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BACKGROUND: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing =20 kg) or 0·25 mg/kg (for individuals weighing

Background Surgery to prevent aspiration has complications related to tracheostomy tube, such as the trachea-brachiocephalic artery fistula. Glottic closure procedure makes tracheostoma at a position higher than the first ring of the trachea and theoretically has a potential to prevent such complications owing to a longer distance between the tip of tracheostomy tube and the tracheal membrane adjacent to the brachiocephalic artery. Our aim is to evaluate the safety of glottic closure in neurologically impaired patients by comparing outcomes with laryngotracheal separation. Methods This study is a single-center retrospective study from 2004 to 2019, using data of 15 and 12 patients who underwent glottic closure (GC) and laryngotracheal separation (LTS). The primary outcome was the incidence of postoperative complications induced by tracheostomy tube placement and adjustment of the tracheostomy tube position to prevent these complications, such as by converting to a length-adjustable tube and/or placing gauze between the skin and tube flange. Additionally, we analyzed the anatomical relationship between the tracheostomy tube tip and brachiocephalic artery and measured the distance between them using postoperative CT images. Results No patients in either group had trachea-brachiocephalic artery fistula. Erosion or granuloma formation occurred in 1 patient (7%) and 4 patients (33%) in the GC and LTS groups, respectively. Adjustment of the tracheostomy tube was needed in 2 patients (13%) and 6 patients (50%) in the GC and LTS groups. CT revealed a higher proportion of patients with the tracheostomy tube tip superior to the brachiocephalic artery in GC than LTS group. The mean tracheostoma-brachiocephalic artery distance was 40.8 and 32.4 mm in the GC and LTS groups. Conclusions Glottic closure reduces the risk of postoperative complications related to a tracheostomy tube. This may be due to the higher position of the tracheostoma at the level of the cricoid cartilage, increasing the distance between the tracheostoma and brachiocephalic artery.

Nerve transfer involves the use of a portion of a healthy nerve to repair an injured nerve, and the process has been used to alleviate traumatic brachial plexus injuries in humans. Study of the neural mechanisms that occur during nerve transfer, however, requires the establishment of reliable experimental models. In this study, we developed an ulnar-musculocutaneous nerve-transfer model wherein the biceps muscle of a mouse was re-innervated using a donor ulnar nerve. Similar muscle action potentials were detected in both the end-to-end suture of the transected nerve (correctrepair) group and the ulnar-musculocutaneous nerve-transfer group. Also, re-innervated acetylcholine receptor (AChR) clusters and muscle spindles were observed in both procedures. There were fewer re-innervated AChR clusters in the nerve transfer group than in the correct repair group at 4 weeks, but the numbers were equal at 24 weeks following surgery. Thus, our ulnar-musculocutaneous nerve-transfer model allowed physiological and morphological evaluation for re-innervation process in mice and revealed the delay of this process during nerve transfer procedure. This model will provide great opportunities to study regeneration, re-innervation, and functional recovery induced via nerve transfer procedures.

To understand the neural mechanisms underlying the therapeutic effects of crossing nerve transfer for brachial plexus injuries in human patients, we investigated the cortical responses after crossing nerve transfer in mice using conventional and tomographic optical imaging. The distal cut ends of the left median and ulnar nerves were connected to the central cut ends of the right median and ulnar nerves with a sciatic nerve graft at 8 weeks of age. Eight weeks after the operation, the responses in the primary somatosensory cortex (S1) elicited by vibratory stimulation applied to the left forepaw were visualized based on activity-dependent flavoprotein fluorescence changes. In untreated mice, the cortical responses to left forepaw stimulation were mainly observed in the right S1. In mice with nerve crossing transfer, cortical responses to left forepaw stimulation were observed in the left S1 together with clear cortical responses in the right S1. We expected that the right S1 responses in the untreated mice were produced by thalamic inputs to layer IV, whereas those in the operated mice were mediated by callosal inputs from the left S1 to layer II/III of the right S1. To confirm this hypothesis, we performed tomographic imaging of flavoprotein fluorescence responses by macroconfocal microscopy. Flavoprotein fluorescence responses in layer IV were dominant compared to those in layer II/III in untreated mice. In contrast, responses in layer II/III were dominant compared to those in layer IV in operated mice. The peak latency of the cortical responses in the operated mice was longer than that in the untreated mice. These results confirmed our expectation that drastic reorganization in the cortical circuits was induced after crossing nerve transfer in mice.

A patient with complex regional pain syndrome type II was successfully treated using free anterolateral thigh flap transfer with digital nerve coaptation to the cutaneous nerve of the flap. Release of the scarred tissue and soft tissue coverage with targeted sensory nerve coaptation were useful in relieving severe pain.

Ataxia-telangiectasia-like disorder (ATLD) is a rare autosomal recessive disorder, and has symptoms similar to ataxia-telangiectasia (AT). ATLD is caused by mutations in the MRE11 gene, involved in DNA double-strand break repair (DSBR). In contrast to AT, ATLD patients lack key clinical features, such as telangiectasia or immunodeficiency, and are therefore difficult to be diagnosed. We report a female ATLD patient presenting with hypergonadotropic hypogonadism and hypersegmented neutrophils, previously undescribed features in this disorder, and potential diagnostic clues to differentiate ATLD from other conditions. The patient showed slowly progressive cerebellar ataxia from 2 years of age, and MRI revealed atrophy of the cerebellum, oculomotor apraxia, mild cognitive impairment, writing dystonia, hypergonadotropic hypogonadism with primary amenorrhea, and hypersegmented neutrophils. Western blot assay demonstrated total loss of MRE11 and reduction of ATM-dependent phosphorylation; thus, we diagnosed ATLD. Genetically, a novel missense mutation (c.140C>T) was detected in the MRE11 gene, but no other mutation was found in the patient. Our presenting patient suggests that impaired DSBR may be associated with hypergonadotropic hypogonadism and neutrophil hypersegmentation. In conclusion, when assessing patients with ataxia of unknown cause, ATLD should be considered, and the gonadal state and peripheral blood smear samples evaluated.

Takeshi Yoshida , Takeo Kato *, Tomonari Awaya , Minoru Shibata , Keiko Saito , Minako Ide , Masao Matsuhashi , Toshio Heike a,1 Department of Pediatrics, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan Human Brain Research Center, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan

We tested a hypothesis that the spinal plasticity induced within a few hours after nerve injury may produce changes in cortical activities and an initial phase of neuropathic pain. Somatosensory cortical responses elicited by vibratory stimulation were visualized by transcranial flavoprotein fluorescence imaging in mice. These responses were reduced immediately after cutting the sensory nerves. However, the remaining cortical responses mediated by nearby nerves were potentiated within a few hours after nerve cutting. Nerve injury induces neuropathic pain. In the present study, mice exhibited tactile allodynia 1–2 weeks after nerve injury. Lesioning of the ipsilateral dorsal column, mediating tactile cortical responses, abolished somatic cortical responses to tactile stimuli. However, nontactile cortical responses appeared in response to the same tactile stimuli within a few hours after nerve injury, indicating that tactile allodynia was acutely initiated. We investigated the trigger mechanisms underlying the cortical changes. Endogenous glial cell line-derived neurotrophic factor (GDNF), found in the Meissner corpuscles, induced basal firing ∼0.1 Hz or less in its Aβ tactile afferents, and disruption of the basal firing triggered the potentiation of nontactile cortical responses. Application of 10 nmLY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid], a specific antagonist of group II metabotropic glutamate receptors (mGluRs), on to the surface of the spinal cord also induced the potentiation of nontactile cortical responses. Together, it is suggested that low-frequency afferent firing produced by GDNF in touch-sensitive nerve fibers continuously activated spinal group II mGluRs and that failure of this activation triggered tactile allodynia.

Using comprehensive genetic studies on neuronal stem/progenitors cells through genome-wide screening with oligonucleotide arrays, we identified an endoplasmic reticulum (ER) -resident protein, Tweety homologue 1 (ttyh1). Ttyh1 encodes a glycosylated protein composed of five predicted transmembrane segments and a C-terminus that is enriched in negatively charged residues capable of Ca2+ binding. Ttyh1-containing membranes changed to segmented tubuloreticular structures during mitosis, suggesting that the ER-containing Ttyh1 could be responsible for Ca2+ sequestration and Ca2+ concentration regulation during mitosis. Ttyh1 inactivation in mice resulted in early embryonic lethality before organization of the nervous system, revealing that ttyh1 is essential in murine embryonic development. Our findings indicate that Ttyh1 plays an indispensable role during mitosis in early embryogenesis, possibly by maintaining Ca2+ homeostasis in the ER. Developmental Dynamics 239:2233–2245, 2010. © 2010 Wiley-Liss, Inc.

Diagnosis of autoimmune hepatitis (AIH) may be challenging. However, early diagnosis is important because immunosuppression is life-saving. Diagnostic criteria of the International Autoimmune Hepatitis Group (IAIHG) were complex and purely meant for scientific purposes. This study of the IAIHG aims to define simplified diagnostic criteria for routine clinical practice. Candidate criteria included sex, age, autoantibodies, immunoglobulins, absence of viral hepatitis, and histology. The training set included 250 AIH patients and 193 controls from 11 centers worldwide. Scores were built from variables showing predictive ability in univariate analysis. Diagnostic value of each score was assessed by the area under the receiver operating characteristic (ROC) curve. The best score was validated using data of an additional 109 AIH patients and 284 controls. This score included autoantibodies, immunoglobulin G, histology, and exclusion of viral hepatitis. The area under the curve for prediction of AIH was 0.946 in the training set and 0.91 in the validation set. Based on the ROC curves, two cutoff points were chosen. The score was found to have 88% sensitivity and 97% specificity (cutoff ≥6) and 81% sensitivity and 99% specificity (cutoff ≥7) in the validation set. Conclusion: A reliable diagnosis of AIH can be made using a very simple diagnostic score. We propose the diagnosis of probable AIH at a cutoff point greater than 6 points and definite AIH 7 points or higher. (HEPATOLOGY 2008.)

Borealin/DasraB is a member of the chromosomal passenger protein complex (CPC) required for proper segregation of chromosomes during mitosis. In Drosophila melanogaster, inactivation of Borealin/DasraB results in polyploidy, delayed mitosis and abnormal tissue development, indicating its critical role for cell proliferation. However, the in vivo role of mammalian Borealin/DasraB remains unclear. Here, we analyzed the expression of Borealin/DasraB and found that borealin is widely expressed in embryonic tissues and later restricted to adult tissues which relies on rapid cell proliferation. To determine the role of borealin during mouse development, we generated borealin-null mice through targeted disruption. While heterozygous mice developed normally, disruption of both borealin alleles resulted in early embryonic lethality by 5.5 dpc (days postcoitus) due to mitotic defects and apoptosis in blastocyst cells that showed microtubule disorganization and no CPC enrichment. At 5.5 dpc, borealin-null embryos exhibited excessive apoptosis and elevated expression of p53. However, loss of p53 did not abrogate or delay embryonic lethality, revealing that Borealin/DasraB inactivation triggered impaired mitosis and apoptosis though p53-independent mechanisms. Our data show that Borealin/DasraB is essential for cell proliferation during early embryonic development, and its early embryonic lethality cannot be rescued by the loss of p53.

沖縄産ヒメサザンカ野生種13系統，芳香性ツバキの花粉親の一つであるヒメサザンカの系統1118（海外経由系統），芳香性ツバキ4品種の香気成分の比較を行った．ヒメサザンカの香気成分について，新たにリモネンおよび6種の芳香族化合物，安息香酸ベンジル，オイゲノール，サリチル酸メチル，o-アニス酸メチル，フェニルアセトアルデヒド，ベンズアルデヒドを同定した．沖縄産野生種13系統の香気成分量は，ほとんどのものが海外経由系統より多く，特に系統3と36が多かった．この二つを比較すると，花様の香調の2-フェニルエタノールやフェニルアセトアルデヒドの割合が多い系統36の香りの方が強く感じられた．ヒメサザンカを花粉親とする芳香性ツバキ‘姫の香’，‘港の曙’，‘春風’，‘フレグラントピンク’の香気成分の組成もヒメサザンカとほぼ同じであったが，組成比は品種ごとに大きく異なり，花様の香調を持つ成分の割合の多い‘姫の香’，‘港の曙’で香りが強く感じられた．

症例は48歳, 男性. 前日夕方より嘔気出現し食事が摂取できなかった. 翌朝トイレで意識レベルが低下しているところを発見された. 血液データで貧血を認め, 上部消化管出血によるショックを疑い胃内視鏡検査施行. 胃内に黒色の凝血塊を多量に認めたが, 明らかな出血源は不明だった. 翌日胃内視鏡検査を再度施行した所, 胃角部対側に中心に潰瘍がある腫瘤を認め, 粘膜下腫瘍の潰瘍形成による出血と診断した. 腫瘤切除のため腹腔鏡補助下胃部分切除術を施行. 腫瘤の大きさは3×2cmで中心に陥凹を形成されていた. 粘膜下層から漿膜下層に相当する部位にランゲルハンス島, 腺房細胞, 導管を有するHeinrich I型の異所性膵組織を認めた. 悪性所見はなかった.胃の迷入膵は稀に出血性ショックをおこす程出血することを考慮して治療に当たらなければならないと考えた.

Although embryonic stem (ES) cells are capable of unlimited proliferation and pluripotent differentiation, effective preparation of neural stem cells from ES cells are not achieved. Here, we have directly generated under the coculture with dissociated primary neurosphere cells in serum-free medium and the same effect was observed when ES cells were cultured with conditioned medium of primary neurosphere culture (CMPNC). ES-neural stem cells (NSCs) could proliferate for more than seven times and differentiate into neurons, astrocytes, and oligodendrocytes in vitro and in vivo . The responsible molecule in CMPNC was confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, which turned out to be cystatin C. Purified cystatin C in place of the CMPNC could generate ES-NSCs efficiently with self-renewal and multidifferentiation potentials. These results reveal the validity of cystatin C for generating NSCs from ES cells.

症例は49歳,女性. 2週間前から左乳腺腫瘤を自覚し来院.左乳房C領域に2cm程の境界不明瞭な腫瘤を触知.マンモグラフィにてカテゴリー3, 乳房超音波検査では乳頭腺管癌を疑った.穿刺吸引細胞診でclassV乳頭腺管癌と診断.乳頭より22mm離れていたため,乳房温存手術を施行. Level IIIのリンパ節腫脹を触知したため, Level IIIまでリンパ節を郭清した.術後の病理診断では癌の拡がりは4×1.5cmでscirrhous+invasive micropapillary carcinoma (IMP), ly3, リンパ節転移3/16, 断端(-), ER(-), PR(-), HER2(1+) だった.術後AC 4クール, weekly paclitaxel 12クール施行後,放射線療法を残存乳腺および鎖骨上窩に施行した.

Morphological reaction of sensory neurons of dorsal root ganglia after peripheral nerve transection was investigated by a nerve tracing method using E. coli lacZ (beta-galactosidase) gene recombinant adenovirus. The sciatic nerve of the rat was transected and inoculated with the gene recombinant adenovirus from the cutting end of nerve fibers. The fixation was accomplished from one to six weeks after inoculation. A whole mount specimen was observed after the reaction in a X-galactocidase substrate. Newly formed sprouting processes of dorsal root ganglion (DRG) cells appeared, all of them sprouting from the primary segment of DRG cells. Developed branches were morphologically categorized in to two types: one was the "linear type" which showed diverged branches running straightly along the major axis of the DRG; the other was the "winding type" which exhibited a random running pattern to the original axons and wound and extended in all directions in dorsal root ganglia with many branches. Many of this type encircled other cell bodies and formed a ring-like structure. There was no difference in the size of cell bodies in either type or between the ring-like structure forming the cells and those cells encircled by them.

The incidence of hepatocellular carcinoma (HCC) in patients with primary biliary cirrhosis (PBC) is not well known. The aims of this study are to determine HCC incidence and survival, and to identify risk factors associated with these outcomes in patients with PBC. We collected information on 396 patients with PBC at enrollment and followed-up from 6 to 271 months. They were all negative for hepatitis B and C virus markers. HCC was detected by scanning with ultrasonography, computed tomography, or both every 4 to 6 months. Life expectancy (LE) was approximated with the declining exponential approximation of LE. A total of 14 patients developed HCC. The cumulative appearance rate of HCC in patients with advanced-stage PBC (Scheuer's stage III or IV) was significantly higher than that for patients with early-stage (stage I or II) (12.3% and 7.7% by the tenth year, respectively. P = .021). Proportional hazards analysis showed 3 factors are independently associated with the development of HCC: age at the time of diagnosis, male gender, and history of blood transfusion. Age, male gender, and advanced-stage PBC were associated with survival, but HCC development was not. The disease-specific annual mortality rate was estimated to be 0.008 for women and 0.028 for men with advanced-stage PBC. In conclusion, HCC develops in old patients with advanced-stage PBC, but HCC does not affect the patients' survival.

The usefulness of recombinant adenovirus with LacZ to trace axons in the peripheral nervous system was investigated. Recombinant adenovirus with LacZ was applied to the cut end of the tibial nerve in rats. The LacZ gene product (B-galactosidase) filled axons of the tibial nerve, which permitted the continuous long-range tracing of axons. Further, the branching and the direction of the branches could also be examined. Labeled axons in the tibial nerves ran parallel to each other without branching and kept this relative position in the tibial and the sciatic nerve. When the virus was introduced to the regenerating nerve using a silicon tube, the regenerating fibers grew tortuously with short branches in the bulge at the proximal end of the silicon tube. The fibers grew straight in the tube and passed through the bulge at the distal end of the tube without branching. These observations indicate that the LacZ gene recombinant adenovirus is a useful tracer for the study of the peripheral nervous system and of the regeneration processes.

The change in contact potential difference (CPD) between YSZ (2% Y 2 O 3 stabilized ZrO 2 and a Pt reference electrode was measured under a controlled oxygen partial pressure ( P O 2 ) with a high temperature Kelvin probe. The work function change of the Pt reference electrode (φ ref. ) was calculated by comparing the results of the YSZ-Pt measurement and that of the Pt-Pt measurement, and thus the work function change of YSZ (φ YSZ ) caused by the change of the flowing gas composition was determined. From the experimental results, the exponent of P o 2 dependence of φ YSZ was estimated to be 1 4.1 in the P o 2 range of 2 × 10 2 -3 x 10 3 Pa. This was in good agreement with the value of 1 4 predicted from the estimate based on defect equilibria.

We report a new type of locomotive robot which is able to avoid standing obstacles and to ascend and descend a flight of stairs. This locomotive robot is of the self-contained navigation type. The structures are composed of three portions : a main element attached to steering gears, the front and rear body. Thus, they are connected by the coupling rod. Each portion has some legs on both sides which are attached to wheels. Fundamentally, ascending/descending, level and steering motions allow the robot to ascend and descend spiral stair cases. Minimum turning radius is small compared to the previous type. We call this structure the leg-vehicle type. Our results show that stable locomotion of the robot can be attained.

Avulsion of spinal nerve roots in the brachial plexus (BP) can be repaired by crossing nerve transfer via a nerve graft to connect injured nerve ends to the BP contralateral to the lesioned side. Sensory recovery in these patients suggests that the contralateral primary somatosensory cortex (S1) is activated by afferent inputs that bypassed to the contralateral BP. To confirm this hypothesis, the present study visualized cortical activity after crossing nerve transfer in mice through the use of transcranial flavoprotein fluorescence imaging. In naïve mice, vibratory stimuli applied to the forepaw elicited localized fluorescence responses in the S1 contralateral to the stimulated side, with almost no activity in the ipsilateral S1. Four weeks after crossing nerve transfer, forepaw stimulation in the injured and repaired side resulted in cortical responses only in the S1 ipsilateral to the stimulated side. At eight weeks after crossing nerve transfer, forepaw stimulation resulted in S1 cortical responses of both hemispheres. These cortical responses were abolished by cutting the nerve graft used for repair. Exposure of the ipsilateral S1 to blue laser light suppressed cortical responses in the ipsilateral S1, as well as in the contralateral S1, suggesting that ipsilateral responses propagated to the contralateral S1 via cortico-cortical pathways. Direct high-frequency stimulation of the ipsilateral S1 in combination with forepaw stimulation acutely induced S1 bilateral cortical representation of the forepaw area in naïve mice. Cortical responses in the contralateral S1 after crossing nerve transfer were reduced in cortex-restricted heterotypic GluN1 (NMDAR1) knockout mice. Functional bilateral cortical representation was not clearly observed in genetically manipulated mice with impaired cortico-cortical pathways between S1 of both hemispheres. Taken together, these findings strongly suggest that activity-dependent potentiation of cortico-cortical pathways has a critical role for sensory recovery in patients after crossing nerve transfer.

According to a recent nationwide survey in Japan, a significant proportion of very low birth weight infants (VLBWI) develop late-onset circulatory collapse after the first week of life. Small doses of glucocorticoid are very effective in these patients, and relative adrenal insufficiency is suspected to be the main cause of the condition. Although the CRH test is required to evaluate the hypothalamic-pituitary-adrenal axis, obtaining multiple blood samples is invasive.The present study was carried out to validate the consistency of the cortisol profiles of matched serum and saliva samples collected as part of the CRH test from VLBWI.In 23 VLBWI with a gestational age of less than 29 wk, we performed CRH tests at 2 wk after birth and at term. Their cortisol values were measured at the baseline and 30 min after the administration of a single dose of human CRH (1 μg/kg) using matched serum and saliva samples.In 26 CRH tests in 19 infants, we were able to measure both serum and salivary cortisol. Significant correlations were detected between the infants' serum and salivary cortisol values (r=0.78; P0.0001), the increases in these values induced in response to the CRH test (r=0.81; P0.0001), and their peak serum and salivary cortisol values (r=0.68; P=0.0001).This study indicated that using salivary cortisol measurements for the CRH test could be a reliable method for evaluating the hypothalamic-pituitary-adrenal axis in VLBWI with gestational age of less than 29 wk.

症例は69歳時,会社の検診で肝機能異常を指摘された. 75歳時,胆道系酵素が高値のため, B病院肝臓外来へ紹介された. ERCPで肝外胆道系疾患はなく,抗ミトコンドリア抗体(AMA)陽性のためPBCが疑われ, 77歳時肝生検目的のため入院となった.肝生検像では, PBCの所見は乏しく, chronic persistent hepatitisの所見のみであった.本抗体の対応抗原が免疫沈降法により95kDaの蛋白で,細胞質のcytosol分画に存在していることから,本抗体を抗p95 cytosol (C)と改名した.本症例はその後の免疫学的検査では, AMAと異なる抗p95 C抗体陽性の他,抗セントロメア抗体も陽性であった.さらに血液生学的検査では,高度の閉塞性肝機能障害を呈していたが,自覚症状では全身倦怠感,〓痒感,黄疸はなく,予後良好の1例と考えられた.本研究所で経験した本抗体陽性の15症例を呈示し,臨床的特徴について考案した.

A 49-year-old asthmatic woman with a history of drug allergy to aspirin and penicillin presented to the hospital with fever, dark urine, general exanthema and fatigue. Physical examination revealed jaundice. She had been taking four different over-the-counter drugs. Laboratory examination showed eosinophilia, elevated Ig E, hyperbilirubinemia and elevated liver function tests. HBs Ag, anti-HCV Ab and Ig M anti-HA were negative. She was initially diagnosed with drug-induced hepatitis and was treated with steroids. However, liver dysfunction with eosinophilia relapsed after discontinuing steroids. Liver biopsy revealed eosinophilic infiltration. Steroids were discontinued after the start of 6-mercaptopurine.

The elbow is an uncommon site for malignant bone tumors. Surgical options for the reconstruction of the elbow joint are limited and technically challenging. In this study, we describe a patient with osteosarcoma of the proximal ulna treated by wide resection and reconstruction with a combined use of free vascularised fibula graft and extracorporeally irradiated osteochondral graft. Ten years after the surgery, the patient is alive, without disease and is able to play golf with no lateral instability or pain of the elbow joint. A vascularised fibula, combined with extracorporeally irradiated osteochondral graft with ligamentous repair is one of the options for the treatment of malignant bone tumor of the proximal ulna.

無症候性原発性胆汁性肝硬変(a-PBC) 25例において,ALPが正常上限の2倍未満に止まり診断基準のALPの中等度以上の上昇を満たさないものをPBC早期例,ALPが正常上限の2倍以上のものをPBC典型例と定義した.早期例は11例(44%)と高率に認められ,典型例と比較して臨床症状,肝組織像,抗ミトコンドリア抗体(AMA)陽性率に差はないが,GOT, γ・GTP, IgM,アデノシンデアミナーゼ,赤沈などの異常は有意に軽度であった.また,ALP正常な4例の組織所見および検査成績の推移を観察し,検査成績正常な時期からPBCとしての異常が顕性化するまでの過程を検討した.早期では組織変化とAMA, anti-M2の出現が検査成績の異常に先行し,検査成績ではIgMが最も早期に上昇し次にγ-GTP,トランスアミナーゼ,赤沈などが上昇した.早期PBCにおいてはALPの上昇は必須条件ではなく,その発見には無症状かつALP正常例の存在を念頭におき,検査成績のなかでは異常率の高いIgMの測定が不可欠であった.

Supplemental Digital Content is available in the text., Summary: The free groin flap results in less donor-site morbidity than other skin flaps and is suitable for use in children and adolescents. However, the vascular pedicle is relatively short and vessel diameter is small, which makes vascular anastomosis technically difficult. To overcome this limitation, we harvested vein and arterial grafts from the flap elevation area without placing additional skin incisions. Use of short (2–3 cm) vein/arterial grafts greatly simplified flap insetting and vascular anastomosis. This procedure may expand the indications for free groin flap transfer.

Supplemental Digital Content is available in the text., Summary: Wide resection of malignant skin tumors in the upper orbital region often results in soft-tissue defects involving the eyebrow. We used composite skin grafts from the area around the sideburns for 1-stage reconstruction of skin and eyebrow defects. The results were aesthetically satisfying because the hair and shape of these regions were similar to those of the original eyebrow, and donor-site closure was easy with inconspicuous scar. The survival of full-thickness skin graft area of composite grafts from sideburn facilitates revascularization of thicker hair follicles in the graft and allows safe, natural eyebrow reconstruction.

Ribavirin-induced hemolytic anemia is one cause for cessation of combination therapy with alpha interferon 2b and ribavirin for hepatitis C infection. Determining cellular ribavirin levels in blood, including the levels of its phosphorylated metabolites, might be useful for predicting ribavirin-induced anemia, because the metabolites accumulate in erythrocytes. We simplified an assay method developed previously to make it suitable for routine monitoring of cellular ribavirin. Whole blood diluted with a sixfold volume of ice-cold distilled water was subjected to acid phosphatase digestion to convert phosphorylated ribavirin metabolites to free ribavirin. The resulting mixture, spiked with an internal standard, was treated by phenyl boronic acid column extraction, followed by reverse-phase high-performance liquid chromatography analysis. The calibration curve for ribavirin levels in whole blood was linear at concentrations of 5.3 to 1,024 μM ( r 2 = 0.9999). Validation coefficients of variation for intra- and interday assays were 2.9 to 5.8% and 4.3 to 8.3%, respectively. We tested this method by monitoring blood ribavirin concentrations in two hepatitis C patients receiving alpha interferon 2b-plus-ribavirin combination therapy.

To elucidate the effects of blood ribavirin disposition on ribavirin-induced anemia, the relationship between erythrocyte ribavirin concentration and change in hematologic parameters was examined in interferon and ribavirin combination therapy for HCV eradication.Nine HCV RNA-positive patients were treated with combination therapy including 11.3 +/- 1.2 mg.kg(-1).day(-1) of ribavirin. Blood concentrations of ribavirin and its phosphorylated metabolites were measured in plasma as well as erythrocyte.Blood ribavirin concentrations gradually increased to steady-state levels of 8.8 +/- 1.4 micromol/L and 1389 +/- 371 micromol/L in plasma and erythrocytes, respectively, within 3-4 weeks of initiating therapy. Erythrocyte phosphorylated metabolite levels (1215 +/- 302 micromol/L) were found to be exceedingly high, i.e., 87% of the measured erythrocyte ribavirin concentration. In contrast, plasma phosphorylated metabolite levels were undetectable. Positive correlation was found to exist between erythrocyte ribavirin concentrations and a decrease in hemoglobin (r = 0.620, P0.001).We concluded that marked elevation of erythrocyte ribavirin including its phosphorylated metabolites was associated with hemoglobin reduction, leading to interferon and ribavirin-induced anemia.

Preaxial polydactyly (PPD) is a common limb malformation in human. A number of polydactylous mouse mutants indicate that misexpression of Shh is a common requirement for generating extra digits. Here we identify a translocation breakpoint in a PPD patient and a transgenic insertion site in the polydactylous mouse mutant sasquatch ( Ssq ). The genetic lesions in both lie within the same respective intron of the LMBR1 / Lmbr1 gene, which resides ≈1 Mb away from Shh . Genetic analysis of Ssq reveals that the Lmbr1 gene is incidental to the phenotype and that the mutation directly interrupts a cis-acting regulator of Shh . This regulator is most likely the target for generating PPD mutations in human.

Objective: Interferon (IFN) therapy has been used as antiviral therapy for chronic hepatitis C (CH-C); however, complete response to the therapy is observed in only about 30% of patients in Japan. Background factors involved in the responsiveness to IFN therapy, and progression to liver cirrhosis (LC) and hepatocellular carcinoma (HCC) after IFN therapy have not yet been sufficiently investigated. Methods: One hundred twenty-one patients with CH-C who received IFN therapy at Showa University Hospital between 1984 and 1999 were analyzed. Results: At 6 months after the termination of IFN therapy, 53 patients achieved a complete response, 11 patients incomplete response, and 57 patients no response. During a mean follow-up of 52.7 months, 12 patients progressed to LC, and 10 patients developed HCC. Multivariate analysis showed that significant independent factors involved in progression to LC were platelet count and the efficacy of IFN therapy. The significant independent factor involved in the development of HCC was platelet count. The factor involved in the therapeutic effect at 6 months after the termination of IFN administration was the serum hepatitis C virus (HCV) RNA levels before IFN therapy. Conclusion: Patients with high HCV RNA levels and low platelet counts should be considered to be at high risk of progressing to LC and developing of HCC and should be carefully followed after IFN therapy using ultrasonography, CT scan and MRI.

The existence of the newly discovered SEN virus (SENV) was investigated in 379 Japanese patients with liver diseases and in 277 blood donors, to determine whether SENV is associated with non-A-E hepatitis. SENV DNA was detected by seminested polymerase chain reaction, with primers directed to 2 SENV strains: SENV-H and SENV-D. SENV was detected in 7 (32%) of 22 patients with fulminant hepatitis, in 15 (17%) of 86 patients with acute hepatitis, in 38 (27%) of 139 patients with chronic hepatitis, in 29 (31%) of 93 patients with liver cirrhosis, in 5 (33%) of 15 patients with autoimmune hepatitis, in 11 (46%) of 24 patients with primary biliary cirrhosis, and in 27 blood donors (10%). Infection occurred more frequently in patients with liver diseases than in blood donors; however, there were no significant differences in SENV-positive rates between patients with non-A-C hepatitis and those with acute or chronic hepatitis due to known hepatitis virus or nonviral liver disease. This study did not suggest SENV as a possible causative agent of non-A-C hepatitis.