over untreated controls. In contrast, LPS-stimulated production of TNF and LTB4 was significantly decreased only in KC of LMPW-fed F-344 rats. No significant changes in these functions were observed in KC isolated from SD rats exposed to LMPW or from KC isolated from control F-344 or SD rats. These data provide evidence that dietary LMPW alters the morphology and functional capacity of KC of F-344 but not SD rats and these changes may ultimately lead to granuloma formation.     

Restoration of sympathetic noradrenergic nerve fibers in the spleen by low doses of L-deprenyl treatment in young sympathectomized and old Fischer 344 rats

It is well-established that noradrenergic (NA) nerve fibers in spleen and lymph nodes influence cell-mediated immune responses. Such responses are diminished in young animals following chemical sympathectomy and in older animals accompanying an age-related decline in NA nerve fibers in spleen and lymph nodes. The purpose of this study was to determine whether treatment with deprenyl, an irreversible monoamine oxidase-B (MAO-B) inhibitor, would hasten the process of splenic NA reinnervation following chemical sympathectomy in young rats and would reverse the age-related loss of sympathetic NA fibers in the spleen of old rats. To examine the effects of deprenyl in young sympathectomized rats, 3-month-old male Fischer 344 (F344) rats were treated with 6-hydroxydopamine (6-OHDA) and administered 0, 0.25, 1.0, 2.5, or 5.0 mg deprenyl/kg body weight (BW)/day intraperitoneally (i.p.) for 1, 15, or 30 days. In another study, 21-month-old male F344 rats were treated with 0, 0.25, or 1.0 mg deprenyl/kg BW/day i.p. for 9 weeks. At the end of the treatment period, spleens were removed and NA innervation was assessed by fluorescence histochemistry, immunocytochemistry, and quantitation of norepinephrine (NE) by high performance liquid chromatography with electrochemical detection (HPLC-EC). In the spleens of young sympathectomized rats, there was faint fluorescence or absence of fluorescence and tyrosine hydroxylase-positive (TH+) fibers around the central arteriole and in the periarteriolar lymphatic sheath of the white pulp one day after administration of 6-OHDA, indicating a severe loss of NA innervation compared with unlesioned control animals. Treatment of sympathectomized rats with 1.0 mg, 2.5 mg, and 5.0 mg/kg deprenyl for 30 days increased the density of NA innervation estimated by both fluorescence histochemistry and immunocytochemistry compared with vehicle-treated controls recovering spontaneously from 6-OHDA. Splenic NE concentration was increased in the hilar region of sympathectomized rats treated with 2.5 mg and 1.0 mg/kg deprenyl after 15 and 30 days, respectively, compared with untreated and vehicle-treated sympathectomized rats. The spleens of untreated and saline-treated old rats showed a reduction in the density of NA innervation in the white pulp compared with young animals. Treatment of old rats for 9 weeks with 1.0 mg/kg deprenyl induced moderate to intense fluorescent fibers and linear TH+ nerve fibers around the central arteriole and in other compartments of the white pulp, and increased splenic NE concentration in the hilar region and NE content in the whole spleen. Taken together, these results provide strong evidence for a neurorestorative property of deprenyl on sympathetic NA innervation of the spleen, which may lead to an improvement in cell-mediated immune responses.     

Possibility of the use of perfluorochemicals (fluorocarbons) as adjuvants in chemotherapy of cancer

In Fischer 344 rats weighing about 100 gr., 7 X 10(5) 9L tumor cells were implanted into right cerebral hemisphere. BCNU. Fluosol-43 (perfluorochemicals blood substitute), or combined therapy BCNU and Fluosol-43 were initiated on Day 7 postimplantation and its therapeutic effect was studied. Mean survival time of control animals was 15.23 +/- 2.84 (SD) days, the group of Fluosol-43 treated in oxygen chamber (95% Oxygen & 5% Carbon Dioxide) was 15.30 +/- 2.11 (SD) days. BCNU treatment alone prolonged the mean survival time to 20.90 +/- 3.80 (SD) days, BCNU plus Fluosol-43 in normal aeration was 21.20 +/- 2.63 (SD) days. On the other hand, BCNU plus Fluosol-43 in oxygen chamber showed a significant increase of mean survival time of 32.27 +/- 4.80 (SD) days (p less than 0.005). From these results, it was concluded that Fluosol-43 (perfluorochemicals) with oxygen might have a synergistic effect for BCNU chemotherapy.     

An experimental study of coronary arteriosclerosis after heart transplantation

The purpose of this study is to evaluate the effects of Cyclosporine (CsA), FK-506 (FK) and 15-Deoxyspergualin (DOS) on coronary arteriosclerosis after rat heart transplantation. Three groups of Lewis rats (n = 7, each) received heterotopic heart transplants from F-344 donors and were treated with CsA (Group Cs), FK (Group FK) and DOS (Group DOS) intraperitoneally. All rats were sacrificed 60 days later and assessed microscopic grading score (GS) of rejection and arteriosclerosis, and measured serum lipid. There was no significant difference in the GS of rejection but the GS of arteriosclerosis in the groups Cs was significantly higher than the group DOS (1.71 +/- 0.24 versus 1.11 +/- 0.34, p < 0.01). Triglyceride in the groups Cs was significantly higher than the group FK and group DOS (99 +/- 23 versus 66 +/- 21, 56 +/- 30 mg/dl, p < 0.02), and LDL in the group Cs and group FK was significantly higher than group DOS (104 +/- 17, 81 +/- 23 versus 31 +/- 17 mg/dl, p < 0.01). We concluded that DOS had a superior protective effect against coronary arteriosclerosis after heart transplantation and it may depend on the different mechanism of immunosuppression and lipid metabolism abnormality causing by immunosuppressants.     

Perfusion quantitation in transplanted rat kidney by MRI with arterial spin labeling

The purpose of this study was to determine the feasibility of using quantitative magnetic resonance imaging (MRI) with non-invasive arterial spin labeling to assess perfusion of transplanted kidneys in rats. MRI studies were performed on five groups of rats: normal Fisher 344 rats, Fisher 344 rats that had received a syngeneic kidney transplant either 3 or seven days prior to study, and Fisher 344 rats that had received an allogeneic kidney (ACI rat as the donor) either three or seven days prior to study. The contralateral native kidney remained in place for comparison. Cortical perfusion was quantitated from a slice through the center of each kidney in anesthetized rats at 4.7 Tesla with a fast gradient-echo MRI sequence following the arterial spin labeling. The spin-lattice relaxation time was measured within the cortex, and the cross sectional area of the kidney was also determined within the same MRI plane. Immediately after the perfusion imaging measurement, transplanted kidneys were removed and scored for rejection using the Banff histological criteria. Renal cortical perfusion in normal kidneys was 7.5 +/- 0.8 ml/g/min (N = 12 rats, 24 kidneys). At the third day post-transplantation, that is, before marked acute rejection, the renal cortical perfusion rate was similar in both syngeneic and allogeneic kidneys [3.3 +/- 1.7 (N = 6) and 3.0 +/- 2.4 ml/g/min (N = 6), respectively]. In contrast, at the seventh day post-transplantation, that is, during severe rejection, the renal cortical perfusion rate in allogeneic kidneys was very low (undetectable) compared to the value in syngeneic kidneys [that is, < or = 0.3 (N = 6) versus 5.2 +/- 2.0 ml/g/min (N = 6), respectively]. Moreover, the renal cortical perfusion rate determined by MRI was significantly (P < 0.05, r = -0.82) correlated with histological rejection. We conclude that the quantitative measurement of renal cortical perfusion by MRI with arterial spin-labeling could provide a non-invasive diagnostic method for monitoring the status of renal transplants without requiring the administration of a contrast agent.     

Fast axonal transport rates are unchanged in 6- and 24-month F344 rats

The maximum rate of fast axonal transport in motor axons at 6 and 24 months was measured in F344 rats. Tritiated proline was injected near sciatic motoneurons and rats were killed after 2-5 h. Nerves were processed for liquid scintillation spectroscopy and fast transport rates calculated. The rates, in 6- and 24-month rats, were 373 +/- 12 mm/day and 368 +/- 10 mm/day, respectively. Thus, the maximum fast transport rate is unchanged with age in F344 rats.     

Glutathione S-transferase-pi is secreted as a monomer into human plasma by platelets and tumor cells

WY-14,643 (WY) and methylclofenapate (MCP) are peroxisome proliferators (PP) and hepatocarcinogens in rats. MCP causes hepatic polyploidization and preferentially induces replicative DNA synthesis in binucleate tetraploid hepatocytes (2 X 2N) in young Alpk:AP rats. To compare the effect of WY and MCP on hepatocyte ploidy and ploidy-specific DNA synthesis, male F344 rats were fed WY (0.1% in diet) or gavaged with MCP (25 mg/kg/day in corn oil) for 2, 5, or 10 days. Four rats per treatment group (including corn oil and diet control groups) were euthanized and the livers perfused at each time point. To identify cells undergoing DNA synthesis, all animals received BrdU by continuous infusion for 2 or 5 days prior to euthanasia. Hepatocyte ploidy and DNA synthesis were determined using one- or two-parameter flow cytometry. Averages +/- SEM for adult male F344 rats as a percentage of total hepatocytes for each ploidy subclass are 2N = 3.4 +/- 0.7%, 4N = 69.9 +/- 1.9%, 2 X 2N = 14.4 +/- 2.4%, 8N = 2.2 +/- 0.4%, and 2 X 4N = 9.6 +/- 0.9%. Significant alterations were not induced in the proportions of 2 X 2N or 4N ploidy subclasses by WY or MCP at any time point. However, WY caused increases in 8N hepatocytes at 2, 5, and 10 days (2 days, 5.2% vs 2.2% for controls; 5 days, 7.0% vs 3.1% for controls; 10 days, 6.4% vs 3.6% for controls) as did MCP at 5 and 10 days (5 days, 6.3% vs 2.5% for controls; 10 days, 5.3% vs 2.9% for controls). In addition, a majority of BrdU-containing hepatocytes were 4N following 5 and 10 days of WY and MCP [34.3% (WY) and 16.8% (MCP) vs 1.8% and 1.1% for controls, respectively, for 2 X 2N (5 days) as a percentage of total hepatocytes]. Hepatocytes with intermediary DNA content (between tetraploid and octaploid) from MCP- and WY-treated rats were predominantly mononuclear, the percentage of binucleate hepatocytes being similar to or less than the percentage of binucleate cells within the total tetraploid hepatocyte population. These data suggest that polyploidization is induced by PP and induction of S-phase by WY and MCP occurs primarily in 4N hepatocytes in mature F344 rats and not within 2 X 2N hepatocytes. Identification of a ploidy subpopulation at risk for tumor development in rodents is essential for clarifying the role of cell replication in risk assessment studies of PP.     

Bone marrow oxygen consumption and erythropoiesis in chronically hypoxic rats

Bone marrow oxygen consumption (VO2) was determined weekly in 16 Holtzman rats exposed to continuous hypobaric hypoxia (CHH) during 30 days. The results were compared with those obtained in 10 sea level control animals (SL). The VO2 expressed as ng.at.O2/min, decreased progressively with time of exposure to hypoxia. VO2 (mean +/- SD) was 0.0936 +/- 0.135 in SL rats. In CHH animals, it was 0.1001 +/- 0.0292 after 8 days of hypoxia, 0.1030 +/- 0.0206 after 16 days, 0.0594 +/- 0.0148 (p = 0.002) after 24 days and 0.0136 +/- 0.404 (p = 0.000) after 30 days. Protein concentration in bone marrow was progressively higher in hypoxics when compared to control, with significant differences since the first week of exposure. Blood hemoglobin increased in parallel to protein concentration in the bone marrow. These findings suggest an increase in the cells of the erythroid series whose oxygen consumption is less than cells in the early stages of differentiation. The increased protein concentration is in agreement with the fact that globin mRNA appears in cells with a progressively increasing anaerobic metabolism at relatively late stages of erythropoiesis.     

Comparison of in vivo mutagenesis in the endogenous Hprt gene and the lacI transgene of Big Blue(R) rats treated with 7, 12-dimethylbenz[a]anthracene

The lacI transgene of Big Blue(R) (BB) rats was evaluated as a reporter of in vivo mutation by comparing mutant frequencies (MFs) in it and in the endogenous Hprt gene. Seven-week old female BB rats were given single doses of 0, 20, 75 and 130 mg/kg of 7, 12-dimethylbenz(a)anthracene (DMBA) by gavage, and Hprt and lacI MFs in splenic lymphocytes were measured over a period of 18 weeks. The Hprt MFs in treated rats increased for 10 weeks and then declined; 130 mg/kg of DMBA produced a maximum Hprt MF of 168+/-11.4x10-6 clonable lymphocytes, while the MF in control rats was 7.4+/-1. 5x10-6. DMBA exposure of generic F344 rats resulted in a similar time-course of mutant induction but produced about 50% higher Hprt MFs with the 75 and 130 mg/kg doses. In contrast, the lacI MFs increased for 6 weeks and then remained relatively constant; 130 mg/kg of DMBA produced a maximum increase in lacI MF of 341+/-83x10-6 PFU compared with 25+/-5x10-6 PFU in control rats. The Hprt mutant frequencies in DMBA-treated BB and F344 rats were significantly increased over control values for every dose-time combination examined, while only the 130 mg/kg dose consistently produced lacI MFs that were significantly above the controls. In addition, the fold-increase in MF for treated vs. control rats was two times higher for the Hprt gene than the lacI gene due to the higher MFs in the lacI gene of control rats. Differences between the lacI and Hprt genes in the kinetics of mutant induction, in the frequency of induced mutants, and in the sensitivity of mutant detection could be explained at least partially by the properties of these two genes.     

A non-randomized comparison of two radiotherapy protocols in inoperable squamous cell carcinoma of the oesophagus

Furosemide (F)-induced nephrocalcinosis (NC) has been traditionally described in low birth weight premature infants. To investigate the role of age on F-induced nephrocalcinosis we studied 24 Sprague-Dawley male rats grouped by age and F therapy vs. control as follows: A (4-week-old control), B (4-week-old + F), C (6-week-old control), D (6-week-old + F), E (10-week-old control), F (10-week-old + F). The rats were placed in metabolic cages for measurement of urine output, food and water intake. At day 14 they were anesthetized, exsanguinated and their kidneys harvested. Renal calcium deposition was assessed using NC score (scale 0-4) and quantitative calcium analysis in the contralateral kidney. Treated animals gained less weight and had higher urine output and fluid intake than the age-matched controls demonstrating the diuretic effect of furosemide. Control groups A, C, and E scored 0 histologically compared with B 2.75 +/- 0.50, D 2.00 +/- 0.58, and F 3.00 +/- 0.82 (p < 0.05 in all three paired groups). Kidney calcium content (micrograms/g dry weight) in B was 2,815.68 +/- 1,553.77 vs. A 202.58 +/- 32.02 (p = 0.04); D 1,574.05 +/- 540.21 vs. C 212.22 +/- 30.91 (p = 0.02); F 2,591.40 +/- 1,269.80 vs. E 210.38 +/- 26.79 (p = 0.02). There was no difference in the magnitude of NC among the three treated groups themselves. To determine the possible effect of age on timing of onset of NC additional 30 4-week-old and 30 10-week-old rats were studied. All 60 rats received furosemide. Six rats from each group were sacrificed on days 1, 3, 5, 7 and 11. In both groups, significant calcifications were seen already on day 3 and maximum calcification noted between days 3 and 5. We conclude that in this model the development of NC occurs within a few days of furosemide administration and that this phenomenon is not age dependent but rather reflects a property of the loop diuretic itself.     

Effects of vesnarinone, a novel orally active inotropic agent with an immunosuppressive action, on experimental cardiac transplantation in rats

BACKGROUND: Vesnarinone (VES) has been used for treatment of patients with congestive heart failure. In addition to inotropic effects, it seems to have immunosuppressive action. We tested the hypothesis that VES suppresses graft rejection, inotropic dysfunction caused by early rejection, and chronic coronary obstruction in a heterotopic rat cardiac transplantation model. METHODS: (1) To study acute rejection, hearts from Lewis-Brown Norway (LBN) rats were transplanted into Lewis rats, which were treated with or without VES (50 or 100 mg/kg/day orally). (2) In a functional study, LBN hearts with or without VES (100 mg/kg/ day) were isolated and perfused on day 3 after transplantation to assess inotropic response to isoproterenol (3 x 10(-8) M). (3) To study chronic rejection, Lewis hearts were transplanted into Fisher 344 rats, which were treated with or without VES (50 mg/kg/day) for 90 days. Coronary obstructive disease was assessed by morphometric analysis. There were five to six animals in each group. RESULTS: (1) VES (100 mg/kg/day) prolonged LBN heart survival (11.7 +/- 0.7 vs. 9.6 +/- 0.7 days in control; P < 0.05). (2) Left ventricular developed pressure was depressed in transplanted hearts regardless of VES treatment (84 +/- 12, 90 +/- 8 vs. 144 +/- 16 mmHg in untransplanted hearts; P < 0.01). The developed pressure after administration of isoproterenol in VES-treated hearts (184 +/- 20 mmHg) was higher than transplanted hearts without VES (118 +/- 16 mmHg; P < 0.05), and similar to untransplanted hearts (203 +/- 27 mmHg; P = NS). (3) Transplanted hearts treated with or without VES showed similar grades of rejection (2.0 +/- 0.3 vs. 2.6 +/- 0.2; P = NS), intimal area (6,996 +/- 3,186 vs. 13,441 +/- 5,165 microns2; NS), and coronary luminal obstruction (45 +/- 16% vs. 67 +/- 14%; NS). CONCLUSIONS: VES produces mild prolongation in survival of rat heart grafts, but has no significant effect on chronic graft atherosclerosis. VES preserves the positive inotropic effects of isoproterenol that are otherwise deteriorated by early acute rejection.     

Minor physical anomalies in schizophrenia and mood disorders

The purpose of the present study was to examine the effect of a two day and a five day administration of 22-oxa-calcitriol (OCT) on calcium metabolism in rats with advanced chronic renal failure and severe secondary hyperparathyroidism. A first series of 27 uremic rats received either placebo, OCT or calcitriol (0.3 microgram i.p./rat) 48 and 24 hours before sacrifice. A second series of 18 uremic rats received either placebo, OCT (0.3 microgram i.p./rat) or calcitriol (0.05 microgram i.p./rat) for five days. We found that after 48 hours (series 1) both calcitriol and OCT increased blood ionized calcium (Ca2+) as compared to vehicle (1.23 +/- 0.04 and 1.10 +/- 0.02 mM, P < 0.01 and P < 0.05, respectively vs. control, 1.02 +/- 0.03 mM). Duodenal Ca transport (S/M) using the everted gut sac technique was not stimulated by OCT, even though it increased from 2.8 +/- 0.4 to 7.0 +/- 0.6 (P < 0.01) with calcitriol. In contrast, duodenal calbindin-D9k mRNA expression and protein content increased to a similar extent with OCT and calcitriol. Calcitriol was more potent in reducing plasma iPTH1-34 levels than OCT: 344 +/- 75 pg/ml (calcitriol) versus 632 +/- 46 pg/ml (OCT) compared with 897 +/- 74 pg/ml (control), P < 0.01. In the second series of rats, the injection of OCT (0.3 microgram i.p./rat) over five days was less effective than the lower dose of calcitriol (0.05 microgram i.p./rat) in reducing circulating iPTH: 110 +/- 26 (calcitriol) and 281 +/- 64 (OCT) versus 624 +/- 135 pg/ml (control), P < 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)     

Learning deficits in congenitally hydrocephalic rats and prevention by early shunt treatment

Shunt surgery is the usual treatment for infantile hydrocephalus; however, the extent to which it avoids subsequent neurological deficits is uncertain. The effect of early-onset hydrocephalus was tested in H-Tx rats using the Morris water maze. Spatial learning was assessed at 21 days after birth in control (n = 18), hydrocephalic (n = 18) and hydrocephalic rats shunt-treated at 4-5 (n = 7) or at 10-12 days of life (n = 13). The time taken to find a hidden platform was measured in five trials on 2 consecutive days and the data analyzed by one- and two-way ANOVA and t-tests. The latencies of the control rats decreased significantly between the first and second trial on the 1st day, and learning was retained until the 2nd day. The hydrocephalic group had longer latencies than controls on both days, with no significant decrease between any trials. Performance was not significantly different between the two shunt groups. Overall, the shunted rats had latencies which were not significantly different from controls but were significantly lower than hydrocephalics. Despite this, the shunted rats did not perform as well as the controls. It is concluded that, although shunt treatment improved learning, some effects of early-onset hydrocephalus may not be reversible and/or a longer recovery time is required.     

Pre-exercise branched-chain amino acid administration increases endurance performance in rats

This study investigated the effects of pre-exercise branched-chain amino acid (BCAA) administration on blood ammonia levels and on time to exhaustion during treadmill exercise in rats. Adult female Wistar rats were trained on a motor driven treadmill. After a 24-h fast, rats were injected intraperitoneally (i.p.) with 1 mL of placebo or BCAA (30 mg), 5 min before performing 30 min of submaximal exercise (N = 18) or running to exhaustion (N = 12). In both cases, rats were sacrificed immediately following exercise, and blood was collected for the measurement of glucose, nonesterified fatty acid (NEFA), lactic acid, BCAA, ammonia, and free-tryptophan (free-TRP) levels. Control values were obtained from sedentary rats that were subjected to identical treatments and procedures (N = 30). Plasma BCAA levels increased threefold within 5 min after BCAA administration. Mean run time to exhaustion was significantly longer (P < 0.01) after BCAA administration (99 +/- 9 min) compared with placebo (76 +/- 4 min). During exercise, blood ammonia levels were significantly higher (P < 0.01) in the BCAA treated compared with those in the placebo treated rats both in the 30-min exercise bout (113 +/- 25 mumol.L-1 (BCAA) vs 89 +/- 16 mumol.L-1) and following exercise to exhaustion (186 +/- 44 mumol.L-1 (BCAA) vs 123 +/- 19 mumol.L-1). These data demonstrate that BCAA administration in rats results in enhanced endurance performance and an increase in blood ammonia during exercise.     

Untreated primary lung and breast cancers: correlation between F-18 FDG kinetic rate constants and findings of in vitro studies

PURPOSE: To compare kinetic modeling of 2-[fluorine-18]fluoro-2-deoxy-D-glucose (F-18 FDG) between untreated primary lung and untreated primary breast cancers by using positron emission tomographic (PET) findings and to correlate these findings with findings of in vitro studies. MATERIALS AND METHODS: Nineteen patients (12 men, seven women; age range, 49-82 years) with untreated primary lung cancer and 17 women with untreated primary breast cancer (age range, 26-65 years) underwent 1-hour dynamic F-18 FDG PET. A three-compartment model was applied to F-18 FDG kinetics in tumors. The standard uptake value normalized for lean body mass (SUVlean) in tumors was measured 50-60 minutes after tracer injection. In vitro, thin-layer chromatography was performed to evaluate the intracellular phosphorylation of tritiated F-18 FDG in human lung cancer and breast cancer cell lines. RESULTS: At PET, lung cancer had a significantly (P < .003) higher rate constant for F-18 FDG phosphorylation (k3) and SUVlean than did breast cancer (0.164 +/- 0.150 [standard deviation] vs 0.043 +/- 0.018 and 8.25 +/- 3.28 vs 3.17 +/- 1.08, respectively). Breast cancer showed a significant correlation between k3 and SUVlean (r = .607, P < .01), although no such correlation was observed in lung cancer. In vitro studies showed phosphorylation of F-18 FDG in breast cancer cells was less complete in hyperglycemia than it was in lung cancer cells. CONCLUSION: A much lower k3 appears to be a rate-limiting factor for F-18 FDG accumulation in breast cancer, while the higher k3 in lung cancer is probably not rate limiting for F-18 FDG accumulation.     

Developmental and behavioral effects of postnatal amitraz exposure in rats

The effects of postnatal amitraz exposure on physical and behavioral parameters were studied in Wistar rats, whose lactating dams received the pesticide (10 mg/kg) orally on days 1, 4, 7, 10, 13, 16 and 19 of lactation; control dams received distilled water (1 ml/kg) on the same days. A total of 18 different litters (9 of them control and 9 experimental) born after a 21-day gestation were used. The results showed that the median effective time (ET50) for fur development, eye opening, testis descent and onset of the startle response were increased in rats postnatally exposed to amitraz (2.7, 15.1, 21.6 and 15.3 days, respectively) compared to those of the control pups (1.8, 14.0, 19.9 and 12.9 days, respectively). The ages of incisor eruption, total unfolding of the external ears, vaginal and ear opening and the time taken to perform the grasping hindlimb reflex were not affected by amitraz exposure. Pups from dams treated with amitraz during lactation took more time (in seconds) to perform the surface righting reflex on postnatal days (PND) 3 (25.0 +/- 2.0), 4 (12.3 +/- 1.2) and 5 (8.7 +/- 0.9) in relation to controls (10.6 +/- 1.2; 4.5 +/- 0.6 and 3.4 +/- 0.4, respectively); the climbing response was not changed by amitraz. Postnatal amitraz exposure increased spontaneous motor activity of male and female pups in the open-field on PND 16 (140 +/- 11) and 17 (124 +/- 12), and 16 (104 +/- 9), 17 (137 +/- 9) and 18 (106 +/- 8), respectively. Data on spontaneous motor activity of the control male and female pups were 59 +/- 11 and 69 +/- 10 for days 16 and 17 and 49 +/- 9, 48 +/- 7 and 56 +/- 7 for days 16, 17 and 18, respectively. Some qualitative differences were also observed in spontaneous motor behavior; thus, raising the head, shoulder and pelvis matured one or two days later in the amitraz-treated offspring. Postnatal amitraz exposure did not change locomotion and rearing frequencies or immobility time in the open-field on PND 30, 60 and 90. The present findings indicate that postnatal exposure to amitraz caused transient developmental and behavioral changes in the exposed offspring and suggest that further investigation of the potential health risk of amitraz exposure to developing human and animal offsprings may be warranted.     

The influence of antenatal corticosteroids on hypoglycemia in newborn rats with intrauterine growth retardation

This study examines the effect of maternally injected glucocorticoid on the pattern of hypoglycemia exhibited by rat pups with intrauterine growth retardation (IUGR). The majority of surgical procedures designed to produce small-for-gestational age (SGA) newborns for biochemical studies were carried out on days 18 and 19 of gestation because of favorable vields of pups with IUGR at those operative days. At birth, normal controls showed a mean +/- SE plasma glucose value of 63 +/- 2 mg/dl; mean glucose for the group with IUGR was significantly lower at 43 +/- 2 mg/dl. There was a further decrease in the plasma glucose concentration of pups with IUGR at 2-4 hr of age, whereas values in the control littermates did not fall during this interval. Through the first 2 hr of neonatal life, 46% of the pups with IUGR exhibited plasma glucose values less than 40 mg/dl, whereas only 18% of the control littermates manifiested hypoglycemia. During the 2-4-hr interval, the incidence of hypoglycemia in animals with IUGR increased to 91%; however, the incidence in control remained at 18% from 2-4 hr and fell to 4% at 4-6 hr of age. At birth, the pups with IUGR had a lower mean liver weight compared to their control littermates, but glycogen concentration of liver was similar to the control mean +/- SE of 25.7 +/- 1.8 (IUGR = 22.2 +/- 1.3 mg/g wet weight). Total hepatic glycogen stores, however, were markedly lower in dysmature rat pups (IUGR = 2.96 +/- 0.17 mg; control = 7.23 +/- 0.43 mg). Concentrations of plasma glucose at birth of individual control and IUGR animals were found to correlate significantly (r = 0.64, p less than 0.001) with total liver glycogen content. The decline in plasma glucose values in pups with IUGR was not present in animals whose dams received glucocorticoid injection 24 and 48 hr before delivery. At 4-6 hr of age, for instance, the mean plasma glucose concentration in the corticoid-treated IUGR group (70.1 +/- 6.9 mg/dl) approximated that of the control group. Instead on the 91% incidence of hypoglycemia noted in the nontreated dysmature pups, an incidence of 55% was found at 2-4 hr of age in offspring of mothers given glucocorticoid. At 4-6 hr, the treated group showed an incidence of 18% compared to a 67% figure in the nontreated IUGR animals. The concentration of liver glycogen in these animals also differed in that the treated IUGR pups showed significantly higher values (26.9 +/- 1.7 mg/g wet weight, mean +/- SE) than nontreated progeny. It is concluded that antenatally administered corticosteroid influence the development of neonatal hypoglycemia in the dysmature rat pup and that the major effect is not at birth, but during the 2-4-hr period of neonatal life.     

Age-related changes in the capacity, rate, and modulation of dopamine uptake within the striatum and nucleus accumbens of Fischer 344 rats: an in vivo electrochemical study

Age-related changes in the capacity, rate, and modulation of dopamine (DA) uptake within the striatum and the nucleus accumbens core of Fischer 344 rats were investigated using in vivo electrochemical recordings coupled with local drug application techniques. Equimolar amounts of DA were pressure ejected into the striatum and the nucleus accumbens of 6-, 12-, 18-, and 24-month old rats. The DA ejections produced larger DA signal amplitudes in the older rats, suggesting age-related differences in the capacity to clear extracellular DA. Within the striatum, the capacity and rate of DA uptake were reduced by 50% in the aged groups (18 and 24 months) compared with the younger rats (6 and 12 months). In the nucleus accumbens, significant reductions in DA uptake capacity and rate were observed in the 24-month group. In both brain regions and in all age groups studied, the rate of DA uptake was found to be concentration-dependent until a maximal rate was reached. The maximum rate of DA transport was significantly reduced in both the striatum and the nucleus accumbens of aged rats (18 and 24 months versus 6 and 12 months). The ability of nomifensine, an inhibitor of the DA transporter, to modulate DA signal amplitudes in the striatum and the nucleus accumbens was also decreased with age (24 months versus 6 months). Taken together, these findings demonstrate substantial age-related deficits in DA uptake processes within the striatum and the nucleus accumbens, consistent with the hypothesis that DA uptake may be slowed in aged animals to compensate for reductions in DA release.     

Differential response of glomerular epithelial and mesangial cells after subtotal nephrectomy

Recent studies in both human and experimental chronic renal disease suggest that there is a linkage between glomerular hypertrophy and glomerulosclerosis. To further define these relationships, we studied the changes in glomerular hypertrophy, procollagen alpha 1(IV) mRNA levels and glomerulosclerosis in rats undergoing 1 2/3 nephrectomy (Nx) or sham nephrectomy (SNx). Glomerular hypertrophy, measured biochemically by RNA/DNA and protein/DNA ratios, was significantly increased in Nx compared to SNx two days after subtotal renal ablation (RNA/DNA: Nx = 133 +/- 8%, SNx = 100 +/- 3% of the mean control value, P < 0.01; protein/DNA: Nx = 164 +/- 22%, SNx = 100 +/- 10%, P < 0.05) and remained elevated after 7 and 15 days (RNA/DNA: seven days Nx = 155 +/- 3%, SNx = 100 +/- 13%, P < 0.01; 15 days Nx = 303 +/- 21%, SNx = 100 +/- 24%, P < 0.001; protein/DNA: seven days Nx = 228 +/- 57%, SNx = 100 +/- 18%, P < 0.05; 15 days Nx = 341 +/- 23%, SNx = 100 +/- 18%, P < 0.01). Light microscopic measures of glomerular tuft volume (GTV) were too insensitive to detect glomerular enlargement until 15 days postoperatively, but GTV measured ultrastructurally demonstrated a 20% increment in Nx compared to SNx as early as two days postoperatively (P < 0.01). The latter increment in GTV was due exclusively to glomerular visceral epithelial cell (GVEC) expansion. Glomerular procollagen alpha 1(IV) mRNA levels were significantly elevated only 15 days after nephrectomy (Nx = 265 +/- 58% of the mean control value, SNx = 100 +/- 12%, P < 0.05; corrected for beta-actin mRNA levels). As this time, exuberant mesangial expansion measured ultrastructurally contributed to a 1.6 +/- 0.1-fold increase in GTV (P < 10(-5)), and to a relative decrement in the GVEC contribution to glomerular cells plus matrix (P < 0.01). Segmental sclerosis was observed only 15 days postoperatively in Nx (Nx = 1.3 +/- 0.4% of glomeruli evaluated, SNx = 0.0%, P < 0.05), and there was a strong correlation between the prevalence of segmental sclerosis and the procollagen alpha 1(IV) mRNA levels in Nx at 15 days (r = 0.93, P < 0.01). There was no significant correlation between the RNA/DNA and protein/DNA ratios and procollagen alpha 1(IV) mRNA levels. Thus, glomerular regions responded differentially to subtotal nephrectomy. Early epithelial cell expansion was followed by later mesangial expansion. Glomerular procollagen alpha 1(IV) mRNA levels were elevated only during the second (mesangial) phase of glomerular hypertrophy, when it correlated with glomerulosclerosis, but not during the initial (epithelial) phase, a pattern consistent with a mesangial origin of the procollagen alpha 1(IV) mRNA.     

Promoting effect of monosodium aspartate, but not glycine, on renal pelvis and urinary bladder carcinogenesis in rat induced by N-butyl-N-(4-hydroxybutyl)nitrosamine

Although the incidences were relatively low, hyperplasias of the renal pelvis and the urinary bladder have been observed in Fischer-344 (F-344) rats after both sodium aspartate and glycine treatments in long-term 2-yr bioassays. In the present study, the effects of these amino acids on development of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-initiated urinary lesions were investigated in male and female F-344/DuCrj rats. F-344 rats of both sexes, 6 wk old at the commencement, were given 0.05% BBN for 4 wk and then treated with one of the amino acids at a level of 5.0% in the drinking water for the following 36 wk. Proliferative lesions in the renal pelvis often associated with necrosis and mineralization were increased in the group treated with BBN followed by sodium aspartate, but not by glycine, in both sexes. The same group demonstrated higher incidences of urinary bladder tumors with increased urinary pH and sodium concentration and decreased creatinine and uric acid, but not accompanying crystallization. These results showed a clear promoting effect of sodium aspartate for urinary carcinogenesis in rats. The mechanisms of the effect on the renal pelvis and urinary bladder might be different.