Vermis lesions in acute cerebellar ataxia: a sequential imaging study

We report a case of acute cerebellar ataxia (ACA) with discrete paleocerebellar clinical symptoms who underwent serial cranial magnetic resonance images not only with conventional spin echo sequences but also fluid attenuated inversion recovery (FLAIR) sequences. The images with the latter sequences demonstrated more conspicuously the high signal intensity lesions in the superior cerebellar vermis and cerebellar peduncle than those with the former sequences. In the convalescent phase, the lesions became markedly atrophic. Thus, the causative lesions for ACA were demonstrated on MRI, and FLAIR provided clear images of the lesion in the vermis.     

Sevoflurane Inhibits Guanosine 5′-[γ-thio]triphosphate-stimulated, Rho/Rho-kinase-mediated Contraction of Isolated Rat Aortic Smooth Muscle

Background: The Rho/Rho-kinase signaling pathway plays an important role in mediating Ca2+ sensitization of vascular smooth muscle. The effect of anesthetics on Rho/Rho-kinase-mediated vasoconstriction has not been determined to date. This study is designed to examine the possible inhibitory effects of sevoflurane on the Rho/Rho-kinase pathway by measuring guanosine 5'-[[gamma]-thio]triphosphate (GTP[gamma]S)-stimulated contraction and translocation of RhoA (one of the three Rho subtypes) and Rock-2 (one of the two Rho-kinase subtypes) from the cytosol to the membrane in rat aortic smooth muscle.

Methods: GTP[gamma]S-induced contraction of rat aortic endothelium-denuded rings was measured using an isometric force transducer, and GTP[gamma]S-stimulated membrane translocation of RhoA and Rock-2 in smooth muscle cells was detected with Western blotting in the presence and absence of sevoflurane.

Results: GTP[gamma]S (10-4 m) induced a sustained contraction, which was significantly inhibited by the Rho-kinase inhibitor, Y27632 (3 x 10-6 m). Before treatment with GTP[gamma]S, RhoA and Rock-2 were detected primarily in the cytosolic fraction. GTP[gamma]S (10-4 m) stimulated the translocation of RhoA and Rock-2 from the cytosol to the membrane, which was sustained for more than 60 min. Sevoflurane (1.7, 3.4, and 5.1%) concentration dependently inhibited the GTP[gamma]S-induced constriction of rat aortic smooth muscle with a reduction of constriction of 52-75% (P < 0.01, n = 8), and attenuated the translocation of RhoA and Rock-2 by 31-66% and 34-78%, respectively (P < 0.05-0.01, respectively; n = 4).     

Visual evoked potentials relating to imagery: Words for concrete objects versus absolute concepts

Summary We recorded visual evoked potentials (VEPs) elicited with high or low imaginable Chinese characters (HIC or LIC), representing concrete objects or absolute concepts, respectively. A closed circle (CC) acts as control stimulus. These were displayed (at 1.6° visual angle) for 35 ms on a TV monitor. Twenty-one channel VEPs (band-pas filter: 0.05–60 Hz), using balanced non-cephalic electrodes, were recorded from –100 to 924 ms for 11 right-handed male volunteers. The VEPs were analyzed by multivariate analysis of variance (MANOVA) and comparison of topographies at four remarkable peaks (P110, N160, P230 and N320). MANOVA showed significant differences (p< 0.001) for both conditions of channel and stimuli (HIC, LIC or CC). P100 for the CC-VEPs, N160 for the HIC-and LIC-VEPs, P230 for the CC-VEPs, and N320 for the HIC-VEPs were remarkable in the posterior scalp regions. Topographies at P100 and N160 showed no difference between the HIC-and LIC-stimuli. However, those at N320 showed difference between the HIC-and LIC-stimuli over the occipital and posterior temporal areas. Those results suggest that the responses at P100 and N160 might segregate Chinese characters from non Chinese characters. N320 suggested certain processes in imagery on recognizing Chinese characters over the occipital and posterior temporal areas.We are grateful to Dr. Yoshiji Kojima of Hamamatsu University for helpful comments.     

EPIDEMIOLOGICAL CHARACTERISTICS OF PROSTATE CANCER IN GUNMA PREFECTURE, JAPAN

Background Prostate cancer is rare in Asia, but the number of patients is increasing in Japan. We conducted an epidemiological study of prostate cancer in Gunma Prefecture, Japan, to investigate the trends and characteristics of the disease.
Methods: The subjects were 1.411 prostate cancer patients newly diagnosed between 1985 and and 656 patients who died from prostate cancer between 1981 and 1992. The incidence and mortality rates were calculated by year, demographic region and age.
Results: The yearly incidence rate showed an increase but the mortality rate showed no marked fluctuations. There was no significant difference between urban and ruraI districts in either incidence or mortality rate. The incidence rate tended to be high in the northern part of the prefecture, but no marked variation in mortality rate was seen. The incidence and mortality rates in districts with a history of manganese mining were high compared to those in districts without mining. In contrast, the incidence and mortality rates in districts with a history of zinc mining were comparatively lower. Both incidence and mortality rates showed a marked increase with age. The age-specific incidence showed a double logarithmic relationship to age.
Conclusions: The increase of the yearly incidence rate might be due to changes in lifestyle and environmental factors, improved diagnostic techniques, and increased awareness among the general public regarding prostate disease. Further investigation is needed to clarify the pattern and the causes of regional differences in the incidence and mortality rates. The possibilities that manganese and zinc might be related to prostatic carcinogenesis are suggested. Int J Urol 1995:2:191–197     

Successful surgical treatment of secondary kwashiorkor after total gastrectomy: Report of a case

We report herein the case of a 56-year-old woman who developed secondary Kwashiorkor 9 years after undergoing a total gastrectomy for early gastric cancer. Until she began developing the symptoms of Kwashiorkor, including general fatigue, edema of the face and extremities, anemia, alopecia, and weight loss, she had been leading a normal life post-gastrectomy. Her symptoms were alleviated by total parenteral nutrition (TPN) therapy, but reappeared soon after TPN therapy was discontinued. Therefore, she required several subsequent courses of TPN. In an attempt to permanently resolve the ongoing Kwashiorkor symptoms, reconstructive surgery involving transposition of the jejunum from the previous Graham method to the interposition method was performed 10 years after the initial gastrectomy. After the second operation, her malnutrition was completely alleviated, and she has been in good health for the 8 years since. To our knowledge, there has been no other report of the symptoms of secondary Kwashiorkor after total gastrectomy being alleviated by altering the procedure of reconstruction of the intestinal tract. Thus, we recommend surgical treatment to alter the digestive continuity to a more physiological pathway for selected patients with secondary Kwashiorkor syndrome.     

Effect of buthionine sulfoximine on orthophenylphenol-induced hepato- and nephrotoxic potential in male rats

A single oral administration of orthophenylphenol (OPP, 1400 mg/kg; about half the LD₅₀) to male Fischer 344 rats produced an elevation of serum transaminase activity 24 h later. Pretreatment with l-buthionine-S,R-sulfoximine (BSO, 900 mg/kg) in the OPP-treated rats potentiated the hepatic and renal damage which was accompanied by necrosis. Six hours after the administration of OPP (700 or 1400 mg/kg), hepatic and renal glutathione (GSH) levels decreased with increasing dosage. Hepatic GSH depletion with OPP was enhanced with BSO pretreatment and the recovery of GSH in both organs was slow in the high-dose OPP group. These results suggest that hepatic and renal damage is associated with a serious and prolonged GSH depletion. When either phenyl-p-benzoquinone (PBQ) or phenylhydroquinone (PHQ), which are intermediates of OPP, was administered orally to rats at 700 or 1400 mg/kg, the mortality with the high dose of PBQ was 75% at 24 h. The serum transaminase activity and UN level increased with the low dose of PBQ, accompanied by necrotic hepatocytes. The toxic effects of PHQ on kidney or liver were less than those on PBQ. These observations suggest that the liver and kidney may be target organs for toxic actions of a large dose of OPP and its intermediate, PBQ.Part of this work was presented at IInd International ISSX Meeting Xenobiotic Metabolism and Disposition, May 16–20, 1988, Kobe, Japan     

Effects of calcitonin gene-related peptide on canine cerebral artery strips and the in-vivo vertebral blood flow in dogs

Summary The effects of calcitonin gene-related peptide (CGRP) on canine cerebral arteries and on vertebral blood flow were investigated in-vivo and in-vitro and the findings compared with the effects of vasoactive intestinal peptide (VIP) and substance P. Administration of CGRP into the vertebral artery caused a dose-dependent and long-lasting increase in blood flow. The in-vivo vasodilatory effects of substance P and VIP were short-lasting. CGRP (0.1 to 100 nmol/l) elicited a concentration-dependent relaxation of the isolated middle cerebral and basilar arteries when the tissues were precontracted by exposure to prostaglandin F₂ (PGF₂). This effect was not antagonized by propranolol, atropine, tetrodotoxin, (N-Ac-Tyr¹, D-Phe²)-growth hormone-releasing factor(1–29)-NH₂ or (D-Pro², D-Trp^7,9) substance P. CGRP also reduced concentration-dependently the contraction of cerebral arteries induced by KCl or 9,11-epithio-11,12-metano-thromboxane A₂ (STXA₂). Mechanical removal of the endothelium did not abolish the vasodilatory response to CGRP. In PGF₂-contracted canine cerebral arteries, VIP (0.1 to 100 nmol/l) was less potent a vasodilator than CGRP. At low concentrations (0.01 to 1 nmol/l) substance P elicited a rapid and short-lasting relaxation, and in the absence of endothelium this relaxation disappeared. These findings are clear evidence that CGRP modulates vascular tone.     

Nephrotoxicity of 5-(N-phenylcarboxamido)-2-thiobarbituric acid in the Fischer 344 rat

Summary In the present investigation, administration of a single i.p. dose of the anticancer drug merbarone [5-(N-phenylcarboxamido)-2-thiobarbituric acid] produced an acute and reversible decrease in renal function in female but not male Fischer 344 rats. The renal lesion in female rats was biochemically characterized as a decrease inp-aminohippuric acid accumulation by renal slices along with polyuria, glucosuria, proteinuria, and enzymuria. These functional changes were accompanied by histopathologic changes of focal tubular necrosis that was confined to the deep cortex and outer stripe of the outer medulla. The changes in these parameters were dose-dependent and were observed at doses as low as 0.2×MELD¹⁰ (12 mg/kg). This low merbarone dose increased urinary glucose and protein excretion by 26- and 9-fold, respectively, in the initial 16-h urine collection in female rats. This increase was accompanied by a 2- to 15-fold increase in the excretion ofN-acetyl--d-glucosaminidase (NAG), -glutamyl transpeptidase (-GTP), and lactate dehydrogenase (LDH) activities. No significant changes in renal function were observed in male rats apart from mild enzymuria after a high dose of merbarone (36 mg/kg). The drug did not increase urea nitrogen levels in male or female rats, reflecting the focal nature of this tubular lesion. Merbarone produced small elevations in serum transaminase activities [i. e., glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT)] at doses that produced marked alterations in renal function in female rats, suggesting only mild hepatotoxicity. The present study establishes the kidney as a possible dose-limiting target organ for merbarone toxicity.     

Discrete breakpoint mapping and shortest region of overlap of chromosome arm 1q gain and 1p loss in human hepatocellular carcinoma detected by semiquantitative microsatellite analysis

Recurrent chromosomal gain at 1q is one of the most common features of human hepatocellular carcinoma (HCC), but how the gain at 1q contributes to hepatocarcinogenesis is still unclear. To identify the target genes, precise determination of the shortest region of overlap (SRO) and of breakpoints is necessary. Similarly, the role of loss at 1p, which is also a major cytogenetic aberration in HCC, needs to be determined. Fifty HCCs were examined with the aid of 59 microsatellite markers distributed throughout both arms of chromosome 1. To detect allelic gain effectively, the cutoff value of the allelic imbalance index was set at 0.70. Alleles showing imbalance were subjected to multiplex PCR, using a retained allele as an internal control, to determine whether the imbalance was the result of chromosomal gain or loss. The SRO of the gains was defined as D1S2878-D1S2619 (1q23.-q25.3, 16.9 Mb), which involved 36 cases (72%). Gains in the number of copies of certain oncogenes within this region seemed to be critical for the pathogenesis of HCC. In contrast, the centromeric breakpoints of these gains varied, but they tended to occur mainly in the pericentromeric region (26 of 50 cases, 52%). Rearrangement of specific genes associated with the gains is unlikely. On the other hand, the SRO of deletion was defined as D1S2893-D1S450 (1p36.32-p36.22, 5.1 Mb). Four known putative tumor-suppressor genes (TP73, RIZ1, NBL1/DAN, and CDKN2C) were outside the SRO, suggesting the presence of other candidate genes with critical roles in hepatocarcinogenesis.     

Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer's disease

Collapsin response mediating protein-2 (CRMP2) has been identified as an intracellular protein mediating Semaphorin3A (Sema3A), a repulsive guidance molecule. In this study, we demonstrate that cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3beta (GSK3beta) plays a critical role in Sema3A signalling. In In vitro kinase assay, Cdk5 phosphorylated CRMP2 at Ser522, while GSK3beta did not induce any phosphorylation of CRMP2. Phosphorylation by GSK3beta was exclusively observed in Cdk5-phosphorylated CRMP2, but barely in CRMP2T509A. These results indicate that Cdk5 primarily phosphorylates CRMP2 at Ser522 and GSK3beta secondarily phosphorylates at Thr509. The dual-phosphorylated CRMP2, but not non-phosphorylated or single-phosphorylated CRMP2, is recognized with the antibody 3F4, which is highly reactive with the neurofibrillary tangles of Alzheimer's disease. 3F4 recognized the CRMP2 in the wild-type but not cdk5-/- mouse embryonic brain lysates. The phosphorylation of CRMP2 at Ser522 caused reduction of its affinity to tubulin. In dorsal root ganglion neurones, Sema3A stimulation enhanced the levels of the phosphorylated form of CRMP2 detected by 3F4. Over-expression of CRMP2 mutant substituting either Ser522 or Thr509 to Ala attenuates Sema3A-induced growth cone collapse response. These results suggest that the sequential phosphorylation of CRMP is an important process of Sema3A signalling and the same mechanism may have some relevance to the pathological aggregation of the microtubule-associated proteins.