Therapeutic Effects of a Sodium Glucose Cotransporter 2 Inhibitor in Diabetic Patients with Chronic Kidney Disease

Multiple large-scale clinical trials have indicated that sodium glucose cotransporter 2（SGLT2）inhibitors reduce the incidence of cardiovascular events, deterioration of renal function and mortality. However, the therapeutic effects of SGLT2 inhibitors are supposed to be limited in patients with reduced renal function considering the mechanism of their action. In this study, a SGLT2 inhibitor, ipragliflozin was given to 30 type 2 diabetic patients with nephropathy whose estimated glomerular filtration rate（eGFR）was not lower than 30 mL/min/1.73 m2. After 12 to 16 weeks, hemoglobin A1c decreased by 0.6％（p＜0.001）, body weight was reduced by 1.8 kg（p＜0.01）and blood pressure was lowered by －10/－6 mmHg（p＜0.001/p ＜0.001）. This was accompanied by reductions in serum uric acid（－0.7 mg/dL, p＜0.001）, triglycerides （－25 mg/dL, p＝0.028）and g-glutamyl transferase（－8 U/L, p＝0.001）. On the other hand, plasma B-type natriuretic peptide also decreased by 12％（p＝0.020）and urinary albumin excretion was reduced by 23％ （p＝0.018）although the eGFR was not significantly changed. It is concluded that ipragliflozin is effective in lowering blood glucose even in patients with diabetic kidney disease and is beneficial in improving theaccompanying obesity and hypertension. In addition, ipragliflozin is thought to have favorable influences on the metabolisms of uric acid and lipids. These properties of ipragliflozin is expected to bring about protective effects against the progression of nephropathy and the development of cardiovascular disease resulting in the improvement of prognosis in diabetic patients with mild to moderate chronic kidney disease

悩みへの否定的構え尺度の信頼性と妥当性の検討

本研究では，「悩みへの否定的構え尺度」の信頼性・妥当性を検討した。本尺度は，専門家による心理相談のもつ特徴から，特に主訴の形成に関わる個人内要因に焦点をあて，自分の悩みの捉えにくさ及び悩みへの否定的認識を測定するものとして開発されたものである。今後，より広い対象に実施できるよう大学生280 名と社会人498 名を調査対象とした。確認的因子分析，多母集団因子分析から一因子構造が確認され，内的一貫性と再検査法により一定の信頼性が確認できた。さらに，心理的過程への関心や洞察の能力を測る心理学的心性と，自身の悩みとの適切な距離・保持の仕方や積極的な捉え方を測る悩み体験スケールとの関連から構成概念妥当性が確認された。これらの結果から，本尺度が自分の悩みに対する態度を明らかにするためにおおむね妥当な尺度であると示された。最後に本研究の限界と今後の展望が示された。We developed the Negative Attitudes Regarding Own Worries Scale to assess factors related to perception of individuals’ psychological processes, and examined the reliability and validity of the scale. The scale assessed difficulties in recognizing a person’s worries and the negative perception of worries. University students (n = 280) and adults (n = 498) responded to the reseach. These responses were analyzed using exploratory and comfirmatory factor analisys, and multi-population factor analysis, which confirmed the one-factor structure of the scale. The adequate reliability of the scale was confirmed by the internal consistency and the test-retest reliability of the scale. Furthermore, the scale\u27s construct validity was assessed by the Psychological Mindedness Scale and the Experience in Being Worried Scale. The overall results indicated that this scale is valid for identifying attitudes about a person’s worries. Finally, the limitations and future research directions are discussed

日本語版「専門家による心理的援助を求める態度尺度 (ATSPPH-S)」の信頼性・妥当性の検討

本研究では,大学の学生相談室活動をどのように広げていくべきかを検討するために,アメリカの大学生を対象に作成された「専門家による心理的援助を求める態度尺度(Attitude toward seeking professional psychological help: ATSPPH-S)(Fisher &Farina, 1995)」の翻訳版について,信頼性・妥当性を検討した。調査対象者は日本の大学生699 名である。はじめに尺度の構造的な妥当性を検討し,翻訳版は2 因子構造であることが明らかになったが,先行研究とは異なり両因子には負の相関が見られた。因子構造における解釈上の妥当性を検討し,それぞれ「専門的援助の求め」と「自己解決志向」と名付けた。さらに,精神的健康,心理的援助への偏見,学生相談室への関心との相関から構成概念妥当性を検討したところ,一定の妥当性が確認できた。We examined the reliability and validity of a Japanese version of the Seeking ProfessionalPsychological Help Scale-Short (ATSPPH-S) scale, a widely cited scale used to explore adolescents\u27attitudes towards mental health services. Participants were 699 Japanese university students. Factoranalysis showed that the two factors of the Japanese version were negatively correlated, indicating adifferent relationship between these factors than was found in the original version. This result maysuggest that Japanese adolescents would seek professional psychological help as part of a self-directedproblem-solving process—in other words, an extension of self-help. Adequate model fit was indicatedafter we converted five items that were originally reverse scored to straight items. This model also hadtwo factors ("seeking professional psychological help" and "self-direction"). Both factors were significantlycorrelated to a mental health scale and an index of concern about the mental health service center attheir university. The second factor was also correlated positively with the Stigma Scale for ReceivingPsychological Help. It indicated that Japanese adolescents might have some ambivalence regarding theuse of mental health services. Thus, the ATSPPH-S showed adequate internal reliability and validity forJapanese adolescents, and differed slightly for this group

Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases

Mitochondrial dysfunction increases oxidative stress and depletes ATP in a variety of disorders. Several antioxidant therapies and drugs affecting mitochondrial biogenesis are undergoing investigation, although not all of them have demonstrated favorable effects in the clinic. We recently reported a therapeutic mitochondrial drug mitochonic acid MA-5 (Tohoku J. Exp. Med., 2015). MA-5 increased ATP, rescued mitochondrial disease fibroblasts and prolonged the life span of the disease model “Mitomouse” (JASN, 2016). To investigate the potential of MA-5 on various mitochondrial diseases, we collected 25 cases of fibroblasts from various genetic mutations and cell protective effect of MA-5 and the ATP producing mechanism was examined. 24 out of the 25 patient fibroblasts (96%) were responded to MA-5. Under oxidative stress condition, the GDF-15 was increased and this increase was significantly abrogated by MA-5. The serum GDF-15 elevated in Mitomouse was likewise reduced by MA-5. MA-5 facilitates mitochondrial ATP production and reduces ROS independent of ETC by facilitating ATP synthase oligomerization and supercomplex formation with mitofilin/Mic60. MA-5 reduced mitochondria fragmentation, restores crista shape and dynamics. MA-5 has potential as a drug for the treatment of various mitochondrial diseases. The diagnostic use of GDF-15 will be also useful in a forthcoming MA-5 clinical trial

Temporally Specific Sensory Signals for the Detection of Stimulus Omission in the Primate Deep Cerebellar Nuclei

The cerebellum is implicated in sensory prediction in the subsecond range. To explore how neurons in the cerebellum encode temporal information for the prediction of sensory events, we trained monkeys to make a saccade in response to either a single omission or deviation of isochronous repetitive stimuli. We found that neurons in the cerebellar dentate nucleus exhibited a gradual elevation of the baseline firing rate as the repetition progressed. Most neurons showed a transient suppression for each stimulus, and this firing modulation also increased gradually, opposed to the sensory adaptation. The magnitude of the enhanced sensory response positively correlated with interstimulus interval. Furthermore, when stimuli appeared unexpectedly earlier than the regular timing, the neuronal modulation became smaller, suggesting that the sensory response depended on the time elapsed since the previous stimulus. The enhancement of neuronal modulation was context dependent and was reduced or even absent when monkeys were unmotivated to detect stimulus omission. Asignificant negative correlation between neuronal activity at stimulus omission and saccade latency suggested that the timing of each stimulus was predicted by the amount of recovery from the transient response. Because inactivation of the recording sites delayed the detection of stimulus omission but only slightly altered the detection of stimulus deviation, these signals might be necessary for the prediction of stimulus timing but may not be involved only in the generation of saccades. Our results demonstrate a novel mechanism for temporal prediction of upcoming stimuli that accompanies the time-dependent modification of sensory gain in the cerebellum

Facilitation of temporal prediction by electrical stimulation to the primate cerebellar nuclei

The cerebellum is known to be involved in temporal information processing. However, the underlying neuronal mechanisms remain unclear. In our previous study, monkeys were trained to make a saccade in response to a single omission of periodically presented visual stimuli. To detect stimulus omission, animals had to predict the timing of each next stimulus. During this task, neurons in the cerebellar dentate nucleus exhibited a transient decrement of activity followed by a gradual increase in firing rate that peaked around the time of the next stimulus (Ohmae et al., 2013). In the present study, to address how these two components of neuronal activity contributed to omission detection, we applied electrical microstimulation to the recording site at different timing during the task. We found that electrical stimulation just before the stimulus omission shortened the latencies of both contraversive and ipsiversive saccades. Because the changes in saccade latency nonlinearly depended on the timing of stimulation in each inter-stimulus interval, and electrical stimulation just before the early stimulus in the sequence failed to evoke saccades, the neuronal activity in the dentate nucleus might regulate temporal prediction rather than facilitating saccade execution. Our results support the hypothesis that the firing modulation in each inter-stimulus interval in the dentate nucleus represents neuronal code for the temporal prediction of next stimulus

Effects of GABAergic and Glutamatergic Inputs on Temporal Prediction Signals in the Primate Cerebellar Nucleus

cerebellum has been shown to be involved in temporal information processing. We recently demonstrated that neurons in the cerebellar dentate nucleus exhibited periodic activity predicting stimulus timing when monkeys attempted to detect a single omission of isochronous repetitive visual stimulus. In this study, we assessed the relative contribution of signals from Purkinje cells and mossy and climbing fibers to the periodic activity by comparing single neuronal firing before and during local infusion of GABA or glutamate receptor antagonists (gabazine or a mixture of 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide hydrate (NBQX) and (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP)). Gabazine application reduced the magnitude of periodic activity and increased the baseline firing rate in most neurons. In contrast, during the blockade of glutamate receptors, both the magnitude of periodic firing modulation and the baseline activity remained unchanged in the population, while a minority of neurons significantly altered their activity. Furthermore, the amounts of changes in the baseline activity and the magnitude of periodic activity were inversely correlated in the gabazine experiments but not in the NBQX + CPP experiments. We also found that the variation of baseline activity decreased during gabazine application but sometimes increased during the blockade of glutamate receptors. These changes were not observed during prolonged recording without drug administration. These results suggest that the predictive neuronal activity in the dentate nucleus may mainly attribute to the inputs from the cerebellar cortex, while the signals from both mossy fibers and Purkinje cells may play a role in setting the level and variance of baseline activity during the task. (c) 2021 IBRO. Published by Elsevier Ltd. All rights reserved