Metformin suppresses epithelial sodium channel hyperactivation and its associated phenotypes in a mouse model of obstructive lung diseases.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the world, and has no radical treatment. Inhibition of amiloride-sensitive epithelial sodium ion channel (ENaC) has now been considered as a potential therapeutic target against COPD. One possible modulator of ENaC is AMP-activated protein kinase (AMPK), a key molecule that controls a wide variety of cellular signals; however, little is known about whether metformin, a clinically available AMPK activator, has a protective role against ENaC-associated chronic pulmonary phenotypes, such as emphysema and pulmonary dysfunction. We first used ENaC-overexpressing human bronchial epithelial cells (ß/γENaC-16HBE14o-) and identified that Metformin significantly reduced ENaC activity. Consistently, in vivo treatment of ENaC-overexpressing COPD mouse model (C57BL/6-ßENaC-Tg mice) showed improvement of emphysema and pulmonary dysfunction, without any detrimental effect on non-pulmonary parameters (blood glucose level etc.). Bronchoalveolar lavage fluid (BALF) and lung tissue analyses revealed significant suppression in the infiltration of neutrophils as well as the expression of inflammatory markers (KC), neutrophil gelatinase (MMP9) and macrophage elastase (MMP12) in metformin-treated C57BL/6-ßENaC-Tg mice. Overall, the present study demonstrates that metformin directly inhibits ENaC activity in vitro and provides the first evidence of therapeutical benefit of Metformin for COPD with higher ENaC activity.

Structural features of free N-glycans in α1,3/4-fucosidase-deficient Arabidopsis thaliana: deletion of α1,3/4-fucosidase activity induced accumulation of plant complex type GN1 free N-glycans.

Deletion of α-1,3/4-fucosidase activity in Arabidopsis thaliana resulted in the accumulation of GN1-type free N-glycans with the Lewis a epitope (GN1-FNG). This suggests that the release of α-fucose residue(s) may trigger rapid degradation of the plant complex-type (PCT) GN1-FNG. The fact that PCT-GN1-FNG has rarely been detected to date is probably due to its easier degradation compared with PCT-GN2-FNG.

A Splice Switch in SIGIRR Causes a Defect of IL-37-Dependent Anti-Inflammatory Activity in Cystic Fibrosis Airway Epithelial Cells.

Cystic fibrosis (CF) is a hereditary disease typically characterized by infection-associated chronic lung inflammation. The persistent activation of toll-like receptor (TLR) signals is considered one of the mechanisms for the CF hyperinflammatory phenotype; however, how negative regulatory signals of TLRs associate with CF inflammation is still elusive. Here, we showed that the cell surface expression of a single immunoglobulin interleukin-1 receptor (IL-1R)-related molecule (SIGIRR), a membrane protein essential for suppressing TLRs- and IL-1R-dependent signals, was remarkably decreased in CF airway epithelial cells compared to non-CF cells. Notably, CF airway epithelial cells specifically and highly expressed a unique, alternative splice isoform of the SIGIRR that lacks exon 8 (Δ8-SIGIRR), which results in the production of a C-terminal truncated form of the SIGIRR. Δ8-SIGIRR was expressed intracellularly, and its over-expression abolished the cell surface expression and function of the full-length SIGIRR (WT-SIGIRR), indicating its dominant-negative effect leading to the deficiency of anti-inflammatory activity in CF cells. Consistently, IL-37, a ligand for the SIGIRR, failed to suppress viral dsRNA analogue poly(I:C)-dependent JNK activation and IL-8 production, confirming the reduction in the functional WT-SIGIRR expression in the CF cells. Together, our studies reveal that SIGIRR-dependent anti-inflammatory activity is defective in CF airway epithelial cells due to the unique splicing switch of the SIGIRR gene and provides the first evidence of IL-37-SIGIRR signaling as a target of CF airway inflammation.

Device nurse intervention facilitates the patients' adaptation to cardiac shock devices in the remote monitoring era.

BACKGROUND: A substantial number of patients with shock devices (implantable cardioverter defibrillators [ICDs] or ICDs with resynchronization [CRTDs]) experience psychological distress. OBJECTIVE: We investigated the device nurse telephone intervention's effect on improving the patient's adaptation to shock devices, quality of life (QOL), and anxiety in the remote monitoring era. METHODS: The patient's adaptation to the device, health-related QOL, and anxiety were investigated by the modified Implanted Devices Adjustment-Japan score (IDAS), Short Form-36, and State-Trait Anxiety Inventory (STAI) before and 1-year after the device nurse telephone intervention, performed every 3 months. A total of 95 patients (median age 69 years and 25 females) participated. Sixty patients had ICDs and 35 CRTDs. Structural heart disease was observed in 72 patients, and idiopathic ventricular arrhythmias in the others. The mean left ventricular ejection fraction was 46% ± 15%. The median duration since the device implantation was 5.2 years. RESULTS: The total IDAS score significantly improved from 28.42 ± 7.11 at baseline to 26.77 ± 7.68 (p = 0.0076) at 1 year. Both the state and trait anxiety significantly improved (from 38.9 ± 9.6 to 35.3 ± 9.0 [<0.0001] and 38.8 ± 10.3 to 36.2±9.8 [p = 0.0044], respectively). The prevalence of patients with a state and trait anxiety of more than 40 decreased from 44 (46%) and 38 (40%) patients before the study to 27 (28 %) and 32 (34 %) at 1 year. The SF-36 mental component summary score significantly increased (50.8 ± 8.3 at baseline to 53.1 ± 7.7 at 1 year, p = 0.0031). CONCLUSIONS: The device nurse intervention facilitated the patient's adaptation to the shock device, increased the health-related QOL, and reduced the patient's anxiety.

Effects of Tablet Size and Head Posture on Drug Swallowing: A Preliminary Examination Using Endoscopy in Healthy Subjects.

Tablet size and head posture have been reported to affect swallowing of medications, but no previous studies have evaluated their effects in detail. Our aim was to investigate for the first time the effect of tablet size and head posture on drug swallowing by endoscopic evaluation in healthy subjects. Round tablets (7 , 10 , 12, and 14 mm in diameter) were swallowed by 15 healthy adults with an endoscope inserted in the neutral, head flex-ion, and head extension positions. Evaluation of swallowing difficulty using a numeric rating scale (NRS), presence or absence of pharyngeal residue and its location, and tablet oral transit time (TOTT) were recorded. In the neutral position, the NRS score was higher with the 14 mm tablets than with the 7 mm tablets. The TOTT with the 7 mm tablets was significantly shorter in the head extension than in the neutral position. Swallowing difficulty increased when the tablet diameter was more than 7 mm. Residues were found in the epi-glottis, pyriform sinus, and tongue base. These findings suggest that head extension shortens the TOTT and assists oral-pharyngeal transport.

Rbm38 Reduces the Transcription Elongation Defect of the SMEK2 Gene Caused by Splicing Deficiency.

Pre-mRNA splicing is an essential mechanism for ensuring integrity of the transcriptome in eukaryotes. Therefore, splicing deficiency might cause a decrease in functional proteins and the production of nonfunctional, aberrant proteins. To prevent the production of such aberrant proteins, eukaryotic cells have several mRNA quality control mechanisms. In addition to the known mechanisms, we previously found that transcription elongation is attenuated to prevent the accumulation of pre-mRNA under splicing-deficient conditions. However, the detailed molecular mechanism behind the defect in transcription elongation remains unknown. Here, we showed that the RNA binding protein Rbm38 reduced the transcription elongation defect of the SMEK2 gene caused by splicing deficiency. This reduction was shown to require the N- and C-terminal regions of Rbm38, along with an important role being played by the RNA-recognition motif of Rbm38. These findings advance our understanding of the molecular mechanism of the transcription elongation defect caused by splicing deficiency.

Degradation pathway of plant complex-type N-glycans: identification and characterization of a key α1,3-fucosidase from glycoside hydrolase family 29.

Plant complex-type N-glycans are characterized by the presence of α1,3-linked fucose towards the proximal N-acetylglucosamine residue and ß1,2-linked xylose towards the ß-mannose residue. These glycans are ultimately degraded by the activity of several glycoside hydrolases. However, the degradation pathway of plant complex-type N-glycans has not been entirely elucidated because the gene encoding α1,3-fucosidase, a glycoside hydrolase acting on plant complex-type N-glycans, has not yet been identified, and its substrate specificity remains to be determined. In the present study, we found that AtFUC1 (an Arabidopsis GH29 α-fucosidase) is an α1,3-fucosidase acting on plant complex-type N-glycans. This fucosidase has been known to act on α1,4-fucoside linkage in the Lewis A epitope of plant complex-type N-glycans. We found that this glycoside hydrolase specifically acted on GlcNAcß1-4(Fucα1-3)GlcNAc, a degradation product of plant complex-type N-glycans, by sequential actions of vacuolar α-mannosidase, ß1,2-xylosidase, and endo-ß-mannosidase. The AtFUC1-deficient mutant showed no distinct phenotypic plant growth features; however, it accumulated GlcNAcß1-4(Fucα1-3)GlcNAc, a substrate of AtFUC1. These results showed that AtFUC1 is an α1,3-fucosidase acting on plant complex-type N-glycans and elucidated the degradation pathway of plant complex-type N-glycans.

Risk of Delayed Healing of Tooth Extraction Wounds and Osteonecrosis of the Jaw among Patients Treated with Potential Immunosuppressive Drugs: A Retrospective Cohort Study.

Bone-modifying or antiresorptive agents that target osteoclasts, such as bisphosphonates, are known to cause delayed wound healing and osteonecrosis of the jaw (ONJ) following tooth extraction. However, there are no data on whether such adverse events are also caused by drugs that may suppress the immune system, including corticosteroids, immunosuppressants, biological agents, and disease-modifying anti-rheumatic drugs (DMARDs). The aim of this retrospective study was to examine the incidence of delayed post-extraction wound healing and identify risk factors among patients treated with potential immunosuppressive drugs undergoing tooth extraction. We performed a retrospective cohort study involving 101 patients by reviewing their medical records. The underlying diseases of the enrolled patients included dilated cardiomyopathy, hematological malignancy, sarcoidosis, rheumatoid arthritis, and systemic lupus erythematosus. The sample comprised 131 cases of tooth extraction among the 101 patients; delayed post-extraction wound healing occurred in 10 patients (12 cases, 9.2%), including ONJ in three patients (3 cases, 2.3%). The surgical tooth extraction performed for impacted teeth or a residual root (P = 0.009), the number of surgical tooth extraction (P = 0.012), decreased lymphocyte counts (P = 0.008), and decreased eosinophil counts (P = 0.009) were significantly related to delayed wound healing. Thus, among patients taking corticosteroids, immunosuppressants, biological agents, and/or DMARDs, there is a risk of delayed wound healing and ONJ. Moreover, the significant risk factors are low lymphocyte counts, low eosinophil counts, and surgical extraction. It is of particular importance to prevent surgical site infection, when the high-risk patients undergo tooth extraction.

Splicing inhibition decreases phosphorylation level of Ser2 in Pol II CTD.

Phosphorylation of the C-terminal domain of the largest subunit of RNA polymerase II (Pol II), especially Ser2 and Ser5 residues, plays important roles in transcription and mRNA processing, including 5' end capping, splicing and 3' end processing. These phosphorylation events stimulate mRNA processing, however, it is not clear whether splicing activity affects the phosphorylation status of Pol II. In this study, we found that splicing inhibition by potent splicing inhibitors spliceostatin A (SSA) and pladienolide B or by antisense oligos against snRNAs decreased phospho-Ser2 level, but had little or no effects on phospho-Ser5 level. In contrast, transcription and translation inhibitors did not decrease phospho-Ser2 level, therefore inhibition of not all the gene expression processes cause the decrease of phospho-Ser2. SSA treatment caused early dissociation of Pol II and decrease in phospho-Ser2 level of chromatin-bound Pol II, suggesting that splicing inhibition causes downregulation of phospho-Ser2 through at least these two mechanisms.

Management for the patients with severe Parkinson's disease during dental treatments and tooth extractions: A retrospective observational study.

Background/purpose: When Parkinson's disease (PD) progresses, oral and swallowing functions decline, and special care is necessary when performing dental treatments. This study aimed to retrospectively investigate the records of patients with PD and analyze dental and general problems to establish countermeasures during dental treatments. Materials and methods: We retrospectively examined the medical records of patients with PD to obtain data on dental treatments and management methods. Results: Of the 27 patients, 40% had severe grade IV or higher Hoehn-Yale (HY) scores, and the wearing-off phenomenon was observed in those with grade III or higher. Additionally, 19% of the patients were receiving levodopa 500 mg/day or more. Intravenous sedation was administered 21 times (three patients) and general anesthesia eight times (three patients). Discontinuation of tooth extraction was observed in four patients: two with difficulty in opening the mouth, one with respiratory failure caused by the wearing-off phenomenon, and one with excessively elevated blood pressure due to the interaction between adrenaline in local anesthesia and the catechol-O-methyltransferase inhibitor. Tooth extraction was performed by adjusting the time of levodopa administration in two patients, under general anesthesia in one patient, and using adrenaline-free local anesthetics under intravenous sedation in one patient. Conclusion: When PD progresses, oral and swallowing functions decline and body motor function deteriorates. Thus, the respiratory and circulatory conditions and the wearing-off phenomenon during dental treatments should be properly managed in patients with severe PD.

T3 Intratracheal Therapy Alleviates Pulmonary Pathology in an Elastase-Induced Emphysema-Dominant COPD Mouse Model.

Chronic obstructive pulmonary disease (COPD) is a complex pulmonary condition characterized by bronchitis, emphysema, and mucus stasis. Due to the variability in symptoms among patients, traditional approaches to treating COPD as a singular disease are limited. This led us to focus on phenotype/endotype classifications. In this study, we explore the potential therapeutic role of thyroid hormone (T3) by using mouse models: emphysema-dominant elastase-induced COPD and airway-dominant C57BL/6-ßENaC-Tg to represent different types of the disease. Here, we showed that intratracheal T3 treatment (40, 80 µg/kg, i.t., every other day) resulted in significant improvements regarding emphysema and the enhancement of respiratory function in the elastase-induced COPD model. T3-dependent improvement is likely linked to the up-regulation of Ppargc1a, a master regulator of mitochondrial biogenesis, and Gclm, a factor associated with oxidative stress. Conversely, neither short- nor long-term T3 treatments improved COPD pathology in the C57BL/6-ßENaC-Tg mice. Because the up-regulation of extrathyroidal T3-producing enzyme Dio2, which is also considered a marker of T3 requirement, was specifically observed in elastase-induced COPD lungs, these results demonstrate that exogenous T3 supplementation may have therapeutic potential for acute but not chronic COPD exacerbation. Moreover, this study highlights the relevance of considering not only COPD phenotypes but also COPD endotypes (expression levels of Ppargc1a and/or Dio2) in the research and development of better treatment approaches for COPD.

Comparison of intravenous sedation using midazolam versus dexmedetomidine in elderly patients with dementia: a randomized cross-over trial.

Differences between the effects of intravenous sedation with midazolam (MID) and dexmedetomidine (DEX) on the cerebral function of elderly patients with severe dementia are unclear. This study aimed to compare the effects of intravenous sedation with MID or DEX on parameters such as brain waves and cerebral blood flow (CBF). This cross-over study analyzed 12 patients with severe dementia, with each patient receiving both drug treatments. Each drug was administered until a Modified Observer's Assessment of Alertness/Sedation (OAA/S) score of 2 was reached. Bispectral index (BIS) and normalized tissue hemoglobin index (nTHI), which reflects CBF using near-infrared spectroscopy, were measured. Mann-Whitney U, Wilcoxon signed-rank, and Friedman tests, and multiple regression analysis were performed. While a similar decline in BIS values was observed in both groups (P < 0.030), there was a significant decrease in nTHI up to 11% in the MID group (P = 0.005). In the DEX group, nTHI values did not differ from baseline. When an OAA/S score of 2 was just achieved, CBF in the MID group (- 5%) was significantly lower than in the DEX group (± 0%). In dementia patients, sedation with MID resulted in a decrease in CBF, while the CBF value was maintained during sedation with DEX.

Effect of masticatory training using confectioneries on oral function in elderly patients - A randomized controlled trial.

Background/purpose: The number of patients with oral hypofunction is increasing with the aging of the population, and such hypofunction increases their risk for dysphagia and malnutrition. The purpose of this study was to measure the hardness of commercially available confectioneries, select a confectionery with a hardness suitable for masticatory training for elderly patients, and evaluate the effects of 1-week masticatory training on oral function (occlusal force, masticatory ability, and tongue pressure). Materials and methods: The average hardness values of 25 confectioneries were determined. Among them, one of the softest confectioneries that the patients felt as "chewable but difficult to chew" was selected as the training confectionery for each patient. The patients in the training group continued training, which involved eating of approximately 5 g of one selected confectionery daily for 7 days. The patients in the control group did not undergo any training. Oral function (occlusal force, masticatory ability, and tongue pressure) on the first day and after 7 days was evaluated and compared between the groups. Results: The occlusal force of the patients in the training group increased significantly. However, their masticatory ability and tongue pressure did not change significantly. Conclusion: Patients aged 65 years and older underwent masticatory training, which involved eating of a confectionery with its hardness adjusted individually for a week. A significant increase in the occlusal force was observed, suggesting that masticatory training using confectioneries with a hardness suitable for each patient is effective.

Feasibility of the automated column agglutination technique for titration of anti-A/B antibodies in ABO-incompatible living kidney transplantation.

INTRODUCTION: Quantitative measurement of anti-A/-B antibody titers is important during ABO-incompatible living kidney transplantation (ABOi-LKT). METHODS: We conducted a multi-institutional study to measure the antibody titers using the automated column agglutination technique (auto-CAT) and tube test (TT) method in ABOi-LKT recipients. Statistical analysis was performed to evaluate the two methods. RESULTS: We examined 111 samples from 35 ABOi-LKT recipients at four institutions. The correlation coefficient of the two methods was >0.9; the concordance rate and clinically acceptable concordance rate for the IgG titers were 60.4% and 88.3%, respectively. Perioperative status did not influence the statistical significance. Parallel changes were observed in the IgG antibody titers measured using the auto-CAT or TT technique by desensitizing therapy in time-course monitoring. CONCLUSION: Auto-CAT is comparable with the TT technique and is feasible for IgG anti-A/B antibody titration in ABOi-LKT recipients.

Analysis of intravenous sedation for dental treatment in elderly patients with severe dementia-a retrospective cohort study of a Japanese population.

BACKGROUND/PURPOSE: Patients with severe dementia require intravenous sedation during dental treatment. However, few reports have compared the outcomes of intravenous sedation management among sedatives. Intravenous sedation in the elderly with severe dementia undergoing dental treatment was evaluated retrospectively. MATERIALS AND METHODS: Patients' characteristics and type of dementia were obtained from medical records. Midazolam (MID), dexmedetomidine (DEX), and propofol (PRO) were administered as sedatives. The systolic blood pressure (SBP), heart rate (HR), SpO2, bispectral index (BIS) values and complications were evaluated. RESULTS: Nineteen patients with severe dementia who underwent 62 instances of sedation were included. There was no difference in patient background between sedatives. The sedation time and permission time to return home were significantly longer in DEX than in MID or PRO group. Half the usual dose in MID and lower limits of the routine dose was effective in DEX and PRO. HR was significantly lower in DEX group. There were 3 cases with airway obstruction requiring nasopharyngeal airway and 4 cases of apnea when MID was administered. Two cases of Cheyne-Stokes-like respiration when MID or DEX was administered. SpO2 <94% was found in 22 cases (35%) irrespective of the sedative. A patient with dementia with Lewy bodies had experienced hallucinations during the recovery period after sedation when MID or DEX was administered. The BIS value of ≤80 was noted during complications. CONCLUSION: Intravenous sedation for dental treatment in the elderly with severe dementia, needs a dose titration. All sedatives had respiratory-related complications which mandate close monitoring.

Comparison of intravenous sedation using midazolam during dental treatment in elderly patients with/without dementia: a prospective, controlled clinical trial.

The effects of intravenous sedation with midazolam on the cerebral function of elderly patients with severe dementia are unclear. This study aimed to evaluate its effects on parameters such as brainwaves and cerebral blood flow (CBF) and compare them between elderly individuals with dementia and without cognitive impairment. Ten patients with severe dementia and 10 without cognitive impairment were registered. The bispectral index (BIS) and normalized tissue hemoglobin index (nTHI), which reflects CBF using near-infrared spectroscopy, were measured. Midazolam was administered until a Modified Observer's Assessment of Alertness/Sedation score of 2 was reached. The chi-squared, Mann-Whitney U, Wilcoxon signed-rank, and Friedman tests and multiple regression analysis were used for comparisons. Whereas a similar decline in BIS values was observed in both groups after midazolam administration (P < 0.018), there was a significant decrease by 9% in the nTHI of the dementia-positive group (P < 0.013). However, there was no significant difference in the nTHI between the dementia-positive and dementia-negative group according to the multiple regression analysis (P = 0.058). In the dementia-negative group, none of the measured values differed from the baseline values. In the dementia-positive group, sedation with midazolam resulted in a 9% decrease in the CBF.

A Retrospective Observational Study of Adverse Reactions Associated With Intravenous Immunoglobulin Infusion.

Background: Although intravenous immunoglobulin (IVIG) therapy is generally safe and well tolerated, adverse reactions (ARs) do occur. The majority of these ARs are mild and transient. Risk factors for ARs associate with IVIG infusions are not well established. This study investigated possible risk factors influencing the occurrence of IVIG-associated ARs. Study Design and Methods: This was a retrospective observational analysis of data accumulated over 5 years, including patient demographics, clinical condition, IVIG dosing regimens, number of IVIG infusions, and any ARs. Results: ARs were associated with IVIG in 4.9% of patients and 2.5% of infusions. By univariate analyses, ARs correlated with female sex, adult age, high dose IVIG, and autoimmune disease. Multivariate logistic regression identified three statistically significant of risk factors: on a per-patient basis, being female (p=0.0018), having neuromuscular disease (p=0.0002), and receiving higher doses of IVIG per patient body weight (p<0.001), on a per-infusion basis, being female (p < 0.001), being adolescents to middle age (p < 0.001), and having neuromuscular disease (p < 0.001). Conclusion: Neuromuscular disease emerged as one of the significant factors for ARs to IVIG.

Effects of preoperative oral carbohydrate intake on catabolism, nutrition and adipocytokines during minor surgery: A randomized, prospective, controlled clinical phase II trial.

BACKGROUND: We investigated the effects of preoperative oral carbohydrate loading on intraoperative catabolism, nutritional parameters, and adipocytokine levels during anesthesia. METHODS: Study participants were randomized to two groups who were allowed to consume either no more than 250 mL of 18% oral carbohydrate solution (Arginaid Water: AW group) or no more than 500 mL of plain water (PW group) within the 2 hours before surgery, with no intraoperative glucose administration. Percentage changes from preoperative values of resting metabolic rate (RMR) and total body water (TBW), determined by bioelectrical impedance analysis (BIA), were compared. Blood levels of serum ketone bodies, free fatty acids (FFAs), insulin, 3-methyl histidine, blood glucose, retinol binding protein, adiponectin, and leptin were measured. BIA measurement and blood sampling were performed on entry to the operating room (M1) and 2 hours after the induction of anesthesia (M2). Chi squared test, Mann-Whitney U test, and Wilcoxon's test were used for comparisons of parameters. P values less than 0.05 constituted a significant difference. RESULTS: Seventeen patients per group (34 patients total) were enrolled. RMR and TBW values did not differ between M1 and M2 measurements. Participants in the AW group had lower blood ketone body and FFA levels and higher insulin levels at M1. However, their ketone body and FFA levels rose and insulin levels fell after 2 hours, although ketone body and FFA levels in the AW group were still lower than those in the PW group. Although retinol binding protein, adiponectin, and leptin levels were not different in terms of preoperative oral carbohydrate loading, the levels of these substances in both groups were lower after 2 hours compared with levels on operating room entry. CONCLUSIONS: Preoperative oral carbohydrate loading without intraoperative glucose administration appears to suppress catabolism for 2 hours after the start of surgery.