Pet's Presence and Owner's Blood Pressures during the Daily Lives of Pet Owners with Pre- to Mild Hypertension

ABSTRACT

As the population ages the number of older adults living with hypertension (HTN) is rising dramatically. Uncontrolled HTN increases cardiovascular and renal mortality. Ambulatory (A) blood pressure (BP) is a better predictor of HTN-related morbidity and mortality than office BP. Lower BP is the most important therapeutic goal in treating HTN. Any reduction in BP has significant benefits for older adults. The current study was designed to evaluate the impact of the presence of pet dogs and cats on ABP during the daily lives of independently living, older pet owners with pre- to mild HTN. A repeated measures observational study of ABP of 32 pet owners (21 dogs, 8 cats, 3 cat and dog; 29 women) aged 50–83 years with BP 120–150/80–100 mmHg or < 150/100 with anti-hypertensive medication was conducted. Owner's ABPs were recorded every 20 minutes for one day during waking hours at study entry, one month, and three months. Activity monitors and diaries were used to obtain information about activity, mood, and whether the pet and/or another person was present in the room (indoors) or in close proximity (outdoors) with the owner at each assessment. Generalized estimating equation (GEE) analyses for hierarchical data (unstructured correlations) were performed for systolic and diastolic ABP. Mean ABPs were significantly (systolic BP/diastolic BP: dog p = 0.008/ p = 0.002; cat p < 0.009/ p < 0.001) different (systolic BP/diastolic BP mmHg: dog 3.1/1.5; cat –3.0/2.2) when pets were present after controlling for participant's mood (p > 0.05/ p < 0.001), activity intensity (p = 0.026/ p = 0.441), location (p = 0.013/ p = 0.004), and the presence of other people (p = 0.947/ p = 0.723). The presence of a dog was associated with lower systolic and diastolic BP and of a cat was associated with lower diastolic BP and higher systolic BP during their owners' normal daily lives. This finding suggests that pets, especially dogs, may be effective as an adjunctive intervention to slow the development or progression of HTN in older adults. Comparison of ABPs of pet owners with non-owners during their daily lives is warranted and underway.     

A Unique Bivalent Binding and Inhibition Mechanism by the Yatapoxvirus Interleukin 18 Binding Protein

Interleukin 18 (IL18) is a cytokine that plays an important role in inflammation as well as host defense against microbes. Mammals encode a soluble inhibitor of IL18 termed IL18 binding protein (IL18BP) that modulates IL18 activity through a negative feedback mechanism. Many poxviruses encode homologous IL18BPs, which contribute to virulence. Previous structural and functional studies on IL18 and IL18BPs revealed an essential binding hot spot involving a lysine on IL18 and two aromatic residues on IL18BPs. The aromatic residues are conserved among the very diverse mammalian and poxviruses IL18BPs with the notable exception of yatapoxvirus IL18BPs, which lack a critical phenylalanine residue. To understand the mechanism by which yatapoxvirus IL18BPs neutralize IL18, we solved the crystal structure of the Yaba-Like Disease Virus (YLDV) IL18BP and IL18 complex at 1.75 Å resolution. YLDV-IL18BP forms a disulfide bonded homo-dimer engaging IL18 in a 2∶2 stoichiometry, in contrast to the 1∶1 complex of ectromelia virus (ECTV) IL18BP and IL18. Disruption of the dimer interface resulted in a functional monomer, however with a 3-fold decrease in binding affinity. The overall architecture of the YLDV-IL18BP:IL18 complex is similar to that observed in the ECTV-IL18BP:IL18 complex, despite lacking the critical lysine-phenylalanine interaction. Through structural and mutagenesis studies, contact residues that are unique to the YLDV-IL18BP:IL18 binding interface were identified, including Q67, P116 of YLDV-IL18BP and Y1, S105 and D110 of IL18. Overall, our studies show that YLDV-IL18BP is unique among the diverse family of mammalian and poxvirus IL-18BPs in that it uses a bivalent binding mode and a unique set of interacting residues for binding IL18. However, despite this extensive divergence, YLDV-IL18BP binds to the same surface of IL18 used by other IL18BPs, suggesting that all IL18BPs use a conserved inhibitory mechanism by blocking a putative receptor-binding site on IL18.     

Major features of immunesenescence,including reduced thymic output,are ameliorated by high levels of physical activity in adulthood

It is widely accepted that aging is accompanied by remodelling of the immune system including thymic atrophy and increased frequency of senescent T cells, leading to immune compromise. However, physical activity, which influences immunity but declines dramatically with age, is not considered in this literature. We assessed immune profiles in 125 adults (55–79 years) who had maintained a high level of physical activity (cycling) for much of their adult lives, 75 age‐matched older adults and 55 young adults not involved in regular exercise. The frequency of naïve T cells and recent thymic emigrants (RTE) were both higher in cyclists compared with inactive elders, and RTE frequency in cyclists was no different to young adults. Compared with their less active counterparts, the cyclists had significantly higher serum levels of the thymoprotective cytokine IL‐7 and lower IL‐6, which promotes thymic atrophy. Cyclists also showed additional evidence of reduced immunesenescence, namely lower Th17 polarization and higher B regulatory cell frequency than inactive elders. Physical activity did not protect against all aspects of immunesenescence: CD28^?veCD57^+ve senescent CD8 T‐cell frequency did not differ between cyclists and inactive elders. We conclude that many features of immunesenescence may be driven by reduced physical activity with age.     

Autoreactive T and B cells from bullous pemphigoid (BP) patients recognize epitopes clustered in distinct regions of BP180 and BP230

Bullous pemphigoid (BP) is a well-characterized model of autoantibody-mediated autoimmunity, which presumably depends on autoreactive Th cells that promote the activation of autoreactive B cells. The two major autoantigens of BP are BP180 and BP230, two components of dermoepidermal adhesion complexes. Both, autoreactive Th cell responses and autoantibody profiles were characterized in 35 patients with acute onset BP using BP180 and BP230 proteins. Our findings indicate the following: 1) autoreactive Th cells recognized epitopes within the NH2-terminal (77.1%), COOH-terminal (65.7%), and central portion (57.1%) of the BP180 ectodomain; 2) IgG autoantibodies were found to exhibit similar or identical reactivity against the NH2-terminal (82.8%), COOH-terminal (77.1%), and central portion (37.1%) of the BP180 ectodomain; 3) T and B cell reactivity with the NH2-terminal portion of the BP180 ectodomain was associated with extensive BP, whereas the central portion was more frequently recognized in limited BP; 4) only 7 of 16 (43.7%) and 6 of 16 (37.5%) BP patients showed a Th cellular response against the COOH- and NH2-terminal regions of BP230, respectively, whereas 5) IgG reactivity against the COOH- and NH2-termini of BP230 was detected in 5 of 16 (31.3%) and 6 of 16 (37.5%) patients, respectively. These results demonstrate that Th and B cell reactivities against BP180, are, in contrast to BP230 reactivity, almost constantly detectable in BP patients, and differential epitope recognition of BP180 seems to be associated with distinct clinical severity. These observations support the concept that BP180, but not BP230, is the primary autoantigen of BP critical for disease development.     

The relationship between 24-hour ambulatory blood pressures and laboratory measures of cardiovascular reactivity

The relationship between 24-hour ambulatory blood pressures (ABP) and blood pressures (BP) obtained during laboratory stressors was examined. Thirty normotensives (equal males and females) underwent ABP monitoring on three occasions separated by a week. They also underwent a laboratory assessment which included standard stressors (i.e., mental arithmetic, cold pressor, orthostatic response, treadmill exercise). Correlational analyses found laboratory pressures to be significantly correlated with ambulatory pressures, with laboratory baseline BPs showing higher correlations to the ambulatory BPs than the BPs obtained during laboratory stressors. In addition, gender effects were examined. In the correlational analyses between ABPs and laboratory BPs, males and females did not differ significantly in the strength of the correlations. In terms of absolute values, males were found to have significantly higher SBP during ambulatory monitoring, random-zero recordings, calibration readings, and during baselines of the laboratory assessment. There were no gender effects for these measures with respect to diastolic blood pressure or heart rate. There were also no gender effects on reactivity to laboratory stressors as measured by change scores. Exploratory analyses found no significant effect of history of familial hypertension on either the ABPs or the laboratory pressures.     

Circadian phase in adults of contrasting ages

There is evidence that aging may impair phase-shifting responses to light synchronizers, which could lead to disturbed or malsynchronized circadian rhythms. To explore this hypothesis, 62 elder participants (age, 58 to 84 years) and 25 young adults (age, 19 to 40 years) were studied, first with baseline 1-wk wrist actigraphy at home and then by 72 h in-laboratory study using an ultra-short sleep-wake cycle. Subjects were awake for 60 minutes in 50 lux followed by 30 minutes of darkness for sleep. Saliva samples were collected for melatonin, and urine samples were collected for aMT6s (a urinary metabolite of melatonin) and free cortisol every 90 minutes. Oral temperatures were also measured every 90 minutes. The timing of the circadian rhythms was not significantly more variable among the elders. The times of lights-out and wake-up at home and urinary free cortisol occurred earlier among elders, but the acrophases (cosinor analysis-derived peak time) of the circadian rhythm of salivary melatonin, urinary aMT6s, and oral temperature were not significantly phase-advanced among elders. The estimated duration of melatonin secretion was 9.9 h among elders and 8.4 h among young adults (p < 0.025), though the estimated half-life of blood melatonin was shorter among elders (p < 0.025), and young adults had higher saliva melatonin and urinary aMT6s levels. In summary, there was no evidence for circadian desynchronization associated with aging, but there was evidence of some rearrangement of the internal phase-angles among the studied circadian rhythms.     

Circadian Phase in Adults of Contrasting Ages

There is evidence that aging may impair phase‐shifting responses to light synchronizers, which could lead to disturbed or malsynchronized circadian rhythms. To explore this hypothesis, 62 elder participants (age, 58 to 84 years) and 25 young adults (age, 19 to 40 years) were studied, first with baseline 1‐wk wrist actigraphy at home and then by 72 h in‐laboratory study using an ultra‐short sleep‐wake cycle. Subjects were awake for 60 minutes in 50 lux followed by 30 minutes of darkness for sleep. Saliva samples were collected for melatonin, and urine samples were collected for aMT6s (a urinary metabolite of melatonin) and free cortisol every 90 minutes. Oral temperatures were also measured every 90 minutes. The timing of the circadian rhythms was not significantly more variable among the elders. The times of lights‐out and wake‐up at home and urinary free cortisol occurred earlier among elders, but the acrophases (cosinor analysis‐derived peak time) of the circadian rhythm of salivary melatonin, urinary aMT6s, and oral temperature were not significantly phase‐advanced among elders. The estimated duration of melatonin secretion was 9.9 h among elders and 8.4 h among young adults (p<0.025), though the estimated half‐life of blood melatonin was shorter among elders (p<0.025), and young adults had higher saliva melatonin and urinary aMT6s levels. In summary, there was no evidence for circadian desynchronization associated with aging, but there was evidence of some rearrangement of the internal phase‐angles among the studied circadian rhythms.     

Oral health in nursing home residents with different cognitive statuses

Objective: To compare oral health in nursing home (NH) residents with different cognitive statuses. Background: Oral health is a significant issue for NH residents because of its relationships to quality of life, systemic health and well‐being. It is known that oral health is poor in NH residents. However, how oral health differs in NH residents with different cognitive statuses remains unclear. Materials and methods: Nine hundred and two NH residents were retrospectively recruited from a community‐based geriatric dental clinic in Minnesota, USA. Comprehensive medical, dental, cognitive and functional assessments were completed for the participants. On the basis of medical history and cognitive status, participants were categorized into three groups: without cognitive impairment (non‐impaired group), with cognitive impairment but no dementia (impaired group) and with dementia (demented group). ANOVA, Chi‐square and Fisher’s exact tests were used to compare medical, dental and functional statuses between groups. Results: Oral hygiene was poor in NH residents. Forty per cent of participants in the impaired group were edentulous, significantly higher than the edentulism rate in the demented group (29%, p = 0.01). More than 60% of the participants lost 16 or more teeth prior to examination. Depending on their cognitive status, 82–92% of the participants arrived with one or more caries or retained root. Dentate participants in the impaired and demented groups averaged about six caries or retained roots, significantly more than 4.7 caries or retained roots in the non‐impaired group (p = 0.01). Conclusion: Oral health was poor but slightly different in NH residents with different cognitive and functional statuses.     

Organ distribution of auxin-binding protein 1 in the etiolated maize seedling

The auxin-binding protein designated ABP1 has been proposed to mediate auxin-induced cellular changes such as cell expansion. Its exact mode of action is unknown, but currently several approaches to elucidate its function are being pursued. One of these approaches, described here, is to determine the organ distribution of this putative auxin receptor in order to correlate spatially the abundance of the protein with some auxin-regulated activity such as cell elongation. The absolute and relative amounts of ABP1 were determined along the entire etiolated shoot, the root, and within the caryopsis of maize. ABP1 can be detected immunologically in all extracts of the etiolated maize seedling except the tip of the primary root and the endosperm. Within the shoot, but excluding the leaf roll, the highest levels compared on a fresh weight basis are in the apical mesocotyl and basal coleoptile regions, the areas of the most rapid cell elongation and the areas where there is the greatest capacity for auxin-induced growth. The relative abundance of ABP1 compared on a fresh weight basis changed more than fivefold in this organ. When compared on a total protein basis, the relative change in ABP1 abundance was approximately two-fold, which is less than the relative change in auxin-induced growth rate along the shoot. Differences in shoot growth rate among varieties of maize were compared with the relative amounts of ABP1 within the apical mesocotyl and basal coleoptile. A statistically significant but not perfect correlation was found between the auxin-induced growth rate of the apical mesocotyl and ABP1 abundance. These results demonstrate a general correlation between the amount of ABP1 and growth along the shoot and within maize hybrid varieties.Abbreviations ABP1 auxin-binding protein 1 - NAA naphthalene-1-acetic acid - SDS sodium dodecyl sulfate - PAGE poly-acrylamide gel electrophoresis.     

牛膝多糖对草鱼免疫和抗氧化功能的影响

为探讨在饲料中添加牛膝多糖(ABP)对草鱼免疫和抗氧化功能的影响, 选取平均体重(88.130.76) g的健康草鱼375尾, 随机分成5个处理, 即基础饲料组、0.05 %、0.10 %、0.20 %、0.40 % ABP添加组, 每个处理3个重复, 每个重复25尾鱼, 饲养65 d。结果表明, 在饲料中添加ABP对草鱼头肾体指数影响不显著(P0.05), 对脾体指数影响显著(P0.05), 与对照组相比, 0.05 %、0.10 %、0.20 %和0.40%添加组脾体指数分别增加6.29% (P0.05)、28.00% (P0.05)、9.14%(P0.05)和13.14% (P0.05); 血液中NBT阳性细胞数随着ABP添加量的增加呈增加的趋势, 但各组间差异不显著(P0.05); 在饲料中添加ABP对草鱼血清白蛋白、白介素-１(IL-1)、白介素-6(IL-6)含量和过氧化氢酶活影响不显著(P0.05), 显著影响草鱼血清总蛋白(TP)、碱性磷酸酶(AKP)、酸性磷酸酶(ACP)、溶菌酶(LZM)、-肿瘤坏死因子(TNF-)、超氧化物歧化酶(SOD)及丙二醛(MDA)含量(P0.05)。与对照组相比, 0.40%添加组的TP和AKP分别增加24.64% (P0.05)和33.56% (P0.05); 0.20 %、0.40 %添加组的LZM活力分别增加34.97% (P0.05)和31.21% (P0.05), SOD活力分别增加27.28% (P0.05)和22.41% (P0.05); 饲料中随着ABP添加剂量的增加, 各组血清ACP活性先增加后缓慢下降, MDA含量先下降后上升。与对照组相比, 0.20%、0.40 %添加组ACP活性分别增加15.33% (P0.05)和11.10% (P0.05), 0.05%、0.10 %、0.20 %及0.40%添加组MDA含量分别下降11.97% (P0.05)、21.33% (P0.05)、32.37% (P0.05)和2.53% (P0.05)。饲料中随着ABP添加量的增加, 各组草鱼血清TNF-含量变化规律不明显, 但与对照组相比, 0.20%添加组TNF-含量显著增加(P0.05)。综上所述, 在草鱼基础日粮中添加适量牛膝多糖可以提高草鱼的免疫和抗氧化能力, 建议添加量为0.20%。       

Relationship between metabolic syndrome, circadian treatment time, and blood pressure non-dipping profile in essential hypertension

There is a strong association between metabolic syndrome (MS) and increased cardiovascular risk. Moreover, elevated nighttime blood pressure (BP) and non-dipping (subjects with <10% decline in the asleep relative to the awake BP mean) have been also linked to increased cardiovascular morbidity and mortality. We investigated the relation between MS, circadian time of hypertension treatment, and impaired nighttime BP decline in a cross-sectional study on 3352 (1576 men/1776 women) non-diabetic hypertensive subjects, 53.7 ± 13.1 (mean ± SD) yrs of age. Among them, 2056 were ingesting all their prescribed hypertension medication upon awakening, and 1296 were ingesting at least one of their BP medications at bedtime. BP was measured by ambulatory monitoring for 48 consecutive hours to substantiate reproducibility of the dipping pattern. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately calculate mean BP when awake and asleep for each subject. MS was present in 52.6% of the subjects. The prevalence of an altered non-dipper BP profile was significantly higher among subjects with MS (52.0% vs. 39.5% in subjects without MS, p < .001). Non-dipping was significantly more prevalent among subjects ingesting all BP-lowering medications upon awakening (56.8%) than among those ingesting at least one of their BP medications at bedtime (29.1%; p < .001). Subjects with MS had significantly higher values of uric acid (6.0 vs. 5.3 g/dL, p < .001), plasma fibrinogen (331 vs. 315 mg/dL, p < .001), and erythrocyte sedimentation rate (14.8 vs. 12.4 mm, p < .001). Non-dipping was significantly associated with the presence of MS and treatment upon awakening in a multiple logistic regression model adjusted by significant confounding factors, including age, creatinine, erythrocyte sedimentation rate, and cigarette smoking. This cross-sectional study documents a significant increase of a blunted sleep-time BP decline in treated hypertensive subjects with MS. Even in the presence of MS, treatment at bedtime is significantly associated with lower prevalence of a high-risk non-dipper BP profile.     

Reduced baroreceptor sensitivity during hypotension in ANP-knockout mice

We studied baroreflex gain in inactin-anesthetized mice that had been genetically modified to be depleted of atrial natriuretic peptide (ANP -/-). Wild-type mice (ANP +/+) served as controls. ANP -/- mice had a significantly higher basal arterial blood pressure (ABP) than ANP +/+ mice [112+/-7 vs. 80+/-5 mmHg (mean +/- SEM)]. Their basal heart rates were not different (491+/-13 vs. 446+/-19 bpm). A third group, composed of ANP +/+ mice only, was rendered acutely hypertensive by an intravenous infusion of arginine vasopressin acetate (0.3 pg bolus followed by 0.3 pg/h) so as to serve as a control for the elevated ABP in the ANP -/- mice. Transient changes in ABP were caused by bolus injections of oxymetazoline hydrochloride (1.5-3 ng) or sodium nitroprusside (20-100 ng). Baroreflex gain was calculated as the ratio of the peak heart rate change that followed the peak change in mean ABP resulting from injection of oxymetazoline or nitroprusside. There were no significant differences among the groups in their responses to transient hypertension. On the other hand, the ANP -/- mice showed a significantly depressed tachycardic response to transient hypotension when compared with the other two groups. We conclude that the ANP -/- mice are unable to increase efferent sympathetic nervous activity adequately above the high basal activity that is a feature of this animal model.     

Role of IL‐18 in atopic asthma is determined by balance of IL‐18/IL‐18BP/IL‐18R

It is recognized that IL‐18 is related to development of asthma, but role of IL‐18 in asthma remains controversial and confusing. This is largely due to lack of information on expression of IL‐18 binding protein (BP) and IL‐18 receptor (R) in asthma. In this study, we found that plasma levels of IL‐18 and IL‐18BP were elevated in asthma. The ratio between plasma concentrations of IL‐18 and IL‐18BP was 1:12.8 in asthma patients. We demonstrated that 13‐fold more monocytes, 17.5‐fold more neutrophils and 4.1‐fold more B cells express IL‐18BP than IL‐18 in asthmatic blood, suggesting that there is excessive amount of IL‐18BP to abolish actions of IL‐18 in asthma. We also discovered that more IL‐18R+ monocytes, neutrophils and B cells are located in asthmatic blood. Once injected, IL‐18 eliminated IL‐18R+ monocytes in blood, but up‐regulated expression of IL‐18R in lung macrophages of OVA‐sensitized mice. Our data clearly indicate that the role of IL‐18 in asthma is very likely to be determined by balance of IL‐18/IL‐18BP/IL‐18R expression in inflammatory cells. Therefore, IL‐18R blocking or IL‐18BP activity enhancing therapies may be useful for treatment of asthma.     

IL 1-like activities present in murine amniotic fluid. A significantly larger amount of IL 1 beta-like activity is present in the amniotic fluid of autoimmune NZB mice

Rapid progress in studies of cytokines have clarified their roles in processes of lymphocyte proliferation and differentiation. However, the involvement of these molecules in lymphopoiesis during embryonic development has not yet been well documented. In this study we screened for possible existence of cytokines that influence lymphopoiesis in murine amniotic fluid (AF) obtained from non-autoimmune prone "normal" strains of mice (CBA/J, BALB/c, A/J, SWR, and C57B/6) and autoimmune-prone NZB mice. Significant colony stimulating activity-1 (CSA-1)-like activities were found in AF of all of the strains tested, but relatively low activities were present in AF of NZB mice. No interleukin 2 (IL 2) or interleukin 3 (IL 3)-like activities were detected, Weak IL 1-like activity was found in AF of most of the strains tested; however, the results of the standard thymocyte proliferation assays varied with each AF sample. This variation is probably related to the presence of nonspecific inhibitors including alpha-fetoprotein in murine AF. Therefore, pooled AF from CBA and NZB strains of mice were subjected to several purification procedures to assess the actual amount of IL 1-like activity present in murine AF. After (NH4)2SO4 precipitation and hydrophobic phenyl-Sepharose chromatography, the measurable level of IL 1-like activity could be increased significantly. With lentil-lectin affinity chromatography, IL 1-like activity was completely dissociated from CSA-like activity. Moreover, a significantly larger amount of IL 1-like activity was found in NZB AF fractions (approximately sixfold higher). Apparent pI values estimated by preparative isoelectric focusing (IEF) were 5.9, 7.2, and 7.4 in CBA AF fractions, and 6.5 and 7.3 in NZB AF fractions. The NZB AF fraction with pI of 7.3 showed significantly higher IL 1 activity than the other fractions studied. These partially purified molecules were found to be resistant to pH 2 and the reducing agent, 2-mercaptoethanol, but were inactivated by heat (56 degrees C, 1 hr) or trypsin. None of the fractions showed IL 2-like activity but some that had IL 1-like activity induced IL 2 production in a IL 1-dependent, IL 2-producing B lymphoma cell line. Apparent m.w. of these IL 1-like activities were 14,000, 14,500, 17,000, 18,000, and 21,000 in CBA AF fractions, and 15,000, 19,000, and 21,000 in NZB AF fractions according to SDS-polyacrylamide gel electrophoresis.(ABSTRACT TRUNCATED AT 400 WORDS)     

Inappropriate Drugs in Elderly Patients with Severe Cognitive Impairment: Results from the Shelter Study

Background

It has been estimated that Nursing Home (NH) residents with impaired cognitive status receive an average of seven to eight drugs daily. The aim of this study was to determine prevalence and factors associated with use of inappropriate drugs in elderly patients with severe cognitive impairment living in NH in Europe.

Methods

Cross-sectional data from a sample of 1449 NH residents with severe cognitive impairment, participating in the Services and Health for Elderly in Long TERm care (SHELTER) study were analysed. Inappropriate drug use was defined as the use of drugs classified as rarely or never appropriate in patients with severe cognitive impairment based on the Holmes criteria published in 2008.

Results

Mean age of participating residents was 84.2±8.9 years, 1087 (75.0%) were women. Inappropriate drug use was observed in 643 (44.9%) residents. Most commonly used inappropriate drugs were lipid-lowering agents (9.9%), antiplatelet agents (excluding Acetylsalicylic Acid – ASA –) (9.9%), acetylcholinesterase, inhibitors (7.2%) and antispasmodics (6.9%). Inappropriate drug use was directly associated with specific diseases including diabetes (OR 1.64; 95% CI 1.21–2.24), heart failure (OR 1.48; 95% CI 1.04–2.09), stroke (OR 1.43; 95% CI 1.06–1.93), and recent hospitalization (OR 1.69; 95% CI 1.20–2.39). An inverse relation was shown between inappropriate drug use and presence of a geriatrician in the facility (OR 0.55; 95% CI 0.39–0.77).

Conclusion

Use of inappropriate drugs is common among older EU NH residents. Determinants of inappropriate drug use include comorbidities and recent hospitalization. Presence of a geriatrician in the facility staff is associated with a reduced rate of use of these medications.     

KDEL-Containing Auxin-Binding Protein Is Secreted to the Plasma Membrane and Cell Wall

The auxin-binding protein ABP1 has been postulated to mediate auxin-induced cellular changes associated with cell expansion. This protein contains the endoplasmic reticulum (ER) retention signal, the tetrapeptide lysine-aspartic acid-glutamic acid-leucine (KDEL), at its carboxy terminus, consistent with previous subcellular fractionation data that indicated an ER location for ABP1. We used electron microscopic immunocytochemistry to identify the subcellular localization of ABP1. Using maize (Zea mays) coleoptile tissue and a black Mexican sweet (BMS) maize cell line, we found that ABP1 is located in the ER as expected, but is also on or closely associated with the plasma membrane and within the cell wall. Labeling of the Golgi apparatus suggests that the transport of ABP1 to the cell wall occurs via the secretory system. Inhibition of secretion of an ABP homolog into the medium of BMS cell cultures by brefeldin A, a drug that specifically blocks secretion, is consistent with this secretion pathway. The secreted protein was recognized by an anti-KDEL peptide antibody, strongly supporting the interpretation that movement of this protein out of the ER does not involve loss of the carboxy-terminal signal. Cells starved for 2,4-dichlorophenoxyacetic acid for 72 h retained less ABP in the cell and secreted more of it into the medium. The significance of our observations is 2-fold. We have identified a KDEL-containing protein that specifically escapes the ER retention system, and we provide an explanation for the apparent discrepancy that most of the ABP is located in the ER, whereas ABP and auxin act at the plasma membrane.     

Mechanism of G551D-CFTR (cystic fibrosis transmembrane conductance regulator) potentiation by a high affinity ATP analog

Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel gated by ATP binding and hydrolysis at its nucleotide binding domains (NBD). The NBDs dimerize in a head-to-tail configuration, forming two ATP binding pockets (ABP) with the ATP molecules buried at the dimer interface. Previous studies have indicated that ABP2, formed by the Walker A and B motifs of NBD2 and the signature sequence of NBD1, is the site critical for the ATP-dependent opening of CFTR. The G551D mutation in ABP2, the third most common cystic fibrosis-associated mutation, abolishes ATP-dependent gating, resulting in an open probability that is approximately 100-fold lower than that of wild-type channels. Interestingly, we found that the ATP analog N6-(2-phenylethyl)-ATP (P-ATP) increases G551D currents mainly by increasing the open time of the channel. This effect is reduced when P-ATP is applied together with ATP, suggesting a competition between ATP and P-ATP for a common binding site. Introducing mutations that lower the nucleotide binding affinity at ABP2 did not alter significantly the effects of P-ATP on G551D-CFTR, whereas an equivalent mutation at ABP1 (consisting of the Walker A and B motifs of NBD1 and the signature sequence of NBD2) dramatically decreased the potency of P-ATP, indicating that ABP1 is the site where P-ATP binds to increase the activity of G551D-CFTR. These results substantiate the idea that nucleotide binding at ABP1 stabilizes the open channel conformation. Our observation that P-ATP enhances the G551D activity by binding at ABP1 implicates that ABP1 can potentially be a target for drugs to bind and increase the channel activity.     

Quantitative changes of CRF-like immunoreactivity in eels treated with reserpine and cortisol

Immunocytochemical techniques were applied to brain and pituitary sections of European eels after experimental manipulation of the pituitary-interrenal activity. A corticotropin-releasing factor (CRF) antiserum allowed the identification of a CRF-like peptide in the preoptic nucleus (PON) and rostral and caudal neurohypophysis (NH). CRF-immunoreactivity (ir) was not affected in solvent-injected eels compared to noninjected eels. Reserpine induced a stimulation of the pituitary interrenal axis, decreased ir-CRF in the rostral NH, but did not affect hypothalamic ir-CRF. Cortisol reduced the immunostaining of hypothalamic CRF-ir perikarya and perikarya cross-sectional area. In the rostral NH, CRF-ir fibers decreased in number and almost disappeared in long-term treated eels. The immunostaining of ACTH cells with ACTH antiserum was greatly reduced. These data suggest that cortisol induces a marked reduction in the activity of the CRF-corticotrop axis. The intensity of the ir-CRF staining observed in the caudal NH, close to the intermediate lobe (IL) was not significantly affected in reserpine-treated eels, and only slightly reduced in long-term cortisol-treated eels. The intensity of ir-CRF staining in the caudal NH did not correlate with melanocorticotropic activity or plasma cortisol level. These data suggest that immunoreactive CRF fibers in the rostral and caudal NH are differently regulated.     

Association between light exposure at night and nighttime blood pressure in the elderly independent of nocturnal urinary melatonin excretion

Circadian misalignment between internal and environmental rhythms dysregulates blood pressure (BP) variability because of disruption of the biological clock, resulting in increased nighttime BP. Although exposure to light-at-night is associated with the circadian misalignment, it remains unclear whether exposure to light-at-night in home settings is associated with nighttime BP. In this cross-sectional analysis of 528 elderly individuals (mean age: 72.8 years), we measured bedroom light intensity at 1-min intervals on two consecutive nights along with ambulatory BP, overnight urinary melatonin excretion and actigraphy. With regard to adjusted mean comparisons using analysis of covariance, the light-at-night group (average: ≥5?lux; n?=?109) showed significantly higher nighttime systolic BP (SBP; adjusted mean: 120.8 vs. 116.5?mmHg, p?=?0.01) and diastolic BP (70.1 vs. 67.1?mmHg, p?<?0.01) compared with the Darker group (average: <5?lux; n?=?419) independently of potential confounding factors including overnight urinary melatonin excretion and actigraphic sleep quality. We observed consistent associations between light-at-night and nighttime BP in different cutoff values for light-at-night intensity (i.e. 3 and 10?lux). In conclusion, exposure to light-at-night in home settings is significantly associated with increased nighttime BP in elderly individuals independently of overnight urinary melatonin excretion. A 4.3?mmHg increase in nighttime SBP is associated with a 6.1% increase in total mortality, which corresponds to approximately 10?000 annual excess deaths in Japanese elderly population.     

Effects of one-year swimming training on blood pressure and insulin sensitivity in mild hypertensive young patients

Swimming is a lifestyle intervention recommended by many clinicians in the prevention and treatment of hypertension. Yet, not all studies have agreed that swimming training can reduce blood pressure (BP). Inclusion of normotensive subjects could be a confounder for discrepancies among studies. In this one-year longitudinal study, long-term effects of swimming training on BP were investigated in 7 mild hypertensive patients (systolic BP (SBP) > 140 mmHg) and 16 normotensive controls. At baseline, these subjects (aged 21.5 +/- 0.1 years) did not participate in any form of sport training activity for the previous 3 months before enrollment into the training program. The training distance progressed from 0 (baseline) to 7 kilometers per week. BP and the homeostasis model assessment for insulin resistance (HOMA-IR) were determined under fasted condition at baseline and 48 h after the last swimming bout. The hypertensive patients displayed significantly greater HOMA-IR than age-matched normotensive controls. When data of all subjects were pooled, plasma glucose concentration was only slightly lowered after training, but weight, height, body mass index, SBP, diastolic BP (DBP) and HOMA-IR values were not significantly altered. However, when observation was restricted to the hypertensive patients, swimming training significantly lowered SBP by approximately 17 mmHg, concurrent with 41% reduction in HOMA-IR. Intriguingly, SBP in the normotensive subjects was elevated by approximately 6 mmHg after training. CONCLUSIONS: The present study found normalization rather than universal reduction effect of swimming training on BP. Furthermore, the BP-lowering effect of training in hypertensive patients appears to be associated with improvement in insulin sensitivity.