Effectiveness of change from suvorexant to lemborexant drug in the treatment of sleep disorders.

BACKGROUND: This study aimed to examine the effects of a change in medication from suvorexant to lemborexant among patients with insomnia. METHODS: Patients with chronic insomnia who had persistent insomnia for 3 months or longer and who had been taking suvorexant for 3 months or longer were selected. The participants were divided into two groups: the 'modified' group and the 'non-modified' group. Four sub-types of insomnia (i.e., difficulty initiating sleep, difficulty maintaining sleep, early-morning awakening, and non-restorative sleep) were investigated. Logistic regression was used to investigate improvements in both the groups after 12 weeks. RESULTS: Among the 77 participants, 43 and 34 patients were in the modified drug group and the non-modified drug group, respectively. Comparing sleep disorders between the two groups, we found significant improvement after 12 weeks in the modified drug group in terms of difficulty initiating sleep, compared with the non-modified drug group (odds ratio = 0.036, P = 0.008, 95% CI = 0.003-0.415). However, no significant differences were found between the two groups in terms of difficulty maintaining sleep, early-morning awakening, and non-restorative sleep. CONCLUSIONS: Sleep disorders can be treated by alleviating difficulties in initiating sleep by changing from suvorexant to lemborexant. In addition, it was confirmed that the drug change caused no serious side effects and that it was highly safe and tolerated.

Amplification-free gene expression analysis of formalin-fixed paraffin-embedded samples using scanning single-molecule counting.

In this paper, we present the applications of our newly developed, highly sensitive fluorescent detection method referred to as scanning single-molecule counting (SSMC). We found that the target RNA added to the total RNA was detected with high sensitivity at 384 aM by combining a magnetic bead-based assay and SSMC (MB-BA + SSMC). Gene expression analysis without reverse transcription or amplification confirmed that the pattern of gene expression was identical to that of real-time polymerase chain reaction (PCR). MB-BA + SSMC was also applied to formalin-fixed paraffin-embedded (FFPE) samples. RNA fragmentation and crosslinking owing to FFPE processing slightly affected gene expression. Conversely, FFPE samples showed an increase in gene Ct values and a decrease in the number of detectable genes when analyzed using real-time PCR. Overall, our results suggested that SSMC is a powerful tool for target RNA detection and amplification-free gene expression analysis.

Continuous lenalidomide treatment after bortezomib-melphalan-prednisolone therapy for newly diagnosed multiple myeloma.

These are the results of phase II study of bortezomib-melphalan-prednisolone (VMP) induction therapy followed by lenalidomide-dexamethasone (Rd) consolidation and lenalidomide maintenance in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rates (ORRs), and safety. Eighty-three eligible patients were enrolled between October 2012 and August 2014. The median PFS was 28.0 months (95% CI 19.6-36.7) and the median OS was 55.3 months (95% CI 51.6-NA). Among the patients who received lenalidomide maintenance therapy, median PFS was significantly improved in patients who had achieved a very good partial response (VGPR) or better (41.8 vs 20.7 months, p = 0.0070). As the best response, the rates of partial response or better were 85.5% comprising stringent complete response (sCR, 21.7%), complete response (CR, 10.8%), VGPR (18.1%), and partial response (PR, 34.9%). The most frequently observed grade 3 or higher adverse events during the VMP therapy were anemia (28.9%), neutropenia (15.6%), thrombocytopenia (6.0%), and peripheral neuropathy (2.4%). The most frequently observed grade 3 or higher adverse events during the Rd therapy were anemia (3.5%), neutropenia (1.8%), and skin rush (5.3%). The most frequently observed grade 3 or higher adverse events during lenalidomide maintenance therapy were anemia (7.4%) and neutropenia (24.1%). Thus, VMP induction therapy followed by Rd consolidation and lenalidomide maintenance is considered a well-tolerated and effective regimen in transplant-ineligible NDMM. This trial is registered with UMIN-CTR with the identification number UMIN000009042.

[End-of-Life Care at Nursing Facilities].

In Japan, it has been more common for elderly people to die in a hospital than at home. However, recently, increasingly more elderly people want to die where they have been living for a long time, such as their homes or nursing care facilities. We have been visiting patients at various types of nursing care facilities for ten years, including terminal care services followed by confirming death for 152 patients. Our study showed that 87 patients died of old age, which was the top cause of death. We also found that nursing care facilities, where nurses work full-time, provided terminal care for the greatest number of residents, which was 124 patients. The average period between admission to a facility and death was 3 years 3 months. The number of patients who receive terminal nursing care at a facility is increasing annually. The number of elderly people who die at home or a nursing care facility, rather than a hospital, will keep increasing in the near future.

Tumor protein D52 expression is post-transcriptionally regulated by T-cell intercellular antigen (TIA) 1 and TIA-related protein via mRNA stability.

Although tumor protein D52 (TPD52) family proteins were first identified nearly 20 years ago, their molecular regulatory mechanisms remain unclear. Therefore, we investigated the post-transcriptional regulation of TPD52 family genes. An RNA immunoprecipitation (RIP) assay showed the potential binding ability of TPD52 family mRNAs to several RNA-binding proteins, and an RNA degradation assay revealed that TPD52 is subject to more prominent post-transcriptional regulation than are TPD53 and TPD54. We subsequently focused on the 3'-untranslated region (3'-UTR) of TPD52 as a cis-acting element in post-transcriptional gene regulation. Several deletion mutants of the 3'-UTR of TPD52 mRNA were constructed and ligated to the 3'-end of a reporter green fluorescence protein gene. An RNA degradation assay revealed that a minimal cis-acting region, located in the 78-280 region of the 5'-proximal region of the 3'-UTR, stabilized the reporter mRNA. Biotin pull-down and RIP assays revealed specific binding of the region to T-cell intracellular antigen 1 (TIA-1) and TIA-1-related protein (TIAR). Knockdown of TIA-1/TIAR decreased not only the expression, but also the stability of TPD52 mRNA; it also decreased the expression and stability of the reporter gene ligated to the 3'-end of the 78-280 fragment. Stimulation of transforming growth factor-ß and epidermal growth factor decreased the binding ability of these factors, resulting in decreased mRNA stability. These results indicate that the 78-280 fragment and TIA-1/TIAR concordantly contribute to mRNA stability as a cis-acting element and trans-acting factor(s), respectively. Thus, we here report the specific interactions between these elements in the post-transcriptional regulation of the TPD52 gene.

[Association of the Types of Dementia and the Incidence of Hypertension, Diabetes Mellitus, or Bone Fracture].

Patients with dementia tend to have other chronic diseases, such as hypertension or diabetes mellitus. As dementia progresses, patients tend to decline to a frail state, resulting in bone fracture. In this study, we examined the relationship of the types of dementia and the incidence of other diseases and bone fracture.

Second-Degree Atrioventricular Block Occurring After Tooth Extraction.

Although cardiac arrhythmias are occasionally associated with dental extractions and dental anesthesia, atrioventricular block is rarely seen during dental procedures. We report a rare case of type I second-degree atrioventricular block (Wenckebach phenomenon) occurring after bilateral extraction of impacted mandibular third molars under general anesthesia in a 16-year-old Japanese girl. Under consultation with a cardiovascular physician, we carefully monitored the patient's vital signs postoperatively, including blood pressure, oxygen saturation, and electrocardiogram, using a bedside monitor. Her postoperative course was uneventful. A 12-lead electrocardiogram the following day revealed no abnormality. In this case, we hypothesize that extubation of the nasotracheal tube or oral/pharyngeal suction might have triggered a vagal reflex that caused type I second-degree atrioventricular block. Our experience indicates that standard cardiovascular monitoring should be used for patients undergoing dental treatment under general anesthesia, even for young, healthy patients, to prevent and detect cardiovascular emergencies.

[Revision of Medical Fee System for Treatment at Nursing Homes - The Influential Consideration of the Introduction of One-Patient-Per-Visit Method on the Welfare of Elderly Patients at Nursing Homes].

The 2014 revision of the medical fee system includes the introduction of a one-patient-per-visit method at nursing homes, which should be followed to avoid a drastic reduction in medical fees. We followed the new method, resulting in much more frequent visits to nursing homes(For example, we visit a facilitythree times per week instead of the previous two times per month). Frequent visits to multiple facilities are time- and effort-consuming on our side as a clinic, but, on the other hand, patients have more opportunities to see a doctor when theyare sick even if theyare not scheduled to do so. In this study, we examined how the new method affects the welfare of elderlypatients at nursing homes.

Clinicopathological characteristics and rituximab addition to cytotoxic therapies in patients with rheumatoid arthritis and methotrexate-associated large B lymphoproliferative disorders.

AIMS: To analyse the clinicopathological characteristics and prognosis of 40 rheumatoid arthritis (RA) patients with methotrexate (MTX)-associated large B cell lymphoproliferative disorders (MTX-BLPD). METHODS AND RESULTS: Soluble interleukin 2 receptor titres (median 1500 U/ml) in 40 patients with MTX-BLPD were lower than those of 24 RA patients with non-MTX- associated (non-MTX) BLPD (5731 U/ml) and 15 with control diffuse large B cell lymphoma (DLBCL, 5918 U/ml) (P < 0.01). Using in-situ hybridization, Epstein-Barr virus (EBV) was detected in tumour cells of 25 of 40 RA patients with MTX-BLPD (63%). Immunohistologically, BCL2 expression was detected in 35% of patients with MTX-BLPD, which was lower than 93% of control DLBCL patients (P < 0.01). Eleven patients with EBV(+) MTX-BLPD (44%) showed remission after MTX withdrawal. In RA patients with clinical stage III/IV BLPD, 15 with rituximab (R)+ cytotoxic therapies pursued better prognosis than 10 with R- cytotoxic therapies (P < 0.05). Among the 15 patients, seven with MTX-BLPD showed better overall survival than nine control DLBCL patients (P < 0.01). CONCLUSIONS: In RA patients with MTX-BLPD, immunosuppression by MTX, EBV infection and low BCL2 expression in tumour cells may play roles in tumorigenesis and tumour regression. R+ cytotoxic therapies as well as MTX withdrawal were highly effective in these patients.

UGT1A1 *6 polymorphism predicts outcome in elderly patients with relapsed or refractory diffuse large B-cell lymphoma treated with carboplatin, dexamethasone, etoposide and irinotecan.

The uridine diphosphate glucuronosyltransferase (UGT) gene 1A1*6 polymorphism, which affects irinotecan metabolism, has been associated with improved survival in lymphoma patients treated with of carboplatin, dexamethasone, etoposide and irinotecan (CDE-11). This study assessed the efficacy of CDE-11 relative to the UGT1A1*6 polymorphism in 27 elderly patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for high-dose chemotherapy plus autologous stem cell transplantation. The 2-year survival rate after initial CDE-11 treatment was significantly higher in patients with than without UGT1A1*6 (57% vs. 5%). The most common grade 4 adverse event in patients with the UGT1A1*6 genotypes was neutropenia (88.9%), but there were no gastrointestinal adverse events or treatment-related deaths. Disease progression was the most frequent cause of death. CDE-11 was well tolerated and provided clinical benefit to elderly patients with relapsed or refractory diffuse large B-cell lymphoma. The response to CDE-11 likely correlated with UGT1A1*6 polymorphisms, but further prospective studies are warranted to optimize irinotecan-based chemotherapies relative to UGT1A1 polymorphism.

Factors prognostic of eligibility for allogeneic HCT among older patients with AML-CR1 and adverse- or intermediate-risk cytogenetics.

The introduction of reduced-intensity conditioning (RIC) regimens has made possible allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML). However, the optimal timing of allo-HCT in these patients and its relative risks and benefits when compared with chemotherapies have not been determined. This retrospective study by the Fukuoka Blood and Marrow Transplant Group compared RIC allo-HSCT with non-transplant therapies, the choice based on donor availability, in AML patients in their first complete remission (CR1). The prognostic value of various patient characteristics and disease-specific variables were investigated in 299 patients aged ≥60 years with AML in CR1. Among the 107 patients aged 60-65 years, 54 of whom received allo-HCT and 53 of whom continued chemotherapies; allo-HCT, adverse-risk group, and hematopoietic cell transplantation-comorbidity index were significant predictors of survival outcomes. Among 192 patients aged ≥66 years deemed ineligible for allo-HCT, relapse and Karnofsky performance status after induction therapy were significant predictors of survival outcomes. Findings from this study may facilitate a new standard of care for older AML patients in CR1 who are considered candidates for allo-HCT.

Role of LRP1 in transport of CCN2 protein in chondrocytes.

Low-density lipoprotein receptor-related protein 1 (LRP1) is known to be a receptor for signal transmission and endocytosis. We have previously reported that LRP1 regulates WNT-ß-catenin and protein kinase C signaling in chondrocytes, represses the hypertrophy of chondrocytes during endochondral ossification and that LRP1 is colocalized with a ligand, CCN family member 2 (CCN2; also known as connective tissue growth factor, CTGF), which conducts endochondral ossification, in chondrocytes. However, the role of LRP1 in the endocytic transport of CCN2 in chondrocytes is not yet understood. In the present study, we investigated the interaction between LRP1 and CCN2 during endocytic trafficking. Small interfering RNA (siRNA)-mediated knockdown of LRP1 in chondrocytic HCS-2/8 cells showed that the amount of exogenous CCN2 binding and/or incorporation was decreased in the LRP1 downregulated cells. Importantly, we observed that CCN2 internalization in chondrocytes was dependent on clathrin, and internalizated CCN2 was colocalized with an early or recycling endosome marker. Transcytosis of CCN2 through HCS-2/8 cells was confirmed by performing experiments with a trans-well apparatus, and the amount of transcytosed CCN2 was decreased by an LRP1 antagonist. These findings rule out possible leakage and confirm the crucial involvement of LRP1 during experimental transcytosis. Moreover, under hypoxic conditions that mimic the cartilaginous microenvironment, the level of LRP1 and the amount of transcytosed CCN2 increased, and these increases were neutralized by treatment with the LRP1 antagonist. The distribution of LRP1 and its antagonist in the growth plate in vivo was consistent with that of CCN2 in this tissue, which is produced by and transported by LRP1 from the chondrocytes in the prehypertrophic layer. These findings suggest that LRP1 mediates the transcytosis of CCN2, which might be a crucial event that determines the distribution of CCN2 in cartilage.

The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis.

Nutrients and bioenergetics are prerequisites for proliferation and survival of mammalian cells. We present evidence that the cyclin-dependent kinase inhibitor p27(Kip1), is phosphorylated at Thr 198 downstream of the Peutz-Jeghers syndrome protein-AMP-activated protein kinase (LKB1-AMPK) energy-sensing pathway, thereby increasing p27 stability and directly linking sensing of nutrient concentration and bioenergetics to cell-cycle progression. Ectopic expression of wild-type and phosphomimetic Thr 198 to Asp 198 (T198D), but not unstable Thr 198 to Ala 198 (p27(T198A)) is sufficient to induce autophagy. Under stress conditions that activate the LKB1-AMPK pathway with subsequent induction of autophagy, p27 knockdown results in apoptosis. Thus LKB1-AMPK pathway-dependent phosphorylation of p27 at Thr 198 stabilizes p27 and permits cells to survive growth factor withdrawal and metabolic stress through autophagy. This may contribute to tumour-cell survival under conditions of growth factor deprivation, disrupted nutrient and energy metabolism, or during stress of chemotherapy.

The role of autophagy in cancer development and response to therapy.

Autophagy is a process in which subcellular membranes undergo dynamic morphological changes that lead to the degradation of cellular proteins and cytoplasmic organelles. This process is an important cellular response to stress or starvation. Many studies have shed light on the importance of autophagy in cancer, but it is still unclear whether autophagy suppresses tumorigenesis or provides cancer cells with a rescue mechanism under unfavourable conditions. What is the present state of our knowledge about the role of autophagy in cancer development, and in response to therapy? And how can the autophagic process be manipulated to improve anticancer therapeutics?

Potential anti-osteoporotic effects of herbal extracts on osteoclasts, osteoblasts and chondrocytes in vitro.

BACKGROUND: Osteoporosis (OP) is one of the most serious diseases in the modern world, and OP patients frequently suffer from fragility fractures in the hip, spine and wrist, resulting in a limited quality of life. Although bisphosphonates (BPs) are the most effective class of anti-bone-resorptive drugs currently available and the most commonly prescribed for the clinical treatment of OP, they are known to cause serious side effects such as bisphosphonate-related osteonecrosis of the jaw. Novel therapeutic materials that can replace the use of BPs have therefore been developed. METHODS: We commenced an institutional collaborative project in which candidates of herbal extracts were selected from more than 400 bioactive herbal products for their potential therapeutic effects not only in OP, but also in oral and skeletal diseases. In the present study, we report on 3 Chinese medical herbal extracts from the root barks of Melia azedarach, Corydalis turtschaninovii, and Cynanchum atratum. RESULTS: All of these extracts inhibited osteoclast proliferation and induced apoptosis by up-regulation of caspase activity and increase of mitochondrial pro-apoptotic proteins expression. Furthermore, the extracts enhanced differentiation, but did not affect proliferation of both osteoblasts and chondrocytes. The osteo-inducible effect was also observed in cultured primary bone marrow cells. CONCLUSIONS: Although these extracts have been utilized in traditional Chinese medicine for hundreds of years, there are no reports to our knowledge, on their therapeutic effects in OP. In this study, we elucidate the potency of these herbal extracts as novel candidates for OP therapy.

Aplastic Anemia With Thrombosis Following the Administration of Immunosuppressant and Thrombopoietin Receptor Agonist (TPO-RA).

Thrombopoietin receptor agonist (TPO-RA) is effective for aplastic anemia (AA) and idiopathic thrombocytopenic purpura (ITP). However, the risk of thrombosis during ITP treatment with TPO-RA is higher than without TPO-RA. It is unclear whether TPO-RA increases the risk of thrombosis in patients with AA. We report a case of a 66-year-old female with severe AA having paroxysmal nocturnal hemoglobinuria (PNH) clones in the peripheral blood who developed ischemic colitis after three days of starting eltrombopag. Contrast-enhanced computed tomography showed ischemic colitis and contrast enhancement defect in the left atrial appendage, which indicated a thrombus in the heart. Stopping eltrombopag and providing supportive care improved her symptoms, and her blood cell counts gradually increased. Thrombosis should be considered when TPO-RA is administered during the immunosuppressive treatment of AA.

[Assessment of the association between nursing care services, hypertension, and Alzheimer's disease in elderly patients with late-stage diabetes].

In an aging society with fewer children, diabetes self-control is difficult for elderly patients. Under these circumstances, it is expected that living in care homes for the elderly and institutions where nursing care services could be provided will help improve the prognosis of diabetic patients. Therefore, we assessed whether HbA(1c). levels (National Glycohemoglobin Standardization Program : NGSP) in 121 elderly patients with late-stage diabetes receiving home medical care in our clinic from March 2008 to March 2013 improved with nursing care services.

Analyses of the Posttranscriptional Regulation of CCN Genes: Approach to Multiple Steps of CCN2 Gene Expression.

Cells generally control the concentration of mRNA via transcriptional and posttranscriptional regulation, so the separate contributions of synthesis and degradation (decay) cannot be discriminated by the quantification of mRNA. To elucidate the contribution of posttranscriptional regulation, all experimental procedures for the analysis of the total transcript level, transcriptional induction, degradation of the target mRNA, and inhibition of mRNA translation are performed either individually or in combination. From our experience, measurement of the steady-state levels of mRNA using quantitative real-time polymerase chain reaction is an essential first step in quantifying the ccn2 gene expression. Subsequently, the effect of transcription rates should be assessed by reporter assays of the ccn2 promoter and nuclear run-on assays. The stability of ccn2 mRNAs is then evaluated in the presence of a metabolic inhibitor actinomycin D, followed by mRNA degradation assays in vitro. Finally, repression of ccn2 mRNA translation can be estimated by comparing the expression of mRNA and protein changes. We herein report the strategic methods used in a series of analyses to elucidate the possible involvement of the posttranscriptional regulatory mechanism of the ccn2 gene and show how this approach can, in theory, be used to elucidate the posttranscriptional regulation of other genes belonging to the CCN family.

Association of the quantitative oral health status of patients with COVID-19 with their organ status and immunity: A single-centre observational study.

OBJECTIVES: To evaluate the prevalence of oral complications in patients with severe COVID-19; investigate the association between their oral health, organ status, and immunity; and determine whether the resazurin disc test is an effective substitute for the Oral Assessment Guide. RESEARCH METHODOLOGY/DESIGN: A single-centre observational study. SETTING: Intensive care unit with restricted access specialising in extracorporeal membrane oxygenation for COVID-19 treatment. MAIN OUTCOME MEASURES: We investigated the oral health of 13 patients with COVID-19 receiving extracorporeal membrane oxygenation therapy between April and December 2021 using the Oral Assessment Guide and colour reactive resazurin disc test. The Sequential Organ Failure Assessment and Prognostic Nutritional Index were used to assess organ status and immunity, respectively. The correlation of oral health status with organ status and immunity was investigated. RESULTS: High bacterial levels, revealed by the resazurin disc test, were associated with elevated Oral Assessment Guide scores, indicating oral health deterioration, particularly in terms of teeth and dentures. Increased Sequential Organ Failure Assessment scores and decreased Prognostic Nutritional Index were correlated with poor oral health, revealed by the Oral Assessment Guide and resazurin disc test. CONCLUSION: Poor oral health is an important risk factor for severe COVID-19 complications in patients admitted to an intensive care unit. The Oral Assessment Guide and resazurin disc test can evaluate oral conditions; however, the resazurin disc test is quantitative and does not require salivary specimens to be transferred outside the patient ward for evaluation. The resazurin disc test can be a useful substitute for the Oral Assessment Guide in intensive care units with restricted access. IMPLICATIONS FOR CLINICAL PRACTICE: The resazurin disc test can be used for quantitative assessment of patients' oral condition in isolation wards. Multidisciplinary management of patients with COVID-19 should be promoted and involve oral healthcare providers such as dentists and dental hygienists.

Serum triglyceride levels and incidence of hypertension in a general Japanese population: ISSA-CKD study.

The aim of this study was to clarify the relationship between fasting and nonfasting serum triglyceride (TG) levels and the incidence of hypertension in a general Japanese population. We conducted a population-based retrospective cohort study using annual health check-up data of residents of Iki City, Nagasaki Prefecture, Japan. A total of 3202 participants without hypertension at baseline were included in the present analysis. TG levels were classified as quartile 1 (<0.82 mmol/L), quartile 2 (0.83-1.13 mmol/L), quartile 3 (1.14-1.70 mmol/L) and quartile 4 (≥1.71 mmol/L) for men, and as quartile 1 (<0.70 mmol/L), quartile 2 (0.71-0.96 mmol/L), quartile 3 (0.97-1.34 mmol/L) and quartile 4 (≥1.35 mmol/L) for women. The outcome was incident hypertension. During an average follow-up of 4.4 years, 983 participants developed hypertension, according to the Cox proportional hazards model. The annual incidence of hypertension increased with an elevation in TG levels for men (5.88% in quartile 1, 8.30% in quartile 2, 7.62% in quartile 3, and 9.82% in quartile 4). This association was significant, even after adjustment for other risk factors: hazard ratio 1.41 [95% CI 1.07-1.85] for quartile 2, 1.30 [0.99-1.71] for quartile 3, and 1.59 [1.22-2.08] for quartile 4 compared with quartile 1 (p = 0.041 for trend). In contrast, there was no clear association between serum TG levels and the incidence of hypertension after adjustment for confounding factors among women (p = 0.240 for trend). High levels of serum TG were associated with the future incidence of hypertension in a general population of Japanese men but were not associated with that in women. Casual serum triglyceride levels and incidence of hypertension in a general Japanese population: ISSA-CKD study.