A Proposal for New Algorithm that Defines Gait-Induced Acceleration and Gait Cycle in Daily Parkinsonian Gait Disorders

We developed a new device, the portable gait rhythmogram (PGR), to record up to 70 hrs of movement-induced accelerations. Acceleration values induced by various movements, averaged every 10 min, showed gamma distribution, and the mean value of this distribution was used as an index of the amount of overall movements. Furthermore, the PGR algorithm can specify gait-induced accelerations using the pattern-matching method. Analysis of the relationship between gait-induced accelerations and gait cycle duration makes it possible to quantify Parkinson’s disease (PD)-specific pathophysiological mechanisms underlying gait disorders. Patients with PD showed the following disease-specific patterns: (1) reduced amount of overall movements and (2) low amplitude of gait-induced accelerations in the early stages of the disease, which was compensated by fast stepping. Loss of compensation was associated with slow stepping gait, (3) narrow range of gait-induced acceleration amplitude and gait cycle duration, suggesting monotony, and (4) evident motor fluctuations during the day by tracing changes in the above two parameters. Prominent motor fluctuation was associated with frequent switching between slow stepping mode and active mode. These findings suggest that monitoring various movement- and gait-induced accelerations allows the detection of specific changes in PD. We conclude that continuous long-term monitoring of these parameters can provide accurate quantitative assessment of parkinsonian clinical motor signs

Long-term efficacy and safety of canagliflozin in combination with insulin in Japanese patients with type 2 diabetes mellitus

Aim: The aim of this study was to assess the long-term efficacy and safety of canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus who had inadequate glycaemic control with insulin. Materials and methods: The study comprised a 16-week, double-blind period in which patients were randomized to either placebo (P; N = 70) or canagliflozin (100 mg, CAN; N = 76), followed by a 36-week open-label period in which all patients received canagliflozin. The efficacy endpoints included the change in HbA1c from baseline to end of treatment. The safety endpoints were adverse events, hypoglycaemic events, and laboratory test values. Results: The changes from baseline (mean ± standard deviation, last observation carried forward) in the P/CAN and CAN/CAN groups, respectively, were −1.09% ± 0.85% and −0.88% ± 0.86% for HbA1c, −1.40% ± 2.54% and −2.14% ± 2.75% for body weight, and 7.84% ± 14.37% and 8.91% ± 10.80% for HOMA2-%B (all, P < .001). Adverse events occurred in 85.1% of the P/CAN group and 92.0% of the CAN/CAN group. Hypoglycaemic events occurred in 43.3% and 54.7%, respectively. All hypoglycaemic events were mild in severity and insulin dose reduction decreased the incidence rate of hypoglycaemic events. Post-hoc ordinal logistic modelling/logistic modelling showed that lower serum C-peptide at Week 0 was a risk factor for hypoglycaemia in both the P and CAN groups in the double-blind period as well as in the canagliflozin all-treatment period. Conclusions: This study demonstrates the long-term efficacy and safety of canagliflozin combined with insulin in Japanese patients

Characteristics of Patent Ductus Arteriosus in Congenital Rubella Syndrome

This study investigated the characteristics of congenital rubella syndrome (CRS)-associated cardiac complications, particularly patent ductus arteriosus (PDA). We reviewed the medical records of patients with CRS who were admitted to the Children’s Hospital 1 in Vietnam between December 2010 and December 2012, and patients with CRS who underwent PDA transcatheter occlusion therapy at the cardiology department between December 2009 and December 2015. We compared the characteristics of PDA treated with transcatheter closure between children with CRS (CRS-PDA) and those without CRS (non-CRS-PDA) who underwent PDA transcatheter closure between July 2014 and December 2015. One-hundred-and-eight children with CRS were enrolled. Cardiac defects (99%), cataracts (72%), and hearing impairment (7%) were detected. Fifty CRS-PDA and 290 non-CRS-PDA patients were examined. CRS-PDA patients had smaller median birthweight (p < 0.001), more frequent pulmonary (p < 0.001) and aortic stenosis (p < 0.001), higher main pulmonary artery pressure, and higher aortic pressure in systole/diastole (p < 0.001 for each) than did non-CRS-PDA patients. The proportion of tubular-type PDA was higher in CRS-PDA patients (16%) than in non-CRS-PDA patients (3%) (p = 0.020). Tubular-type PDA was frequently seen in patients with CRS and accompanied by pulmonary/systemic hypertension and pulmonary/aortic stenosis; in these patients, more cautious device selection is needed for transcatheter PDA closure

Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy

none67si: Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities.This work was supported by Telethon Grant GGP15171 to E.B. and R.D.G. and by a donation from Kobe city to the Department of General Pediatrics, Kobe University Graduate School of Medicine (K550003302). S.C. was supported by a Dutch Cancer Foundation grant (KWF11011). V.C. and A.M. were supported by the Italian Ministry of Health (“Ricerca Corrente” funding). R.D.G. is the recipient of grants from University of Ferrara (FAR and FIR funds).openBonora, Elena; Chakrabarty, Sanjiban; Kellaris, Georgios; Tsutsumi, Makiko; Bianco, Francesca; Bergamini, Christian; Ullah, Farid; Isidori, Federica; Liparulo, Irene; Diquigiovanni, Chiara; Masin, Luca; Rizzardi, Nicola; Cratere, Mariapia Giuditta; Boschetti, Elisa; Papa, Valentina; Maresca, Alessandra; Cenacchi, Giovanna; Casadio, Rita; Martelli, Pierluigi; Matera, Ivana; Ceccherini, Isabella; Fato, Romana; Raiola, Giuseppe; Arrigo, Serena; Signa, Sara; Sementa, Angela Rita; Severino, Mariasavina; Striano, Pasquale; Fiorillo, Chiara; Goto, Tsuyoshi; Uchino, Shumpei; Oyazato, Yoshinobu; Nakamura, Hisayoshi; Mishra, Sushil K; Yeh, Yu-Sheng; Kato, Takema; Nozu, Kandai; Tanboon, Jantima; Morioka, Ichiro; Nishino, Ichizo; Toda, Tatsushi; Goto, Yu-Ichi; Ohtake, Akira; Kosaki, Kenjiro; Yamaguchi, Yoshiki; Nonaka, Ikuya; Iijima, Kazumoto; Mimaki, Masakazu; Kurahashi, Hiroki; Raams, Anja; MacInnes, Alyson; Alders, Mariel; Engelen, Marc; Linthorst, Gabor; de Koning, Tom; den Dunnen, Wilfred; Dijkstra, Gerard; van Spaendonck, Karin; van Gent, Dik C; Aronica, Eleonora M; Picco, Paolo; Carelli, Valerio; Seri, Marco; Katsanis, Nicholas; Duijkers, Floor A M; Taniguchi-Ikeda, Mariko; De Giorgio, RobertoBonora, Elena; Chakrabarty, Sanjiban; Kellaris, Georgios; Tsutsumi, Makiko; Bianco, Francesca; Bergamini, Christian; Ullah, Farid; Isidori, Federica; Liparulo, Irene; Diquigiovanni, Chiara; Masin, Luca; Rizzardi, Nicola; Cratere, Mariapia Giuditta; Boschetti, Elisa; Papa, Valentina; Maresca, Alessandra; Cenacchi, Giovanna; Casadio, Rita; Martelli, Pierluigi; Matera, Ivana; Ceccherini, Isabella; Fato, Romana; Raiola, Giuseppe; Arrigo, Serena; Signa, Sara; Sementa, Angela Rita; Severino, Mariasavina; Striano, Pasquale; Fiorillo, Chiara; Goto, Tsuyoshi; Uchino, Shumpei; Oyazato, Yoshinobu; Nakamura, Hisayoshi; Mishra, Sushil K; Yeh, Yu-Sheng; Kato, Takema; Nozu, Kandai; Tanboon, Jantima; Morioka, Ichiro; Nishino, Ichizo; Toda, Tatsushi; Goto, Yu-Ichi; Ohtake, Akira; Kosaki, Kenjiro; Yamaguchi, Yoshiki; Nonaka, Ikuya; Iijima, Kazumoto; Mimaki, Masakazu; Kurahashi, Hiroki; Raams, Anja; MacInnes, Alyson; Alders, Mariel; Engelen, Marc; Linthorst, Gabor; de Koning, Tom; den Dunnen, Wilfred; Dijkstra, Gerard; van Spaendonck, Karin; van Gent, Dik C; Aronica, Eleonora M; Picco, Paolo; Carelli, Valerio; Seri, Marco; Katsanis, Nicholas; Duijkers, Floor A M; Taniguchi-Ikeda, Mariko; De Giorgio, Robert

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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