Effects of Sustained‐Release Beraprost in Patients With Primary Glomerular Disease or Nephrosclerosis: CASSIOPEIR Study Results

TRK‐100STP, a sustained‐release preparation of the orally active prostacyclin analogue beraprost sodium, targets renal hypoxia. This study aimed to show the superiority of TRK‐100STP over placebos in patients with chronic kidney disease (with either primary glomerular disease or nephrosclerosis) to determine the recommended dose. CASSIOPEIR (Chronic Renal Failure Asian Study with Oral PGI₂ Derivative for Evaluating Improvement of Renal Function) was a randomized, double‐blind, placebo‐controlled study conducted at 160 sites in seven Asia‐Pacific countries and regions. Eligible patients (n = 892) were randomized to TRK‐100STP 120, 240 μg, or placebo for a treatment period of up to 4 years. The primary efficacy endpoint was time to first occurrence of a renal composite: doubling of serum creatinine or occurrence of end‐stage renal disease. No significant differences were observed in composite endpoints between TRK‐100STP and placebo (P = 0.5674). Hazard ratios (95% CI) in the TRK‐100STP 120 and 240 μg vs. placebo groups were 0.98 (0.78, 1.22) and 0.91 (0.72, 1.14), respectively. The overall incidence of adverse events and adverse drug reactions was comparable between treatment arms.     

Insulin and heparin challenge tests are useful for choosing an optimal insulin regimen in a case of subcutaneous insulin resistance

A 38‐year‐old woman with type 1 diabetes, whose fasting plasma glucose levels were >500 mg/dL under 176 U/day of subcutaneous insulin injection, was admitted to Nippon Medical School Hospital, Tokyo, Japan. When insulin was administered intravenously, she was able to maintain favorable glycemic control even under 24 U/day of regular insulin, showing that she was accompanied by subcutaneous insulin resistance. To choose an optimal insulin regimen, we carried out subcutaneous insulin challenge tests without or with heparin mixture, and found a cocktail of insulin lispro and heparin could reduce blood glucose levels markedly. As a consequence, she achieved favorable blood glucose control by continuous subcutaneous insulin infusion of the cocktail. In summary, the insulin and heparin challenge tests are useful for choosing an optimal insulin regimen in cases of subcutaneous insulin resistance.     

Glucocorticoids Induce Cardiac Fibrosis via Mineralocorticoid Receptor in Oxidative Stress: Contribution of Elongation Factor Eleven-Nineteen Lysine-Rich Leukemia (ELL)

Background

Cardiac fibrosis is considered to be a crucial factor in the development of heart failure. Blockade of the mineralocorticoid receptor (MR) attenuated cardiac fibrosis and improved the prognosis of patients with chronic heart failure but the ligand for MR and the regulatory mechanism of MR pathway in the diseased heart are unclear. Here, we investigated whether glucocorticoids can promote cardiac fibrosis through MR in oxidative stress and the involvement of elongation factor eleven-nineteen lysine-rich leukemia (ELL), a co-activator of MR, in this pathway.

Methods and Results

The MR antagonist eplerenone attenuated corticosterone-induced collagen synthesis assessed by [³H]proline incorporation in rat neonatal cultured cardiac fibroblasts in the presence of H₂O₂, as an oxidative stress but not in the absence of H₂O₂. H₂O₂ increased the ELL expression levels and MR-bound ELL. ELL expression levels and MR-bound ELL were also increased in the left ventricle of heart failure model rats with significant fibrosis and enhanced oxidative stress. Eplerenone did not attenuate corticosterone-induced increase of [³H]proline incorporation in the presence of H₂O₂ after knockdown of ELL expression using small interfering RNA in cardiac fibroblasts.

Conclusion

Glucocorticoids can promote cardiac fibrosis via MR in oxidative stress, and oxidative stress modulates MR response to glucocorticoids through the interaction with ELL. Preventing cardiac fibrosis by modulating glucocorticoid-MR-ELL pathway may become a new therapeutic strategy for heart failure.     

Tyrosine 201 of the cytoplasmic tail of CTLA‐4 critically affects T regulatory cell suppressive function

Cytotoxic T lymphocyte antigen‐4 (CTLA‐4) is a major negative regulatory molecule for T‐cell activation with a complex biology and function. CTLA‐4 is known to regulate homeostatic lymphoproliferation as well as tolerance induction and has been proposed to be an important effector molecule by which Treg cells suppress immunity. The immunoregulatory properties of CTLA‐4 are primarily mediated by competition with the costimulator CD28 for ligand binding but also by delivering negative signals to T cells through its cytoplasmic tail. In this study, we addressed the effect of directly mutating the amino acid residue, Tyrosine 201 (Tyr201), of the intracellular domain of CTLA‐4 in situ and its implications in T‐cell function in the context of autoimmunity. Therefore, a novel CTLA‐4 knock‐in mouse (Y201V KI) was generated, in which Tyr201 was replaced by a valine that could not be phosphorylated. Mice expressing the CTLA‐4 mutant molecule were generally healthy and did not show signs of disruption of T‐cell homeostasis under steady‐state conditions seen in CTLA‐4 deficient mice. However, T cells isolated from Y201V KI mice expressed higher levels of CTLA‐4 on the cell surface and displayed a Th2‐biased phenotype following TCR stimulation. Furthermore, Y201V KI mice developed exacerbated disease as compared to wild‐type upon antigen‐specific T‐cell activation in an in vivo model of EAE. Importantly, the Y201V mutation resulted in impaired suppressive activity of Treg cells while T effector function remained intact. These data suggest that effects associated with and mediated through Tyr201 of CTLA‐4s intracellular domain are critical for Treg‐cell function.     

Clinical utility of treatment method conversion during single-session endoscopic ultrasound-guided biliary drainage

BACKGROUND Although several techniques for endoscopic ultrasound-guided biliary drainage(EUS-BD)are available at present,an optimal treatment algorithm of EUS-BD has not yet been established.AIM To evaluate the clinical utility of treatment method conversion during single endoscopic sessions for difficult cases in initially planned EUS-BD.METHODS This was a single-center retrospective analysis using a prospectively accumulated database.Patients with biliary obstruction undergoing EUS-BD between May 2008 and April 2016 were included.The primary outcome was to evaluate the improvement in EUS-BD success rates by converting the treatment methods during a single endoscopic session.Secondary outcomes were clarification of the factors leading to the conversion from the initial EUS-BD and the assessment of efficacy and safety of the conversion as judged by technical success,clinical success,and adverse events(AEs).RESULTS A total of 208 patients underwent EUS-BD during the study period.For 18.8%(39/208)of the patients,the treatment methods were converted to another EUSBD technique from the initial plan.Biliary obstruction was caused by pancreatobiliary malignancies,other malignant lesions,biliary stones,and other benign lesions in 22,11,4,and 2 patients,respectively.The reasons for the difficulty with the initial EUS-BD were classified into the following 3 procedures:Target puncture(n=13),guidewire manipulation(n=18),and puncture tract dilation(n=8).Technical success was achieved in 97.4%(38/39)of the cases and clinical success was achieved in 89.5%of patients(34/38).AEs occurred in 10.3%of patients,including bile leakage(n=2),bleeding(n=1),and cholecystitis(n=1).The puncture target and drainage technique were altered in subsequent EUSBD procedures in 25 and 14 patients,respectively.The final technical success rate with 95%CI for all 208 cases was 97.1%(95%CI:93.8%-98.9%),while that of the initially planned EUS-BD was 78.8%(95%CI:72.6%-84.2%).CONCLUSION Among multi-step procedures in EUS-BD,guidewire manipulation appeared to be the most technically challenging.When initially planned EUS-BD is technically difficult,treatment method conversion in a single endoscopic session may result in successful EUS-BD without leading to severe AEs.     

Masticatory function and bite force of mandibular single-implant overdentures and complete dentures: a randomized crossover control study

PurposeThe study aimed to compare the mixing ability (MA), comminuting ability (CA), and maximum bite force (MBF) of single-implant overdentures (IODs) and clinically acceptable complete dentures (CDs) through a randomized crossover control trial.MethodsNew CDs were fabricated for 22 patients. One implant was inserted in the middle of the symphyseal region for each patient. The patients were randomly allocated into two groups: group IC received an IOD, whereas group CI received a CD, for 2 months; the treatments were interchanged for the next 2 months. The MA, CA, and MBF were evaluated with the old CDs, new CDs (at the end of CD treatment period), and IODs (at the end of IOD treatment period).ResultsThe MA, CA, and MBF of the IODs were significantly higher than those of the old and new CDs (p < 0.01). New CDs only showed a significant improvement in MA (p < 0.05), while there were no significant differences in CA and MBF between the old and new CDs.ConclusionsCompared with the CD, IOD is more effective in restoring the MA, CA, and MBF of edentulous mandibles.     

Volume analyzer SYNAPSE VINCENT for liver analysis

In recent years, there has been an active movement to ensure the greater safety of actual surgeries, by simulating it preoperatively with the use of three‐dimensional image visualization technologies. Along with this movement, the Ministry of Health, Labour and Welfare has named “Image‐supported navigation in hepatectomy” as part of advanced medical techniques. This method aims to improve the safety during a surgery by calculating the volume of the liver dominated by each blood vessel or simulating, prior to surgery, the volume of resection zone or the remaining liver volume. These calculations and simulations are carried out using the three‐dimensional images produced by extractions of the liver, vascular and tumor regions from the computed tomography images, which were collected using the tomography apparatus prior to hepatectomy. In order to facilitate the achievement of such preoperative simulations, the volume analyzer SYNAPSE VINCENT (VINCENT, hereafter) by Fujifilm, in its Liver Analysis Application, comes equipped with unique features. This paper will introduce the technologies behind those unique features and provide a direction for future research and developments.     

Patterns of sensory nerve conduction abnormalities in Fisher syndrome: More predominant involvement of group Ia afferents than skin afferents

ObjectiveTo elucidate the features of sensory nerve involvement in Fisher syndrome (FS), this study extensively investigated sensory electrophysiology.MethodsIn 47 consecutive FS patients, results of sensory nerve conduction studies in the median, ulnar and sural nerves, soleus H-reflexes, and median or tibial somatosensory-evoked potentials (SEP) were reviewed. Because of the large effects of age on amplitude of sensory nerve action potentials (SNAP), we strictly defined reduction of SNAP amplitudes by using a nomogram which age and amplitude obtained from 87normal subjects.ResultsIn routine nerve conduction studies, SNAP amplitude was reduced only in 32% of the patients, and conduction velocity was decreased in 2%. In contrast, soleus H-reflexes were frequently absent or reduced (67%). SEPs were abnormal only in 17%.ConclusionsIn FS, absent soleus H-reflexes are the most frequent electrophysiologic abnormalities, whereas SNAPs amplitudes are rarely affected. The pattern is characterized by predominant involvement of group Ia afferents with relatively preserved cutaneous afferents without evidence suggestive of demyelination.SignificanceThe major targets of immune attack by anti-GQ1b antibodies in FS appear to be group Ia neurons in the dorsal root ganglia, and this is presumably responsible for ataxia and areflexia in FS.     

Localized Potentiation of Sleep Slow-Wave Activity Induced by Prefrontal Repetitive Transcranial Magnetic Stimulation in Patients with a Major Depressive Episode

BackgroundThe effects of repetitive transcranial magnetic stimulation (rTMS) on sleep structure in major depression are currently unknown.ObjectiveTo determine the effects of prefrontal rTMS on sleep electroencephalography (EEG) in major depression.MethodsIn this open-label pilot study, twelve male patients with relatively mild depression, who had been medication-resistant, underwent 10 daily rTMS sessions over the left dorsolateral prefrontal cortex (DLPFC). Polysomnographic (PSG) data were recorded over four nights: Adaptation, Baseline, Post-1 (after the fifth rTMS session), and Post-2 (after the tenth rTMS session). Discrete Fourier Transform (DFT) band power analyses were performed to quantify delta and sigma band activities during Stages II–IV, and determine time courses of these activities between Baseline and Post-1 (first five sessions) and between Post-1 and Post-2 (last five sessions).ResultsPost-hoc tests based on a three-way ANOVA model indicated significant delta power increase at F3 (t₁₁ = ?2.762, P = 0.018) during the first five sessions; however, sigma power was unchanged. No significant band power changes were observed during the second half. Stages II–IV (percent total sleep time) increased significantly during the first half (t₁₂ = ?2.43, P = 0.033). No other significant changes in sleep parameters or clinical correlations were observed.ConclusionsThe first five sessions of high frequency rTMS to the left DLPFC increase slow-wave activity (SWA) at F3, possibly reflecting locally enhanced synaptic plasticity induced by rTMS. This increased activity was not observed during the last half, possibly due to a homeostatic regulation mechanism intrinsic to SWA.