Chemopreventive Effects of a Flavonoid Antioxidant Silymarin on N-Butyl-N-(4- hydroxybutyl)nitrosamine-induced Urinary Bladder Carcinogenesis in Male ICR Mice

The modifying effects of dietary administration of a flavonoid antioxidant, silymarin, a mixture of three flavonoids isolated from milk thistle seeds, on N -butyl-. N -(4-hydroxybutyl)nitrosamine (OH- BBN)-induced urinary bladder carcinogenesis were examined in male ICR mice. Animals were divided into 5 groups, and groups 1 to 3 were given OH-BBN (500 ppm) in drinking water for 6 weeks. Mice in group 2 were fed a diet containing 1000 ppm silymarin for 8 weeks during the initiation phase starting 1 week before OH-BBN exposure, and mice in group 3 were fed the diet for 24 weeks during the postinitiation phase. Animals in group 4 were given only the test compound, and those in group 5 were given the basal diet alone throughout the experiment. Animals were sacrificed at the end of week 32. The frequency of bladder lesions, cell proliferation and cell cycle progression activity estimated in terms of the 5-bromodeoxyuridine (BrdU) labeling index or cyclin Dl-positive cell ratio were compared among the groups. Administration of silymarin in the initiation or postinitiation phase significantly decreased the incidences of bladder neoplasms and preneoplastic lesions. Dietary exposure to this agent significantly reduced the labeling index for BrdU and the cyclin Dl-positive cell ratio in various bladder lesions. These findings suggest that silymarin is effective in preventing OH-BBN-induced bladder carcinogenesis in mice.     

Inhibitory Effects of Toremifene on N-Methyl-N-nitrosourea and Estradiol-17β-induced Endometrial Carcinogenesis in Mice

Short- and long-term experiments were designed to determine the effects of toremifene (TOR) on estrogen-related endometrial carcinogenesis in mice. In the short-term experiment, a single low dose of TOR (0.2 mg/30 g body weight) decreased expression of c- fos , interleukin (IL)-1α, estrogen receptor (ER)-α mRNAs and corresponding proteins induced by estradiol-l7β (E₂), in the uteri of the ovariectomized mice. Expression of ER-β mRNA was increased by the TOR treatment, compared with the control. In the long-term experiment, 106 female ICR mice were given N -methyl N -nitrosourea (MNU) into their uterine corpora. The animals were divided into four groups as follows: group 1, E₂ diet (5 ppm) plus TOR (0.2 mg/30 g body weight, subcutaneously, every four weeks); group 2, E₂ diet alone; group 3, basal diet plus TOR. Group 4 served as the control. TOR treatment decreased the incidence of MNU and E₂-induced endometrial adenocarcinoma and atypical hyperplasia at the termination of the experiment (30 weeks after the start). These results suggest that TOR exerts preventive effects against estrogen-related endometrial carcinogenesis in mice, through the suppression of c- fos as well as IL-1α expression induced by E₂. Such suppressive effects of TOR may be related to the decreased ER-α and increased ER-β expressions.     

U-shaped Effect of Drinking and Linear Effect of Smoking on Risk for Stomach Cancer in Japan

A case-control study was conducted to evaluate the relationship between smoking or drinking doses and risk for stomach cancer, and to clarify whether the relationship is dose-dependent or U-shaped. Smoking dose was categorized as 0,1–399, 400–799, or 800+ cigarette-years, and drinking dose as 0, occasional/0.1–134.9, 135–1349.9, or 1350+ alcohol-years (ml of pure alcohol intake per day multiplied by years of drinking). Helicobacter pylori status was determined by serology for adjustment. Using logistic regression, the adjusted effects of smoking and drinking doses on risk for stomach cancer were calculated for both genders. Among male subjects, the odds ratios (95% confidence intervals (CIs)) were 1.29 (0.76, 2.18) for 1–399, 1.71 (1.05, 2.80) for 400–799 and 2.46 (1.49, 4.07) for 800+ cigarette-years compared with never-smokers, and 1.89 (0.97, 3.69) for never-drinkers, 2.82 (1.63, 4.86) for 135–1349.9 and 2.84 (1.97, 4.83) for 1350.0+, compared with occasional/0.1–134.9 alcohol-years. Among female subjects, they were 0.44 (0.20, 1.00) for 1–399 and 2.471 (0.91, 6.68) for 400+ cigarette-years compared with never-smokers, and 1.54 (0.90, 2.63) for never-drinkers and 1.39 (0.66, 2.93) for 135.0+ alcohol-years. Smoking seems to exert a linear effect and drinking, a J- or U-shaped effect on risk for stomach cancer, although there might be a dip of risk in light smokers among female subjects.     

Analysis of the Genetic Alterations in a Case of Juvenile Multiple Colon Carcinoma With Hypogammaglobulinemia

Background: We have previously reported the clinical characterization of a case of juvenile multiple colorectal carcinoma with hypogammaglobulinemia. Several recent studies have determined that agammaglobulinemia was caused by the loss of Brutons tyrosine kinase (Btk) function. However, any genetic alterations associated with carcinoma formation in individuals with this immunodeficient disease have not been reported.Methods: DNA from eight carcinoma tissues and nine adenoma tissues from this reported case were examined for mutations in p53 by single strand conformation polymorphism analysis, K-ras by mutant allele specific analysis, and replication error or loss of heterozygosity of the TP53 locus on chromosome #17.Results: We found that p53 and K-ras were mutated in the carcinoma tissues. However, each tumor showed unequal and diverse results.Conclusions: The progression of individual tumor was not due to a common genetic event caused directly under the influence of the primary disease at the genetic level.     

Expression of brain specific chondroitin sulfate proteoglycans, neurocan and phosphacan, in the developing and adult hippocampus of Ihara's epileptic rats

Ihara's epileptic rats (IER) is an animal model of temporal lobe epilepsy with mycrodysgenesis, that exhibit abnormal migration of hippocampal neurons and recurrent spontaneous seizures. As an attempt to elucidate the roles of extracellular matrix molecules in the epileptogenecity and mossy fiber sprouting, immunohistochemical localization of brain specific chondroitin sulfate proteoglycans (CSPGs), neurocan and phosphacan, was examined in the hippocampus of postnatal IER and Sprague-Dawley (SD) rats using monoclonal antibodies 1G2 against neurocan and 6B4 against phosphacan. There was no difference in the expression of these two CSPGs between IER and SD rats in the 1st postnatal week. However, the expression of neurocan was poor in the hippocampus of IER in the 2nd and 3rd weeks whereas intense labeling of neurocan was present throughout the hippocampus of SD rats. Labeling of neurocan was almost absent in the hippocampus, while phosphacan was diffusely expressed in the stratum oriens and radiatum of Ammon's horn, and in the hilus and inner one-third molecular layer of the dentate gyrus at the 2nd month after birth. There was no difference in the expression of neurocan and phosphacan between IER and SD rats at the 2nd month after birth. By contrast, phosphacan was reduced in the inner molecular layer of the dentate gyrus in 8-month-old IER, while neurocan was reexpressed in the outer molecular layer and hilus in 3- and 8-month-old IER. It was suggested that the insufficient expression of neurocan may affect the development of neuronal organization in the hippocampus, and that the remodeling of extracellular matrix in the dentate gyrus may contribute to the mossy fiber sprouting into the inner molecular layer.     

Effects of nociceptin on cardiac norepinephrine and acetylcholine release evoked by ouabain

We investigated whether the novel peptide, nociceptin, modulates neuronal transmission at autonomic nerve endings. Using a cardiac dialysis technique, the effects of locally applied nociceptin on cardiac acetylcholine (ACh) and norepinephrine (NE) release were examined in anesthetized cats. Dialysis probes were implanted in the left ventricular wall, with the concentration of dialysate NE or ACh serving as an indicator of NE or ACh output at cardiac sympathetic or parasympathetic nerve endings. Locally applied ouabain evoked increases in NE and ACh output. Nociceptin suppressed the ouabain induced ACh increment. The ouabain induced NE release was not altered by nociceptin. However, in the presence of desipramine (a NE uptake inhibitor), nociceptin suppressed the ouabain-induced NE release. Inhibition by nociceptin of ouabain-induced release of NE or ACh was blocked by pretreatment with nocistatin (a nociceptin action blocking peptide). Nociceptin-induced inhibition of ACh or NE release is attributable to pre-synaptic modulation rather than a reversal of the ouabain effect. These findings demonstrate that nociceptin inhibits cardiac autonomic neurotransmission via a presynaptic opioid receptor-like1(ORL1) receptor.     

Clinical features and prognosis of Miller Fisher syndrome

The authors reviewed the clinical features and outcome of Miller Fisher syndrome (MFS) for 50 consecutive patients with MFS including 28 patients who received no immunotherapy. Besides the characteristic clinical triad (ophthalmoplegia, ataxia, and areflexia), pupillary abnormalities, blepharoptosis, and facial palsy are frequent in MFS, whereas sensory loss is unusual despite the presence of profound ataxia. Patients with MFS usually had good recovery and no residual deficits.     

Role of the medial medullary reticular formation in relaying vestibular signals to the diaphragm and abdominal muscles

Changes in posture can affect the resting length of respiratory muscles, requiring alterations in the activity of these muscles if ventilation is to be unaffected. Recent studies have shown that the vestibular system contributes to altering respiratory muscle activity during movement and changes in posture. Furthermore, anatomical studies have demonstrated that many bulbospinal neurons in the medial medullary reticular formation (MRF) provide inputs to phrenic and abdominal motoneurons; because this region of the reticular formation receives substantial vestibular and other movement-related input, it seems likely that medial medullary reticulospinal neurons could adjust the activity of respiratory motoneurons during postural alterations. The objective of the present study was to determine whether functional lesions of the MRF affect inspiratory and expiratory muscle responses to activation of the vestibular system. Lidocaine or muscimol injections into the MRF produced a large increase in diaphragm and abdominal muscle responses to vestibular stimulation. These vestibulo-respiratory responses were eliminated following subsequent chemical blockade of descending pathways in the lateral medulla. However, inactivation of pathways coursing through the lateral medulla eliminated excitatory, but not inhibitory, components of vestibulo-respiratory responses. The simplest explanation for these data is that MRF neurons that receive input from the vestibular nuclei make inhibitory connections with diaphragm and abdominal motoneurons, whereas a pathway that courses laterally in the caudal medulla provides excitatory vestibular inputs to these motoneurons.     

Malignant hemangiopericytoma of the breast

A55-year-old woman presented with 1-year history of mass in the right breast. Incisional biopsy showed the tumor to be malignant hemangiopericytoma from its histology. The tumor showed low--intermediate density and peripheral contrast enhancement on CT, and inhomogeneous mixed-signal intensity both on T1W and T2W images, and peripheral enhancement with Gd-DTPA on MRI with no invasion of the duct.