Endothelial nitric oxide synthase (eNOS) dysfunction is known to exacerbate the progression and prognosis of diabetic kidney disease (DKD). One of the mechanisms through which this is achieved is that low eNOS levels are associated with hypercoagulability, which promotes kidney injury. In the extrinsic coagulation cascade, the tissue factor (factor III) and downstream coagulation factors, such as active factor X (FXa), exacerbate inflammation through activation of the protease-activated receptors (PARs). Recently, it has been shown that the lack of or reduced eNOS expression in diabetic mice, as a model of advanced DKD, increases renal tissue factor levels and PAR1 and 2 expression in their kidneys. Furthermore, pharmaceutical inhibition or genetic deletion of coagulation factors or PARs ameliorated inflammation in DKD in mice lacking eNOS. In this review, we summarize the relationship between eNOS, coagulation, and PARs and propose a novel therapeutic option for the management of patients with DKD.

Promoting generic drugs can reduce the financial burden on patients and improve healthcare finances. The insurers have been conducting promotional efforts, such as direct-mail campaigns, but little is known about the public’s perception of generic drugs and effective message strategies for promotion. In 2018, we conducted a web-based survey of middle-aged Japanese men and women that investigated: (i) their perceptions of generic drugs, (ii) the association between perceptions and willingness-to-pay for brand-name drugs relative to generic drugs, and (iii) potentially effective forms of information provision to alter individuals’ perceptions. Of the 1,005 respondents, over half perceived generic drugs as having the same level of efficacy and safety as brand-name drugs. While willingness-to-pay was dispersed among respondents, two factors were associated with small willingness-to-pay: (a) perceiving generic drugs as having the same level of efficacy and safety as brand-name drugs and (b) perceiving that promoting the use of generic drugs is important for controlling medical expenditures. Moreover, presenting potential savings over five years by choosing generic drugs was a potentially effective tool for altering perceptions, relative to showing monthly savings. Our findings suggest that certain parts of the population still have high willingness-to-pay for brand-name drugs, and strategic communication to alter perception could be effective in promoting the use of generic drugs among those who are price-inelastic.

Airborne fine particulate matter with an aerodynamic diameter equal to or smaller than 2.5 μm (abbreviated as PM_2.5) increases the risk of nasal lesions, but the underlying molecular mechanism has not been fully elucidated. In the atmosphere, the composition of PM_2.5 collected varies in physical and chemical properties, which affects its damage to human health. Thus, we constructed artificial PM_2.5 particles based on actual PM_2.5 and investigated the in vivo effects of artificial PM_2.5 exposure on the oxidative stress, inflammatory response, and nasal mucosa morphology of rats. The results showed that artificial PM_2.5 is comparable in composition ratio, size, and morphology to actual PM_2.5. This in vivo study indicated that artificial PM_2.5 exposure reduces total superoxide dismutase and glutathione peroxidase activities, elevates malondialdehyde content in the nasal mucosa, and induces increased levels of pro-inflammatory mediators, including interleukin-1, interleukin-6 and tumor necrosis factor-α. Our data shows that artificial PM_2.5 particles could be used for experimental study of PM_2.5 toxicology, ensuring that the physical and chemical properties of experimental PM_2.5 are relatively constant and allowing for repeatability of this research. Oxidative damage and inflammatory response may be the toxic mechanisms that cause nasal lesions after exposure to artificial PM_2.5.

Langerhans cell neoplasms, which include Langerhans cell histiocytosis and Langerhans cell sarcoma, are tumors that originate from dendritic cells. Langerhans cell sarcoma is defined as a high-grade neoplasm with overtly malignant cytological features and the Langerhans cell-like phenotype, and generally has a poorer prognosis and more aggressive phenotype than Langerhans cell histiocytosis. Insulin-like growth factor 2 messenger RNA-binding protein 3 (IGF2BP3 or IMP3) is an oncofetal protein that is expressed in various cancer types; its expression is often associated with a poor prognosis and aggressive phenotype. Here, we used immunohistochemistry to evaluate IGF2BP3 expression in Langerhans cell neoplasms. IGF2BP3 expression was scored as negative (< 1%) or positive (≥ 1%) by immunohistochemistry. All 4 patients with Langerhans cell sarcoma (100%) and 6 of 22 pediatric (age < 18 years) patients with Langerhans cell histiocytosis (27.3%) had positive results for IGF2BP3; however, 16 of 22 pediatric patients with Langerhans cell histiocytosis (72.7%) and all 15 adult (age ≥ 18 years) patients with Langerhans cell histiocytosis (100%) had a negative result. Among patients with Langerhans cell histiocytosis, IGF2BP3 expression was independent of sex, location, prognosis, and BRAF V600E staining results. Taken together, these results indicate that IGF2BP3 expression may be a helpful marker for distinguishing Langerhans cell sarcoma from Langerhans cell histiocytosis in adult patients.

The onset age of ulcerative colitis has been increasing in several countries. Furthermore, the number of elderly patients with ulcerative colitis has been increasing in an aging society. We investigated the incidence of ulcerative colitis patients in Japan using a large-scale health insurance claims database to survey the ulcerative colitis incidence ratio and the clinical characteristics in late-onset ulcerative colitis patients. Newly diagnosed 2,791 ulcerative colitis between 2015 and 2018 was investigated. Medical treatment within 12 months of diagnosis was analyzed among 0-19, 20-39, 40-59 and 60-75 age groups. The mean age at diagnosis was 40.3 years (SD: 12.9), and the incidence ratio peaked in the 40’s. Most of patients received 5-aminocylitic acid (91.7%), a subset of patients received prednisolone (20.1%), and a small number of patients took immunomodulator (6.8%), cytapheresis (3.3%), anti-TNFα therapy (4.3%), and colectomy (1.0%) within 12 months after diagnosis. All treatments except colectomy were most frequent in the 0-19 age group; however, colectomy was most frequent in 60-75 age group. The clinical course of ulcerative colitis that developed in adults did not differ significantly in terms of medical treatment within 12 months from the onset; meanwhile, the surgery rate was high in elderly patients. It is necessary to pay close attention to future trends regarding the aging of the onset age and the treatment, especially for late-onset ulcerative colitis patients.

Effective Helicobacter pylori (H. pylori) eradication is a major public health concern; however, eradication failure rates with the standard triple therapy remain high. We aimed to investigate the effectiveness and tolerability of ranitidine bismuth citrate (RBC) pretreatment before standard triple therapy for H. pylori eradication. A prospective, randomized, controlled, and open-label clinical trial was conducted from June to December 2019. H. pylori eradication rate, safety, and tolerability were compared between the standard treatment group (esomeprazole, amoxicillin, and clarithromycin for 7 days) and RBC pretreatment group (RBC for 2 weeks before standard triple therapy). This trial ended earlier than estimated owing to the N-nitrosodimethylamine concerns with ranitidine. Success rates of H. pylori eradication were 80.9% and 67.3% in the RBC pretreatment (n = 47) and standard treatment (n = 52) (p = 0.126) groups, respectively. Our trial was discontinued earlier than planned; however, a statistical significance would be achieved by expansion of our data (p = 0.031) if patient enrollment numbers reached those initially planned. Adverse event rates were comparable between groups (25.5% in the pretreatment group vs. 28.8% in the standard treatment group), without serious event. Tolerability was excellent in both groups, recorded as 97.9% and 100% in the pretreatment and standard treatment groups, respectively. Compared with the standard triple regimen, RBC pretreatment for 2 weeks may achieve higher H. pylori eradication rates, with excellent safety and tolerability. However, this study necessitates further validation as it was discontinued early owing to the N-nitrosodimethylamine issues of ranitidine.

Diamond-Blackfan anemia is a congenital bone marrow failure syndrome characterized by red blood cell (RBC) aplasia with varied malformations in infants. Elevated activity of adenosine deaminase (ADA) has been considered as a useful biomarker of Diamond-Blackfan anemia, and ADA assay has been shown to be more sensitive than genetic diagnosis. Approximately, 80% of the examined patients showed elevated ADA activity, whereas genetic tests of ribosome subunit genes identified mutations in approximately 60% of the patients. We previously reported that reduced glutathione (GSH) levels in RBCs may serve as a biomarker of Diamond-Blackfan anemia. In this study, to confirm the universality of our data, we extended the analysis to seven RBC enzymes and GSH of 14 patients with Diamond-Blackfan anemia and performed a cross-analysis study using enzyme activity assay and recently reported proteome data. Statistical analysis revealed that both data exhibited high similarity, upregulation in the hexokinase and pentose-phosphate pathway, and downregulation in glycolytic enzymes such as phosphofructokinase and pyruvate kinase, in the RBCs obtained from the subjects with Diamond-Blackfan anemia. The only discrepancy between enzyme activity and proteome data was observed in glucose-6-phosphate dehydrogenase (G6PD), as increased G6PD activity showed no relation with the significant elevation in protein levels. These results suggest that our enzymatic activity data of Diamond-Blackfan anemia are universal and that the enzymatic activation of G6PD via a hitherto-unveiled mechanism is another metabolic feature of RBCs of Diamond-Blackfan anemia.

Pediatric inflammatory bowel disease is associated with growth failure due to chronic inflammation, nutrient disorder, and the side effects of drugs, such as corticosteroids. Biological agents are therapeutic drugs that significantly improve the prognosis of patients with inflammatory bowel disease. The effectiveness of ustekinumab has been reported in the management of adult patients with inflammatory bowel disease. There are very few reports regarding the effectiveness and safety of ustekinumab in pediatric patients with inflammatory bowel disease, especially those who are biologically naive. A 10-year-old girl presented with chronic abdominal pain, diarrhea, and weight loss. Colonoscopy showed a longitudinal ulcer and cobblestone appearance in the ileum and discontinuous inflammation of the colon; therefore, she was diagnosed with Crohn’s disease. She was prescribed a fat-restricted diet, elemental diet, 5-aminosalicylic acid, transient prednisolone, and ustekinumab. She achieved clinical and endoscopic remission based on the weighted Pediatric Crohn’s Disease Activity Index, fecal calprotectin, and colonoscopy findings at week 75. This patient developed no adverse events, such as infusion reaction or susceptibility to infection over the 75 weeks. The use of ustekinumab as the first biological agent may be an effective and safe treatment for pediatric Crohn’s disease.

North Italy emerged as an epicenter of COVID-19 in the Western world. The majority of studies of patients with COVID-19 have focused on hospitalized patients, and data on early outpatient treatment are limited. This research retrospectively examines consecutive symptomatic adults who did not present to a hospital but who experience laboratory confirmed (nasopharyngeal swabs) or probable COVID-19 infection. From March 12 to April 12, 2020, 124 consecutive patients with laboratory-confirmed COVID-19 infection (84%) or with epidemiologically linked exposure to a person with confirmed infection (16%) were managed at home. The diagnosis of pneumonia was made with a portable ultrasound. COVID-19 treatment was based on low-dose hydroxychloroquine with or without darunavir/cobicistat or azithromycin and enoxaparine for bedridden patients. The patients were monitored by telemedicine. The primary endpoints were clinical improvement or hospitalization, and the secondary endpoints were mortality at day 30 and at day 60. Forty-seven (37.9%) patients had mild COVID-19 infection, 44 (35.5%) had moderate COVID-19 infection, and 33 (26.6%) had severe COVID-19 infection. Four patients (3.2%) were hospitalized and there were no deaths at day 30 and at day 60. Only mild side effects were reported. Early home treatment of COVID-19 patients resulted in a low hospitalization rate with no deaths, with the limitations of the small sample size and that it was conducted within a single geographic area. We believe that this model may be easily reproduced in both cities and rural areas around the world to treat COVID-19 infection.

COVID-19 has caused an unprecedented global pandemic. Premenstrual symptoms include mood-related, behavioral, and physical symptoms that are limited to the luteal phase of the menstrual cycle. Psychosocial stress is a risk factor for premenstrual symptoms. The aim of this study was to examine the association between premenstrual symptoms and stress caused by COVID-19. We analyzed data from 871 students with regular menstrual cycles who completed the Premenstrual Symptoms Questionnaire (PSQ), Fear of COVID-19 Scale, and Impact of Event Scale-Revised version (IES-R). The total PSQ score was significantly higher in women with COVID-19-induced posttraumatic stress symptoms (PTSS) than in non-PTSS groups. Compared with pre-pandemic data (2019), the total PSQ score did not change in non-PTSS, but increased in PTSS groups. All symptoms were more severe in PTSS groups than in non-PTSS groups. Compared with 2019, PTSS groups had more severe symptoms for all symptoms except ‘physical symptoms’ and ‘decreased social activity’, and non-PTSS groups only exhibited improvements in the ‘decreased social activity’. Multiple regression analysis revealed that the IES-R score was a significant exacerbation factor of the total PSQ score, along with age and menstrual pain. This study revealed the association between pandemic-associated PTSS and the severity of premenstrual symptoms.

In Japan, reports on the association of individual characteristics, and geographical distance and time with clinical outcomes for neurological emergencies involving helicopter emergency medical services (HEMS) are scarce. Using Tochigi HEMS data (2010-2018), we assessed the characteristics of 1,170 emergency neurological patients (e.g., stroke, neurotrauma, and seizure) at the base hospital, which covered 58% of all HEMS patients in the prefecture. After initial treatment in the emergency room, emergency physicians confirmed the clinical outcomes of each patient compared to those at the incident sites (recovery/non-recovery). We calculated the geographic distance from the base hospital to each incident site, and estimated and adjusted odds ratios (aOR) and 95% confidence intervals (CI) for non-recovery against distance. The mean distance between the incident site and base hospital was 22.0 ± 11.7 km, and 77.4% of patients recovered following initial treatment. Two peak age groups were observed among emergency neurological diseases, including seizures in patients who were aged < 5 years and stroke and neurotrauma in patients who were aged 70-80 years. The percentages of stroke, traumatic head and brain injury, and seizure were 35.8%, 29.2%, and 22.8%, respectively. The incidence of stroke (aOR = 11.8, 95% CI 6.86-20.3) and neurotrauma (aOR = 4.86, 95% CI 2.78-8.51) independently predicted a poor prognosis. However, no significant association was observed with the distance from the base hospital. Therefore, in the Tochigi prefecture, geographical disparities may not affect the short-term prognosis of patients with neurological emergencies who were transported by HEMS.