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Ammonia is a metabolite of amino acids in dietary proteins. Excess ammonia is toxic to the man body and causes central nervous system dysfunctions. Therefore, it is catabolized into urea, a non-toxic substance, by the urea cycle in the liver. Measurements of blood ammonia levels are used to clinically detect liver dysfunctions; however, the methods currently used to assess ammonia levels have a number of limitations and require complex technical methods as well as expensive analytical instruments. In the present study, we attempted to develop a quick and easy method to detect ammonia using a spectrophotometer. We observed color changes and analyzed the absorption spectrum of aqueous ammonia after the addition of phenol and sodium hypochlorite pentahydrate (NaOCl·5H2O), which is a strong oxidant. We also examined the oxidation reaction of ammonia using liquid chromatography time-of-flight mass spectrometry (LC/TOF-MS). The results obtained showed that aqueous ammonia turned blue in color and showed unique absorption and mass spectra following the addition of phenol and NaOCl·5H2O. This spectrophotometric method may enable ammonia to be detected in sample solutions without expensive analytical instruments or complex methods. アンモニアは，飲食物中のタンパク質に含まれるアミノ酸が体内で代謝される過程で生成される．しかし，過剰なアンモニアは人体にとって毒性が高く，中枢神経系障害を引き起こす．そのため，アンモニアは肝臓における尿素サイクルの働きにより，毒性のない尿素に代謝され尿中に排泄される．このように，アンモニアは肝臓で代謝されるため，血中アンモニア濃度は肝機能を反映する指標の一つとして利用されているが，現在のアンモニア測定法は煩雑な手技や高価な分析装置を必要とする等の制限がある．本研究では，分光光度計を用いた簡易・迅速なアンモニア測定法の開発を目的とし，強力な酸化剤である次亜塩素酸ナトリウム五水和物（NaOCl·5H2O）およびフェノールをアンモニア水に添加後，色調変化の観察や分光法により吸光度を測定した．さらに，液体クロマトグラフィー飛行時間型質量分析（LC/TOF-MS）によりアンモニアの発色反応を解析した．本研究により，フェノールおよびNaOCl·5H2Oを添加したアンモニア水は青色に変化し，特徴的な吸光度およびマススペクトルを示すことが明らかとなった．以上の結果から，高価な分析装置や煩雑な手技を必要とすることなく，検体中のアンモニアを簡易に測定する検査法の開発には，本法が有用である可能性が示唆された．

TAMによる卵巣過剰刺激作用はかねてより問題となっているが，性腺系への作用，経時的変化の実態は明らかになっていない．初発の乳がん患者において術前から術後TAM内服22か月までのホルモン値を測定し，高エストロゲン血症の発症頻度を含む経時的変化を明らかにした．乳腺外科クリニックにて，同意の得られた閉経前ホルモン感受性陽性乳がん患者に対し，術前から術後（4,10,16,22か月）の定期フォロー時エストラジオール（E2），性腺刺激ホルモン（LH，FSH）を測定した．20例の平均年齢は44.9±2.81(40-50)歳であった．術前の月経は19例で順調であり，LH高値のPCOを疑わせる月経不順の1例のみ術前高E2（>400pg/ml）を示した．術後の総測定回数は78回で，そのうち18回（12例）で高E2がみられた．３か月間無月経でも異常高値をみるものが２例あった．今回の検討症例は40代の症例がほとんどであったにもかかわらず，高エストロゲン血症の発生頻度が今まで報告されてきたより多く，患者の年齢により高エストロゲン血症の発症頻度がかわることはなかった．年齢は少なくとも独立した因子ではなく，卵巣の予備能や環境因子の影響が大きいと考える．予想以上に多くの症例でE2は高値を示すことがわかったが，持続して高値を示すことは多くないこともわかった．内膜への影響の報告もあり，TAM治療の際には乳腺外科と婦人科の連携が必須である． Adjuvant hormone therapy for hormone-sensitive breast cancer has established the efficacy of tamoxifen (TAM). TAM is widely used in premenopausal patients. In the present study, hormone levels were measured beginning preoperatively to 22 months after oral administration of TAM in patients with first-episode breast cancer. Changes over time, including the frequency of hyperestrogenism, were evaluated. With patient consent, estradiol (E2) and gonadotropin (luteinizing hormone [LH], follicle-stimulating hormone [FSH]) levels were measured at regular follow-up at 4, 10, 16, and 22 months in premenopausal, hormone-sensitive, positive breast cancer patients treated at a Breast Surgery Clinic. The mean age of 20 patients was 44.9 ± 2.81 (40-50) years. Preoperative menstruation was regular in 19 patients. Only one patient with high LH and suspected polycystic ovary syndrome had high preoperative E2 (>400 pg/mL). The total number of postoperative measurements was 72. Of these, 18 (12 cases) showed high E2. There were two cases in which abnormally high values were observed even after amenorrhea for 3 months. Most of the patients in this study were in their 40s. However, the frequency of hyperestrogenism was higher than previously reported, and the frequency of hyperestrogenism did not change with patient age. Age was at least not an independent factor. However, ovarian reserve and environmental factors are believed to have significant impacts. E2 was high in more cases than expected, but was not often persistently high. Effects on the endometrium have been reported, and breast surgery and gynecological cooperation are essential for TAM treatment.

本稿は, 臨床検査技師として多職種連携に必要なノンテクニカルスキルを概説する．香川県立保健医療大学保健医療学部臨床検査学科の学生対象にノンテクニカルスキルを学習する新授業科目「地域チーム医療論」を紹介する．The present paper reviews the current state of nontechnical skills required for interprofessional collaboration as medical technologists. The authors have developed a new class "Community and Team Medicine" for medical technology students to learn nontechnical skills.

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and administered worldwide. There have been reports of neurological adverse events following immunization (AEFIs). We herein report a case of refractory longitudinally extensive transverse myelitis in a 75-year-old Japanese man following the first dose of the BNT162b2 vaccine. The patient developed total sensory loss below the umbilicus and complete paralysis in both legs. Although he was treated with steroid therapy and plasma exchange, his recovery was limited, and severe sequelae remained. Further studies, including large epidemiological studies, are required to understand the association between SARS-CoV-2 vaccines and neurological AEFI.

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Purpose: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations.Experimental Design: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non–small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases).Results: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%–100%).Conclusions: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies. Clin Cancer Res; 23(3); 757–65. ©2016 AACR.

Supplementary Table 1- List of the 244 cancer related genes of the target capturing panel Supplementary Table 2 - The coverage statistics for each sample of large cell neuroendocrine carcinoma (LCNEC) Supplementary Table 3 - The coverage statistics for each sample of advanced small cell lung cancer (SCLC) Supplementary Table 4 - Validation of the mutations detected in this study using the Oncomine® Cancer Research Panel (OCP) Supplementary Table 5- Primer Sequences: Sanger Sequencing Supplementary Table 6 - Antibody for immunohistochemical staining Supplementary Table 7 - Candidate somatic mutations of large cell neuroendocrine carcinoma (LCNEC) Supplementary Table 8 - Candidate somatic mutations in advanced small cell lung cancer (SCLC) Supplementary table 9 - Hotspot mutations detected in small cell lung cancer (SCLC) Supplementary Table 10- Variant frequency of candidate somatic mutations of large cell neuroendocrine carcinoma (LCNEC) combined with non-small cell lung cancer (NSCLC) Supplementary Table 11- Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analysis for the top six most frequently mutated genes in large cell neuroendocrine carcinoma (LCNEC)

Supplementary methods for Sanger sequencing, copy number analysis with quantitative PCR, and Immunohistochemical staining

Supplementary Figure 1: Representative example of tissue microarray (TMA) punched out from a combined large-cell neuroendocrine carcinoma (LCNEC) with adenocarcinoma. Supplementary Figure 2: Validation of five mutations on the PI3K/AKT/mTOR pathway by Sanger sequencing (LCNEC 68c: PIK3CA E545K, LCNEC 9c: PTEN K342*, LCNEC 13c: PTEN S59*, LCNEC 4c: RICTOR R910H, LCNEC 11p: MTOR E2419K). Supplementary Figure 3: Correlation of gene copy number, calculated using the total depth on the covered region of each of 244 targeted genes and those obtained from the Oncomine® Cancer Research Panel (OCP). Supplementary Figure 4: Validation of the copy number gains or amplifications of 13 samples (8 LCNEC samples, 1 SCLC biopsy samples and 4 SCLC surgically resected cases) for MYCL1, MYC and FGFR1 by a quantitative real-time polymerase chain reaction (qPCR). Supplementary Figure 5: Overview of the key driver alterations and other activating alterations in small cell lung cancer (SCLC). Genetic alterations in the PI3K/AKT/mTOR pathway were detected in 24 (17%) of the tumors: PIK3CA (4%), PTEN (6%), AKT2 (2%) and RICTOR (6%). Copy number gains of each MYC family member were mutually exclusive. Supplementary Figure 6: Relationship between RB1 mutation and IHC staining of RB and p16. The mutual exclusivity of the protein expression between RB and p16 was distinct. Supplementary Figure 7: Relationship between genetic alteration and protein expression in large-cell neuroendocrine carcinoma (LCNEC) of the lung. Comparison of the over expression of receptor tyrosine kinases (RTKs) with the genetic alterations in resected LCNEC specimens (51 of 65 resected cases) revealed no significant relationship between strongly positive RTKs (KIT, EGFR, IGF1R, KDR, ERBB2) expression and genetic alterations.

© 2020 Elsevier Ltd. All rights reserved., Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Amyotrophic lateral sclerosis (ALS) causes deterioration of respiratory function. Muscle weakness of the orbicularis oris interferes with the accurate assessment of respiratory function using spirometry. Reduced forced vital capacity (FVC) is an indicator that helps determine the appropriate timing to provide noninvasive ventilation (NIV) for the survival of ALS patients. We employed ultrasonography to evaluate changes in respiratory function by measuring the thickness of the rectus abdominis (RA) muscle as a possible alternative to spirometry.Sixteen subjects with ALS were included in this study. The thickness of RA muscles was measured using ultrasonography, and respiratory fluctuations, such as vital capacity (VC), FVC, FEVSixteen subjects underwent assessment by ultrasonography. A positive correlation was observed between the percent change in RA muscle thickness evaluated from maximal expiration to maximal inspiration and %VC (RA ultrasonography was useful for predicting a reduction in VC in subjects with ALS and may help determine the best timing for introducing NIV.

BACKGROUND: Levodopa‐carbidopa intestinal gel (LCIG) therapy is used in advanced Parkinson's disease (PD) and consists of continuous administration of levodopa directly into the jejunum through a percutaneous endoscopic gastro‐jejunal (PEG‐J) tube. Recently, the metabolism of levodopa by Enterococcus faecalis (E. faecalis) has been reported. Intestinal bacteria can also affect this therapy. OBJECTIVES: To investigate intestinal bacteria and examine its impact on levodopa blood concentration in patients with PD receiving LCIG therapy. METHODS: We enrolled 6 patients receiving LCIG therapy in our department. After PEG‐J tube replacement, intestinal bacteria were collected from the tip of the tube and were identified using culture and polymerase chain reaction (PCR) tests. Moreover, the presence of tyrosine decarboxylase, which metabolizes levodopa, was also confirmed by PCR test. The ability of these bacteria to metabolize levodopa was confirmed in vitro. Levodopa blood concentrations were also examined before PEG‐J tube replacement. RESULTS: Bacteria were detected in all 6 patients. E. faecalis was present in 4 patients. Moreover, tyrosine decarboxylase was detected in 2 patients. The identified bacteria displayed in vitro metabolization to dopamine in the 4 E. faecalis positive samples. The addition of carbidopa did not inhibit the metabolism of levodopa. However, there was no difference in the mean blood concentration of levodopa, regardless of the presence of E. faecalis. CONCLUSIONS: We found bacteria, including E. faecalis in the PEG‐J tube. We observed levodopa metabolism in vitro, but there was no association with levodopa blood concentration. The effect of intestinal bacteria may be limited in patients receiving LCIG therapy.

We investigated the relationship between sleep disturbances and 123I-meta-iodobenzylguanidine (MIBG)-uptake during myocardial scintigraphy in patients with Parkinson’s disease (PD). We studied consecutive PD patients who underwent MIBG scintigraphy at our institution. Collected data included Hoehn and Yahr (HY) stage, the heart/mediastinum (H/M) ratio of MIBG scintigraphy, Epworth Sleepiness Scale score, PD Sleep Scale (PDSS)-2 score (total PDSS-2 score and its three subscales: motor problems at night, PD symptoms at night, and disturbed sleep), levodopa daily dose, total levodopa-equivalent daily dose (LEDD), and LEDD of dopamine agonists. We determined the specific binding ratio (SBR) in patients who underwent DaTSPECT to examine the relationship between each sleep disturbance scale and SPECT changes and the other evaluated items. We examined 31 patients with PD. There was a significant negative correlation between the H/M ratio and the score for disturbed sleep. The more the decreased the cardiac MIBG uptake, the higher the score for disturbed sleep (p = 0.040). There was no correlation between the H/M ratio and other sleep scales. The HY stage correlated with the score for PD symptoms at night (p = 0.0244), but not with other sleep scales. Twenty-one patients were evaluated by DaTSPECT; there was no correlation between SBR and any other scores used to evaluate sleep disturbances. The score for disturbed sleep on the PDSS-2 is mainly related insomnia symptoms. Thus, MIBG myocardial scintigraphy detects the severity of sleep disturbance in PD patients.

Objective Assessing daily motor fluctuations is an important part of the disease management for patients with Parkinson's disease (PD). However, the frequent recording of subjective and/or objective assessments is not always feasible, and easier monitoring methods have been sought. Previous studies have reported that the spontaneous eye-blink rate (EBR) is correlated with the dopamine levels in the brain. Thus, the continuous monitoring of the EBR may be useful for predicting the motor status in patients with PD. Methods Electrooculograms (EOGs) were recorded for up to 7.5 hours from three PD patients using a wearable device that resembled ordinary glasses. An receiver operating characteristic (ROC) analysis was performed to compare the ability of the EBR estimates at each time-point (Blink Index) and the plasma levodopa levels to predict the motor status. Results The Blink Index was correlated with the plasma levodopa levels. When an indicator for the first hour of the observation period was included in the model, the Blink Index discerned wearing-off and dyskinesia as accurately as the plasma levodopa level. Conclusion Our study provides preliminary evidence regarding the utility of continuous EBR monitoring for the non-invasive evaluation of the motor status in patients with PD.

There is some phenotypic overlap between MS, AQP4-IgG positive NMOSD, and MOG-IgG associated disease (MOGAD), and distinguishing a true relapse and a pseudorelapse can be difficult. CSF neopterin, a marker of inflammation-immune-mediated processes in the CNS, may be a useful marker in a wide range of CNS infectious and inflammatory diseases. We compared CSF neopterin levels and other CSF parameters in patients with MS, AQP4-IgG-positive NMOSD, and MOGAD and also investigated whether CSF neopterin levels can distinguish between active and inactive phases of the diseases.We retrospectively reviewed the medical records of 22 patients with MS, 18 with AQP4-IgG-positive NMOSD, and five with MOGAD. CSF neopterin concentrations were measured by HPLC with fluorometric detection.CSF neopterin levels at diagnosis were significantly higher in patients with AQP4-IgG-positive NMOSD (52.77 ± 34.56 pmol/mL) than patients with MS (16.92 ± 5.03 pmol/mL, p 0.001), and tended to be higher in patients with MOGAD (28.87 ± 9.66 pmol/mL) than patients with MS (p = 0.092). ROC analysis revealed that CSF neopterin most accurately discriminated between MS and AQP4-IgG-positive NMOSD (AUC, 0.912; sensitivity, 75.0%; specificity, 100.0%). At diagnosis/relapse and during remission, CSF neopterin most accurately discriminated between the disease phases in patients with MS (AUC, 0.779; sensitivity, 58.1%; specificity, 94.7%) and patients with AQP4-IgG-positive NMOSD (AUC, 0.934; sensitivity, 83.3%; specificity, 94.1%).Measurement of CSF neopterin may be useful for differential diagnosis and assessment of disease activity in CNS demyelinating diseases. Further studies with larger cohorts, including comparisons with other biomarkers, are needed to validate the utility of CSF neopterin.

Introduction Some patients with Parkinson's disease (PD) undergoing levodopa‒carbidopa intestinal gel (LCIG) treatment experience motor fluctuations in the afternoon. The migrating motor complex, a specific periodic migrating contraction pattern occurring in the stomach and small intestine during the fasting state, can affect drug absorption. We aimed to compare the pharmacokinetic parameters between two conditions (with and without lunch) and assessed the influence of the fasting state on the levodopa pharmacokinetics in LCIG treatment. Methods We evaluated the levodopa pharmacokinetics from 12:00 p.m. to 6:00 p.m. in 10 LCIG-treated PD patients in the presence and absence of lunch. Results The maintenance dose of LCIG correlated strongly with the mean plasma concentration of levodopa in the absence (r = 0.94, coefficient of determination (R2) = 0.89, p Conclusions Plasma concentrations of levodopa fluctuated more in patients undergoing LCIG treatment without than with lunch. Our results indicate that a small amount of food intake may be a better corrective approach for worsening of symptoms in the fasting state rather than additional levodopa.

Rheumatoid meningitis (RM) is a rare but treatable central nervous system (CNS) manifestation of rheumatoid arthritis (RA) with various clinical presentations and atypical cerebrospinal fluid (CSF) findings. There are no established biomarkers for RM, making diagnosis a challenge. Herein, we present three cases of RM: two patients with RA diagnosis and one without. CSF analysis showed pleocytosis in only one case. In contrast, CSF neopterin levels were elevated in all three cases and decreased after steroid therapy. This study suggests that CSF neopterin levels may be a useful biomarker for diagnosing and therapeutically monitoring CNS inflammation in patients with RM.

Myoclonus epilepsy associated with ragged-red fibers (MERRF) is traditionally characterized by myoclonus, generalized epilepsy and ragged-red fibers. We herein report a 42-year-old man who complained of falling after starting running, symptoms resembling those of paroxysmal kinesigenic dyskinesia. He showed only slight muscle weakness of the right quadriceps femoris. Muscle pathology and a genetic analysis identified him as having MERRF with a 8344A>G mtDNA mutation. We diagnosed his symptoms as having been caused by slight quadriceps femoris muscle weakness and exercise intolerance. This case suggests that mitochondrial myopathy should be considered in cases with strong muscle symptoms for muscle weakness.

A 20-year-old woman suffered right facial paralysis. The patient showed an abnormality in the perception of speech at an age of 25 years. At an age of 32 years, she developed acute headache and fever. Brain magnetic resonance imaging (MRI) showed an expanded high signal intensity lesion with gadolinium enhancement in the white matter of the left frontal lobe, which was suggestive of tumefactive demyelinating lesion (TDL). A brain tumor was suspected because TDL is a large demyelinating brain lesion mimicking a primary brain tumor. After initiation of steroid therapy, the symptoms and MRI abnormalities improved. At an age of 34 years, she was referred to our hospital with the main complaint of weakness of lips on the left side. Brain MRI showed hyperintense lesions involving the left frontal and the right parietal white matter lobes, and the left ventrolateral pons, which was suggestive of acute disseminated encephalomyelitis (ADEM). Analysis of anti-MOG antibodies identified anti-MOG antibodies both in the serum and in the CSF. Steroid therapy led to complete clinical recovery. MOG antibodies in both serum and CSF were negative six months after the previous measurement. The patient fulfilled the diagnostic criteria for multiple sclerosis (MS) and TDL is one of the rare variants of MS. This study suggests that anti-MOG antibodies can be associated with repetitive encephalitis including TDL and ADEM-like presentation.

Introduction Although spinocerebellar ataxia type 2 (SCA2) is classified as hereditary spinocerebellar degeneration, some patients present with parkinsonism before developing cerebellar ataxia. Methods 123 I-metaiodobenzyl guanidine ( 123 I-MIBG) myocardial scintigraphy and/or dopamine transporter single photon emission computed tomography (DAT SPECT) using 123 I-ioflupane ( 123 I-FP-CIT) were performed for the six patients from three SCA2 families. Results 123 I-MIBG myocardial scintigraphy showed reduced cardiac uptake in four of five patients and an association with Lewy body disease was suggested. DAT SPECT showed decreased uptake in the striatum in all four patients who were scanned, including one patient without parkinsonism. When patterns of uptake were compared to those with Parkinson's disease, most of the patients had minimal reduction of uptake in the putamen. Conclusion DAT SPECT is expected to be useful in differentiating SCA2 from Parkinson's disease, making an early diagnosis, and allowing early therapeutic intervention.

Highlights • LHON cases can show brainstem lesions without visual impairment. • There can be inconsistency between MRI finding and clinical symptom in LHON cases. • Auditory pathways may be often involved in LHON cases.

Background Duloxetine proved effective for treating pain in people with Parkinson's disease in a single-arm, open-label study. Objective To evaluate the efficacy of duloxetine in a double-blind, randomized, placebo-controlled trial. Methods We randomly assigned 46 patients with Parkinson's disease with pain to either the duloxetine 40 mg/day arm or the placebo arm. After 10 weeks, we tested the change from baseline in 24-hour average pain severity measured by a visual analogue scale. Results We could not confirm the effect of duloxetine on pain. Exploratory analyses indicated that treatment with duloxetine was associated with improved scores on the Unified Parkinson's Disease Rating Scale Part III and 3 domains of the Parkinson's Disease Questionnaire – 39. Conclusions The study failed to provide evidence for the use of duloxetine for treating pain in people with Parkinson's disease.

Background Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder associated with spinal motor neuron loss and characterized by generalized muscle weakness. Only a few reports exist on SMA epidemiology in Japan. Additionally, nusinersen recently became available as a treatment for this condition. We estimated the prevalence of each type of SMA on Shikoku, Japan’s fourth-largest major island. Methods We sent a questionnaire to all 131 hospitals in Shikoku that have pediatrics or neurology departments from March to September 2019, asking whether each hospital had SMA patients at that time. If so, we sent a second questionnaire to obtain more detailed information on the clinical data and treatment of each patient. Results A total of 117 hospitals (89.3%) responded to our first questionnaire, and 21 SMA patients were reported, 16 of whom had homozygous deletion of SMN1. Of the 21, nine had SMA type 1, five were type 2, five were type 3, one was type 4, and one was unidentified. The estimated prevalence for all instances of SMA and 5q-SMA was 0.56 and 0.43 per 100,000 people, respectively. Thirteen patients had received nusinersen therapy. Its outcomes varied from no obvious effects and being unable to sit to being able to sit independently. Conclusion Our data showed the prevalence of SMA types 2 and 3 was relatively low on Shikoku compared with previous reports from other countries, suggesting delayed diagnosis may affect the results. Remaining motor function may be one predicting factor. Greater awareness of SMA among clinicians and patients seems necessary for more accurate epidemiological studies.

Background We investigated a high-throughput and high-precision forward ABO blood typing screening method that utilizes a general-purpose biochemical analyzer to perform direct red blood cell sampling. Methods The blood group antisera used were Ortho® BioClone® Anti-A Serum and Ortho® BioClone® Anti-B Se-rum. AFFIRMAGEN® Reagent Red Blood Cells (Ortho Clinical Diagnostics) were used for AB standard red blood cells. The general-purpose biochemical analyzer employed was the TBATM-120FR HbA1c measurement unit (Canon Medical Systems). Results ABO blood group of patient samples was determined based on values relative to amount of change in the AFFIRMAGEN® response. Repeatability was CV5% or lower, and testing of 1,112 patient samples showed 100% agreement between the results obtained using the proposed method and those obtained using the tube test method. Conclusions The proposed method allows ABO blood typing to be performed simply, quickly, and with a high degree of precision.

Austrian syndrome is a rare condition caused by invasive Streptococcus pneumoniae, comprising a triad of pneumococcal meningitis, endocarditis, and pneumonia. Herein, we report a 59-year-old male patient who presented with fever and tenderness of the right shoulder. Although the initial diagnosis was acromioclavicular joint septic arthritis, the present case showed a reduced level of consciousness, pulmonary infiltrates, cerebral infarcts, and destruction of the mitral valve. This case suggests that acromioclavicular joint arthritis could be an initial presentation of pneumococcal infection inclusive of Austrian syndrome, especially in patients with some risk factors of invasive pneumococcal infections, such as chronic alcoholism.

Background Epidemiological studies have repeatedly reported that increased serum urate level is associated with a slower progress of Parkinson's disease (PD). The urate precursor, inosine, raises the serum urate level and is therefore a candidate for a disease modifying treatment. However, an elevated serum urate level is a risk factor for gout, urolithiasis, and cardiovascular diseases. Although there have been previous clinical studies, the use of inosine in a clinical setting is still limited, and its safety is unclear, especially in an Asian population. Methods We conducted a single-arm, single-center clinical trial to assess the safety of inosine for PD patients with relatively low urate levels. After informed consent, 10 subjects were orally administered inosine to maintain a target urate level between 6.0 mg/dl and 8.0 mg/dl for one year. All adverse effects were recorded and categorized by severity. Also, the efficacy of using inosine to raise the serum urate level was reported. Results We did not observe any adverse events requiring termination or reduction of the study drug, although uric acid crystalluria was transiently observed in a single subject. An inosine dosage of 1070 (SD = 501) mg/day significantly raises the urate level from 3.5 (0.84) mg/dl at baseline to 6.68 (1.11) mg/dl at the 52nd week. Conclusions Inosine was safely used for one year and effectively raised urate levels in a small group of subjects. Our study is the first report to use inosine for patients with PD in an Asian population.

Background Biopyrrins are end products of oxidation reactions of bilirubin with reactive oxygen, and urinary biopyrrin (UBP) levels might increase under oxidative stress. The authors examined the reference UBP level for healthy adults and its physiological variation in 40 healthy volunteers recruited from among students of our university (20 students each from third-year and fourth-year), and compared the results with data on 8-hydroxy-2-deoxyguanosine (8OHdG). Methods UBP and 8OHdG levels could be considered as oxidative stress markers. The UBP levels were measured with a competitive ELISA kit using biopyrrin antibody 24G7, according to the manufacturer's protocol. 8OHdG levels were measured with a Highly Sensitive 8-OHdG Check kit. UBP and 8OHdG measurements were performed in triplicate and means values calculated. For both parameters, creatinine (Cr) correction was performed using urinary creatinine levels measured by an enzymatic method. Results A comparison of the UBP levels between different grades revealed that the third-year students under high stress from clinical training and other course work tended to have a higher UBP level than fourth-year students. Therefore, we compared the current UBP levels in fourth-year students (samples collected in 2018) with their UBP level when they were in the third-year (samples collected in 2017) to examine the annual change. We found that the UBP level in 2017 samples was significantly higher than that in 2018 samples (P < 0.05). No difference in the 8OHdG level. Additionally, no effect of menstrual stress on the UBP level was observed. Conclusions These results suggest that the UBP levels may be related to school-related stress and menstruation has no effects on urinalysis results., Health Professions; Biological Sciences; Analytical chemistry; Oxidative Stress; Quality of Life; Occupational Health; Educational Psychology; Health Education; urinary biopyrrins, 8OHdG, oxidative stress, reference value, school-related stress

Myoclonus epilepsy associated with ragged-red fibers (MERRF) is traditionally characterized by myoclonus, generalized epilepsy and ragged-red fibers. We herein report a 42-year-old man who complained of falling after starting running, symptoms resembling those of paroxysmal kinesigenic dyskinesia. He showed only slight muscle weakness of the right quadriceps femoris. Muscle pathology and a genetic analysis identified him as having MERRF with a 8344AG mtDNA mutation. We diagnosed his symptoms as having been caused by slight quadriceps femoris muscle weakness and exercise intolerance. This case suggests that mitochondrial myopathy should be considered in cases with strong muscle symptoms for muscle weakness.

Purpose: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations. Experimental Design: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non–small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases). Results: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%–100%). Conclusions: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies. Clin Cancer Res; 23(3); 757–65. ©2016 AACR.

To minimize patient suffering, the smallest possible volume of blood should be collected for diagnosis and disease monitoring. When estimating insulin secretion capacity and resistance to insulin in diabetes mellitus (DM), increasing insulin assay immunosensitivity would reduce the blood sample volume required for testing. Here we present an ultrasensitive ELISA coupled with thio-NAD cycling to measure immunoreactive insulin in blood serum. Only 5 µL of serum was required for testing, with a limit of detection (LOD) for the assay of 10−16 moles/assay. Additional recovery tests confirmed this method can detect insulin in sera. Comparisons between a commercially available immunoreactive insulin kit and our ultrasensitive ELISA using the same commercially available reference demonstrated good data correlation, providing further evidence of assay accuracy. Together, these results demonstrate our ultrasensitive ELISA could be a powerful tool in the diagnosis and treatment of not only DM but also many other diseases in the future.

According to Sidonius Apollinaris, Anianus was the bishop of Orleans and the defender of the city against the attack of the Huns under Attila in 4 51.1 This paper will examine the process of the development of Anianus's cult in the Carolingian period. Who evolved the cult? How did they do so? Many scholars have referred to the deeds of Anianus and the history of Saint-Aignan, the focal point of his cult in Orleans.2 In the view of modern scholarship, however, Genevieve Renaud has made great progress in studying the cult of Anianus. She has completed the list of the hagiographical texts on Anianus and their manuscripts, and has dated each composition. Moreover, she has located the trace of his cult and concluded that it spread all over modern France, especially in the former dioceses of Orleans, Bourges, and Chartres, and his legend had achieved its full development before the end of tenth century or at the latest by the beginning of the eleventh century. However, she has hardly stated the concrete situations behind the process of its development.3 Recently, Thomas Head has studied the cult of Anianus in his systematic research on the cult of saints in the Orleanais though he seems to be more concerned about monastic saints than episcopal ones like Anianus. He enumerates the promoters of Anianus's cult. The shrine of Anianus was "apparently under the control of the Gallo-Romans" in the times of Gregory of Tours. Queen Balthild "supported the reform of the house of Saint-Aignan" in the seventh century.4 "The Robertians directly controlled the monastery of Saint-Aignan throughout the tenth century."5 Then, who were the promoters in the eighth and the ninth centuries? This paper will contribute to fill the gap of the previous scholarship, as mentioned above, and then will examine how the cult of Anianus was evolved in the Carolingian period. St. Anianus had already gained a reputation by the seventh century, but his cult experienced great progress in the Carolingian period. Charlemagne and Bishop Theodulf of Orleans seem to have refurbished and extended the shrine of Saint-Aignan.6 Such behavior did not merely mean material re-foundation but contributed to the veneration for saints because shrines were thought of as the extension of their coffins. Theodulf devoted himself to prayers on the altar dedicated to the saint.7 In 814 and 818, Louis the Pious visited Saint-Aignan and asked the saint for his own protection.8 The emperor's visits must have heightened the saint's reputation. Sometime in the first half of the ninth century, canons of the cathedral chapter wrote the First Life of St. Evurtius and second Life of St. Evurtius? The author of the latter called himself Subdeacon Lucifer. These lives admire the deeds of Anianus alongside of Evurtius, the fourth-century bishop of Orleans. In 854, Bishop Agius of Orleans gave Saint-Aignan permission to build a new churchyard in the east suburbs of the city.10 This new cemetery could accommodate the gradually increasing people who wished to get to eternal rest with Anianus. Around 870, Bishop Walter instructed his priests to observe the feast of Anianus as well as those of other saints. [The priests] should observe the celebrated feasts of the saints with solemn cult and should know them beforehand to let people observe themiThat is the natal day of the Lord, [the feasts] of Blessed Stephen, of St. John the Evangelist, of the Innocents, the octave of the Lord, the Epiphany, the nativity of Holy Mary, the purification of Holy Mary, the Assumption of Holy Mary, Holy Saturday the octave of Easter, the Rogation Days, the Ascension of the Lord, Pentecost, [the feasts] of St. John the Baptist, of St. Peter, of St. Paul, of St. Martin, and of St. Andrew, as well as [the feasts] of our fathers, by whose pious local patronage we are assisted in the presence of the Lord, [that is] of the death of Blessed Evurtius, of the death of Blessed Anianus, of Blessed Benedict, of Blessed Maximinus, similarly of the death of Blessed Lifardus, and of the invention of the Cross bringing eternal bliss and of the exaltation of the same Cross vivifying people. …

Objective— The abundance of HDL particles correlates inversely with the incidence of coronary heart disease. The human scavenger receptor B1 (hSR-B1/CLA-1) is a receptor for HDL. Expression of hSR-B1/CLA-1 mRNA and protein in human platelets was determined using reverse transcriptase–polymerase chain reaction and Western blot, respectively. Presence of the protein on the surface of platelets was shown using flow cytometry. Methods and Results— Immunochemical staining for hSR-B1/CLA-1 showed that it was expressed in megakaryocytes, the platelet precursors of human bone marrow. These findings prompted us to ask whether hSR-B1/CLA-1 was differentially expressed on platelets obtained from patients with atherosclerotic disease compared with those in control subjects. Our findings showed that abundance of hSR-B1/CLA-1 was significantly reduced on the surface of platelets from patients with atherosclerotic disease. The reduced levels of hSR-B1/CLA-1 were associated with increased cholesterol ester content in platelets from patients with atherosclerotic disease compared with control subjects. A negative correlation existed between hSR-B1/CLA-1 expression and platelet aggregation. In summary, our studies show that the HDL receptor hSR-B1/CLA-1 is expressed in platelets and their precursor, the megakaryocyte. The levels of hSR-B1/CLA-1 expression correlate inversely with cholesterol ester content and platelet aggregation. Conclusion— These findings suggest that determining the level of hSR-B1/CLA-1 expression on the platelets may be a useful clinical marker for atherosclerotic diseases.

The bishops of Liège became concerned with Christianisation throughout the whole diocese in the Carolingian period. This study examines the concrete measures that they took. The field chosen is the Ardennes region in the south of the diocese, where they reorganised the abbey of St-Hubert as a religious centre. The bishops reformed the community and offered it economic support. They also encouraged the cult of St Hubert and introduced the new custom of annual processions. This approach throws light on the pastoral situation in a way that their episcopal capitularies cannot.

GaAs semiconducting microtips for scanning tunneling microscopy (STM) were fabricated by a wet etching method. A solution of H 3 PO 4 -H 2 O 2 -H 2 O (10 :1 :1) and an etching temperature of 5°C were chosen to fabricate a sharp GaAs point. The apex of the GaAs tip was constructed of four {150} facets, and the radius of curvature at the top was less than about 50 nm. The surface of the GaAs tip was passivated by sulfur atoms by dipping it into (NH 4 ) 2 S x and annealing at 400°C. Using the GaAs tip with sulfur passivation, a stable tunneling current was obtained even in air. As a result, a clear atomic arrangement was observed repeatedly in STM imaging of a graphite surface.

We conducted a quantitative study of an animal community associated with clumps of submerged drifting algae on a sand/mud bottom at Fildes Bay, King George Island. The algae clumps were found at depths between 5 and 20 m in the inner part of the bay. The clumps mainly consisted of Desmarestia anceps covering about 5% of the bottom. A large number of a nemertinean (0-220 individuals/m^2), Nacella concinna (0-65 individuals/m^2), Glyptonotus antarcticus (adults 0-8 individuals/m^2, juvenile 0-80 individuals/m^2) and gammaridean amphipods (490-25020 individuals/m^2) were found associated with the clumps. Schools of Trematomus newnesi young (0-18 individuals/m^2) hovered over the clumps. Stomach contents of T. newnesi consisted mainly of gammaridean amphipods. The algae clump seemed to be an important habitat as a nursery ground for G. antarcticus and T. newnesi.

From 1991 to 1993 we conducted underwater observations on communities of fish and epibenthic invertebrates four times during the austral summer in Fildes Bay, King George Island Antarctica. We defined eight distinctive habitat types in the inshore areas (depths between 0 and 40 m), each having a characteristic community of fish and epibenthic invertebrates. Species compositions of animal communities varied according to the bottom substrates, depths and the presence or absence of macroalgal colonies. The habitat types of the major animal species are described, and characteristics of each habitat type and its faunal composition are noted.