A Heterodimeric Cytokine, Consisting of IL-17A and IL-17F, Promotes Migration and Capillary-Like Tube Formation of Human Vascular Endothelial Cells.

The interleukin (IL)-17 family, consisting of six homodimeric cytokines IL-17A, IL-17B, IL-17C, IL-17D, IL-17E/IL-25, and IL-17F, mediates a variety of biological activities including regulation of chemokine secretion and angiogenesis. Among the IL-17 family members, IL-17A and IL-17E/IL-25 are angiogenesis stimulators, while IL-17B and IL-17F are angiogenesis inhibitors. Recently, IL-17A/F heterodimer, comprised of the IL-17A and IL-17F subunits, was found as another member of the IL-17 cytokine family. However, to date, it has been unknown whether IL-17A/F has biological actions to affect the angiogenesis-related vascular endothelial functions. Therefore, in this study, we investigated the biological effects of IL-17A/F on the growth, migration and capillary-like tube formation of vascular endothelial cells. Recombinant IL-17A/F protein had no direct effects on the growth of human dermal microvascular endothelial cells (HMVECs), whereas, after 4-hour incubation in a modified Boyden Chemotaxicell chamber, IL-17A/F significantly induced migration of HMVECs over a wide range of doses via the phosphatidylinositol-3 kinase (PI3K) signaling pathway. We further investigated the biological effect of IL-17A/F on capillary-like tube formation using a co-culture system of human umbilical vein endothelial cells (HUVECs) and human dermal fibroblasts (HDFs), which mimicked the in vivo microenvironment. In this co-culture system, IL-17A/F significantly promoted capillary-like endothelial tube formation in a dose-dependent fashion via the PI3K and extracellular signal-regulated kinase (ERK) signaling pathways. Additionally, IL-17A/F up-regulated secretion of angiogenic growth factors such as IL-8 and growth-related oncogene (GRO)-α by HDFs. These findings identify a novel biological function for IL-17A/F as an indirect angiogenic agent.

Pulmonary function and chest CT abnormalities 3 months after discharge from COVID-19, 2020-2021: A nation-wide multicenter prospective cohort study from the Japanese respiratory society.

BACKGROUND: No comprehensive analysis of the pulmonary sequelae of coronavirus disease 2019 (COVID-19) in Japan based on respiratory function tests and chest computed tomography (CT) has been reported. We evaluated post-COVID-19 conditions, especially focusing on pulmonary sequelae assessed by pulmonary function tests and chest CT. METHODS: For this prospective cohort study, we enrolled 1069 patients who presented pneumonia at the time of admission in 55 hospitals from February 2020 to September 2021. Disease severity was classified as moderateⅠ, moderate II, and severe, defined primarily according to the degree of respiratory failure. The data on post-COVID-19 conditions over 12 months, pulmonary function, and chest CT findings at 3 months were evaluated in this study. Additionally, the impact of COVID-19 severity on pulmonary sequelae, such as impaired diffusion capacity, restrictive pattern, and CT abnormalities, was also evaluated. RESULTS: The most frequently reported post-COVID-19 conditions at 3 months after COVID-19 were muscle weakness, dyspnea, and fatigue (48.4%, 29.0%, and 24.7%, respectively). The frequency of symptoms gradually decreased over subsequent months. In pulmonary function tests at 3 months, the incidence of impaired diffusion capacity and restrictive pattern increased depending on disease severity. There also were differences in the presence of chest CT abnormalities at the 3 months, which was markedly correlated with the severity. CONCLUSION: We reported a comprehensive analysis of post-COVID-19 condition, pulmonary function, and chest CT abnormalities in Japanese patients with COVID-19. The findings of this study will serve as valuable reference data for future post-COVID-19 condition research in Japan.

Metabolic predictors of ischemic heart disease and cerebrovascular attack in elderly diabetic individuals: difference in risk by age.

BACKGROUND: High LDL-cholesterol (LDL-C) and glucose levels are risk factors for ischemic heart disease (IHD) in middle-aged diabetic individuals; however, the risk among the elderly, especially the very elderly, is not well known. The aim of this study was to identify factors that predict IHD and cerebrovascular attack (CVA) in the elderly and to investigate their differences by age. METHODS: We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) with 5.5 years of follow-up. A total of 4,014 patients with type 2 diabetes and without previous IHD or CVA (1,936 women; age 67.4 ± 9.5 years, median 70 years; <65 years old, n = 1,261; 65 to 74 years old, n = 1,731; and ≥ 75 years old, n = 1,016) were recruited on a consecutive outpatient basis from 40 hospitals throughout Japan. Lipids, glucose, and other factors related to IHD or CVA risk, such as blood pressure (BP), were investigated using the multivariate Cox hazard model. RESULTS: One hundred fifty-three cases of IHD and 104 CVAs (7.8 and 5.7/1,000 people per year, respectively) occurred over 5.5 years. Lower HDL-cholesterol (HDL-C) and female gender were correlated with IHD in patients ≥75 years old (hazard ratio (HR):0.629, P < 0.01 and 1.132, P < 0.05, respectively). In contrast, systolic BP (SBP), HbA1C, LDL-C and non-HDL-C were correlated with IHD in subjects <65 years old (P < 0.05), and the LDL-C/HDL-C ratio was correlated with IHD in all subjects. HDL-C was correlated with CVA in patients ≥75 years old (HR: 0.536, P < 0.01). Kaplan-Meier estimator curves showed that IHD occurred more frequently in patients <65 years old in the highest quartile of the LDL-C/HDL-C ratio. In patients ≥75 years old, IHD and CVA were both the most frequent among those with the lowest HDL-C levels. CONCLUSIONS: IHD and CVA in late elderly diabetic patients were predicted by HDL-C. LDL-C, HbA1C, SBP and non-HDL-C are risk factors for IHD in the non-elderly. The LDL-C/HDL-C ratio may represent the effects of both LDL-C and HDL-C. These age-dependent differences in risk are important for developing individualized strategies to prevent atherosclerotic disease. TRIAL REGISTRATION: UMIN-CTR, UMIN00000516.

Exhaled carbon monoxide levels in preschool-age children with episodic asthma.

BACKGROUND: The concentration of exhaled carbon monoxide (eCO) in young children with stable asthma and during acute asthma attack is not known. METHODS: A sampling bag was developed to collect the exhaled air of preschool children. A total of 257 preschool-age children (≥ 3 years and ≤ 6 years old) were studied; 111 had a diagnosis of asthma (43 suffering a mild asthma attack and 68 without active asthmatic symptom), 99 had upper respiratory infection (URI) and 47 were healthy. RESULTS: In preschool-age children, eCO levels of those with asthma attacks (mean ± SE, 2.7 ± 0.3 p.p.m., n= 43) were significantly higher than those of subjects with asymptomatic asthma (0.5 ± 0.1 p.p.m., P < 0.05), URI (0.8 ± 0.1 p.p.m., P < 0.05) and healthy children (0.4 ± 0.1 p.p.m., P < 0.05). A multivariate linear regression model showed that eCO was higher in children with asthma attacks independent of age and gender. In 33 asthmatic children followed before and after treatment, eCO levels during asthma attacks significantly decreased after inhalation therapy with a combination of salbutamol and sodium cromoglycate (before therapy, 2.9 ± 0.4 p.p.m.; after therapy, 0.6 ± 0.1 p.p.m., P < 0.0001). CONCLUSIONS: The measurement of eCO using a novel collecting system is useful in the recognition of asthma in preschool children.

[Alzheimer disease--contribution of renin-angiotensin system to Alzheimer disease progression].

There is increasing evidence that certain components of the renin-angiotensin system (RAS) may have a crucial role in learning and memory processes. We have previously shown that brain-penetrating ACE inhibitors can reduce the incidence of Alzheimer diseases (AD) in elderly hypertensive patients and that hypertension treatment with brain penetrating ACE inhibitors slowed the rate of cognitive decline in mild-to-moderate AD patients with hypertension. We speculate that the favorable effects might be due to the direct effects of brain-penetrating ACE inhibitors on RAS in the brain, since no significant differences were found in the levels of blood pressure among the groups treated with several antihypertensive drugs. Brain penetrating ACE inhibitors might have benefits not only for the prevention but also for the treatment of mild to moderate AD with hypertension.

Age, gender, insulin and blood glucose control status alter the risk of ischemic heart disease and stroke among elderly diabetic patients.

BACKGROUND: We analyzed the effects of insulin therapy, age and gender on the risk of ischemic heart disease (IHD) and cerebrovascular accident (CVA) according to glycemic control. METHODS AND RESULTS: We performed a prospective cohort study (Japan Cholesterol and Diabetes Mellitus Study) of type 2 diabetes patients (n = 4014) for 2 years. The primary endpoint was the onset of fatal/non-fatal IHD and/or CVA, which occurred at rates of 7.9 and 7.2 per 1000 person-years, respectively. We divided diabetic patients into four groups based on age (≤ 70 and > 70) and hemoglobin A1C levels (≤ 7.0 and > 7.0%). Multiple regression analysis revealed that IHD was associated with high systolic blood pressure and low HDL-C in patients under 70 years of age with fair glycemic control and was associated with low diastolic blood pressure in the older/fair group. Interestingly, insulin use was associated with IHD in the older/poor group (OR = 2.27, 95% CI = 1.11-5.89; p = 0.026) and was associated with CVA in the older/fair group (OR = 2.09, 95% CI = 1.06-4.25; p = 0.028). CVA was associated with lower HDL-C and longer duration of diabetes in younger/poor glycemic control group. Results by stepwise analysis were similar. Next, patients were divided into four groups based on gender and diabetic control(hemoglobinA1C < or > 7.0%). Multiple regression analysis revealed that IHD was associated with high systolic blood pressure in male/fair glycemic control group, age in male/poor control group, and short duration of diabetic history in females in both glycemic control groups. Interestingly, insulin use was associated with IHD in the male/poor group(OR = 4.11, 95% CI = 1.22-8.12; p = 0.018) and with CVA in the female/poor group(OR = 3.26, 95% CI = 1.12-6.24; p = 0.02). CVA was associated with short duration of diabetes in both female groups. CONCLUSIONS: IHD and CVA risks are affected by specific factors in diabetics, such as treatment, gender and age. Specifically, insulin use has a potential role in preventing IHD but may also be a risk factor for CVA among the diabetic elderly, thus revealing a need to develop improved treatment strategies for diabetes in elderly patients. The Japan Cholesterol and Diabetes Mellitus Study was formulated to evaluate them(Umin Clinical Trials Registry, clinical trial reg. no. UMIN00000516; http://www.umin.ac.jp/ctr/index.htm).

[The benefit of angiotensin converting enzyme inhibitor for geriatric syndrome in the elderly].

Angiotensin converting enzyme (ACE) inhibitor plays an important role not only as an antihypertensive drug but also for prevention of various complications related to geriatric syndrome. Pneumonia in the disabled elderly is mostly due to silent aspiration of oropharyngeal bacterial pathogens to the lower respiratory tract. Aspiration is related to the dysfunction of dopaminergic neurons by cerebrovascular disease, resulting in impairments in both the swallowing and cough reflexes. ACE inhibitor can increase in the sensitivity of the cough reflex particularly in older post-menopausal women, and improvement of the swallowing reflex. In a 2-year follow-up study in stroke patients, patients who did not receive ACE inhibitors had a higher risk of mortality due to pneumonia than in stroke patients who were treated with ACE inhibitor. Moreover, the mortality of pneumonia was significantly lower in older hypertensive patients given ACE inhibitors than in those treated with other antihypertensive drugs. On the other hand, we found a new benefit of ACE inhibitor on the central nervous system. The mortality in Alzheimer's disease patients who received brain-penetrating ACE inhibitor was lower than in those who received other antihypertensive drugs. In a 1-year follow-up study, cognitive decline was lower in patients receiving brain-penetrating ACE inhibitors than in patients receiving a non-brain-penetrating ACE inhibitor or a calcium channel blocker. Brain-penetrating ACE inhibitors may slow cognitive decline in patients with mild to moderate Alzheimer's disease. ACE inhibitor might be effective for the disabled elderly, resulting in the prevention of aspiration pneumonia and Alzheimer's disease for the elderly.

Exhaled carbon monoxide levels in school-age children with episodic asthma.

Carbon monoxide (CO) can be detected in exhaled air and is increased in adult and childhood persistent asthmatic patients. However, little is known about the exhaled CO concentration in episodic childhood asthma. This study aimed to clarify whether measurement of exhaled CO is useful in monitoring disease activity in children with episodic asthma. We measured exhaled CO concentration by modified Micro-Smokerlyzer in 217 elementary school children (132 boys; mean age, 10 +/- 1 (SE) years; range, 9-12 years), in whom 29 had infrequent episodic asthma without current exacerbations. We also measured exhaled CO concentrations in 22 children with episodic asthma (13 boys; mean age, 10 +/- 3 years; range, 8-12 years), who had acute mild asthmatic attacks during examination. In these patients with mild asthmatic attacks, exhaled CO was measured both before and after combination therapy with salbutamol and sodium cromoglycate (SCG) by powered nebulizer. Among 217 schoolchildren, exhaled CO levels in infrequent episodic asthmatic children (1.1 +/- 0.1 parts per million (ppm), n = 29) were not significantly different from those in healthy schoolchildren (1.0 +/- 0.1 ppm, n = 188, P > 0.68). The exhaled CO concentrations during asthma attacks in children with episodic asthma were significantly higher (5.1 +/- 0.4 ppm, n = 22) compared with those in healthy children (P < 0.001) or those in asymptomatic asthmatic children (P < 0.001). The elevated exhaled CO levels were significantly decreased after inhalation therapy of a combination of salbutamol and SCG (3.2 +/- 0.5 ppm, n = 22, P < 0.02). In conclusion, exhaled CO levels were significantly elevated during acute asthma exacerbations, and partially recovered after treatment with beta(2)-agonist and SCG in children with mild episodic asthma. These findings indicate that measurement of exhaled CO might provide another noninvasive measurement of asthma exacerbations that would be suitable for use in children with acute mild episodic asthma.

[Role of certified geriatric medical doctors in university hospitals in Japan].

The role of certified specialists in geriatric medicine in Japanese University Hospitals is discussed in this section. First, they should act as geriatric general physicians to provide a comprehensive medical care for elderly patients against a background complicatedly divided medical departments in university hospitals. Second, they should create attractive undergraduate programs for geriatric education in medical schools and training programs in geriatric medicine for doctors to develop certified specialists in geriatric medicine in the future. Finally, they should perform clinical research to provide an evidence to construct better social policies to keep older people healthy.

Screening Tool for Older Persons' Appropriate Prescriptions for Japanese: Report of the Japan Geriatrics Society Working Group on "Guidelines for medical treatment and its safety in the elderly".

AIM: In 2005, the Japan Geriatrics Society published a list of potentially inappropriate medication that was an extract from the "Guidelines for medical treatment and its safety in the elderly 2005." The 2005 guidelines are due for a revision, and a new comprehensive list of potentially inappropriate medications is required. METHODS: A total of 15 diseases, conditions and special areas related to their clinical care were selected. We originated clinical questions and keywords for these 15 areas, carried out a systematic review using these search criteria, and formulated guidelines applying the Grading of Recommendations Assessment, Development and Evaluation system advocated by Minds2014. If we did not find good evidence despite the drug being clinically important, we looked for evidence of efficacy and for disease-specific guidelines, and incorporated them into our guidelines. RESULTS: We selected 2098 articles (140 articles per area), and extracted another 186 articles through a manual search. We further added guidelines based on disease entity and made two lists, one of "drugs to be prescribed with special caution" and the other of "drugs to consider starting," primarily considering individuals aged 75 years or older or those who are frail or in need of special care. CONCLUSIONS: New lists of potentially inappropriate medications and potential prescribing omissions called "Screening Tool for Older Person's Appropriate Prescriptions for Japanese" were constructed. We anticipate that future studies will highlight more evidence regarding the safety of high-quality drugs, further improving the provision of appropriate medical care for the elderly. Geriatr Gerontol Int 2016: 16: 983-1001.

[Prevention of elderly pneumonia by pneumococcal, influenza and BCG vaccinations].

Pneumonia is a major cause of morbidity and mortality in elderly people, especially in those with chronic medical conditions such as chronic heart and lung diseases. We prospectively examined the effect of influenza and pneumococcal vaccinations on the rate of hospitalization for and complications of pneumonia, all respiratory tract conditions and mortality in elderly bedridden patients and found that both febrile days and pneumonia cases decreased. Thus, these results show that it is valuable to vaccinate for influenza elderly people even if they are confined to bed. Furthermore, the tuberculin skin test is an easy method to check the cell-mediated immunity in the elderly people. In the tuberculin skin test, all Japanese over 65 years old should have positive status. A negative result indicates depressed cell-mediated immunity. We undertook a trial to vaccinate tuberculin negative elderly people with BCG vaccine and found that the risk of pneumonia is decreased to a similar degree to that in subjects with positive tuberculin test results. We conclude that vaccination might be an effective strategy for the prevention of pneumonia in elderly people with limited activities of daily living.

Oral care reduces pneumonia in older patients in nursing homes.

OBJECTIVES: Aspiration of oral secretions and their bacteria is increasingly being recognized as an important factor in pneumonia. We investigated whether oral care lowers the frequency of pneumonia in institutionalized older people. DESIGN: Survey. SETTING: Eleven nursing homes in Japan. PARTICIPANTS: Four hundred seventeen patients randomly assigned to an oral care group or a no oral care group. INTERVENTION: Nurses or caregivers cleaned the patients' teeth by toothbrush after each meal. Swabbing with povidone iodine was additionally used in some cases. Dentists or dental hygienists provided professional care once a week. MEASUREMENTS: Pneumonia, febrile days, death from pneumonia, activities of daily living, and cognitive functions. RESULTS: During follow-up, pneumonia, febrile days, and death from pneumonia decreased significantly in patients with oral care. Oral care was beneficial in edentate and dentate patients. Activities of daily living and cognitive functions showed a tendency to improve with oral care. CONCLUSION: We suggest that oral care may be useful in preventing pneumonia in older patients in nursing homes.

Care for older people.

Aging is often seen as disadvantageous in human history. However, longevity reduces medical costs of the whole life compared with that of short life. Therefore, in order to reduce medical cost, we have to take care of the elderly in order to promote health and longevity. Health problems in the elderly should be solved by both medical and elderly care facilities. However, few studies have analyzed the care problems of the elderly. In this review, we describe the recent methods of care for the elderly.

[Criteria of impairment of pulmonary function using Japanese standard values].

According to the law of functional impairment, cases of impairment of pulmonary function are designated as 1st, 3rd and 4th grade impairment. The criteria of pulmonary function a based on Baldwin's predicted values. Recently, the Japanese Respiratory Society reported the Japanese standard values for pulmonary function. In the present study, we compared the numbers of patients classified into the three grades using the Japanese values and Baldwin's values. We found that from about 10 to 20 percent of patients appeared in a higher grade when Japanese standard values were used instead of Baldwin's values. We suggest that Japanese standard values should be used in order to judge the impairment of these patients.