Quantification of fibrosis extend and airspace availability in lung: A semi-automatic ImageJ/Fiji toolbox.

The evaluation of the structural integrity of mechanically dynamic organs such as lungs is critical for the diagnosis of numerous pathologies and the development of therapies. This task is classically performed by histology experts in a qualitative or semi-quantitative manner. Automatic digital image processing methods appeared in the last decades, and although immensely powerful, tools are highly specialized and lack the versatility required in various experimental designs. Here, a set of scripts for the image processing software ImageJ/Fiji to easily quantify fibrosis extend and alveolar airspace availability in Sirius Red or Masson's trichrome stained samples is presented. The toolbox consists in thirteen modules: sample detection, particles filtration (automatic and manual), border definition, air ducts identification, air ducts walls definition, parenchyma extraction, MT-staining specific pre-processing, fibrosis detection, fibrosis particles filtration, airspace detection, and visualizations (tissue only or tissue and airspace). While the process is largely automated, critical parameters are accessible to the user for increased adaptability. The modularity of the protocol allows for its adjustment to alternative experimental settings. Fibrosis and airspace can be combined as an evaluation of the structural integrity of the organ. All settings and intermediate states are saved to ensure reproducibility. These new analysis scripts allow for a rapid quantification of fibrosis and airspace in a large variety of experimental settings.

Association between social network and dietary variety among community-dwelling older adults.

OBJECTIVE: Social networks are critical social health factors for older adults. This study examined the association between social networks and dietary variety among community-dwelling older adults. DESIGN: A cross-sectional study, using the dietary variety score (DVS) developed for older Japanese people to assess dietary variety and the Lubben Social Network Scale (LSNS-6) to assess social networks. SETTING: N City, H Prefecture, Japan. PARTICIPANTS: Community-dwelling older adults aged ≥ 65 years (n 1229). RESULTS: The LSNS-6 score in the low DVS group was lower than that in the middle and high DVS groups (12·2 ± 5·6 v. 13·4 ± 5·4 and 14·4 ± 5·7, P < 0·001). The population of social isolation (LSNS-6, < 12) in the low DVS group was higher than that in the middle and high DVS groups (43·5 % v. 35·8 % and 31·0 %, P = 0·005). Multivariate linear regression analysis showed that the LSNS-6 score was positively correlated with DVS (standardised coefficient, 0·092; P = 0·002). Social isolation was also significantly associated with a low DVS in the multivariate-adjusted logistic analysis model (OR, 1·30; 95 % CI 1·00, 1·68; P = 0·048). Stratified analysis results revealed the LSNS-6 and DVS were significantly associated in participants with the following characteristics: younger age (< 75 years), women and those living with someone. CONCLUSIONS: Social networks were associated with dietary variety; social isolation was related to poor dietary variety among community-dwelling older adults. An association between social networks and dietary variety was observed among young-old older adults, women and those living with someone.

Association between asymmetric dimethylarginine and sarcopenia in community-dwelling older women.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelium nitric oxide synthesis and causes endothelial dysfunction that may be related to sarcopenia. However, the association between ADMA and sarcopenia has not been studied. We evaluated the correlations between plasma ADMA levels and sarcopenia in community-dwelling older women. In total, 144 community-dwelling older women participated in this study. Plasma ADMA levels were measured using a competitive enzyme-linked immunosorbent assay. Skeletal muscle mass, measured in terms of bioimpedance and grip strength, was used to assess sarcopenia. Plasma ADMA levels were significantly higher in participants with sarcopenia than in those without sarcopenia. Through receiver-operating characteristic curve analysis, the cutoff value of plasma ADMA level for sarcopenia was estimated at 0.57 µM. Sarcopenia was significantly more prevalent in participants with higher plasma ADMA levels than in those with lower plasma ADMA levels. According to logistic regression analysis, the crude odds ratio of higher plasma ADMA levels in participants with sarcopenia was 4.57 (95% confidence interval, 1.82-11.47; p = 0.001). Reductions in the skeletal muscle mass index over 2 years were significantly greater in participants with higher plasma ADMA levels. In conclusion, plasma ADMA levels were significantly associated with sarcopenia in community-dwelling older women.

Low Dietary Variety Is Associated with Incident Frailty in Older Adults during the Coronavirus Disease 2019 Pandemic: A Prospective Cohort Study in Japan.

BACKGROUND: Stagnation of social activity due to the COVID-19 pandemic probably reduces motivation to maintain a healthy diet. It is important to report on the dietary changes observed in older adults during a period of restriction on outings and to clarify the relationship between dietary variety and frailty. This one-year follow-up study examined the association between frailty and dietary variety during the COVID-19 pandemic. METHODS: Baseline and follow-up surveys were conducted in August 2020 and August 2021, respectively. The follow-up survey was distributed by mail to 1635 community-dwelling older adults aged ≥65 years. Of the 1235 respondents, 1008 respondents who were non-frail at baseline are included in this study. Dietary variety was examined using a dietary variety score developed for older adults. Frailty was assessed using a five-item frailty screening tool. The outcome was frailty incidence. RESULTS: In our sample, 108 subjects developed frailty. A linear regression analysis revealed a significant association between dietary variety score and frailty score (ß, -0.032; 95% CI, -0.064 to -0.001; p = 0.046). This association was also significant in Model 1, adjusted for sex and age, (ß, -0.051; 95% CI, -0.083 to -0.019; p = 0.002) and in a multivariate analysis that added adjustments for living alone, smoking, alcohol use, BMI, and existing conditions to Model 1 (ß, -0.045; 95% CI, -0.078 to -0.012; p = 0.015). CONCLUSIONS: A low dietary variety score was associated with an increased frailty score during the COVID-19 pandemic. The restricted daily routine caused by the COVID-19 pandemic will probably continue to have a long-term effect in terms of reduced dietary variety. Thus, vulnerable populations, such as older adults, might require dietary support.

Social contact impacts physical activity and sedentary behavior among older adults in Japan due to COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has adversely affected social contact and physical activity. This study investigated the correlation between physical activity, social contact, and sedentary time among adults aged 65 years and above during the COVID-19 pandemic. METHODS: This study was conducted in N City, H Prefecture, Japan. The authors randomly selected 4,996 adults, aged 65 years and above (mean age 74.1 ± 6.1 years), living in N City, and survey forms were distributed by mail in mid-August 2020. Altogether, 1,925 participants were included in this study. The survey comprised questions concerning the participants' sex, height, weight, age, smoking and drinking habits, living arrangements, social contact assessments, physical activity levels, and sedentary time. Moreover, linear regression analysis was utilized to investigate the associations between the variables. RESULTS: The reported median physical activity was 1272 metabolic equivalent of task-min/week (interquartile range 528-2628), and the reported median sedentary time was 360 min/week (interquartile range 240-600). COVID-19 "somewhat," "quite a lot," or "completely" hindered the frequency of in-person contact with friends among 75.5% of the respondents and hampered the frequency of virtual contact with friends among 38.8% of the respondents. Physical activity was associated significantly with in-person contact indicators: "interaction with friends" (B = -0.111; 95%CI: -0.187, -0.035; p = 0.004) and "social participation" (B = -0.163; 95%CI: -0.248, -0.079; p < 0.001). These associations remained significant for both multivariate analysis Models 1 (sex and age) and 2 (addition of body mass index [BMI], alcohol use, smoking, living alone, and the number of illnesses to Model 1). Additionally, sedentary time was significantly associated with the social contact variable of "interaction with friends" (B = 0.04; 95%CI: 0.016, 0.064; p = 0.001). This association remained significant in both multivariate analysis models. CONCLUSIONS: Significant associations were confirmed between reduced social contact, decreased physical activity, and more sedentary behavior among older adults due to COVID-19. Hence, continuous monitoring and support for social activities among susceptible older adults in extraordinary circumstances are essential.

Difamilast Ointment in Japanese Adult and Pediatric Patients with Atopic Dermatitis: A Phase III, Long-Term, Open-Label Study.

INTRODUCTION: Phosphodiesterase 4 (PDE4), which regulates inflammatory cytokine production leading to atopic dermatitis (AD), is selectively inhibited by difamilast. The objective of this phase III, long-term, open-label study was to evaluate the safety and efficacy of topical difamilast in Japanese adult and pediatric patients with AD. METHODS: Adult patients (n = 166) began treatment with difamilast 1% ointment, and pediatric patients began treatment with difamilast 0.3% ointment (n = 144) or difamilast 1% ointment (n = 56). Treatment was continued twice daily for 52 weeks. All patients had an Investigator's Global Assessment (IGA) score of 2 (mild), 3 (moderate), or 4 (severe/very severe), and an AD-affected body surface area (BSA) of ≥ 5% before treatment, with no restriction on the upper limit for the AD-affected BSA. RESULTS: During therapy, 120 adult patients (72.3%) and 178 pediatric patients (89.0%) experienced treatment-emergent adverse events (TEAEs), most of which were mild or moderate in severity. Discontinuation due to TEAEs was reported in 13 adult patients (7.8%) and in 7 pediatric patients (3.5%). Treatment-related adverse events were reported in 14 adult patients (8.4%) and 16 pediatric patients (8.0%), most frequently dermatitis atopic (1.8%) and acne (1.2%) in adult patients and dermatitis atopic and pigmentation disorder (each 2.0%) in pediatric patients. The cumulative success rates in Eczema Area and Severity Index (EASI)-75 in adult and pediatric patients were 55.4% and 73.5%, respectively, at week 52, and the cumulative success rates increased from week 4 to week 52. The cumulative success rates in IGA score showed the same trend as those in EASI -75. CONCLUSIONS: This study demonstrates that difamilast ointments are well tolerated and effective in Japanese adult and pediatric patients with AD when applied twice daily for 52 weeks, and are expected to be used for a long-term treatment for AD. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov identifier: NCT03961529.

[Lung Transplantation at a Low Volume Center].

The number of lung transplantation performed in Japan is extremely low compared to other countries, whereas we have 10 facilities certified as cadaveric lung transplantation in Japan, meaning that there are low volume centers. By August 2021, we performed lung transplantation in 21 cases for 12 years, therefore, our facility should be considered as low volume center. Surgical outcomes at low volume centers are generally considered poor. However, the overall five-year survival rate of total cases was 84.8%, and that of cadaveric cases was 94.4% in our hospital. It was better than the average of about 73% of all facilities in Japan. These data suggested that the accreditation system in Japan is functioning well. On the other hand, there may be a disparity between facilities. At our facility, we are actively performing inverted lung transplantation so as not to lose the opportunity for transplantation, and we have performed it in three cases so far and have achieved good results.

Lower dietary variety is associated with worse sleep quality in community-dwelling elderly Japanese women.

BACKGROUND AND OBJECTIVES: Sleep disturbance is a common health problem in the elderly population. We examined the association between dietary variety and subjective sleep quality in community-dwelling elderly Japanese women. METHODS AND STUDY DESIGN: This cross-sectional study recruited 160 community-dwelling elderly women aged ≥65 years. Subjective sleep quality and dietary variety were assessed by Pittsburgh Sleep Quality Index (PSQI) and dietary variety score (DVS), respectively. DVS was calculated from the eating frequency of 10 food groups. Sleep disturbance was defined as PSQI score of ≥6. RESULTS: The DVS in subjects with sleep disturbance was significantly lower than that of those without the disturbance (4.1±2.1 vs 5.3±2.1, p<0.01). In the multivariable regression model, the PSQI score was negatively correlated with the DVS score in age-adjusted model (standardized coefficient; -0.234, p<0.01). In the further adjusted model that included depression levels, the negative association between PSQI score and DVS score was retained (standardized coefficient; -0.211, p<0.05). Among 10 food groups comprising DVS, the eating frequency of soybean and soybean products was the determinant of sleep disturbance in the stepwise liner regression analysis. In the further model that contained DVS, DVS was the independent determinant of sleep disturbance, while the eating frequency of soybean and soybean products was excluded. CONCLUSIONS: A worse sleep quality was associated with lower DVS in elderly Japanese women. Diet comprising various food groups was better for sleep quality than consuming only a particular food in the elderly.

Human cardiac fibroblasts expressing VCAM1 improve heart function in postinfarct heart failure rat models by stimulating lymphangiogenesis.

Cardiovascular diseases are a leading cause of death worldwide. After an ischemic injury, the myocardium undergoes severe necrosis and apoptosis, leading to a dramatic degradation of function. Numerous studies have reported that cardiac fibroblasts (CFs) play a critical role in heart function even after injury. However, CFs present heterogeneous characteristics according to their development stage (i.e., fetal or adult), and the molecular mechanisms by which they maintain heart function are not fully understood. The aim of this study is to explore the hypothesis that a specific population of CFs can repair the injured myocardium in heart failure following ischemic infarction, and lead to a significant recovery of cardiac function. Flow cytometry analysis of CFs defined two subpopulations according to their relative expression of vascular cell adhesion molecule 1 (VCAM1). Whole-transcriptome analysis described distinct profiles for these groups, with a correlation between VCAM1 expression and lymphangiogenesis-related genes up-regulation. Vascular formation assays showed a significant stimulation of lymphatic cells network complexity by VCFs. Injection of human VCAM1-expressing CFs (VCFs) in postinfarct heart failure rat models (ligation of the left anterior descending artery) led to a significant restoration of the left ventricle contraction. Over the course of the experiment, left ventricular ejection fraction and fractional shortening increased by 16.65% ± 5.64% and 10.43% ± 6.02%, respectively, in VCF-treated rats. Histological examinations revealed that VCFs efficiently mobilized the lymphatic endothelial cells into the infarcted area. In conclusion, human CFs present heterogeneous expression of VCAM1 and lymphangiogenesis-promoting factors. VCFs restore the mechanical properties of ventricular walls by mobilizing lymphatic endothelial cells into the infarct when injected into a rat heart failure model. These results suggest a role of this specific population of CFs in the homeostasis of the lymphatic system in cardiac regeneration, providing new information for the study and therapy of cardiac diseases.

Severe ileus and urinary retention in a patient with tuberculous meningitis.

An acute ileus and/or urinary retention are recognized as emergent complications requiring appropriate depressurizing treatments. Meningitis should be suspected as a cause of these autonomic disturbances.

Estimation of activity of administered 18F-fluorodeoxyglucose by measurement of the dose equivalent rate on the right temporal region of the head.

BACKGROUND: Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is now a routine procedure for the management of cancer patients. Intravenous administration of FDG is sometimes halted due to troubles. In such cases, estimations of the FDG dosage injected prior to halting administration may be helpful. We have established a method of estimating the activity of FDG to patients on the basis of the dose equivalent rate on the surface of the right temporal region of the head. The correlation of actual administered dosage with independent variables, such as the dose equivalent rate on the right temporal region of the head, age, sex, and body weight, was analyzed using multiple regression analysis to obtain linear, quadratic, and cubic regression equations. RESULTS: When entering independent variables, the cubic regression equation could be used to estimate an administered dosage with an accuracy of ±10 % for 62 % of all patients and ±20 % for 90 % of all patients. CONCLUSIONS: We conclude that this method is useful for estimating the administered dosage from the dose equivalent rate on the temporal region of the head.

Identification of hepta-histidine as a candidate drug for Huntington's disease by in silico-in vitro- in vivo-integrated screens of chemical libraries.

We identified drug seeds for treating Huntington's disease (HD) by combining in vitro single molecule fluorescence spectroscopy, in silico molecular docking simulations, and in vivo fly and mouse HD models to screen for inhibitors of abnormal interactions between mutant Htt and physiological Ku70, an essential DNA damage repair protein in neurons whose function is known to be impaired by mutant Htt. From 19,468 and 3,010,321 chemicals in actual and virtual libraries, fifty-six chemicals were selected from combined in vitro-in silico screens; six of these were further confirmed to have an in vivo effect on lifespan in a fly HD model, and two chemicals exerted an in vivo effect on the lifespan, body weight and motor function in a mouse HD model. Two oligopeptides, hepta-histidine (7H) and Angiotensin III, rescued the morphological abnormalities of primary neurons differentiated from iPS cells of human HD patients. For these selected drug seeds, we proposed a possible common structure. Unexpectedly, the selected chemicals enhanced rather than inhibited Htt aggregation, as indicated by dynamic light scattering analysis. Taken together, these integrated screens revealed a new pathway for the molecular targeted therapy of HD.

Convulsion and cerebellar ataxia associated with maternally inherited diabetes and deafness: a case report.

Convulsion in diabetics is often considered as a result from fluctuation of blood glucose level. However, if a diabetic patient also presents abnormal neurological signs, mitochondrial diseases need to be considered in the differential diagnosis.

Sodium bicarbonate protects uranium-induced acute nephrotoxicity through uranium-decorporation by urinary alkalinization in rats.

To evaluate the effectiveness of sodium bicarbonate (SB) in removing uranium and protecting animals from uranium toxicity, we intramuscularly administered 1 mg/kg of uranyl nitrate to 8-wk-old male SD rats, and 20 min after administration of uranyl nitrate, the animals were given a single oral administration of SB at 0.1, 0.3 or 1 g/kg. The SB treatment at a dose of 0.3 g/kg or more raised the pH of the rats' urine until 4 h after treatment, and it significantly reduced the uranium amounts in the kidneys at 1 day after treatment. In another experiment, rats were intramuscularly administered 1 mg/kg of uranyl nitrate, and 20 min later, the animals were treated with sodium bicarbonate (0.1 or 1 g/kg). The rats were autopsied at 1, 3 and 7 days after uranium treatment. High-dose SB resulted in a significant increase in urinary uranium excretion in the first 24 h and a reduction of uranium deposition in the kidneys and femurs, and it also significantly suppressed uranium-induced renal toxicity, as shown by both histopathology and clinical chemistry at 3 days after uranium treatment. Low-dose SB did not show such marked effects. Our findings demonstrated that the uranium decorporation effect of sodium bicarbonate was observed at the dosage showing urine alkalinization in rats and that decorporation effect of sodium bicarbonate might be beneficial if it is administered immediately after incorporation of soluble uranium.

The long-term effects of pitavastatin on blood lipids and platelet activation markers in stroke patients: impact of the homocysteine level.

To examine the impact of the plasma homocysteine level on the anti-atherosclerotic effects of pitavastatin treatment, we retrospectively examined 59 patients who had a history of stroke and had been prescribed pitavastatin for the treatment of dyslipidemia at the Neurology department of Toho University Ohashi Medical Center Hospital. The patients were classified into two groups according to their homocysteine levels. Carotid artery plaque progression was determined before and after pitavastatin treatment. Plasma levels of high-sensitivity C-reactive protein, platelet molecular markers, and von Willebrand factor were measured. Pitavastatin treatment had beneficial effects on the lipid profiles of these patients and slowed atherosclerosis progression. These effects were observed in both the high and low homocysteine groups. Proactive lipid intervention using pitavastatin may inhibit the progression of atherosclerosis and contribute to secondary prevention of stroke in high-risk patients. We conclude that this statin could inhibit progression at any stage of disease and should therefore be proactively administered to these patient groups, regardless of disease severity.

The course of incidental intraorbital cavernous hemangioma in a patient with myasthenia gravis treated with cyclosporine: a case report.

A 69-year-old woman presented with generalized myasthenia gravis and a left orbital cavernous hemangioma (OCH), which elevated the optic nerve and displaced the external eye muscles. Cyclosporine treatment induced a gradual size reduction in the OCH, and consequently contributed to improved external ocular symptoms in combination with immunosuppressant effects.

MCA1 and MCA2 that mediate Ca2+ uptake have distinct and overlapping roles in Arabidopsis.

Ca(2+) is important for plant growth and development as a nutrient and a second messenger. However, the molecular nature and roles of Ca(2+)-permeable channels or transporters involved in Ca(2+) uptake in roots are largely unknown. We recently identified a candidate for the Ca(2+)-permeable mechanosensitive channel in Arabidopsis (Arabidopsis thaliana), named MCA1. Here, we investigated the only paralog of MCA1 in Arabidopsis, MCA2. cDNA of MCA2 complemented a Ca(2+) uptake deficiency in yeast cells lacking a Ca(2+) channel composed of Mid1 and Cch1. Reverse transcription polymerase chain reaction analysis indicated that MCA2 was expressed in leaves, flowers, roots, siliques, and stems, and histochemical observation showed that an MCA2 promoter::GUS fusion reporter gene was universally expressed in 10-d-old seedlings with some exceptions: it was relatively highly expressed in vascular tissues and undetectable in the cap and the elongation zone of the primary root. mca2-null plants were normal in growth and morphology. In addition, the primary root of mca2-null seedlings was able to normally sense the hardness of agar medium, unlike that of mca1-null or mca1-null mca2-null seedlings, as revealed by the two-phase agar method. Ca(2+) uptake activity was lower in the roots of mca2-null plants than those of wild-type plants. Finally, growth of mca1-null mca2-null plants was more retarded at a high concentration of Mg(2+) added to medium compared with that of mca1-null and mca2-null single mutants and wild-type plants. These results suggest that the MCA2 protein has a distinct role in Ca(2+) uptake in roots and an overlapping role with MCA1 in plant growth.

beta-Carotene and beta-cryptoxanthin but not lutein evoke redox and immune changes in RAW264 murine macrophages.

The mechanism of immunological benefits induced by carotenoids has not been fully elucidated. Here, we investigated some of the immunity-related properties of beta-carotene and two other carotenoids, beta-cryptoxanthin, and lutein, on the murine macrophages cell line RAW264. beta-Carotene added to the culture medium accumulated in the cells in a time- and dose-dependent manner. The accumulation was positively correlated with cellular lipid peroxidation, demonstrating the pro-oxidative activity of beta-carotene, and also with the synthesis of glutathione, an intracellular antioxidant. Conversely, accumulation of beta-carotene was negatively correlated with the transcription of immune-active molecules, such as IL-1beta, IL-6, and IL-12 p40, in cells stimulated by LPS and INF-gamma. The transcription of the pro-inflammatory cytokines IL-1beta and IL-6 was more sensitive to the accumulation of beta-carotene than was IL-12 p40. The accumulation of beta-cryptoxanthin in cells resulted in effects similar to those of beta-carotene. However, lutein accumulated minimally and did not significantly affect the cells. These results demonstrate that beta-carotene, and beta-cryptoxanthin as well, can accumulate in RAW264 cells and induce changes in intracellular redox status, which in turn regulate the immune function of macrophages.

Beta-carotene modulates the immunological function of RAW264, a murine macrophage cell line, by enhancing the level of intracellular glutathione.

The activities of beta-carotene on redox status and the immune functions of RAW264 cells, a murine macrophage cell line, were investigated. Supplementation with beta-carotene for RAW264 cells resulted in apparently inconsistent redox indices: lipid peroxidation was enhanced but intracellular oxidation was moderately attenuated. Attenuated intracellular oxidation was endorsed by an increase in glutathione accompanied by up-regulated transcription of a subunit of gamma-glutamylcysteine synthetase, the rate-limiting enzyme for glutathione synthesis. alpha-Tocopherol, which can quench lipid peroxidation by free radical, neither inhibited that by beta-carotene nor influenced the intracellular redox status. Lipopolysaccharide-stimulated transcriptions of IL-1beta and IL-12 p40 in RAW264 were inhibited by beta-carotene but not by alpha-tocopherol. These results indicate that beta-carotene, which can modulate the intracellular redox status of macrophages by enhancing the level of intracellular glutathione, is related to the immune functions of macrophages.