Persistent effect of a low dose of preadministered diethylnitrosamine on the induction of enzyme-altered foci in rat liver

The effect of a low dose of preadministered diethylnitrosamine(DEN) on the induction of enzyme-altered foci in the liversof male full-grown Fischer 344 rats was studied. As a pretreatment,DEN at a dose of 10 mg/kg body wt was injected i.p. At varioustimes after DEN pretreatment a complete initiation, consistingof administration of the same dose of DEN by the same routein rats subjected to partial hepatectomy (PH), was performed,followed by application of selection pressure. Enzyme-alteredfoci stained with -glutamyltrans-peptidase (-GTP) and glutathioneS-transferase placental form (GST-P) were then assayed. Decreasesin the numbers and areas of foci in the rats which receivedsaline + PH 14 or 28 days after DEN pretreatment were observedin comparison with rats which received saline + PH immediatelyafter DEN. On the other hand, the numbers and areas of fociwere not decreased in rats which received the complete initiation,consisting of DEN + PH, at various times after DEN pretreatmentwhen compared with rats which received these at the same timeas the DEN pretreatment. This persistent effect of DEN pretreatmenton the complete initiation lasted up to 182 days after the timeof DEN pretreatment. In this experiment, GST-P was found tobe a more sensitive marker for the detection of putative preneoplasticliver-cell foci than -GTP.     

Brighton epistaxis balloon: application for cranio-facial injury

Head injury patients often complicate facial and/or multiple injuries other than cranio-cerebral insults and perplex the emergency staffs. The authors used Brighton epistaxis balloon for such patients with massive nasal bleeding and reported the utility of the balloon not only in such state of emergency but also for a few days to control the hemorrhage mostly caused by craniobasal fractures or rupture of the adjacent vessels. One hundred and twenty-nine patients were transported and hospitalized in Department of Emergency Medicine, University of Tokyo Hospital, Tokyo, Japan during the period from October, 1981 to January, 1983. Nasal bleeding was noted in 29 cases of them and the balloon was used in 10 cases, who were from 19 to 76 years of age, all males and suffered from basal fractures or craniofacial injuries. Six cases of them were also accompanied with fractures in the extremities or pelvis, hemopneumothorax and/or intra-abdominal bleeding and could not but put on "Military anti-shock trousers" for the management of hypovolemic shock, hence the nasal bleeding should be managed immediately in the emergency room. In these situations the balloon was inserted into both nasal cavities in all the patients, to control successfully the nasal hemorrhages one of which contaminated cerebrospinal fluid and three of which were sure to be pulsatile due to arterial injury. The Brighton epistaxis balloon is to be removed within twelve or twenty-four hours, but in the authors' cases the mean duration for the hemostasis was 58.9 hours for 6 survivors and 49.6 hours for all 10 cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Retrosigmoid Approach in the Supine Position Using ORBEYE: A Consecutive Series of 14 Cases

One of the merits of recently introduced exoscopes, including ORBEYE, is that they are superior to a conventional microscope in terms of ergonomic features. Taking advantage of it, the retrosigmoid approach can be performed in the supine position using ORBEYE. We report a consecutive series of 14 operations through the retrosigmoid approach in the supine position using ORBEYE. Fourteen consecutive patients who underwent surgery through the retrosigmoid approach for cerebellopontine (CP) angle lesions in the supine position using ORBEYE were targeted, and surgical outcomes and complications were examined. We evaluated the posture of the operator and the surgical field during this approach compared with those using a conventional microscope. In all 14 cases, all operative procedures were accomplished only using the ORBEYE. There were no operative complications due to this approach. Using ORBEYE, even when the angle of the operative visual axis was horizontal, the operators could manipulate in a comfortable posture. They were not forced to be in an uncomfortable posture that extended their arms, as is often the case with a conventional microscope. Therefore, they could use shorter surgical instruments. As the cerebellum shifted downward with gravity even using slight retraction during this approach, the working space of the surgical field was easily secured. Through this approach, the operators can perform stable microsurgery of CP angle lesions in a comfortable posture. This approach can reduce the burden on the operator and the patient, leading to a refined surgical procedure.     

Correlation between mutated genes and forearm deformity in patients with multiple osteochondroma

BackgroundsExostosin-1 (EXT1) and exostosin-2 (EXT2) cause multiple osteochondromas (MO). In this study, we investigated the correlation between forearm deformity and mutant EXTs in Japanese families with MO.MethodsWe evaluated 112 patients in 71 families with MO. Genomic DNA was isolated from peripheral blood leucocytes. Of these, 28 patients were selected and underwent radiography for their forearms since they had gross forearm deformities. We measured the radial articular angle (RAA), ulna variance (UV), carpal slip (CS), and percentage of radial bowing (%RB) to compare between patients with mutant EXT1 or EXT2 and those with missense or other mutations using Student's t-test.ResultsTwenty-two (78.6%) and 6 (11.4%) out of 28 patients had mutations in EXT1 and EXT2, respectively. Nine (32.1%) and 19 (67.9%) of the 28 patients had missense and other mutations, respectively. The mean age of patients with EXT1 and EXT2 were 25.9 ± 20.3 and 33.5 ± 25.4 years, respectively and those with missense mutation and other mutations were 28.7 ± 27.0 and 24.6 ± 17.0 years, respectively. There were no significant differences in RAA, UV, and RB between patients harbouring mutant EXT1 or EXT2 (RAA, 40.1 ± 8.7 and 31.5 ± 13.9°; UV, ?2.7 ± 5.7 and ?3.1 ± 3.7 mm; %RB, 8.6 ± 1.5 and 8.3 ± 2.0%). CS was significantly greater in patients with mutant EXT1 than that in those with mutant EXT2 (EXT1, 44.1 ± 16.8%; EXT2, 18.6 ± 14.0%). There were no significant differences in RAA, UV, CS and %RB between patients with missense and other mutations.ConclusionsPatients with mutant EXT1 displayed greater CS than patients with mutant EXT2, indicating that patients with MO harbouring EXT1 mutations sustain more severe ulnar drift deformities than those with EXT2 mutations.     

Risk factors for hepatocellular carcinoma at baseline and 1 year after initiation of nucleos(t)ide analog therapy for chronic hepatitis B

Nucleos(t)ide analogs (NAs) cannot completely suppress the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to identify the risk factors for HCC development in naïve CHB patients treated with current NA. Patients receiving NA (n = 905) were recruited retrospectively from the 17 hospitals of the Japanese Red Cross Liver Study Group. All treatment-naïve patients had been receiving current NA continuously for more than 1 year until the end of the follow-up. We analyzed the accuracy of predictive risk score using the area under receiver operating characteristic curve. The albumin–bilirubin (ALBI) score was significantly improved by NA therapy (−0.171 ± 0.396; p < 0.001 at Week 48). A total of 72 (8.0%) patients developed HCC over a median follow-up of 6.2 (1.03–15.7) years. An independent predictive factor of HCC development was older age, cirrhosis, lower platelet counts at baseline and ALBI score, and alpha-fetoprotein (AFP) at 1 year after NA therapy according to multivariate analysis. The accuracy was assessed using the PAGE-B, mPAGE-B, aMAP, APA-B, and REAL-B scores that included these factors. Discrimination was generally acceptable for these models. aMAP and REAL-B demonstrated high discrimination with 0.866/0.862 and 0.833/0.859 for 3- and 5-year prediction from the status of 1 year after NA therapy, respectively. Baseline age and platelet count, as well as ALBI and AFP one year after NA, were useful for stratifying carcinogenesis risk. The aMAP and REAL-B scores were validated with high accuracy in Japanese CHB patients.     

Boron neutron capture therapy: Preliminary study of BNCT with sodium borocaptate (Na2B1 2H1 1SH) on glioblastoma

To plan the optimal BNCT using BSH for glioblastoma patients, the¹⁰B concentration in tumor and blood was investigated in 11newly diagnosed glioblastoma patients. All patients received 20 mg BSH/kgbody weight 2.5–16 hrs prior to tumor removal. The quantitativedistribution of ¹⁰B was determined by prompt gamma rayspectrometry and/or -track autoradiography. ¹⁰Bdistribution in tumors was heterogeneous, ± 25% of scatteringat the microscopic level, and the distribution was also heterogeneous at thetissue level. ¹⁰B concentration in blood decreased inbi-exponential decay as a function of the time after the end of theadministration. The T/B ratio showed non-exponential increase with largevariation. The maximum T/B ratio would be around 1. The tumor/normal brain(T/N) ratio of ¹⁰B concentration was 11.0 ± 3.2. The¹⁰B content in normal brain is originated in vascular¹⁰B in parenchyma, since the ¹⁰B content innormal brain to blood (N/B ratio) being compatible with the blood content inparenchyma. These values allow for BNCT, using thermal neutrons, on braintumors located less than approximately 3.3 cm in depth from the brainsurface of neutron incidence, providing that the dose on the normalendothelium is controlled to less than the tolerance limit. In ourpreliminary study of BNCT, a 31% 3-year survival was achieved overall for 16 glioblastoma patients and a 50% 2-year survival wasachieved on 8 glioblastoma patients in our recent dose escalation studybased on these data.     

Pax-1 in the development of the cervico-occipital transitional zone

The Pax-1 gene has been found to play an important role in the development of the vertebral column. The cervico-occipital transitional zone is a specialized region of the vertebral column, and malformations of this region have frequently been described in humans. The exact embryonic border between head and trunk is a matter of controversy. In order to determine a possible role of Pax-1 in the development of the cervico-occipital transitional zone we studied the expression of this gene in a series of quail embryos and murine fetuses with in situ hybridization and immunohistochemistry. Pax-1 is expressed in all somites of the embryo, including the first five occipital ones. During embryonic days 3–5 the gene is down-regulated in the caudal direction within the first five somites, whereas more caudally Pax-1 is strongly expressed in the cells of the perinotochordal tube. In 5-day-old quail embryos, the cartilaginous anlage of the basioccipital bone has developed and there is no more expression of Pax-1 in this region. The fusion of the dens axis with the body of the axis also coincides with switching off of the Pax-1 gene. More caudally, the gene is continuously expressed in the intervertebral discs of murine embryos and therefore seems to be important for the process of resegmentation. Quail embryos do not possess permanent intervertebral discs. Hyper- or hyposegmentation defects may be explained by an over- or under-expression of Pax-1 during development. We also reinvestigated the border between the head and trunk in chick embryos by performing homotopical grafting experiments of the 5^th somite between chick and quail embryos. Grafted quail cells formed mainly the caudal end of the basioccipital bone. They were also located in the cranial half of the ventral atlantic arch, and only a few cells were found in the tip of the dens axis.     

Relationship of amyloid β/A4 protein to the neurofibrillary tangles in Guamanian parkinsonism-dementia

The Chamorro population of the island of Guam is highly susceptible to a disease called lytico-bodig (LB), wich clinically resembles a mixture of amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer disease (AD). The disease is characterized by the widespread development of neurofibrillary tangles in the central nervous system. These tangles have an immuno-histochemical profile indistinguishable from that seen in AD. We studied by immunohistochemistry the occurrence of intracellular and extracellular neurofibrillary tangles in LB in the entorhinal cortex, hippocampus and substantia nigra using antibodies to tau protein and ubiquitin. We also studied the relationship of these tangles to amyloid precursor protein (APP) and its -amyloid fragment (BAP), using multiple antibodies to BAP and other APP sequences. In advanced cases of LB, the development of neurofibrillary tangles was far more severe than in advanced cases of AD. Virtually all neurons of CA-1 and the subiculum were lost and only ghost tangles remained. In areas dominated by such extracellular tangles, BAP deposits were frequently observed developing around the fibers of ghost tangles. In some cases, the deposits covered only a few of the fibers, but in others, they seemed to envelope the complete tangle. The deposits were thiolavin S and Congo red positive, indicating that the BAP was in a consolidated form. We describe these entities as tangle-associated amyloid deposits. Such BAP deposits have previously eeen described in some cases of AD, dementia pugilistica and LB. However, we found them in all cases of LB with dementia in the hippocampal-entorhinal areas and in most cases in the substantia nigra. They do not evolve from diffuse BAP deposits since they are remote from them, and they do not trap dystrophic neurites. The fact that extracellular tangle material can act as a nidus for BAP build-up in LB suggests that further consideration needs to be given to the ways in which extracellular BAP deposits are formed.     

Suppression of conditioned fear by administration of CCKB receptor antagonist PD135158

In order to examine the involvement of CCK in the formation of anxiety, we have investigated whether CCKB receptor antagonist PD135158 suppressed conditioned fear stress. Rats were individually subjected to 30 min of inescapable electric footshock in a chamber with a grid floor. First, the rats were individually subjected to 30 min of footshock. Twenty-four h after the footshock, the rats were again placed in the chamber and observed for 5 min without shocks. PD135158 was administered 30 min before placing the rats in the chamber again. Secondly, PD135158 was administered 30 min before footshock. Thirdly, PD135158 was administered 5 min after footshock. Administration of PD135158 30 min before conditioned fear stress significantly reduced freezing behavior. Administration of PD135158 30 min before footshock also significantly reduced freezing behavior. But, administration of PD135158 5 min after footshock did not significantly reduce freezing behavior. PD135158 blocked not only the acquisition but also the expression of conditioned fear. These results suggest that the CCKB receptor might play an important role in conditioned fear stress and that it might be related to anxiety.     

Lipoprotein(a) levels and apolipoprotein(a) isoforms related to life style risk factors

Lipoprotein(a) [Lp(a)] has been considered to be a predictor of premature coronary heart disease and other cardiovascular diseases. Lp(a) levels are largely genetically determined, but the detailed mechanism of Lp(a) elevation is uncertain. We examined the association between Lp(a) levels and apolipoprotein(a) [apo(a)] phenotypes as well as that of Lp(a) level and other various conditions. The subjects were 280 healthy Japanese (102 males and 178 females) aged 39 to 70 years who were living in a rural community in 1992. We obtained apo(a) phenotypes determined by SDS-PAGE as well as Lp(a) levels and other cardiovascular risk factors. We combined apo(a) phenotypes form 4 groups according to molecular weights (from high apo(a) molecular weight to low: I, II, III and IV). Lp(a) levels were associated with apo(a) phenotype-groups, that is, they were inversely associated with apo(a) molecular weight. Small apo(a) phenotypes were less frequent than large ones. The median Lp(a) level was higher in smoking (29.2 mg/dL) than in non-smoking subjects (18.5 mg/dL) in phenotype-group III. Adjusted means of total cholesterol and fibrinogen levels in apo(a) phenotype-group IV were the highest of all phenotype-groups. Age, apo(a) phenotype, smoking status, total cholesterol and fibrinogen were positively correlated with Lp(a) levels by multiple regression analysis. Lp(a) levels were found to be mainly associated with apo(a) phenotype, but varied broadly within the same apo(a) phenotype at various conditions, such as smoking status and high total cholesterol.