Since the role of excitatory amino acids such as glutamate and aspartate and their receptors mediating cellular injury through various mechanisms were known in hypoxic-ischemic injury and associated diseases of central nervous system, blocking agents for transmitter release or receptors have been tried to reduce the cellular damages and subsequent sequelae experimentally. Several in vitro studies suggested two kinds of glutamate neurotoxicity: (1) rapid toxicity due to influx of sodium or chloride with resultant cellular edema and consequent damage, which is associated with N-methyl-D-Aspartate(NMDA) as well as non-NMDA receptors, (2) calcium mediated delayed toxicity associated mainly with NMDA receptor. This study was conducted to investigate the role of rapid toxicity in hypoxic-ischemic injury. Early lesions of 30 minutes to 24 hours after hypoxic-ischemic insult were examined by autoradiography with radiolabelled glutamate and kainitic acid (KA) as well as light and electron microscopy. Late changes were evaluated on formaldehyde-acetic acid-methanol(FAM) fixed brain 1 week after the insult. Cornus ammonis(CA) l of hippocampus showed the highest density of NMDA receptors, which was decreased constantly from 2 hours to 24 hours. In contrast, CA3 of hippocampus showed the highest density of KA receptors, which was the lowest at 6 hour and increased thereafter. Light microscopic examination showed the worst changes during 30 minutes to 6 hours. After 1 week, most of the cases showed degeneration of neurons and CAI and CA3 did not show the difference. Electron microscopic examination showed marked degenerative changes of neurons as well as neuropils starting from 30 minutes after the insult. In conclusion, rapid toxicity mediated by non-NMDA(KA) receptor seen in CA3 lead to permanent damage in 1 week old lesion.
Rats ; Animals

The purpose of this study was to determine the immunohistochemical expression of nm23-H1, a putative metastatic suppressor gene, and to correlate its expression with clinicopathologic variables in 75 cases of surgically resected colorectal carcinomas. There appeared to be a trend between increasing relative nm23 protein expression and Dukes' stage, vessel invasion, and metastasis of lymph nodes. nm23 was expressed in 67 cases (89.3%) and increased in cases with lower Dukes' stage (P<0.05) and in cases without vessel invasion (P<0.01) or lymph node metastasis (P<0.01). No significant relationship was observed between the nm23 protein expression and other parameters, such as tumor size, location and differentiation of the tumor. The results suggest that the nm23 protein expression plays a role in the suppression of nodal metastasis and vessel invasion in colorectal carcinomas.
Colorectal Neoplasms* ; Genes, Suppressor ; Lymph Nodes ; Neoplasm Metastasis

BACKGROUND: Glucocorticoids (GCs) are essential for normal development and the maturation of the central nervous system. The aim of this study was to determine the effects of antenatal dexamethasone (DEXA) treatment on neuronal morphogenesis and on the glial cell line-derived neurotrophic factor (GDNF) protein expression in neonatal rat. METHODS: Pregnant Sprague-Dawley rats were injected with saline (the control), or 0.2 mg/kg/day DEXA or 0.8 mg/kg/day DEXA at 17th, 18th and 19th day of gestation. The newborn rat brains were examined at postnatal days 1 (n=75) and 10 (n=78). RESULTS: The DEXA-treated groups showed distorted architectures of neurons in the cerebral cortex, hippocampus and cerebellar cortex at postnatal days 1 and 10 with an increased number of proliferating cell nuclear antigen (PCNA)-positive cells. The cerebellar cortex in the DEXA-treated groups showed delayed development with more PCNA-positive cells in the internal granular cell layer. The Purkinje cells showed a markedly decreased number and the decreased length of the dendritic processes. The GDNF positive reaction was decreased in the DEXA-treated groups in a dose-dependent manner. CONCLUSIONS: The developmental changes and neuronal degeneration at postnatal days 1 and 10 in the newborn rats that were exposed to DEXA at the late gestational age were associated with increased proliferative activity and a decreased level of GDNF protein expression.
Animals ; Brain ; Central Nervous System ; Cerebellar Cortex ; Cerebral Cortex ; Dexamethasone* ; Gestational Age ; Glial Cell Line-Derived Neurotrophic Factor ; Glucocorticoids ; Hippocampus ; Humans ; Infant, Newborn ; Morphogenesis* ; Neurons* ; Pregnancy ; Proliferating Cell Nuclear Antigen ; Purkinje Cells ; Rats ; Rats, Sprague-Dawley

PURPOSE: Paclitaxel is a chemotherapeutic agent with potent microtubule stabilizing activity that arrests cells in G2-M phase. Because G2 and M are the most radiosensitive phase of the cell cycle, paclitaxel has potential role as a cell-cycle specific radiosensitizer. This study was performed to see the effects of paclitaxel on the radiation-induced damage of gastric mucosa of the rat. MATERIALS AND METHODS: The rats were divided into the three groups i.e., paclitaxel alone group, radiation alone group and, a combination of paclitaxel and radiation in combined group. A single intraperitoneal infusion of paclitaxel (10 mg/kg) was done in paclitaxel alone group. In radiation alone group, a single fraction of irradiation (8 Gy, x-ray) to the whole abdomen and, a combination of a single fraction of irradiation (8 Gy, x-ray) to the whole abdomen was given 24 hrs after paclitaxel infusion in combined group of paclitaxel and radiation. The incidence of mitosis and apoptosis as well as histologic changes of the gastric mucosa were evaluated at 6 hrs, 24 hrs, 3 days and 5 days after treatment. RESULTS: The number of the mitosis was not increased by paclitaxel infusion. The incidence of the apoptosis was similar from 6 hrs to 3 days after paclitaxel infusion and was decreased at 5 days. Paclitaxel induced minimal glandular dilatation and cellular atypia of gastric mucosa at 24 hrs and 3 days. In irradiation group, the incidence of apoptosis was 6.0% in 6 hrs and 1.25% in 24 hrs after irradiation and minimal glandular dilatation and cellular atypia were noted throughout the experimental period. The incidence of apoptosis in the combined group of paclitaxel and irradiation (4.5%) was significantly higher than irradiation alone group (1.25%) at 3 days (p<0.05). CONCLUSION: Paclitaxel had no effect on mitotic arrest in gastric mucosa of the rat. Increased number of apoptosis in combined paclitaxel and irradiation group suggested the additive effects of paclitaxel on irradiation.
Abdomen ; Animals ; Apoptosis ; Cell Cycle ; Dilatation ; Gastric Mucosa* ; Incidence ; Infusions, Parenteral ; Microtubules ; Mitosis ; Paclitaxel* ; Rats* ; Stomach

Phospholipase C (PLC) and related enzymes in signal transduction system are closely linked to cellular damage in ischemic encephalopathy. This study was undertaken to elucidate the time sequential changes of PLC isoenzymes (beta and gamma) in vulnerable areas of hippocampus in global ischemia and infarcted area in focal infarction. Mongolian gerbils were used because of their susceptibility to ischemic encephalopathy and divided into the following groups: the bilateral ischemia with various reperfusion periods group, unilateral progressive ischemia group, and focal ischemia group induced by infusion of iron particles through the femoral artery. The changes of PLC isoenzymes were observed immunohistochemically and matched with morphological changes. In the global ischemia with reperfusion group, the changes were most significant in hippocampus. Sequential changes of neurons such as red neurons at an early stage progressed to pknotic neurons at a later stage were noted with typical delayed neuronal damage in the corns ammonis (CA) 1 subfield of hippocampus. Red neurons and pyknotic neurons as well as intracytoplasmic inclusion in 3 to 24 hours of reperfusion showed loss of PLC isoenzymes as well as tubulin. The changes of PLC expression were corresponding to the degeneration of neurons with no discernible time sequential changes in remaining neurons. In the unilateral hemispheric progressive ischemia group, ischemic damage was far more marked and extensive with no selective injury pattern according to time and location. At 1 day, there was diffuse vacuolization and necrosis of neuropil with a loss of neuron. Admixed surviving neurons and vacuolated neuropil showed increased reaction to anti-PLC antibodies, which could be either an evidence of protein synthesis responding to ischemic insult or an artifactual change. Focal ischemia group showed time sequential changes of blood vessels and white blood cells with necrosis of surrounding tissue. Degenerating hippocampal neurons in infarction also showed a strong positive reaction to anti-PLC antibody, which was most likely due to condensation of cytoplasm rather than increased synthesis. This study showed different changes of PLC expression in global ischemic encephalopathy with reperfusion, progressive ischemia, and focal infarction, which suggested different pathophysiologic mechanism between these conditions.
Animal ; Brain Ischemia/*metabolism/pathology ; Cerebral Infarction/metabolism/pathology ; Female ; Gene Expression ; Gerbillinae ; Hippocampus/*enzymology ; Immunoenzyme Techniques ; Isoenzymes/*biosynthesis ; Male ; Neurons/enzymology/ultrastructure ; Phospholipase C/*biosynthesis ; Support, Non-U.S. Gov't ; Time Factors

The causes of congenital hydrocephalus vary widely and have an important effect in determining the future counseling of affected cases. We analyzed the postmortem findings of 49 autopsies diagnosed as hydrocephalus to find the causes and related conditions. The cases were collected during the last 10 years (1981-1990). The cases consisted of 25 cases associated with various congenital malformations of the central nervous system (CNS), 14 cases of posthemorrhagic hydrocephalus, 4 cases of postinfection hydrocephalus, and 2 cases of hydranencephaly. Four cases were associated with supracerebellar arachnoid cyst (1) and unknown causes (3). Twenty-five cases associated with congenital malformation of the CNS consisted of 10 cases of holotelencephaly, 5 cases of stenosis of the Sylvian aqueduct, 4 cases of agenesis of the corpus callosum, and 3 cases each of Dandy-Walker malformation and Arnold-Chiari malformation. Various malformations of other organs were associated with these cases. Cardiovascular malformations were common, consisting of 11 cases of patent ductus arteriosus (PDA), 7 cases of atrial septal defect (ASD), and 6 cases of patent foramen ovale (PFO). Among the anomalies of the respiratory system, abnormal lobation was commonly associated, as well as hypoplasia of the lung. Gastrointestinal malformations included Meckel's diverticulum, diaphragmatic hernia, mobile intestine, and midline small liver. Cryptorchidism was the most common malformation in the genitourinary system. Holotelencephaly cases showed multiple craniofacial anomalies, as well as other malformations in the central nervous system. Skeletal malformations included polydactyly, simian crease, and flexion deformity. There were no specific constellations of malformations in these different groups of CNS malformations associated with hydrocephalus.
*Abnormalities, Multiple/pathology ; Autopsy ; Central Nervous System/abnormalities ; Cerebral Hemorrhage/complications ; Female ; Fetal Diseases ; Herpes Simplex/complications ; Humans ; Hydrocephalus/complications/embryology/*etiology/pathology ; Infant, Newborn ; Male

Vincristine has been extensively need in chemotherapy to treat leukemia, lymphoma, and a variety of solid tumor. The major antitumor effect has been known to be associated with its high affinity binding to the basic protein sub unit of microtubule, tubulin, which causes disruption of the mitotic spindle apparatus and arrest of calls in metaphase. The principal side effect that has commonly limited the use of this agent is peripheral sensori-motor neuropathy, a feature probably related to the disruption of microtubule in neural tissues. There has been a need for animal experimental models w study the peripheral neuropathy induced by vincristine. However, it was not easy to develop an adequate model due to reported interspecies difference of susceptibility to vincristine. In addition, electrophysiologic test methods to confirm peripheral neuropathy in small experimental animals has not been properly addressed. The purpose of this experiment is to find out whether rat can be used as an animal experimental model of vincristine neuropathy. The authors also incorporated serial noninvasive electrophysiololgic tests, in attempt to correlate morphologic alterations induced by vincristine and functional status of peripheral nerve and muscle. Experiment Group 1 of 14 rats were given 0. 2mg/kg vincristine sulfate once a week, Group 2 of 14 rats were given same does twice a week and Group 3 of 14 rats were given 0. 4mg/kg intravenously, through tail veins for 6 weeks, to delineate the possible different effects from dosage and frequency of injections. The 14 rats for control were given only normal saline with the same methods. The electrophysiologic tests including motor nerve conduction study, sensory nerve conduction study and cervical somatosensory evoked potential were per formed 2 weeks interval. The morphologic examinations of posterior tibial nerves using light microscope and electron microscope were done 4 weeks interval up to 16 weeks. The H&E, modified Gomori-trichrome and histochemical stain(ATPase & NADH) 1. Vincristine induced peripheral neuropathy was successfully established in rat.. This was confirmed not only by morphologic measurements but also by noninvasive serial electrophysiologic examinations of peripheral nerves. 2. The vincristine neuropathy in rats was sensori-motor type similar to those in human. 3. The motor and sensory conduction velocity of posterior tibial nerve in rats fell significantly at ter 2-4 weeks in the vincristine injected groups A tendency of recovery was noted, but the conduction velocity failed to return to normal level up to 16 weeks follow up study. However, the amplitude of compound muscle action potentials as well as compound nerve action potentials showed a great deal of fluctuation during the genesis of neuropathy. Therefore, these electrophysiologic parameters were not optimal predictors in assessment of functional integrity of given nerves with the electrophysiologic test methods used in this experiments. 4, Morphologic examinations revealed that vincristine neuropathy I rats are clearly these of axonal degeneration, compatible to the findings of electrophysiologic examination. 5. The higher dose of vincristine induced the more damage to the peripheral nerves but it also resulted in high mortality rate. Administration of 0.2mg/kg/week would be adequate in generation of experimental neuropathy. 6. The examinations of gastrocnemius and soleus muscle showed same evidence of mild degree of myopathy but it was felt to be direct toxic effect, rather than secondary changes due to the neuropathy.
Action Potentials ; Animal Experimentation ; Animals ; Axons ; Drug Therapy ; Evoked Potentials, Somatosensory ; Follow-Up Studies ; Humans ; Leukemia ; Lymphoma ; Metaphase ; Microtubules ; Mortality ; Muscle, Skeletal ; Muscular Diseases ; Neural Conduction ; Peripheral Nerves* ; Peripheral Nervous System Diseases ; Rats* ; Spindle Apparatus ; Tibial Nerve ; Tubulin ; Veins ; Vincristine*

A 40-year-old man with chronic hepatitis B complained of progressive weakness of the proximal muscles and edema of both legs. He had been receiving long-term clevudine (nucleoside analogue reverse transcriptase inhibitor, NRTI) therapy for his hepatitis. The serum creatine kinase level was increased on the laboratory tests. His electromyography showed a generalized myopathic process. The muscle biopsy showed numerous ragged-red fibers, degenerating myofibers with variable sized cytoplasmic bodies, the prominence of type 1 fibers with type 2 fiber atrophy and an endomysial mononuclear cell infiltration. The electron microscopic examination revealed necrotic myofibers, including extremely dysmorphic mitochondria with extensive loss, blunting and focal clumping of the cristae and concentric cristae. Although clevudine is known to be a less cytotoxic agent among the various NRTIs, careful clinical attention should be paid to the patients who are receiving long-term clevudine therapy for the occurrence of myopathy.
Adult ; Arabinofuranosyluracil ; Atrophy ; Biopsy ; Creatine Kinase ; Cytoplasm ; Edema ; Electromyography ; Electrons ; Hepatitis ; Hepatitis B, Chronic ; Humans ; Leg ; Mitochondria ; Mitochondrial Myopathies ; Muscles ; Muscular Diseases ; RNA-Directed DNA Polymerase

BACKGROUND: The clinical presentation of microscopic colitis (MC) consists of chronic non-bloody watery diarrhea for weeks or months at a time, abdominal pain, and changes in bowel habits with a normal mucosal appearance upon performing colonoscopy. MC includes two relatively well established histopathologic entities: collagenous colitis (CC) and lymphocytic colitis (LC) as well as atypical forms. The recognition of the microscopic findings of this heterogeneous entity is very important for making the correct diagnosis and providing proper treatment. METHODS: We studied the colonoscopic biopsy specimens that were obtained from 26 patients who had clinical findings that were suggestive of MC. RESULTS: Fifteen patients (M:F=9:6) and 9 patients (M:F=5:4) showed the microscopic features of LC and MC, not otherwise specified, respectively. CONCLUSIONS: The clinicopathologic findings (the incidence of the subtypes, the patients' ages and the male/female ratio) of the 24 cases of MC in this study showed differences from the previously reported findings from other countries. Further studies with a sufficient number of patients from multi-centers would be necessary to confirm the regional or ethnic influence.
Abdominal Pain ; Biopsy ; Colitis, Collagenous ; Colitis, Lymphocytic ; Colitis, Microscopic ; Colonoscopy ; Diarrhea ; Humans ; Incidence ; Lymphocyte Count

PURPOSE: Captopril (angiotension converting enzyme inhibitor) is known to have a radioprotective effect in the lungs, intestines and skin, but its effect in the heart is unclear. To investigate the radioprotective effect and mechanism of captopril in the heart, the histopathological changes and immunohistochemical stains were compared with radiation alone, and radiation combined with captopril, in the rats. MATERIALS AND METHODS: The histopathological changes and immunohistochemical stains (TNF alpha, TGFbeta1, PDGF and FGF2) were examined in the radiation alone and the combined captopril and radiation groups, 2 and 8 weeks after irradiation. Each group consisted of 8 to 10 rats (Sprague-Dawley). Irradiation (12.5 Gy) was given to the left hemithorax in a single fraction. Captopril (50 mg/Kg/d) mixed with water, was given orally and continuously from the first week prior to, up to the 8th week of the experiment. RESULTS: In the radiation alone group, the ventricle at 2 weeks after irradiation showed prominent edema (p=0.082) and fibrin deposit (p=0.018) compared to the control group. At 8 weeks, the edema was decreased and fibrosis increased compared to those at 2 weeks. The histopathological changes of the combined group were similar to those of the control group, due to the reduced radiation toxicity at 2 and 8 weeks. The endocardial fibrin deposit (p=0.047) in the atrium, and the interstitial fibrin deposit (p=0.019) and edema (p=0.042) of the ventricle were reduced significantly in the combined group compared to those in the radiation alone group at 2 weeks. The expressions of TNF-alpha, TGF-beta1, PDGF and FGF-2 in the radiation alone group were more increased than in the control group, especially in the pericardium and endocardium of the atrium at 2 weeks. At 8 weeks, the pericardial TNF-alpha and TGF-beta1 in the radiation alone group continuously increased. The expressions of TNF-alpha, TGF-beta1 and PDGF were decreased in the combined group at 2 weeks. At 8 weeks, the expressions of TNF-alpha in the atrial and ventricular pericardia were markedly reduced (p=0.049, p=0.009). CONCLUSIONS: This study revealed that the early heart damage induced by radiation can be reduced by the addition of captopril in a rat model. The expressions of TNF-alpha, TGF-beta1 and PDGF were further decreased in the combined compared to the radiation alone group at both 2 and 8 weeks. From these results, it may be concluded that these cytokines probably play roles in the radioprotective mechanism of captopril from the radiation-induced heart toxicity, similarly to in other organs.
Animals ; Captopril* ; Coloring Agents ; Cytokines ; Edema ; Endocardium ; Fibrin ; Fibroblast Growth Factor 2 ; Fibrosis ; Heart ; Intestines ; Lung ; Models, Animal ; Pericardium ; Rats* ; Skin ; Transforming Growth Factor beta1 ; Tumor Necrosis Factor-alpha ; Water