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The aim of this study was to propose a risk assessment method for infectious diseases, using reclaimed water as a case study. To evaluate the infectious risk of norovirus (NoV) in various applications of the reclaimed water, five types of ultrafiltration (UF) membrane treatments were considered: (1) coagulation with low pH + UF membrane process, (2) UF membrane process alone, (3) UF + ultraviolet (UV) irradiation process, (4) UF + nanofiltration (NF) membrane process, and (5) UF + reverse osmosis (RO) membrane process. These treatments were used in a pilot plant and the NoV concentration after each treatment process was studied over the long term (2010–2014). Infectious risk was described using disability-adjusted life-year (DALY) when the reclaimed water was applied for agricultural irrigation, landscape irrigation, recreational enhancement, and toilet and urinal flushing. The results show that reclaimed water could be considered acceptable for recreational enhancement by adding a UV, an NF membrane, or an RO membrane treatment to the UF membrane treatment process.

Long-term follow-up of patients with adhesive capsulitis (AC) reveals that approximately half of them suffer from a limited range of shoulder motion, particularly external and/or internal rotation. We report the surgical technique and short-term clinical outcomes of ultrasound-guided release of the thickened coracohumeral (CH) ligament in 8 patients (9 shoulders) with AC. Passive external rotation with the arm by the side significantly increased from an average of 18° preoperatively to 47° immediately after CH ligament release. VAS and ASES scores were improved at 3months follow-up in all 9 shoulders, and maintained at 6months follow-up in 6 shoulders. No procedure-related adverse events developed over the 6-month follow-up period. Ultrasound-guided release for thickened CH ligament is a reliable and effective minimally invasive surgery for persistent limited external rotation due to AC of the shoulder.

The prognosis of high-risk retinoblastoma (RB) with extraocular disease, relapse, or invasion of the cut end of the optic nerve is extremely poor. Following the discontinuation of thiotepa production in Japan, BU- and melphalan (Mel)-based regimens have been used, followed by the standard treatment for neuroblastoma. This study retrospectively analyzed 14 high-risk RB patients who underwent high-dose chemotherapy (HDC) and hematopoietic SCT; 8 received a BU/Mel conditioning regimen and 6 received other regimens. The disease status at HDC was relapse in 8 patients and extraocular involvement in 5. All patients received peripheral blood stem cell infusion >1.5 × 10(6)/kg. Engraftment occurred within a median of 11 days (BU/Mel: 10-13, others: 9-13). Primary toxicities included mucositis (⩾grade 3) in 9 patients (4 with BU/Mel, 5 with others). Veno-occlusive disease (VOD) occurred in two 1-year-old patients in the BU/Mel group. There were no treatment-related deaths. Of 4 (2 with BU/Mel, 2 with others) patients with central nervous system (CNS) relapse after HDC, 3 died. In conclusion, the BU/Mel regimen may be feasible for high-risk RB under careful monitoring for VOD, particularly in younger patients. CNS relapse associated with a lethal prognosis occurred after all regimens; therefore, further evaluation of HDC efficacy for high-risk RB is required.

Hepatic hydrothorax is defined as the presence of a significant pleural effusion that develops in a patient with cirrhosis of the liver who does not have an underlying cardiac or pulmonary disease. There have been few published case reports dealing with hepatic hydrothorax treated surgically. Recently, we treated a patient with refractory hepatic hydrothorax by directly suturing the diaphragmatic defect during VATS. During surgery, the diaphragmatic defect was identified by using abdominal insufflation with CO(2) . The defect was sutured and the diaphragm was covered by polyglycolic acid felt and fibrin glue. After surgery, the patient's pleural effusion improved, his postoperative course was uneventful and he did not require a drainage tube at discharge.

We investigated the effects of AT-877, a Ca2+ antagonist, on rat middle-cerebral artery occlusion. All rats had 6-h ischemia, and treated animals received either 3 or 10 mg/kg AT-877 s.c. just after the occlusion. Control animals received an equal volume of the vehicle. Prior to sacrifice, significant changes in the decrease of blood pressure and the increase of plasma glucose were observed in the treated rats. Although the infarct size tended to decrease, this decrease was not significant. Only when the blood pressure- or plasma glucose-matched subgroups were compared, the infarct volume decreased significantly in the drug-treated animals. Thus, AT-877 failed to reduce ischemic brain damage unless the blood pressure or plasma glucose were controlled.

The demand for precisely controlled etching is increasing as semiconductor device geometries continue to shrink. To fulfill this demand, cyclic atomic level/layer etching will become one of the key technologies in semiconductor device manufacturing at nanometer dimensions. This review describes recent trends in semiconductor devices and some of the latest results on cyclic atomic-level etching. In particular, it focuses on two types of cyclic etching that use different heating procedures: infrared irradiation for isotropic etching and Ar+ ion bombardment for anisotropic etching. It describes how an inductively-coupled-plasma down-flow etching apparatus with infrared lamps can be used for isotropic cyclic etching. The isotropic cyclic etching of SiN involves the formation and thermal desorption of ammonium hexafluorosilicate-based surface modified layers. This method features high selectivity with respect to SiO2, atomic-level control of the amount of SiN etching, and isotropic etched features. On the other hand, the anisotropic cyclic etching with Ar+ ion bombardment uses a microwave electron-cyclotron-resonance plasma etching apparatus. The anisotropic process for poly Si is composed of cyclic repetitions of chlorine adsorption and Ar+ ion bombardment. The anisotropic process for SiN is composed of cyclic repetitions involving an adsorption step using hydrofluorocarbon chemistry and a desorption step using Ar+ ion bombardment. Potential applications of these isotropic/anisotropic cyclic etching processes are described.

Recent studies suggest that mild hypothermia significantly alleviate damage following cerebral ischemia though the precise mechanism is poorly defined. In the present study, middle cerebral artery occlusion (MCAo) was induced in Sprague-Dawley (SD) rats for 1 h followed by varying periods of reperfusion. Cerebral infarcts identified by hematoxylin & eosin (H&E) staining revealed extensive lesion in normothermic (NT) 37 degrees C and small lesion in hypothermic (HT) 33 degrees C group of rats. Immunohistochemical analysis revealed Bcl-2 was induced in many neurons of HT group, while Bax and cytochrome c was induced in few neurons. In situ detection of DNA fragmentation using 3'-OH end labeling method (terminal dUTP nick-end labelling (TUNEL)) indicated, higher number of TUNEL-positive cells in NT group, but significantly decreased in HT group. The expression pattern revealed many neurons at the penumbra region could survive in HT group whereas, many neurons are committed to die in NT group. Our results suggest that hypothermia is selectively interfering at more than one place and providing protection.

Objective: The nocturnal serum melatonin (MT) level increases after ingestion of fluvoxamine (FLU) – a selective serotonin re-uptake inhibitor (SSRI) with antidepressive properties. The mechanism behind the MT increase is unknown. Citalopram (CIT) is another SSRI. It is not known whether CIT affects the serum MT level. It may well be that these two compounds affect serum MT levels differently, inasmuch as the ways they inhibit cytochrome P 450 (CYP) enzymes in the liver differ markedly. FLU inhibits CYP1A2 potently, and to some extent also CYP2C19, whereas CIT is without such an effect. CYP enzymes are probably involved in the hepatic metabolism of MT. If FLU, but not CIT, inhibits liver enzymes involved in the metabolism of MT, different serum MT concentrations should probably ensue. The objective of this investigation was to test this hypothesis. Methods: Seven healthy subjects participated in three different experiments, which were performed in random order 6–8 days apart. In experiment A, placebo was given, in experiment B 40 mg CIT and in experiment C 50 mg FLU. All doses were given orally at 1600 hours. Serum MT concentrations were determined at regular intervals between 1600 hours and noon next day (20 h). Plasma concentrations of CIT were measured repeatedly in experiment B, and plasma FLU concentrations in experiment C. MT areas under the curve representing the 20-h period (MT-AUC0–20) were compared in the three experiments, and differences were statistically evaluated. Results: FLU augmented the MT-AUC0–20 by a factor of 2.8 compared with the effect of placebo (P

Our aim was to study the relationship between cerebral blood flow (CBF) responses to induced hypotension and to CO2 inhalation in patients with occlusive disease of the carotid or middle cerebral arteries. In 13 patients (8 men, 5 women) aged 31-73 years (mean +/- 1 SD = 63.2 +/- 10.6), regional CBF values during the resting state (CBFrest), 7% CO2 inhalation (CBFhypercapnia), and hypotension induced by 10-20 microg/kg/min intravenous trimethaphan (CBFhypotension) were measured using positron-emission tomography (PET) with H2(15)O. The % CBF change during induced hypotension (% CBFhypotension) was defined as (CBFhypotension - CBFrest)/CBFrest multiplied by 100. The % CBF change during CO2 inhalation (% CBFhypercapnia) was defined as (CBFhypercapnia - CBFrest)/CBFrest/mm Hg arterial partial pressure of CO2 x 100. We defined symptomatic hemispheres as those with a stenotic or occlusive lesion with neurological symptoms or signs and asymptomatic hemispheres as those which had a similar lesion and/or were influenced by the collateral flow pattern without neurological symptoms. In the territory of the occlusive lesion, % CBFhypotension correlated significantly with % CBFhypercapnia (r = 0.793, P0.002) in the symptomatic hemispheres. In the brain regions in which trimethaphan did not induce a reduction in CBF. % CBFhypercapnia was 6.13 +/- 1.79. In those in which % CBFhypotension ranged from 0 to -5, from -5 to -10, and more than -10%, % CBFhypercapnia was 4.05 +/- 1.99, 3.21 +/- 1.17, and 1.73 +/- 1.61, respectively, with significant differences between each pair of groups. In the asymptomatic hemispheres, % CBFhypotension also correlated with % CBFhypercapnia (r = 0.979, P0.0001). Failure to maintain CBF during induced hypotension was associated with diminished cerebrovascular vasoreactivity to hypercapnia in patients with arterial disease. This may indicate that failure of autoregulation can be assessed by the CBF response to both induced hypotension and CO2 inhalation. From the technical point of view, estimation of the CO2 response may be useful for assessing failure of autoregulation.

We developed a rat model of limb lengthening to study the basic mechanism of distraction osteogenesis, using a small monolateral external fixator. In 11-week-old male rats we performed a subperiosteal osteotomy in the midshaft of the femur with distraction at 0.25 mm every 12 hours from seven days after operation. Radiological and histological examinations showed a growth zone of constant thickness in the middle of the lengthened segment, with formation of new bone at its proximal and distal ends. Osteogenic cells were arranged longitudinally along the tension vector showing the origin and the fate of individual cells in a single section. Typical endochondral bone formation was prominent in the early stage of distraction, but intramembraneous bone formation became the predominant mechanism of ossification at later stages. We also showed a third mechanism of ossification, ‘transchondroid bone formation’. Chondroid bone, a tissue intermediate between bone and cartilage, was formed directly by chondrocyte-like cells, with transition from fibrous tissue to bone occurring gradually and consecutively without capillary invasion. In situ hybridisation using digoxigenin-11-UTP-labelled complementary RNAs showed that the chondroid bone cells temporarily expressed type-II collagen mRNA. They did not show the classical morphological characteristics of chondrocytes, but were assumed to be young chondrocytes undergoing further differentiation into bone-forming cells. We found at least three different modes of ossification during bone lengthening by distraction osteogenesis. We believe that this is the first report of such a rat model, and have shown the validity of in situ hybridisation techniques for the study of the cellular and molecular mechanisms involved in distraction osteogenesis.

直腸癌治療の変遷を, 外科的治療とその予後を中心に1975年から1983年を前期, 1984年から1990年を後期と分類して検討した. 外科的治療は拡大郭清による根治手術の確立と括約筋温存を主とした機能温存手術が, 近年の重要な課題であった. 根治度AおよびBが施行された直腸癌においては前期に比し後期のほうが有意に生存率の向上が認められ, とくに根治度Aのstage別にはIII aで有意に改善されていた. この結果は系統的なリンパ節郭清など術式の進歩や転移巣の積極的な切除に帰することが大きいと考えられた. 拡大郭清により直腸癌のリンパ節転移様式が明らかになるにつれて, 側方郭清の重要性が指摘されて積極的に行なわれるようになった. しかし, 側方郭清によって明らかな予後の改善は得られず方法と適応について課題が残されている. 一方, 括約筋温存手術の普及もめざましく, 後期には下部直腸癌の半数以上に本法が施されるようになった. 括約筋温存手術は従来の腹会陰式直腸切断術に比し予後の低下は認められず, さらに術式の改良によって本法の増加と適応の拡大が見込まれる. 今後は, 予後の改善をみなかったstage III bとくに側方移転陽性例に対する集学的治療の確立や, 郭清と自律神経温存の両立などが直腸癌治療の主たる課題となろう.

Novel hybrid-waveguide EMLs for 100 Gb/s CFP2 transceivers have been demonstrated. They were operated with low modulation voltage below 1.5 Vpp and under high chip temperature of 55°C at 28 Gb/s satisfying 100GbE and OTU4 specs.

Hepatic hydrothorax is defined as the presence of a significant pleural effusion that develops in a patient with cirrhosis of the liver who does not have an underlying cardiac or pulmonary disease. There have been few published case reports dealing with hepatic hydrothorax treated surgically. Recently, we treated a patient with refractory hepatic hydrothorax by directly suturing the diaphragmatic defect during VATS. During surgery, the diaphragmatic defect was identified by using abdominal insufflation with CO(2) . The defect was sutured and the diaphragm was covered by polyglycolic acid felt and fibrin glue. After surgery, the patient's pleural effusion improved, his postoperative course was uneventful and he did not require a drainage tube at discharge.

Theoretical and experimental analysis of turbulent upward flame spread along a vertical solid is presented A conventional flame spread model based on a linearized flame height approximation is generalized to incorporate burnout effects. The model is verified against full-scale flame spread tests using material heat release data obtained from intermediate-scale tests in which the time history of surface heat flux during the flame spread tests was reproduced.

Clinical characteristics and the outcomes of 50 patients with confirmed subarachnoid haemorrhage (SAH) of unknown aetiology were evaluated. Twenty-nine of these patients were interviewed with a mean follow-up of 7.7 years. Seven patients experienced early rebleeding during hospitalization, and one patient experienced late rebleeding during the follow-up period. On admission to the hospital the consciousness level was "clear" in 43 of the patients, "drowsy" in 6, and "semicomatose" in only 1. Of 10 patients who underwent computerized tomography (CT) within 3 days after SAH, 6 showed no abnormal CT findings and 3 had mild subarachnoid blood. Another patient showed severe SAH. Neurological deficit due to symptomatic vasospasm persisted in only 1 case. Two patients died after re-bleeding during hospitalization, and two others died during the follow-up, thereby representing an overall mortality rate of 8%. Of the latter cases, one died of an unrelated disease, and the other died suddenly from an unknown cause. The remaining forty-six patients (92%) had a good outcome. These results confirm previously reported clinical characteristics, namely that the symptoms of the majority of such cases are mild, the incidence of symptomatic vasospasm is rare, the risk of late re-bleeding is very low (less than 1% per year), and the prognosis is good. The CT findings suggest that some of these features resulted from only mild SAH. Thus, SAH of unknown aetiology seems to be a disease entity with a good prognosis.

A lane recognition system has been developed with a transputer network. The system includes two algorithms one for the lane recognition and one for the vehicle location recognition in relation to the lane. Hough transform is used to fit the extracted numerical white line data to a straight line for the lane boundary. The location of the vehicle is identified in relation to the lane which is expressed as a triangle that consists of two white lines being recognized and the lower side of the image frame. >

A meander-line antenna consisting of two strips (two-strip MLA) is applied to a conducting box as a handset model in order to increase the bandwidth of a built-in antenna. The analysis of an MLA mounted on a conducting box leads to its resonant frequency f/sub r/, and radiation resistance R/sub r/ at f/sub r./ Using the two-strip MLA with balance mode impedance, broadbanding of the antenna in the impedance characteristics is considered.

Mild hypothermia is thought to have a brain protective effect to pathophysiological conditions, which are caused by severe brain damage including brain injury and cerebral stroke. In this paper, general aspects of this treatment as history, pathophysiological effect, and problems are summarized. Also, the clinical effects of hypothermic therapy for a subarachnoid hemorrhage are reviewed. Main targets of the therapy for this disease are severe primary brain damage caused by the attack itself and secondary ischemic brain damage after delayed vasospasm. But even now, there are no fully established data about the effect of hypothermia at such conditions after subarachnoid hemorrhage. The results of our study of cerebral blood flow and cerebral oxygen metabolism using positron emission tomography are presented to show the physiological effect of hypothermia on human brain after severe brain damage caused by subarachnoid hemorrhage. In conclusion, effect of hypothermia on subarachnoid hemorrhage is not confirmed yet and reported data is limited, so that additional studies, especially controlled studies, would be recommended.

Both haloperidol and risperidone have been widely used in the treatment of schizophrenia. Because of wider therapeutic spectrum of risperidone, switching from haloperidol to risperidone is recommended in patients who do not sufficiently respond to haloperidol. The present study investigated the correlation between the steady-state plasma concentrations of haloperidol and risperidone together with the effects of CYP2D6 status on the steady-state kinetics of both drugs. Subjects were 22 schizophrenic inpatients. Eleven patients first received risperidone 6 mg/day and then haloperidol 12 mg/day, while the remaining 11 patients received these two treatments in the opposite sequence. The steady-state plasma concentrations of risperidone, 9-hydroxyrisperidone, haloperidol, and reduced haloperidol were measured after the subjects had been on the treatment for at least 2 weeks, and CYP2D6 genotypes were identified in all subjects. Neither the correlation between the steady-state plasma concentrations of haloperidol and those of risperidone (r = 0.061, ns) nor the active moiety (sum of concentration of risperidone and 9-hydroxyrisperidone) of risperidone (r = 0.141, ns) was significant. The mean (+/- SD) plasma concentration of risperidone in patients with mutated allele(s)for CYP2D6 was significantly higher than those without mutated allele (1.5 +/- 0.7 vs. 8.5 +/- 11.0, p0.05), while such a tendency for haloperidol was not observed. The present study suggests that the steady-state plasma concentration of risperidone is not predicted from that of haloperidol in the same individual, probably because of the much greater involvement of CYP2D6 in the metabolism of risperidone than in that of haloperidol.

Reduction of mechanical stress on bone inhibits osteoblast-mediated bone formation and accelerates osteoclast-mediated bone resorption, and leads to what has been called disuse osteoporosis. Prolonged therapeutic bed rest, immobilization due to motor paralysis from injury of the central nervous system or peripheral nerves, application of cast to treat fractures, a common causes of disuse osteoporosis. Imaging diagnosis shows coarse trabecular pattern and thinning of cortical bones. Bone metabolism markers have been used to evaluate bone metabolism. From the viewpoint of bone metabolism, antiresorptive agents should be administered to inhibit bone resorption. Rehabilitation, including bed positioning, therapeutic exercise and electrical stimulation, should be prescribed to subject the atrophied bone to an appropriate level of mechanical stress. In spite of these aggressive and continuous treatments, most cases of disuse osteoporosis require a long time for bone to recover its bone mineral density and strength. Hence, we have to keep in mind that there are no treatments better than prophylaxis of disuse osteoporosis.

Chordomas are histologically benign tumours which are locally invasive. We present an unusual case of recurrent chordoma with subcutaneous implantation and widespread meningeal dissemination after surgery. Contrast-enhanced MRI was useful for determining the extent of the tumour.

The antipsychotic agent risperidone, is metabolized by different cytochrome P-450 (CYP) enzymes, including CYP2D6, to the active 9-hydroxyrisperidone, which is the major metabolite in plasma. Two enantiomers, (+)- and (-)-9-hydroxyrisperidone might be formed, and the aim of this study was to evaluate the importance of CYP2D6 and CYP3A4/CYP3A5 in the formation of these two enantiomers in human liver microsomes and in recombinantly expressed enzymes. The enantiomers of 9-hydroxyrisperidone were analyzed with high pressure liquid chromatography using a chiral alpha-1 acid glycoprotein column. A much higher formation rate was observed for (+)-9-hydroxyrisperidone than for (-)-9-hydroxyrisperidone in microsomes prepared from six individual livers. The formation of (+)-9-hydroxyrisperidone was strongly inhibited by quinidine, a potent CYP2D6 inhibitor, whereas ketoconazole, a CYP3A4 inhibitor, strongly inhibited the formation of (-)-9-hydroxyrisperidone. Recombinant human CYP2D6 produced only (+)-9-hydroxyrisperidone, whereas a lower formation rate of both enantiomers was detected with expressed CYP3A4 and CYP3A5. In vivo data from 18 patients during treatment with risperidone indicate that the plasma concentration of the (+)-enantiomer is higher than that of the (-)-enantiomer in extensive metabolizers of CYP2D6. These findings clearly suggest that CYP2D6 plays a predominant role in (+)-9-hydroxylation of risperidone, the major metabolic pathway in clinical conditions, whereas CYP3A catalyzes the formation of the (-)-9-hydroxymetabolite. Further studies are required to evaluate the pharmacological/toxic activity of both enantiomers.

Combined treatment of interleukin-2 (IL-2), 5-fluorouracil (5-FU) and mitomycin C (MMC) is reported to be effective against hepatic metastasis of colon carcinoma. To clarify this modality, we investigated lymphokine activated killer (LAK) activity of human peripheral lymphocytes on colon cancer cell lines by 51Cr release assay. LAK activity against Colo 205 cells by untreated lymphocytes was 12%, which increased to 25% upon the addition of 5-FU, but remained unchanged upon the addition of MMC. The combined antitumour activity of MMC or 5-FU with or without LAK-supernatant was evaluated by MTT assay; antitumour activity of MMC was increased by the addition of LAK-supernatant. The concentration of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) was increased in LAK-supernatant, and the antitumour activity of combined IFN-gamma and MMC was synergistic. The mechanism of this therapy seemed to be associated with both increased LAK activity by 5-FU and increased antitumour activity of MMC with IFN-gamma.

Cbfa1, a transcription factor that belongs to the runt-domain gene family, plays an essential role in osteogenesis. Cbfa1-deficient mice completely lacked both intramembranous and endochondral ossification, owing to the maturational arrest of osteoblasts, indicating that Cbfa1 has a fundamental role in osteoblast differentiation. However, Cbfa1 was also expressed in chondrocytes, and its expression was increased according to the maturation of chondrocytes. Terminal hypertrophic chondrocytes expressed Cbfa1 extensively. The significant expression of Cbfa1 in hypertrophic chondrocytes was first detected at embryonic day 13.5 (E13.5), and its expression in hypertrophic chondrocytes was most prominent at E14.5-16.5. In Cbfa1-deficient mice, whose entire skeleton was composed of cartilage, the chondrocyte differentiation was disturbed. Calcification of cartilage occurred in the restricted parts of skeletons, including tibia, fibula, radius, and ulna. Type X collagen, BMP6, and Indian hedgehog were expressed in their hypertrophic chondrocytes. However, osteopontin, bone sialoprotein, and collagenase 3 were not expressed at all, indicating that they are directly regulated by Cbfa1 in the terminal hypertrophic chondrocytes. Chondrocyte differentiation was severely disturbed in the rest of the skeleton. The expression of PTH/PTHrP receptor, Indian hedgehog, type X collagen, and BMP6 was not detected in humerus and femur, indicating that chondrocyte differentiation was blocked before prehypertrophic chondrocytes. These findings demonstrate that Cbfa1 is an important factor for chondrocyte differentiation.

A combined antitumor activity of mitomycin C (MMC) and interferon gamma-1a (IFN-gamma) was evaluated to be synergistic by the 3-(4, 5-dimethylthiazol-2yl)-2,5-diphenyl-2H tetrazolium bromide assay and human tumor xenografts/severe combined immunodeficient (SCID) mouse system using colon cancer cell lines. The experimental metastasis of WiDr cells in SCID mouse was inhibited by MMC and IFN-gamma with their synergism. Intracellular uptake of MMC in WiDr cells in vitro was significantly increased by IFN-gamma, suggesting the mode of synergism of these agents. This model may also partly explain the antitumor activity of combined MMC, 5-fluorouracil and interleukin-2 treatment on hepatic metastasis of colon cancer.

The CYP2D6*10 (*10) allele that causes decreased CYP2D6 activity is present in Asians with a high frequency of about 50%. In this study we studied the effects of the *10 allele on the steady-state plasma concentrations (Css) of haloperidol and reduced haloperidol.The subjects were 67 Japanese inpatients with schizophrenia who had only the wild-type or *10 alleles. Thirty-four patients were homozygous for the wild-type allele, and 26 were heterozygous and 7 were homozygous for the *10 allele. All patients had been receiving 12 mg/day haloperidol for at least 2 weeks. Plasma concentrations of haloperidol and reduced haloperidol were measured by HPLC.The mean +/- SD values of haloperidol Css in the patients with 0, 1, and 2 *10 alleles were 22.8+/-11.0, 30.1+/-10.6, and 31.2+/-21.2 nmol/L, respectively, and those values for reduced haloperidol were 6.1+/-2.9, 9.5+/-3.7, and 9.9+/-6.2 nmol/L, respectively. The mean haloperidol Css was significantly (P.05) higher in the patients with 1 *10 allele than in those with no *10 alleles. The mean Css of reduced haloperidol was significantly (P.05) higher in the patients with 1 and 2 *10 alleles than in those with no *10 alleles.This study suggests that the *10 allele plays an important role in controlling the Css of both haloperidol and reduced haloperidol, especially in Asian subjects.

OBJECTIVES: Anticipation has been linked to unstable trinucleotide repeats in many neurological disorders. We examined the hypothesis of genetic anticipation in familial cavernous angioma (FCA) of the central nervous system. MATERIAL AND METHODS: The mean ASO of affected individuals was compared between successive generations in 55 families. Intergenerational pair-wise comparisons were employed to avoid several ascertainment biases. Regarding severity of disease both type of manifestation and number of cavernous angiomas were compared between generations. RESULTS: The mean ASO decreased significantly both from the first to the second generation (31.6 vs 17.8 years; P = 0.000) and from the second to the third generation (17.8 vs 6.7 years; P = 0.002). The pair-wise comparisons also showed significantly earlier ASO. No clear evidence for anticipation with regard to severity of disease was found. CONCLUSIONS: Molecular genetic studies will determine whether trinucleotide repeats are the underlying mechanism for our observation of anticipation in FCA.

Hypophosphatasia is associated with a defect of the tissue-nonspecific alkaline phosphatase (TNSALP) gene. The onset and clinical severity are usually correlated in hypophosphatasia; patients with perinatal hypophosphatasia die approximately at the time of birth. In contrast, we describe a male neonatal patient with hypophosphatasia who had no respiratory problems and survived. He was compound heterozygous for the conversion of Phe to Leu at codon 310 (F310L) and the deletion of a nucleotide T at 1735 (delT1735), causing the frame shift with the result of the addition of 80 amino acids at the C-terminal of the protein. Because the C-terminal portion of TNSALP is known to be important for TNSALP to bind to the plasma membrane, the localization of wild-type and mutated TNSALP proteins was analyzed using green fluorescent protein chimeras. The expression vectors containing the complementary DNA of fusion proteins consisting of signal peptide, green fluorescent protein, and wild-type or mutated TNSALP, caused by delT1735 or F310L mutation, were introduced transiently or stably in Saos-2 cells. The delT1735 mutant failed to localize at the cell surface membrane, whereas the wild-type and the F310L mutants were located in the plasma membrane and cytoplasm. The assay for enzymatic activity of TNSALP revealed that the delT1735 mutant lost the activity and that the F310L mutant exhibited an enzymatic activity level that was 72% of the normal level. The F310L mutation was also detected in another neonatal patient with relatively mild (nonlethal) hypophosphatasia (reported in J Clin Endocrinol Metab, 81:4458-4461, 1996), suggesting that residual ALP activity of the F310L mutant contributes to the less severe phenotype. The patient is unique, with respect to a discrepancy between onset and clinical severity in hypophosphatasia.

The grading scale for subarachnoid hemorrhage (SAH) with inter-grade outcome differences is essential for evaluating the effectiveness of newly developed therapeutic modalities. Although Hunt's grade and WFNS scale have been widely used, these grading scales do not meet this requirement. We previously proposed a revised WFNS scale based solely on the Glasgow Coma Scale (GCS) that has intergrade outcome differences of high-level significance. The Japan Coma Scale (JCS) has been long and widely used in Japan. The purpose of this study is to show whether it is possible to determine a reasonable SAH grading scale based on the JCS and to show a way to determine an SAH grading scale.We retrospectively analyzed 1398 consecutive cases of aneurysmal SAH operated on within Day 7 of the latest onset. The preoperative JCS and GCS were evaluated just before the surgery and the Glasgow Outcome Scale (GOS), analyzed with numerical transformation (1 = dead to 5 = good recovery), was estimated at 6 months after the onset. All 510 possible combinations of scores of JCS were statistically tested under the following 2 assumptions; (1) JCS = 0 and JCS = 100 fall into a single independent grade. (2) No other single JCS score should fall into a single grade.The outcome differences between JCS 0 and 1, and 100 and 200 are significant. The outcome difference between JCS 30 and 100 is relatively higher than any other set of 2 scores of JCS. Only 5 combinations are practical among the candidates to be analyzed. Out of 510 combinations, the following combination shows the highest inter-grade outcome differences; I (JCS = 0, n = 375, mean GOS = 4.78) II (JCS = 1, 2; n = 310; mean GOS = 4.47) III (JCS = 3-30; n = 476; mean GOS = 3.96) IV (JCS = 100; n = 96; mean GOS = 3.10) V (JCS = 200, 300; n = 141; mean GOS = 2.33). In JCS, the mean outcome of JCS = 3 is worse than those of JCS = 10, 20, and 30. The outcome difference between JCS 0 and 1 is only significant in patients over 60 years old.Taking all the 510 possible combinations of JCS into consideration, we obtained a reasonable combination containing 5 grades. Although this grading scale showed good inter-grade outcome differences, JCS is not preferable to GCS as a consciousness evaluation system in the acute phase of SAH. We emphasize the importance of this way to determine a grading scale with a combinatorial approach, which can be applicable for re-evaluating the grading scales in the future.

To investigate osteoclastogenesis in bone marrow cells from patients with various pathogenic backgrounds known to induce osteoporosis, to identify specific factors that may cause generalized osteoporosis in patients with rheumatoid arthritis (RA).Bone marrow blood was obtained from 59 women, 36 with RA and 23 without RA. Patients with RA were classified as severe (26) and mild RA (10: 5 patients with and 5 without corticosteroid therapy). The non-RA subjects were divided into 3 groups, premenopausal (7), menopausal (8), and elderly (8). As a marker of bone resorption, the pyridinoline crosslinked telopeptide domain of type I collagen (ICTP) concentration in the bone marrow supernatant was measured by radioimmunoassay. The bone marrow cells were cultured 14 days in the presence or absence of autologous bone marrow supernatant; then the number of tartrate resistant acid phosphatase positive multinucleated cells (TRAP positive MNC) was counted as an indicator of osteoclastogenesis.ICTP concentration of the bone marrow supernatant and the number of TRAP positive MNC showed remarkable enhancement in some patients with severe RA, but these features were not observed in the 3 control groups.Increased bone resorption and enhanced osteoclastogenesis were specifically observed in the iliac bone marrow of patients with RA, especially those with severe RA. These phenomena can be considered to accompany generalized osteoporosis in RA.

In seven patients who underwent ventricular puncture as a procedure for either continuous ventricular drainage or ventriculoperitoneal shunt between April 1983 and December 1988, the changes between pre- and postoperative regional cerebral blood flow (rCFB) and the regional cerebral metabolic rate of oxygen (rCMRO2) around the regions along the tract of puncture were evaluated. In each patients, rCBF and rCMRO2 were measured using Positron Emission Tomography (PET) by the steady state method. The regions of interest (ROIs) with diameters of 2cm were set as follows: The gray matter (PSG) and white matter (PSW) along the tract of the puncture, the same regions on the opposite side (OSG and OSW) and the bilateral motor cortex (PSM and OSM) as control. All changes, as well as lateralities at each region were studied. In 4 of 7 patients long term follow up PET studies (mean = 657 days after the procedure) were performed. After the procedure values of rCBF significantly increased in OSG and OSW (p0.05) and tended to increase in PSG and PSW. But compared with OSG and OSW, the degree of increase in PSG and PSW were suppressed. In the motor cortex evident changes were not recognized. Lateralities between PSG and OSG and those between PSW and OSW tended to increase after procedure. In long term follow up studies the values further increased in all regions including PSG and PSW and lateralities tended to decrease, but suppression of improvement around the puncture site was prolonged. The changes of rCMRO2 had the same tendency but it was not significant. The rCBF and rCMRO2 generally increased following the procedure accompanying ventricular puncture. Perhaps this was because of adjustment of increased intracranial pressure or cerebrospinal fluid circulation. But the degree of improvement around the puncture site was suppressed. Minor brain injury caused by the procedure was considered to be the cause of reduction of improvement of cerebral blood flow and cerebral oxygen metabolism.

Ten human colorectal cancer (CRC) cell lines were implanted orthotopically into the ceca and also into the livers, muscles and peritoneal cavities of SCID mice in order to analyze the characteristics regulating metastatic behaviors of CRCs. All the CRC cell lines formed tumors in the muscle and cecum, but they could be classified into two groups: (1) six cell lines with high tumorigenicity in the liver (HTLs) forming differentiated tumors, and (2) four with no tumorigenicity in the liver (NTLs) forming poorly differentiated tumors in SCID mice. After orthotopic implantation, NTLs never metastasized to the liver, whereas HTLs did. Therefore, intrahepatic tumorigenicity and differential status were closely associated with liver metastasis whereas differentiation was not associated with lung metastasis. The 6 HTLs demonstrated an inverse correlation between liver metastases and peritoneal dissemination, and immunohistochemistry indicated expression of sLeX, CA19-9 and carcinoembryonic antigen in tumors which correlated well with the liver metastatic rate. We found a strong correlation between liver metastasis and intrahepatic tumorigenicity and could reproduce the clinical correlations between the pattern of the metastatic spread and the differentiation phenotype of CRC in vivo. We consider further examination using this model will be useful for analyzing the complex mechanisms involved in clinically metastasizing CRCs.

Aberrant tyrosine phosphorylation of beta-catenin inactivates the E-cadherin-mediated cell adhesion and invasion suppressor system in cancer cells. Elucidation of the association between beta-catenin and c-erbB-2 protein prompted us to investigate whether interference with this interaction can change the invasive phenotype. In a human gastric cancer cell line, TMK-1, N-terminally deleted beta-catenin, which binds to c-erbB-2 but not to cadherin, inhibited the association between endogenous beta-catenin and c-erbB-2 protein, and suppressed the tyrosine phosphorylation of beta-catenin. Cells expressing truncated beta-catenin exhibited markedly reduced invasiveness in vitro and peritoneal metastasis in vivo, and developed an epithelial morphology. These results suggest that tyrosine phosphorylation of beta-catenin regulated by c-erbB-2 protein may play an important role in the invasion, metastasis and morphogenesis of cancer cells and that inhibition of the aberrant tyrosine phosphorylation of beta-catenin effectively prevents invasion and metastasis of cancer cells.