Nagoya City University Hospital

The 'Clinical Guidelines for Obstetrical Practice, 2011 edition' were revised and published as a 2014 edition (in Japanese) in April 2014 by the Japan Society of Obstetrics and Gynecology and the Japan Association of Obstetricians and Gynecologists. The aims of this publication include the determination of current standard care practices for pregnant women in Japan, the widespread use of standard care practices, the enhancement of safety in obstetrical practice, the reduction of burdens associated with medico-legal and medico-economical problems, and a better understanding between pregnant women and maternity-service providers. The number of Clinical Questions and Answers items increased from 87 in the 2011 edition to 104 in the 2014 edition. The Japanese 2014 version included a Discussion, a List of References, and some Tables and Figures following the Answers to the 104 Clinical Questions; these additional sections covered common problems and questions encountered in obstetrical practice, helping Japanese readers to achieve a comprehensive understanding. Each answer with a recommendation level of A, B or C was prepared based principally on 'evidence' or a consensus among Japanese obstetricians in situations where 'evidence' was weak or lacking. Answers with a recommendation level of A or B represent current standard care practices in Japan. All 104 Clinical Questions and Answers items, with the omission of the Discussion, List of References, and Tables and Figures, are presented herein to promote a better understanding among English readers of the current standard care practices for pregnant women in Japan.

PURPOSE: The purpose of this study was to determine the physiological responses of elderly women to a well-rounded exercise program performed in water (WEX). METHODS: The participants (60-75 yr of age) were randomly divided into a training (TR) group (N = 15) and a control group (N = 15). The TR group participated in a 12-wk supervised WEX program, 70 min x day(-1), 3 d x wk(-1). The WEX consisted of 20 min of warm-up and stretching exercise, 10 min of resistance exercise, 30 min of endurance-type exercise (walking and dancing), and 10 min of cool-down exercise. RESULTS: The WEX led to an increase (P < 0.05) in peak VO2 (12%) and VO2 at lactate threshold (20%). Muscular strength evaluated by a hydraulic resistance machine increased significantly at resistance dial setting 8 (slow) for knee extension (8%), knee flexion (13%), chest press (7%) and pull (11%), shoulder press (4%) and pull (6%), and back extension (6%). Vertical jump (9%), side-stepping agility (22%), trunk extension (11%), and FEV1.0 (7%) also increased significantly. There was a significant decrease in skin-fold thickness (-8%), low-density lipoprotein (LDL) cholesterol (-17%), and total cholesterol (-11%). There were no significant changes in these variables in the control group. CONCLUSION: These results indicate that WEX elicits significant improvements in cardiorespiratory fitness, muscular strength, body fat, and total cholesterol in older adult women. Water-based exercise appears to be a very safe and beneficial mode of exercise that can be performed as part of a well-rounded exercise program.

PURPOSE: The structure and function of chromatin can be altered by modifications to histone. Histone acetylation in vivo is a dynamic reversible process governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC6 is a unique isoform among the HDACs, and a gene expression pattern study, with cDNA microarray in MCF-7 cells, showed the HDAC6 gene to be late responsive, estrogen induced, and up-regulated. This led us to hypothesize that there was a link between levels of HDAC6 expression and the metastatic potential of breast cancer and also, therefore, the prognosis of these patients. EXPERIMENTAL DESIGN: In the present study, the level of HDAC6 mRNA expression was analyzed with quantitative real-time reverse transcription-PCR, in 135 female patients with invasive breast cancer. HDAC6 protein expression was also determined by immunohistochemistry. An association was sought between HDAC6 expression and various clinicopathologic factors. RESULTS: HDAC6 mRNA was expressed at significantly higher levels in breast cancer patients with small tumors measuring less than 2 cm, with low histologic grade, and in estrogen receptor alpha- and progesterone receptor-positive tumors. By contrast, no relationship was found between HDAC6 mRNA expression and any of the other clinicopathologic factors, namely, age, menopausal status, and axillary lymph node involvement. Patients expressing high levels of HDAC6 mRNA and protein had a better prognosis than those expressing low levels, in terms of disease-free survival. However, multivariate analysis failed to show that HDAC6 mRNA and protein are an independent prognostic factors for disease-free survival and overall survival. Furthermore, the patients with high levels of HDAC6 mRNA tended to be more responsive to endocrine treatment than those with low levels. Specific HDAC6 staining was found in the nucleus of some normal epithelial cells and in the cytoplasm of the majority of cancer cells. Although postmenopausal patients showed higher HDAC6 protein expression, there were no relationship between protein expression and any other clinicopathologic factors. CONCLUSIONS: We conclude that the levels of HDAC6 mRNA expression may have potential both as a marker of endocrine responsiveness and also as a prognostic indicator in breast cancer. Additional investigations are warranted concerning the relationship between HDAC6 expression and response to endocrine therapy.

OBJECTIVE: To investigate the effects of valacyclovir and prednisolone in comparison with those of placebo and prednisolone for the treatment of Bell's palsy, excluding zoster sine herpete. STUDY DESIGN: Prospective, multicenter, randomized placebo-controlled study. SETTING: Six academic tertiary referral centers. PATIENTS: Ultimately, 221 patients with Bell's palsy who were treated within 7 days of the onset. Serological and polymerase chain reaction examinations were performed to distinguish Bell's palsy from zoster sine herpete. INTERVENTION: The patients were treated with either valacyclovir (dosage, 1,000 mg/d for 5 days) plus prednisolone (VP [n = 114]) or placebo plus prednisolone (PP [n = 107]) administered orally. MAIN OUTCOME MEASURE: Recovery from the palsy was defined as a score higher than 36 using Yanagihara 40-point scoring system without facial contracture or synkinesis. The patients were followed up until complete recovery occurred or for more than 6 months in cases with a poor prognosis. RESULTS: The overall rate of patient recovery among those treated with VP (96.5%) was significantly better (p < 0.05) than the rate among those treated with PP (89.7%). The rate of patient recovery was also analyzed by classifying the initial severity of facial palsy. In cases of complete or severe palsy, the rates of patients treated with VP and PP who recovered were 95.7% (n = 92) and 86.6% (n = 82), respectively; the recovery rate for treatment with VP was significantly better than that with PP (p < 0.05). CONCLUSION: The valacyclovir and prednisolone therapy was more effective in treating Bell's palsy, excluding zoster sine herpete, than the conventional prednisolone therapy. To our knowledge, this is the first controlled study of an antiviral agent in the treatment of a sufficient number of Bell's palsy cases based on an etiologic background.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by congenital malformation of the great toes and by progressive heterotopic bone formation in muscle tissue. Recently, a mutation involving a single amino acid substitution in a bone morphogenetic protein (BMP) type I receptor, ALK2, was identified in patients with FOP. We report here that the identical mutation, R206H, was observed in 19 Japanese patients with sporadic FOP. This mutant receptor, ALK2(R206H), activates BMP signaling without ligand binding. Moreover, expression of Smad1 and Smad5 was up-regulated in response to muscular injury. ALK2(R206H) with Smad1 or Smad5 induced osteoblastic differentiation that could be inhibited by Smad7 or dorsomorphin. Taken together, these findings suggest that the heterotopic bone formation in FOP may be induced by a constitutively activated BMP receptor signaling through Smad1 or Smad5. Gene transfer of Smad7 or inhibition of type I receptors with dorsomorphin may represent strategies for blocking the activity induced by ALK2(R206H) in FOP.

BACKGROUND: Previously, we demonstrated that indoxyl sulphate (IS), a uraemic toxin, induced aortic calcification in hypertensive rats. This study aimed to determine if IS induces the production of reactive oxygen species (ROS) and the expression of osteoblast-specific proteins in human aortic smooth muscle cells (HASMCs). METHODS: In order to achieve these goals, HASMCs were incubated with IS. ROS were detected using probes with a fluorescence detector. The expression of alkaline phosphatase (ALP), osteopontin and organic anion transporters (OAT1, OAT3) was studied by western blotting. The expression of core binding factor 1 (Cbfa1), ALP, osteopontin and NADPH oxidases (Nox1, Nox2 and Nox4) was analysed by reverse transcription-polymerase chain reaction (RT-PCR). Knockdown of Nox4 was performed by RNA interference (RNAi). RESULTS: IS induced ROS generation and the expression of Nox4, Cbfa1, ALP and osteopontin in HASMCs. A NADPH oxidase inhibitor and antioxidants inhibited IS-induced ROS production and mRNA expression of Cbfa1 and ALP. Knockdown of Nox4 using small interfering RNA (siRNA) inhibited IS-induced ROS production and mRNA expression of Cbfa1, ALP and osteopontin. OAT3 was expressed in HASMCs. CONCLUSIONS: IS induces ROS generation by upregulating Nox4, and the expression of osteoblast-specific proteins such as Cbfa1, ALP and osteopontin in HASMCs.

Communication between nerves and mast cells is a prototypic demonstration of neuroimmune interaction. However, whether mast cell activation occurs as a direct response to neuronal activation or requires an intermediary cell is unclear. Addressing this issue, we used an in vitro coculture approach comprising cultured murine superior cervical ganglia and rat leukemia basophilic cells (RBLs; possesses properties of mucosal-type mast cells). Following loading with the calcium fluorophore, Fluo-3, neurite-RBL units (separated by <50 nm) were examined by confocal laser scanning microscopy. Addition of bradykinin, or scorpion venom, dose-dependently elicited neurite activation (i.e., Ca2+ mobilization) and, after a lag period, RBL Ca2+ mobilization. Neither bradykinin nor scorpion venom had any direct effect on the RBLs in the absence of neurites. Addition of a neutralizing substance P Ab or a neurokinin (NK)-1 receptor antagonist, but not an NK-2 receptor antagonist, dose-dependently prevented the RBL activation that resulted as a consequence of neural activation by either bradykinin or scorpion venom. These data illustrate that nerve-mast cell cross-talk can occur in the absence of an intermediary transducing cell and that the neuropeptide substance P, operating via NK-1 receptors, is an important mediator of this communication. Our findings have implications for the neuroimmune signaling cascades that are likely to occur during airways inflammation, intestinal hypersensitivity, and other conditions in which mast cells feature.

Background: Little is known about the effect of hepatitis C virus (HCV) infection on gut microbiota and the relationship between alteration of gut microbiota and chronic hepatitis C (CHC) progression. We performed a comparative study of gut microbiota composition between CHC patients and healthy individuals. Methods: Fecal samples from 166 CHC patients were compared with those from 23 healthy individuals; the gut microbiota community was analyzed using 16S ribosomal RNA gene sequencing. CHC patients were diagnosed with persistently normal serum alanine aminotransferase without evidence of liver cirrhosis (LC) (PNALT, n = 18), chronic hepatitis (CH, n = 84), LC (n = 40), and hepatocellular carcinoma in LC (n = 24). Results: Compared with healthy individuals, bacterial diversity was lower in persons with HCV infection, with a decrease in the order Clostridiales and an increase in Streptococcus and Lactobacillus. Microbiota dysbiosis already appeared in the PNALT stage with the transient increase in Bacteroides and Enterobacteriaceae. Predicted metagenomics of microbial communities showed an increase in the urease gene mainly encoded by viridans streptococci during CHC progression, consistent with a significantly higher fecal pH in CH and LC patients than in healthy individuals or those in the PNALT stage. Conclusions: HCV infection is associated with gut dysbiosis, even in patients with mild liver disease. Additionally, overgrowth of viridans streptococci can account for hyperammonemia in CH and LC. Further studies would help to propose a novel treatment strategy because the gut microbiome can be therapeutically altered, potentially reducing the complications of chronic liver disease.

INTRODUCTION: Many laboratories are currently evaluating the usefulness of determination of HER2, p53, and Ki67 proliferation indices using immunohistochemical techniques in cancer. Although the available studies suggest that these factors might indeed be helpful in making treatment decisions in cancer patients, their clinical usefulness is still controversial. METHODS: Expression of HER2, p53, and Ki67 was examined by immunohistochemistry in samples of breast tissue from 506 patients with invasive ductal carcinoma, obtained between 1981 and 1999 (median follow up period 82 months), and their significance for prognosis was analyzed. RESULTS: Of the 506 carcinoma tissue samples, 20.1%, 29.0%, and 53.6% were positive for HER2 over-expression, p53 protein accumulation, and Ki67 expression, respectively. Over-expression of HER2 significantly reduced disease free (P = 0.02) and overall survival (P = 0.005). Accumulation of p53 protein significantly decreased disease free (P = 0.01) and overall survival (P = 0.01). Patients with tumors that were positive for both HER2 and p53 relapsed and died within a significantly shorter period of time after surgery (P = 0.0001 and P < 0.0001, respectively). In multivariate analysis, patients with both HER2 and p53 positive tumors had considerably decreased overall survival (P = 0.04), as did patients with larger tumor size and positive lymph node status. CONCLUSION: The findings of the present study indicate that the coexistence of HER2 over-expression and p53 protein accumulation is a strong prognostic molecular marker in breast cancer.

SUMMARY A follow‐up study was made on 200 children (115 boys, 85 girls) who had had infantile spasms, in order to compare their present condition over the age of six years with various prognostic factors. 48 of the children (30 males and 18 females) had died, and all the rest were aged six years or older at the time of final follow‐up. 139 of the children had received ACTH therapy: at final follow‐up, spasms had ceased in 43.5 per cent, and about the same proportion showed normal physical development; 23 per cent had normal mental development and 15.4 per cent were attending ordinary schools. Complete recovery (normal mental and physical development and attending ordinary schools) was achieved in only 19 cases (9.5 per cent). Of the cryptogenic cases, 44.4 per cent had made a full recovery. The poor prognostic factors for continuing seizures were evolution into other types of fits, relapse of seizures after ACTH therapy, seizures concomitant with spasms, and convulsions before the onset of spasms. Poor prognostic factors for physical development were delayed development before the onset of spasms, neurological abnormalities, PEG abnormality, symptomatic aetiology, neonatal convulsions, low birthweight, perinatal asphyxia and being female. Poor prognostic factors for mental development were delayed development before the onset of spasms, neurological abnormalities, PEG abnormality, prenatal and perinatal aetiology, relapse after initial ACTH therapy, laughing attacks, and evolution into other types of fits. Only in the cryptogenic cases was there significant correlation between the delay in treatment and the long‐term prognosis for mental development. Poor prognostic factors for educability were very similar to those for mental development. In spite of conflicting views as to the long‐term effects of ACTH, prompt treatment seems to be mandatory, at least in cryptogenic cases of infantile spasms. RÉSUMÉ Pronostic á long terme des spasmes infantiles: étude stalistique des facteurs pronostiques dans 200 cas Une étude longitudinale a été entreprise chez 115 garçons et 85 filles ayant eu des spasmes infantiles dans le but de comparer leur condition présente à &amp;#x006c;̂âge de six ans ou plus avec des facteurs pronostiques variés. 48 des enfants (30 garçons et 18 filles) sont morts, tous les autres étaient âgés de six ans au moins à la fin de &amp;#x006c;̂étude longitudinale. 139 des enfants avaient reçu un traitement d̂ACTH. A la fin de &amp;#x006c;̂étude, les spasmes avaient cessé dans 43,5 pour cent des cas et une proportion identique présentait un développement physique normal; 23 pour cent avaient un développement mental normal et 15,4 pour cent fréquentaient une école ordinaire. La ‘guérison complète’ (développement mental et physique normaux, fréquentation d̂une école ordinaire) n'était observée que dans 19 cas (9,5 pour cent). Parmi les cas d̂origine inconnue, 44,4 pour cent presentaient une guerison complète. Les facteurs de mauvais pronostic pour la continuation des crises étaient &amp;#x006c;̂évolution vers d̂autres types de crises, la rechute des crises aprés traitement par &amp;#x006c;̂ACTH, des crises s'associant aux spasmes et &amp;#x006c;̂existence de convulsions avant le début des spasmes. Les facteurs de mauvais pronostic pour le développement physique étaient le retard de développement avant le début des spasmes, les anomalies neurologiques, &amp;#x006c;̂anomalie PEG, une étiologie symptomatique, des convulsions néonatales, le faible poids de naissance, &amp;#x006c;̂asphyxie périnatale et le sexe féminin. Les facteurs de mauvais pronostic pour le développement mental étaient le retard de développement avant le début des spasmes, les anomalies neurologiques, &amp;#x006c;̂anomalie PEG, &amp;#x006c;̂étiologie pré et péri‐natale, la rechute après le traitement initial d̂ACTH, les crises de fou rire, et &amp;#x006c;̂évolution vers d̂autres types de crises. La corrélation entre le délai dans &amp;#x006c;̂institution de la thérapeutique et le pronostic à long terme pour le développement mental n'est apparu significative que pour les cas d̂origine inconnue. Les facteurs de mauvais pronostic pour &amp;#x006c;̂éducabilité étaient trés semblables à ceux du développement mental. En dépit d̂opinions contradictoires sur les effets à long terme de &amp;#x006c;̂ACTH, un traitement immédiat parait s'imposer, au moins dans les cas de spasmes infantiles d̂origine inconnue. ZUSAMMENFASSUNG Langzeitprognose der myoklonischen Anfälle: eine statistische Studie prognostisch wichtiger Faktoren bei 200 Fällen Bei 115 Jungen und 85 Mädchen, die myoklonische Anfälle gehabt hatten, wurde eine Kontrollstudie durchgeführt, um ihr derzeitiges klinisches Bild im Alter von über sechs Jahren mit verschiedenen prognostischen Faktoren zu vergleichen. 48 der Kinder waren gestorben (30 Jungen und 18 Mädchen). Der Rest war sechs Jahre oder älter zum Zeitpunkt der abschlieïenden Kontrolluntersuchung. 139 Kinder waren mit ACTH behandelt worden. Bei der Abschluïuntersuchung hatten 43.5 Prozent der Kinder keine Krämpfe mehr und ihre physikalische Entwicklung war normal; 23 Prozent hatten sich geistig normal entwickelt und 15.4 Prozent besuchten allgemeine Schulen. Eine vollständige Ausheilung (normale geistige und körperliche Entwicklung und der Besuch einer allgemeinen Schule) fand sich nur in 19 Fällen (9.5 Prozent). Bei den kryptogenen Fällen fand sich in 44.4 Prozent der Fälle eine vollständige Ausheilung. Die ungünstigen prognostischen Faktoren für das Fortbestehen eines Anfallsleidens waren der Übergang in einen anderen Anfallstyp, das Wiederauftreten von Anfällen nach der ACTH Behandlung, Krampfanfälle einhergehend mit Myoklonien und Convulsionen vor Beginn der Myoklonien. Die ungünstigen prognostischen Faktoren für die körperliche Entwicklung waren eine verzögerte Entwicklung vor Beginn der Myoklonien, neurologische Auffälligkeiten, abnorme PEG‐Befunde, symptomatische Aetiologie, Neugeborenenkrämpfe, niedriges Geburtsgewicht, perinatale Asphyxie und weibliches Geschlecht. Die ungünstigen prognostischen Faktoren für die gestige Entwicklung waren verzögerte Entwicklung vor Beginn der Myoklonien, neurologische Auffälligkeiten, abnorme PEG‐Befunde, praenatale und perinatale Aetiologie, Rückfall nach initialer ACTH‐Therapie, Lachattacken und der Übergang in einen anderen Anfallstyp. Nur bei den cryptogenen Fällen fand sich eine signifikante Korrelation zwischen dem verzögerten Einsetzen der Therapie und der Langzeitprognose für die geistige Entwicklung. Trotz der widersprüchlichen Ansichten im Hinblick auf die Auswirkungen der ACTH‐Behandlung, scheint eine sofortige Therapie zumindestens bei den cryptogenen Fällen der myoklonischen Anfälle dringend erforderlich. RESUMEN Fronóstico a largo plazo de los espasmos infantiles: estudio estadistico de los factores de pronóstico en 200 casos Se realizó un estudio continuado en 115 muchachos y 85 chicas que habían tenido espasmos infantiles, con el objeto de comparar su situación presente a la edad de más de seis años, con diversos factores pronósticos. 48 de los niños (30 varones y 18 hembras) habían muerto, y el resto tenían seis años o más en el momento de la observación final. 139 de los niños habían recibido terapia con ACTH. En la observación final los espasmos habian cedido en el 43.5 por ciento y la misma proportión mostraban un desarrollo fisico normal; 23.0 por ciento tenian un desarrollo mental normal y un 15.4 por ciento acudían a escuelas normales. ‘La recuperación completa’ (desarrollo mental y físico normales y escuela normal) se consiguió solamente en 19 casos (9.5 por ciento). De los casos criptogénicos, 44.4 por ciento habían conseguido una recuperación total. Los factores de mal pronóstico frente a los ataques contínuos eran una evolución hacia otros tipos de convulsiones, recaida en los ataques después de la terapia con ACTH, convulsiones concomitantes con los espasmos, convulsiones antes del inicio de los espasmos. Los malos factores de pronóstico para el desarrollo fisico, eran un retraso en el desarrollo antes del inicio de los espasmos, anomalías neurológicas, PEG anómalo, sintomatologia de una etiologia determinada, convulsiones neonatales, bajo peso al nacer, asfixia perinatal y sexo femenino. Los factores de mal pronóstico para el desarrollo mental eran retraso en el desarrollo antes del inicio de los espasmos, anomalías neurológicas, PEG anómalo, etiologia prenatal y perinatal, recaída después de iniciar la terapia con ACTH, ataques de risa, y evolución hacia otros tipos de ataques. Solo en los casos criptogénicos había una correlatión significativa entre el retraso del tratamiento y el pronóstico a largo tiempo para el desarrollo mental. Los factores de mal pronóstico a la educabilidad eran muy semejantes a los del desarrollo mental. A pesar de opiniones conflictivas acerca de los efectos a largo término del ACTH, parece que un tratamiento precoz es obligado, por lo menos en los casos criptogénicos de espasmos infantiles.

In this paper, a new hand exoskeleton device using a three-layered sliding spring mechanism is presented. In contrast to state of the art hand exoskeleton mechanisms (typically link, wire or pneumatically driven), the proposed mechanism is driven through large deformations of the compliant mechanism body. The mechanism can be made compact and lightweight by adequately positioning the compliant elements. In addition, the mechanism is designed to distribute 1-DOF actuated linear motion into three rotational motions of the finger joints, which translate into natural finger flexion/extension. The primary application of the proposed mechanism is to provide robotic support during physical therapy at the hospital (e.g. Continuous Passive Motion). However, thanks to its light and wearable structure, the proposed device could also be used at home as an assistive/therapeutic device to support activities of daily living. We introduce the mechanical structure of the three-layered sliding spring mechanism, present a prototype implementation as a hand exoskeleton device, and provide a preliminary evaluation.

BACKGROUND: Sustained heart rate abnormalities produce electrical remodeling and susceptibility to arrhythmia. Uncontrolled tachycardia produces heart failure and ventricular tachyarrhythmia susceptibility, whereas bradycardia promotes spontaneous torsade de pointes (TdP). This study compared arrhythmic phenotypes and molecular electrophysiological remodeling produced by tachycardia versus bradycardia in rabbits. METHODS AND RESULTS: We evaluated mRNA and protein expression of subunits underlying rapid (IKr) and slow (IKs) delayed-rectifier and transient-outward K+ currents in ventricular tissues from sinus rhythm control rabbits and rabbits with AV block submitted to 3-week ventricular pacing either at 60 to 90 bpm (bradypaced) or at 350 to 370 bpm (tachypaced). QT intervals at matched ventricular pacing rates were longer in bradypaced than tachypaced rabbits (eg, by approximately 50% at 60 bpm; P<0.01). KvLQT1 and minK mRNA and protein levels were downregulated in both bradypaced and tachypaced rabbits, whereas ERG was significantly downregulated in bradypaced rabbits only. Kv4.3 and Kv1.4 were downregulated by tachypacing only. Patch-clamp experiments showed that IKs was reduced in both but IKr was decreased in bradypaced rabbits only. Continuous monitoring revealed spontaneous TdP in 75% of bradypaced but only isolated ventricular ectopy in tachypaced rabbits. Administration of dofetilide (0.02 mg/kg) to mimic IKr downregulation produced ultimately lethal TdP in all tachypaced rabbits. CONCLUSIONS: Sustained tachycardia and bradycardia downregulate IKs subunits, but bradycardia also suppresses ERG/IKr, causing prominent repolarization delays and spontaneous TdP. Susceptibility of tachycardia/heart failure rabbits to malignant tachyarrhythmias is induced by exposure to IKr blockers. These results point to a crucial role for delayed-rectifier subunit remodeling in TdP susceptibility associated with rate-related cardiac remodeling.

Hepatitis B virus (HBV) cannot be eliminated completely from infected hepatocytes because of the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), it is important to manage CHB to prevent HCC development in high-risk patients with high viral replicative activity or advanced fibrosis. Serum biomarkers are noninvasive and valuable for the management of CHB. Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients with undetectable serum HBV DNA or loss of HBsAg, HBcrAg still can be detected and the decrease in HBcrAg levels is significantly associated with hopeful outcomes. Therefore, HBcrAg can predict HCC occurrence or recurrence. Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. Because elevated M2BPGi in CHB is related to liver fibrosis and the prediction of HCC development, monitoring its progression is essential. Because alpha fetoprotein (AFP) has insufficient sensitivity and specificity for early-stage HCC, a combination of AFP plus protein induced by vitamin K absence factor II, or AFP plus Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein might improve the diagnosis of HCC development. Additionally, Dickkopf-1 and circulating immunoglobulin G antibodies are the novel markers to diagnose HCC or assess HCC prognosis. This review provides an overview of novel HBV biomarkers used for the management of intrahepatic viral replicative activity, liver fibrosis, and HCC development.

OBJECTIVES: To investigate the significance of low hemoglobin concentration and longevity in older people. DESIGN: Randomized prospective study. SETTING: Nursing home and geriatric hospital ward in a metropolitan welfare center. PARTICIPANTS: Apparently stable older residents from 1990 to 1996. MEASUREMENTS: Survival rates were estimated by statistical analysis. Sixty-three older subjects with low hemoglobin (Hb<11 g/dl) and age/sex-matched normal controls (Hb> or =11 g/dl) were observed for 60 months. Scores of activities of daily living (ADLs) did not significantly differ between the two groups. Cerebrovascular disease was the main complication in both, and malignant neoplasms were not apparent initially. RESULTS: After 60 months, the 5-year survival rate (FSR) of normal controls was significantly higher than that of cases with anemia (P =.0078). FSR was 67% in normal controls and 48% in anemic individuals age 70 to 79. The figures for individuals age 80 to 89 were 62% and 41%, respectively, and for individuals age 90 to 99 were 25% and 13%, respectively, the survival rate significantly decreasing with age in both groups (P <.001). FSR with severe anemia (Hb< or = 8.9 g/dl) was 0% in males, and 27% in females. Values for moderate anemia (9.0 g/dl to 10.9 g/dl) were 25% and 51%, respectively, for normal hemoglobin (11.0 g/dl to 12.9 g/dl) were 44% and 61%, respectively, and for high hemoglobin (13.0 g/dl< or =Hb) were 50% and 70%, respectively. Advanced carcinomas were often detected at autopsy in anemic individuals. No death by cancer occurred in normal controls. CONCLUSION: Low hemoglobin concentration predicts early death in nursing home residents. Anemia-associated conditions that might be life-threatening risks in older people require further investigation.

OBJECTIVE: Brain iron accumulation has been proposed as one of the pathomechanisms in Parkinson's disease (PD). This study aimed to examine the whole-brain pattern of iron accumulation associated with cognitive impairment in patients with PD using voxel-based quantitative susceptibility mapping analysis. METHODS: We enrolled 24 patients with PD and mild cognitive impairment, 22 patients with PD and normal cognition, and 20 age-matched healthy controls in this cross-sectional study. All participants underwent global cognitive and physical assessments and brain MRI. Using a combined method of voxel-based morphometry and quantitative susceptibility mapping, we compared the voxel-wise magnetic susceptibility of the whole brain between the groups and analyzed its correlation with the cognitive and behavioral data. RESULTS: The PD and mild cognitive impairment group had lower Montreal Cognitive Assessment (MoCA) score than the PD and normal cognition and healthy control groups. There were no gray matter volumetric differences between the groups. In contrast, the voxel-based quantitative susceptibility mapping analysis showed that the PD and mild cognitive impairment group had significantly higher quantitative susceptibility mapping values in the cuneus, precuneus, caudate head, fusiform gyrus, and orbitofrontal cortex than did the PD and normal cognition group. These quantitative susceptibility mapping values were negatively correlated with the MoCA scores in the PD patients (cuneus: r = -0.510, P < .001; caudate head: r = -0.458, P = 0.002). CONCLUSIONS: This study suggests that cognitive impairment in PD is associated with cerebral iron burden and highlights the potential of quantitative susceptibility mapping as an auxiliary biomarker for early evaluation of cognitive decline in patients with PD. © 2019 International Parkinson and Movement Disorder Society.

OBJECTIVES: Dendritic cell (DC) therapy frequently induces a measurable immune response. However clinical responses are seen in a minority of patients, presumably due to insufficient expansion of antigen-specific cytotoxic T lymphocytes (CTLs) capable of eradicating tumor cells. To increase therapeutic efficacy of DC-based vaccination, we have undertaken the first clinical trial involving a combination therapy of gemcitabine (GEM) with immunotherapy for patients with inoperable locally advanced pancreatic cancer. METHODS: Patients (n = 5) received the treatment course, which consisted of intravenous GEM administration at 1000 mg/m (day 1) and the endoscopic ultrasound-guided fine-needle injection of OK432-pulsed DCs into a tumor, followed by intravenous infusion of lymphokine-activated killer cells stimulated with anti-CD3 monoclonal antibody (CD3-LAKs) (day 4), at 2-week intervals. RESULTS: No serious treatment-related adverse events were observed during the study period. Three of the 5 patients demonstrated effective responses to this clinical trial; 1 had partial remission and 2 had long stable disease more than 6 months. In the patient with partial remission, it has been shown that DC-based vaccination combined with GEM administration induces tumor antigen-specific CTLs. CONCLUSION: This combined therapy was considered to be synergistically effective and may have a role in the therapy of pancreatic cancer for inducing tumor antigen-specific CTLs.

Aims: To evaluate AMG 701, a BiTE® molecule binding BCMA on MM cells and CD3 on T cells, in RR MM (Amgen, NCT03287908); primary objective was to evaluate safety and tolerability and estimate a biologically active dose; secondary objectives were to characterize pharmacokinetics (PK), anti-myeloma activity per IMWG criteria, and response duration. Methods: Patients with MM RR or intolerant to ≥3 lines [proteasome inhibitor (PI), IMiD, anti-CD38 Ab as available] received AMG 701 IV infusions weekly in 4-week cycles until disease progression (PD). A 0.8-mg step dose was added prior to target doses ≥1.2 mg to prevent severe cytokine release syndrome (CRS). Target dose was achieved by day 8 or sooner with earlier escalation. Exclusion criteria included: solely extramedullary disease; prior allogeneic stem cell transplant (SCT) in the past 6 months; prior autologous SCT in the past 90 days; CNS involvement; prior anti-BCMA therapy. The first 3 cohorts (dose 5-45 μg) had 1 patient each, the next cohorts (0.14-1.2 mg) had 3-4 patients each, and subsequent cohorts (1.6-12 mg) were to have 3-10 patients each. Minimal residual disease (MRD) was measured by next-generation sequencing (NGS, ≤10-5 per IMWG) or flow cytometry (≤3×10-5). Results: As of July 2, 2020, 75 patients received AMG 701. Patients had a median age of 63 years, a median time since diagnosis of 5.9 years, and a median (range) of 6 (1-25) prior lines of therapy; 27% of patients had extramedullary disease, 83% prior SCT, and 93% prior anti-CD38 Ab; 68% were triple refractory to a PI, an IMiD, and an anti-CD38 Ab. Median (Q1, Q3) treatment duration was 6.1 (3.1, 15.3) weeks and median follow-up on treatment was 1.7 (1.0, 3.7) months. Patients discontinued drug for PD (n=47), AEs (adverse events, n=4, 3 CRS, 1 CMV / PCP pneumonia), withdrew consent (4), other therapy (1), investigator discretion (1), and CNS disease (1); 17 patients remain on AMG 701. The most common hematological AEs were anemia (43%), neutropenia (23%), and thrombocytopenia (20%). The most common non-hematological AEs were CRS (61%), diarrhea (31%), fatigue (25%), and fever (25%). CRS was mostly grade 1 (n=19) or 2 (n=21) per Lee Blood 2014 criteria. All grade 3 CRS (n=5, 7%) were assessed as dose-limiting toxicities (DLTs); all were reversible with corticosteroids and tocilizumab, with median duration of 2 days. CRS grade 3 drivers included transient LFT increases in 3 patients and hypoxia in 2 patients. Other DLTs were 1 case each of transient grade 3 atrial fibrillation, transient grade 3 acidosis, and grade 4 thrombocytopenia. Serious AEs (n=29, 39%) included infections (13), CRS (7), and asymptomatic pancreatic enzyme rise (2, no imaging changes, 1 treatment related). There were 4 deaths from AEs, none related to AMG 701 (2 cases of sepsis, 1 of retroperitoneal bleeding, and 1 of subdural hematoma). Reversible treatment-related neurotoxicity was seen in 6 patients, with median duration of 1 day, all grade 1-2, and associated with CRS in 4 patients. The response rate was 36% (16/45) at doses of 3-12 mg; at ≤1.6 mg (n=27), there was 1 response at 0.8 mg in a patient with low baseline soluble BCMA (sBCMA). With earlier dose escalation with 9 mg, the response rate was 83% (5/6, 3 PRs, 2 VGPRs), with 4/5 responders being triple refractory and 1 DLT of grade 3 CRS in this group. Across the study, responses included 4 stringent CRs (3 MRD-negative, 1 not yet tested), 1 MRD-negative CR, 6 VGPRs, and 6 PRs (Table). Median (Q1, Q3) time to response was 1.0 (1.0, 1.9) month, time to best response was 2.8 (1.0, 3.7) months, and response duration was 3.8 (1.9, 7.4) months, with maximum duration of 23 months; responses were ongoing at last assessment in 14/17 patients (Figure). MRD was tested in 4 patients (3 sCR, 1 CR) and all were negative (3 by NGS, 1 by flow); MRD negativity was ongoing at last observations up to 20 months later. AMG 701 exhibited a favorable PK profile in its target patient population of RR MM, with AMG 701 exposures increasing in a dose-related manner. Patient baseline sBCMA levels were identified as a determinant of AMG 701 free drug exposures; at higher doses, encouraging preliminary responses were seen even at the higher end of baseline sBCMA values. Summary: In this FIH study with ongoing dose escalation, AMG 701, an anti-BCMA BiTE® molecule, demonstrated a manageable safety profile, encouraging activity, and a favorable PK profile in patients with heavily pre-treated RR MM, supporting further evaluation of AMG 701. Disclosures Harrison: Janssen: Honoraria; Novartis: Consultancy, Honoraria, Patents &amp; Royalties: wrt panobinostat; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; Haemalogix: Consultancy; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria. Minnema:Amgen: Honoraria; Servier: Honoraria; Gilead: Honoraria; Celgene Corporation: Honoraria, Research Funding; Janssen Cilag: Honoraria. Lee:Celgene: Consultancy, Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech: Consultancy; Regeneron: Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Amgen: Consultancy, Research Funding. Spencer:AbbVie: Consultancy, Honoraria, Research Funding; Roche: Honoraria; Takeda: Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; HaemaLogiX: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria; Pharmamar: Research Funding. Kapoor:Cellectar: Consultancy; Amgen: Research Funding; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria. Madduri:Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Foundation Medicine: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Celgene: Consultancy, Honoraria. Larsen:Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ailawadhi:Cellectar: Research Funding; BMS: Research Funding; Medimmune: Research Funding; Amgen: Research Funding; Takeda: Honoraria; Janssen: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; Phosplatin: Research Funding. Kaufman:Amgen: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria; AbbVie: Consultancy; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Tecnopharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi/Genyzme: Consultancy, Honoraria. Raab:Takeda: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:BMS: Consultancy; Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy; Incyte Corporation: Consultancy; Takeda: Consultancy. Iida:AbbVie: Research Funding; Merck Sharpe Dohme: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Sanofi: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Davies:Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Dire

An investigation of genetic structures underlying autistic traits was performed with samples from twins for which at least one proband had been ascertained as having autism spectrum disorders (ASDs) in our catchment area. In order to adjust for recent concepts of autism, we employed criteria for the broad spectrum of disease and the childhood autism rating scale (CARS) for quantitative assessment. The CARS test was performed on 45 twin pairs (19 monozygotic, 26 dizygotic) detected with a regional routine screening system. The obtained CARS scores were subjected to structural equation modeling (SEM), incorporating sex differences for each causal influence ascertainment correction, using the Mx software. A best fitting model of causal influences on autistic traits measured continuously, incorporating additive genetic (A) and non-shared environmental influences (E), was generated. With this AE model, the estimated heritability was 0.73 for males and 0.87 for females, based on the continuous CARS scores. There was no evidence for the existence of sex-specific genetic influences. Autistic traits were highly heritable in twins with even broad spectrum of autism, corresponding to the results of early studies based on classical autism. Additive genetic factors were more influential in females than males.

OBJECTIVE: Few studies have investigated the prevalence of the unmet needs among advanced or recurrent breast cancer patients in Asian countries and little is known about the relation between their unmet needs and psychological distress/quality of life. METHODS: The participants (n = 87) comprised randomly selected ambulatory female patients with advanced or recurrent breast cancer attending the Outpatient Department of Oncology, Immunology and Surgery of Nagoya City University Hospital. The patients were asked to complete self-administered questionnaires assessing the level of their physical and psychological symptoms, supportive care needs and socio-demographic and biomedical factors. The association between the patients' perceived needs and psychological distress/quality of life was then analyzed statistically. RESULTS: The patients had a mean ± standard deviation of 11 ± 7.7 and a median of 10 unmet needs. The prevalence of the 17 most frequent unmet needs was over 50%, and almost all of these unmet need items belonged to the Psychological or the Health system and information domain. The total Short-form Supportive Care Needs Survey Questionnaire with cancer score was significantly associated with the indices of psychological distress and quality of life. Most of the Short-form Supportive Care Needs Survey Questionnaire with cancer domains except Sexuality domain were also significantly associated with all the indices of psychological distress. CONCLUSIONS: Psychosocial needs were strongly associated with psychological distress and quality of life. Quality of life and psychological distress may be improved if interventions for unmet needs, especially psychological and information needs, are made.

2B1 is a monoclonal antibody against a large proteoglycan isolated from human yolk sac tumor (M. Sobue et al., Histochem. J., 21: 455-460, 1989). The antigen is expressed in a variety of embryonal tissues as well as most if not all malignant tumor tissues. However, the expression in normal adult tissues is limited to some tissues, such as the smooth muscle layers of the aorta. We characterized the 2B1 antigen isolated from the conditioned medium of human malignant fibrous histiocytoma and found that immunological and biochemical properties are identical to those of a large chondroitin sulfate proteoglycan, PG-M/versican. Partial amino acid sequences of peptides obtained from the core protein by V8 protease digestion and subsequent SDS-PAGE were detected in the reported amino acid sequence of human PG-M/versican with a complete identity. Furthermore, 2B1 was distinctly reactive to the expressed protein by transfection of the cDNA for the shortest form into mouse cells. The results indicate that the antigen is the PG-M core protein, and the epitope may be in one of the globular domains. It is thus likely that PG-M/versican is one of the extracellular matrix components characteristic of human malignant tumors.