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Daily feed intake (DFI) is an important consideration for improving feed efficiency, but measurements using electronic feeder systems contain many missing and incorrect values. Therefore, we evaluated three methods for correcting missing DFI data (quadratic, orthogonal polynomial, and locally weighted (Loess) regression equations) and assessed the effects of these missing values on the genetic parameters and the estimated breeding values (EBV) for feeding traits. DFI records were obtained from 1622 Duroc pigs, comprising 902 individuals without missing DFI and 720 individuals with missing DFI. The Loess equation was the most suitable method for correcting the missing DFI values in 5-50% randomly deleted datasets among the three equations. Both variance components and heritability for the average DFI (ADFI) did not change because of the missing DFI proportion and Loess correction. In terms of rank correlation and information criteria, Loess correction improved the accuracy of EBV for ADFI compared to randomly deleted cases. These findings indicate that the Loess equation is useful for correcting missing DFI values for individual pigs and that the correction of missing DFI values could be effective for the estimation of breeding values and genetic improvement using EBV for feeding traits., (© 2017 The Authors. Animal Science Journal published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Animal Science.)

Objectives: To control carbapenem-resistant Pseudomonas aeruginosa, we implemented a hospital-wide policy concerning the selective use of carbapenems based on the monitoring of P. aeruginosa isolates for susceptibility to five carbapenems using a customized dry plate method. In this study, we retrospectively investigated the outcome of our measures to control carbapenem-resistant P. aeruginosa., Methods: To select effective carbapenems, 100 clinical isolates were collected, and the minimum inhibitory concentration (MIC) to 5 carbapenems (IPM/CS, MEPM, DRPM, BIPM and PAPM/BP) was monitored using a customized dry plate method from 2006 to 2013. Carbapenems, which were associated with a high rate of drug resistance in P. aeruginosa, were restricted from use during our intervention study. The antimicrobial use density per 100 bed-days (AUD 100 ) of carbapenems and the detection rates of carbapenem (IPM/CS and MEPM)-resistant P. aeruginosa were determined during the period of the intervention., Results: The isolates consistently showed higher rates of drug-resistant P. aeruginosa in IPM/CS and PAPM/BP. Thus, DRPM, MEPM and BIPM were adopted for hospital-wide use. The detection rates of all IPM/Cs and MEPM-resistant P. aeruginosa significantly decreased. Meanwhile, the consumption of carbapenems showed an increasing trend., Conclusions: The outcome of the hospital-wide implementation of the selective use of carbapenems based on periodic monitoring of the susceptibility of P. aeruginosa isolates was retrospectively studied. Implementation of this measure might have contributed in part to the control of carbapenem-resistant P. aeruginosa in our hospital.

Ulcerative colitis (UC) is a chronic lifelong condition characterized by alternating flare-ups and remission. There is no single known unifying cause, and the pathogenesis is multifactorial, with genetics, environmental factors, microbiota, and the immune system all playing roles. Current treatment modalities for UC include 5-aminosalicylates, corticosteroids, immunosuppressants (including purine antimetabolites, cyclosporine, and tacrolimus), and surgery. Therapeutic goals for UC are evolving. Medical treatment aims to induce remission and prevent relapse of disease activity. Infliximab, an anti-tumor necrosis factor (TNF)-α monoclonal antibody, is the first biological agent for the treatment of UC. Over the last decade, infliximab and adalimumab (anti-TNF-α agents) have been used for moderate to severe UC, and have been shown to be effective in inducing and maintaining remission. Recent studies have indicated that golimumab (another anti-TNF-α agent), tofacitinib (a Janus kinase inhibitor), and vedolizumab and etrolizumab (integrin antagonists), achieved good clinical remission and response rates in UC. Recently, golimumab and vedolizumab have been approved for UC by the United States Food and Drug Administration. Vedolizumab may be used as a first-line alternative to anti-TNF-α therapy in patients with an inadequate response to corticosteroids and/or immunosuppressants. Here, we provide updated information on various biological agents in the treatment of UC.

Although severe combined immune deficiency (SCID) is a very important research model for mice and SCID mice are widely used, there are only few reports describing the SCID pig models. Therefore, additional research in this area is needed. In this study, we describe the generation of Recombination activating gene-1 (Rag-1)-deficient neonatal piglets in Duroc breed using somatic cell nuclear transfer (SCNT) with gene targeting and analysis using fluorescence-activated cell sorting (FACS) and histology. We constructed porcine Rag-1 gene targeting vectors for the Exon 2 region and obtained heterozygous/homozygous Rag-1 knockout cell colonies using SCNT. We generated two Rag-1-deficient neonatal piglets and compared them with wild-type neonatal piglets. FACS analysis showed that Rag-1 disruption causes a lack of Immunoglobulin M-positive B cells and CD3-positive T cells in peripheral blood mononuclear cells. Consistent with FACS analysis, histological analysis revealed structural defects and an absence of mature lymphocytes in the spleen, mesenteric lymph node (MLNs), and thymus in Rag-1-deficient piglets. These results confirm that Rag-1 is necessary for the generation of lymphocytes in pigs, and Rag-1-deficient piglets exhibit a T and B cell deficient SCID (T-B-SCID) phenotype similar to that of rodents and humans. The T-B-SCID pigs with Rag-1 deficiency generated in this study could be a suitably versatile model for laboratory, translational, and biomedical research, including the development of a humanized model and assessment of pluripotent stem cells.

We evaluated multiple effects of genetic variations of five candidate loci (LEP, LEPR, MC4R, PIK3C3 and VRTN) on four production traits (average daily weight gain (ADG); backfat thickness (BFT); loin eye muscle area (EMA); and intramuscular fat content (IMF)) in a closed nucleus herd of pure Duroc pigs. Polymorphisms in LEPR, MC4R and PIK3C3 had significant single gene effects on ADG and BFT. The additive genetic variance in ADG and BFT (16.99% and 22.51%, respectively) was explained by genetic effects of these three loci. No correlations were observed between the LEP genotype and production traits in this study. Although we detected marginally epistatic interactions between LEPR and PIK3C3 on the eye muscle area, there were no significant epistatic effects on any traits among all loci pairs. These results suggest that LEPR, MC4R, PIK3C3 and VRTN may independently influence growth rate and fat deposition. Furthermore, the statistical models for predicting the breeding values of each trait had the lowest Akaike's information criterion values when considering the effect of the MC4R, LEPR, PIK3C3 and VRTN genotype simultaneously. These results suggest that LEPR, MC4R, PIK3C3 and VRTN are useful markers for accurately predicting breeding values in Duroc pigs., (© 2013 Japanese Society of Animal Science.)

We performed a genome-wide association study using the porcine 60K SNP array to detect QTL regions for nine traits in a three-generational Duroc samples (n = 651), viz. generations 1, 2 and 3 from a population selected over five generations using a closed nucleus breeding scheme. We applied a linear mixed model for association mapping to detect SNP effects, adjusting for fixed effects (sex and season) and random polygenic effects (reflecting genetic relatedness), and derived a likelihood ratio statistic for each SNP using the efficient mixed-model association method. We detected a region on SSC6 for backfat thickness (BFT) and on SSC7 for cannon bone circumference (CANNON), with a genome-wide significance of P < 0.01 after Bonferroni correction. These regions had been detected previously in other pig populations. Six genes are located in the BFT-associated region, while the CANNON-associated region includes 66 genes. In the future, significantly associated SNPs, derived by sequencing the coding regions of the six genes in the BFT region, can be used in marker-assisted selection of BFT, whereas haplotypes constructed from the SSC7 region with strong LD can be used to select for the CANNON trait in our resource family., (© 2012 The Authors, Animal Genetics © 2012 Stichting International Foundation for Animal Genetics.)

Vertnin (VRTN) is involved in the variation of vertebral number in pigs and it is located on Sus scrofa chromosome 7. Vertebral number is related to body size in pigs, and many reports have suggested presence of an association between body length (BL) and meat production traits. Therefore, we analyzed the relationship between the VRTN genotype and the production and body composition traits in purebred Duroc pigs. Intramuscular fat content (IMF) in the Longissimus muscle was significantly associated with the VRTN genotype. The mean IMF of individuals with the wild-type genotype (Wt/Wt) (5.22%) was greater than that of individuals with the Wt/Q (4.99%) and Q/Q genotypes (4.79%). In addition, a best linear unbiased predictor of multiple traits animal model showed that the Wt allele had a positive effect on the IMF breeding value. No associations were observed between the VRTN genotype and other production traits. The VRTN genotype was related to BL. The Q/Q genotype individuals (100.0 cm) were longer than individuals with the Wt/Q (99.5 cm) and Wt/Wt genotypes (98.9 cm). These results suggest that in addition to the maintenance of an appropriate backfat thickness value, VRTN has the potential to act as a genetic marker of IMF., (© 2012 Japanese Society of Animal Science.)

A C↔T single nucleotide polymorphism (SNP) on exon 24 of the porcine class 3 phosphoinositide-3-kinase (PIK3C3) gene is considered a possible genetic marker for selecting backfat (BF) thickness and carcass fat, although only one study has published results on its effects by performing experiments on a single resource family. We analyzed the association of this PIK3C3 polymorphism with production traits in 739 Duroc pigs. The C allele frequency was 67.9% in our study population. PIK3C3 polymorphism showed significant effects on average daily weight gain (ADG), BF thickness, intermuscular fat content (IMF), and the size of the loin eye muscle area (EMA). The C alleles increased ADG, BF and IMF, and decreased EMA. The predicted differences in traits between the homozygous pigs of the C and T alleles were 40 g/day for DG, 1.2 mm for BF, 0.44% for IMF, and 1.6 cm(2) for EMA. Furthermore, the statistical models for estimating the breeding values of each trait had lower Akaike's information criterion values when adding PIK3C3 genotype information. We therefore confirmed that the polymorphism in PIK3C3 (C2604T) has the potential to be a genetic marker for production traits in Duroc pigs., (© 2010 The Authors. Journal compilation © 2010 Japanese Society of Animal Science.)

Leg weakness in pigs is a serious problem in the pig industry. We performed a whole genome quantitative trait locus (QTL) analysis to find QTLs affecting leg weakness traits in the Landrace population. Half-sib progeny (n = 522) with five sires were measured for leg weakness traits. Whole genome QTL mapping was performed using a half-sib regression-based method using 190 microsatellite markers. No experiment-wide significant QTLs affecting leg weakness traits were detected. However, at the 5% chromosome-wide level, QTLs affecting leg weakness traits were detected on chromosomes 1, 3, 10 and 11 with QTL effects ranging from 0.07 to 0.11 of the phenotypic variance. At the 1% chromosome-wide level, QTLs affecting rear feet score and total leg score were detected on chromosomes 2 and 3 with QTL effects of 0.11 and 0.13 of the phenotypic variance, respectively. On chromosome 3 and 10, some QTLs found in this study were located at nearby positions. The present study is one of the first reports of QTLs affecting fitness related traits such as leg weakness traits, that segregate within the Landrace population. The study also provides useful information for studying QTLs in purebred populations.

An insertion/deletion variant of a thymine base (T5 and T6) in exon 2 of porcine beta 3-adrenergic receptor (ADRB3) gene has been described. In the current study, we made an association study between the ADRB3 polymorphisms and production traits in 735 Duroc pigs. The allele frequencies for the T5 and T6 alleles in our study population were 0.433 and 0.567, respectively. Any associations between ADRB3 genotype and average daily weight gain during test period, or backfat thickness and intramuscular fat content were not detected in either sex. However the size of the loin eye muscle area (EMA) was significantly associated with ADRB3 genotypes in gilts. T6-homozygous gilts had a higher mean of EMA (40.6 +/- 0.6 cm(2)) than T5-homozygous (38.1 +/- 0.4 cm(2), P = 0.002) and heterozygous (38.8 +/- 0.3 cm(2), P = 0.034) gilts. This association was not detected in males. In addition, a multiple traits animal model best linear unbiased predictor (BLUP) analysis revealed that the T6-homozygous genotype had positive effects on breeding value of EMA. Accordingly, we suggest that ADRB3 polymorphism has the potential to be an important genetic marker for prediction of EMA in Duroc pigs.

The purpose of this study was to develop a measuring system of contact force in finger-tapping of Parkinson's disease patients and to show its effectiveness for quantitative diagnosis. This system was composed of a pair of 3-axis accelerometers, a touch sensor an analog to digital converter and a personal computer (PC). Firstly, a transfer function representing relation between the contact force and the accelerometer output during the finger contact phase of finger-tapping was determined. This means that the finger-tapping contact force could be estimated from the measured acceleration by using the determined transfer function. Secondly the developed system was applied to 27 normal subjects and 16 Parkinson's diseases subjects. Score of UPDRS finger tap test was evaluated for each subject by a neurologist. Finally, these sensors were attached to subject's index finger and thumb, and sensor signals were recorded and processed within the PC. The subjects were asked to execute continuous finger taps movement for 60 s. It was shown that the contact force was smaller as the subject was with the larger UPDRS score of tap test.

A new HPLC method has been developed for measuring clonazepam (CZP) in plasma, using a reversed-phase non-porous silica column packed with 2 microm particles. CZP in plasma was first purified with a column extraction technique and injected onto a non-porous silica column. The calibration curve was linear from 5-200 ng/ml. The recoveries of CZP added to plasma were more than 94.0%, with a coefficient of variation in the range of 5.1-13.8%. We developed a rapid routine method using a non-porous silica column that was accurate and improved solvent consumption in the measurement of CZP.

Background: Successful engraftment of human hematopoietic stem and progenitor cells (HSPCs) in a large animal may serve not only as a model to study human hematopoiesis but also as a bioreactor to expand human HSPCs in vivo. The aim of this study was to accomplish xenotransplantation of human HSPCs into pig., Methods: Total mononuclear or CD34-positive HSPCs obtained from human cord blood were xenotransplanted percutaneously under an ultrasonographic guidance into preimmune pig fetuses. Peripheral blood and bone marrow (BM) cells of recipient pigs were collected and analyzed for the presence of human cells by a polymerase chain reaction to detect human specific Alu sequence on DNA extracted from those cells. Fluorescence-activated cell sorting (FACS) analysis was also performed to detect human hematopoietic cells., Results: Transplantation of human cord blood cells into pig fetuses aged less than 52 days postcoitus resulted in a good engraftment rate. In one case, engraftment was detected up to 315 days posttransplantation by polymerase chain reaction. Human hematopoietic cells were detectable also by FACS in peripheral blood and BM. Furthermore, human CD34+ HSPCs were also observed in the BM of recipients. Those CD34+ cells in BM were sorted by FACS and subjected to further analyses. First, in vitro colony formation assay resulted in formations of multilineage colonies. Second, when they were transplanted into an immunodeficient mouse they were engrafted in the mouse., Conclusions: These data indicate an engraftment of human HSPCs in pig BM. In utero transplantation of human HSPCs into a preimmune pig fetus is useful to establish a pig reproducing human hematopoiesis.

Effects of lysozyme(LY) alone and combination with various antitumor agents were examined using syngeneic tumors mainly Meth-A and MH 134 transplanted into Balb/c and C3H/He mice, respectively. The effects of LY on pulmonary metastases were also examined in BDF1 mice bearing Lewis lung carcinoma (3LL). LY inhibited the growth of Meth-A tumor and enhanced antitumor effects of mitomycin C (MMC). bleomycin (BLM) and 5-fluorouracil (5-FU), LY activated antitumor effects of MMC, BLM and 5-FU on MH 134 tumor, however, LY alone did not show any significant antitumor effect on it. The combination treatments using LY with MMC or 5-FU showed a marked inhibition on pulmonary metastases of 3LL. The pre-treatment of LY inhibited the tumor growth of Sarcoma-180 in ICR mice.

In previous literature, we reported that the rats whose dams had been administerd pentazocine HCl 200 mg/kg/day during the perinatal and postnatal periods, showed no differences between control rats in the physiological function and psychotic activity tests. Brain tissues of the rats were observed histologically herein to confirm the result of previous tests. Abnormal findings such as deficits, undevelopment and metamorphosis, in the shape, size and configuration of nerve cells, myelin sheaths and vessels in consecutive transverse sections stained by Nissl and Klüver-Barrera method were not evident on examination under light microscope, and in cell bodies, dendrites, axons, myelin sheaths, synaptic complexes of nerve cell, neuroglia and vessels in the cerebral cortex, under electron microscope. The lack of abnormal findings in the histological observation of brain tissues supports the result of previously conducted physiological function and psychotic activity tests in which no significant differences were found between treated and control rats. Pentazocine HCl had no effect on the brain tissues of rat offspring from dams administered the drug during perinatal and postnatal periods.

The anti-inflammatory, analgesic, antipyretic and ulcerogenic activities and acute toxicity of 2-oxo-3-[4-(1-oxo-2-isoindolinyl)-phenyl]-butanamide (GP 650) were investigated in laboratory animals and compared with those of phenylbutazone, acetylsalicylic acid (ASA), ibuprofen, tiaramide-HCl and tinoridine-HCl. The anti-inflammatory and analgesic activities of GP 650 were found to be almost equivalent to those of phenylbutazone on the basis of various anti-inflammatory and analgesic tests while its antipyretic activity was less marked, and its ulcerogenic action and acute toxicity were much lower than those of the other agents. It is interesting to note that GP 650 possesses marked anti-inflammatory activity similar to acidic anti-inflammatory agents in chronic inflammatory models along with mild antipyretic and ulcerogenic activities found in basic anti-inflammatory agents. Therefore, GP 650 appears to be a promising anti-inflammatory and analgesic agent.

A number of N-acyl and N-(alkoxycarbonyl)-5-fluorouracil derivatives possessing, for example, benzoyl, o-toluyl, acetyl, propionyl, heptanoyl, ethoxycarbonyl, phenoxycarbonyl, and benzyloxycarbonyl groups as N1 and/or N3 substituents were synthesized, and their antitumor activities were evaluated. The synthesis was achieved by a direct and two-step acylation of 5-fluorouracil and by selective N1-deacetylation of N1-acetyl-N3-substituted-5-fluorouracil under appropriate reaction conditions. Several N3-benzoyl- and N3-o-toluyl-5-fluorouracil derivates and showed significant activity against experimental tumor, and N1-acetyl-N3-o-toluyl-5-fluorouracil was found to be most promising among them. Further investigation revealed 12 to retain higher activity toward various tumors, with lower toxicity and good blood level, than either 1 or FT-207, even for oral administration.

The progress of acetic acid-induced gastric ulcers in rats were sequentially observed with an endoscope for 365 days, and the influences of the ulcer-induced site, age and sex on the healing, recurrence and relapse of these ulcers were investigated. Submucosal injections of 20% acetic acid at the region between the fundus and the pylorus on the anterior wall of the stomach (site A) in 7 weeks old male rats produced active round-shaped ulcers with blood coagulation and debris on the 3rd day after ulcer induction. The ulcers diminished in size with the progress of time (10--50 days), and 50% of the ulcerated rats healed with convergences of mucosal folds (35--154 days). On and after the 50th day, some diminished or healed ulcers showed signs of relapse (37% of used rats) or recurrence (40% of healed rats, 21% of used rats), with the cumulative relapse and recurrence percentage (CR%) reaching 59% on the 365th day. Ulcers in the glandular portion on the greater curvature (site B) healed significantly faster than those in site A. All of the ulcers in site B healed within 133 days and did not recur or relapse. The cumulative healing percentage (CH%) and the CR% of the ulcers in site A in 25 weeks old male rats were 33% and 67%, respectively, and those of the ulcers in site A in 7 weeks old female rats were 60% and 60%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in tension of spiral strips of saphenous, femoral and external carotid arteries and veins were measured isometrically. DEM stimulated 6 preparations in almost the same concentration ranges (pD2 values were 8.64 to 8.40). However, the dose-response curves for DEM indicted variations in responsiveness among the different arteries and veins. Compared with norepinephrine (NE) (1)( the intrinsic activity of DEM was 0.002 on saphenous arteries, 0.05 on saphenous veins, 0.03 on femoral arteries, 0.18 on femoral veins, 0.13 on external carotid arteries and 0.13 on external carotid jugular veins. Thus DEM contracted more potently the venous strips from the hind limbs. IN femoral and external carotid arteries, antagonism of serotonin by DEM or methysergide was investigated. DEM displaced the dose-contractile response curves for serotonin in a noncompetitive manner, and the antagonistic response of DEM to serotonin was about 8 times more effective in external carotid arteries (pD'2 value=6.96) than in femoral arteries (pD'2 value=6.05). Methysergide, unlike DEM, antagonized the response to serotonin in a competitive manner at low doses but in a noncompetitive manner in high doses, and was fairly equal in antagonizing response to serotonin in external carotid arteries (pA2 value=that the therapeutic value of DEM in the treatment of orthostatic hypotension is due to its selective anti-serotonin activity on the external carotid arteries.

Thrombophlebitis similar to that which is frequently observed following i.v. injection of irritative drugs in clinical treatment has been successfully reproduced in experimental animals by utilizing a newly devised technique. Thrombophlebitis at a high rate resulted within a few days by allowing the sample to remain in the sealed section of the V. retroauricularis in rabbits for 3 min after injection. The effects of several drug preparations on the thrombus as well as on the inflammation formed by means of this technique were examined, and the results were in good parallel with clinical cases reported in medical literature. Histopathologically, it was observed that each thrombus was formed by the irritative effect of drugs on the portion on the veneous wall damaged when needles had been inserted.

We studied the response time of drugs in relation to the feedback mechanism in animals. The time from drug administration to onset of loss and recovery of righting reflex or death by hexobarbital in mice were measured at several dose levels and it was demonstrate that in every case the time (t)- response rate (R) function could be expressed as: (formula: see text) These parameters could be obtain by use of only a small number of animals at every dose level. The result suggests that the pharmacological activity of not only pure drugs but also of commercial chemicals with fixed standard of purity and concentrations may be expressed by the parameter t63 transposed as ET63. t63: time when cummulative response rate reaches 63%. t1: latency.

In our studies with drug combinations, we search for mixtures which would enhance the effectiveness of the related active substances. Ethenzamide was found to possess a specific suppressive effect on the gastric damage induced by aspirin. Such effect could not be demonstrated in analgesic agents such as salicylamide, bucetin, acetaminophen and phenacetin. The combination of aspirin with ethenzamide had a potentiating effect on analgesic activity and reduced motor incoordination and loss of righting reflex. We calculated the safety margins of various ratios of combinations and concluded that the best was aspirin and ethenzamide at a ratio of 2:3.

A method is described for evaluating antinociceptive activity in rats using writhing responses induced by 4% sodium chloride solution. Narcotic and nonnarcotic analgesics, narcotic antagonists except naloxone, and antipyretic and nonsteroidal antiinflammatory drugs were effectively evaluated at relatively low doses using this method. Parenteral ED50 values of these compounds ran parallel to their clinical doses. The method detected not only the analgesic action of the above drugs but also that of methamphetamine. In spite of its high sensitivity, the method was specific in the sense that CNS-depressant, muscle relaxant, anticholinergic, and antihistamine drugs and anesthetics were inactive even at toxic doses. On the other hand, the decrease in the analgesic activity of morphine upon chronic injection was also observed with this method. The writhing test with 4% sodium chloride in rats was concluded to be a sensitive and specific test for analgesic drugs and useful for examining changes in analgesic activity of drugs during chronic administration.

Effects of DEM on the cardiovascular, autonomic, and central nervous systems were studied using dogs, rats and rabbits. DEM showed relatively weak effects on the EEG in curarized rabbits and on ambulatory and drinking activities in rats. DEM suppressed dose-dependently the pressor responses induced by norepinephrine, serotonin and bilateral carotid occlusion, but had no effect on the depressor responses induced by acetylcholine and electrical stimulation to the postganglionic vagus nerve in anesthetized dogs. DEM produced a dose-dependent increase in blood pressure, a dose-dependent decrease in heart rate, a transient decrease in respiration rate, and little change in the ECG of anesthetized dogs. The pressor responses induced by DEM were inhibited by phentolamine, methysergide, and indomethacin in anesthetized dogs. With canine femoral arteries, DEM-induced contractions were blocked 10% by phentolamine, 60% by methysergide, and enhanced 10% by indomethacin. On the other hand, DEM-induced contractions of the femoral veins were blocked 30% by phentolamine, 60% by indomethacin, and 10% by methysergide. DEM provoked a significant increase in the level of prostaglandin E in the bathing fluid of the veins but not in that of the arteries. The results suggest that the arterioconstrictor responses induced by DEM are mediated mainly through the serotonin receptors, and the venoconstrictor responses induced by DEM mainly through the enhanced synthesis of prostaglandin E.

The pharmacological actions of iprazochrome (IC) on the vascular system were studied, and the following results were obtained: No death nor abnormal behaviors were observed in acute toxicity tests conducted on male and female mice and rats despite the administration of large doses of IC (10,000 mg/kg, p.o. and 80 mg/kg, i.v., respectively). IC inhibited dose-dependently platelet aggregation in vitro induced by arachidonate and ADP, whereas no effect was observed on ADP-induced respiratory depression in mice, which is closely related to platelet aggregation in vivo. The antiserotonergic actions of IC on the isolated external carotid arteries and femoral arteries in dogs observed in a noncompetitive manner were found to be 1/24 to 1/65 that of methysergide. On the other hand, IC showed no inhibitory effect on the paw edema of rats in vivo induced by serotonin. The inhibitory effect of IC on peritoneal dye leakage in mice was less than half that of phenylbutazone. IC prevented apoplexy in stroke-prone SHR (SHRSP) without lowering the blood pressure. Histological changes in the cerebrum of SHRSP were ischemic changes such as swelling of the neurons and shrinkage of the nuclei, mainly in the cerebral cortex and corpus striatum area.

Adjuvant arthritic rats develop marked changes in the distal limb joints. These changes were observed by soft X-ray photography at appropriate intervals. It was confirmed that the "cotton wool appearance" surrounding the bones, which was readily discernible from the radiographs, was a good indicator for following the progression of bone damages. Standard radiographs were selected to represent the various bone changes based on the "cotton wool appearance". When the incidence rates of bone deformation confirmed on the basis of the above method were plotted against Weibull Probability Paper, the plots conformed with the Weibull distribution function. Thus, it was possible to evaluate bone changes in adjuvant arthritic rats by observing the "cotton wool appearance" surrounding the bones.

The influence of adjuvant arthritis in rats on main urinary metabolites (MUM) of prostaglandin (PG) F and E type was studied. 1) In our model rats, urinary excretion of PGE-MUM increased on day 11 prior to the appearance of secondary lesions, but that of PGF-MUM did not change significantly during the observed period (21 days). The excretion of PGE-MUM was not proportional to the increase in both hind paws volume. 2) Indomethacin, which diminished primary lesions but did not suppress secondary lesions, reduced the increase in urinary excretion of PGE-MUM. 3) Prednisolone and azathiopurine, which suppressed both primary and secondary lesions, increased the excretion of PGE-MUM over adjuvant control values on days 4 and 8. The facts described above suggest that the increase of endogenous PGE during days 4 to 8 may be important in the suppression of secondary lesions in adjuvant arthritis in rats.

The following results were obtained as the result of the sequential observations with an endoscope of the gastric ulcer produced by submucosal injection of acetic acid in rats. 1) The size of the ulcer produced by acetic acid injection observed on the 3rd day after ulcer induction depended on the concentration and volume of acetic acid. 2) The natural reducing rates of the size of ulcers in the region between the fundus and pylorus on the anterior wall (A) and in the glandular region on the greater curvature (B) were compared. The reducing rate of B ulcer was significantly faster than that of A ulcer. 3) No significant difference was observed in the reducing processes of untreated ulcers in 7 weeks old rats and 25 weeks old rats. 4) The ulcer reducing rate of female rats was found to be slightly faster than that of male rats. 5) The ulcer reducing rates of the aldioxa (ALD) and sucralfate (SUC) treated group were significantly faster than that of the control group. However, no difference in the ulcer reducing process between the cimetidine (CIM) treated group and the control group was observed. 6) The ulcer indices (UI) of both the combinations of ALD and SUC and of ALD and CIM were found to be significantly less than that of the control group on the 20th day. Treatment with drug combinations shortened the healing period of ulcers more than treatment with one drug alone. The percent healing by the combination of ALD and SUC was the highest among the groups treated. 7) An approximately linear relationship exists between the logarithm of the days after ulcer induction (x) and logarithm of UI (y), and the following equation was obtained: log y = a log x + b. Slope (a) indicates the ulcer reducing rate in evaluating the ulcer reducing process.

The effects of drug administration on the dams (F0) and their offspring (F1), particularly on the central nervous and reproductive functions of F1, were studied by oral administration of pentazocine HCl to rats during the perinatal and postnatal periods. No significant differences were observed between administered and control rats regarding body weight changes and food intake during perinatal and postnatal periods in F0 at all dosages, but temporary salivation was observed in the 200 and 100 mg/kg groups, and decline of spontaneous activity and respiratory rate, disappearance of righting reflex, clonic convulsion were observed in some of the 200 mg/kg group. No significant differences were observed regarding litter size, birth rate, state and timing of differentiation as postnatal development, sex maturity, reproductive function in F1, although some groups were slightly inferior in body weight at birth and during the nursing period. Furthermore, no differences were observed in respect to the nervous functions of balance, exercise and psychotic related activity in the open-field test.

In the present study, a sequential observation of the gastric lesions or ulcers in rats weighing from 100 g was made with an endoscope. It was found that bleeding, edema, hyperemia, fur of ulcer and convergences of the mucosal folds in the stomach could be observed in rats with a SES-1717S (phi = 1.7 mm) or SES-2217S (phi = 2.2 mm) endoscope. Furthermore, we have devised a method which we named the "sohmen method" for measuring ulcer-sizes with an endoscope. The ulcer-size was compared with 5 mm lengths of sohmen (Japanease vermicelli) which were inserted through the sheath of the endoscope into the stomach. Therefore, the ulcer-size could be accurately measured by this method. By this observation method, it is possible to observe repeatedly over a long term the changes in gastric lesions or ulcers, to measure changes in ulcer-sizes and to evaluate the relapse or recurrence of ulcers in the same rats.