Ефективність рофлуміласту у хворих на хронічне обструктивне захворювання легень із ожирінням

Хронічне обструктивне захворювання легень (ХОЗЛ) – проблема, актуальність якої в усьому світі стрімко зростає. ХОЗЛ є четвертою провідною причиною смерті в світі, являє собою важливу проблему охорони здоров'я [19]. Розуміння проблеми ХОЗЛ значно змінилося за останнє десятиліття. Зараз це не просто обмеження швидкості повітряного потоку, а складний і гетерогенний стан зі значними позалегеневими проявами, які включають в себе хвороби серцево-судинної системи, дисфункцію скелетних м'язів, і діабет [27]. Особливої актуальності набуває проблема асоціації ХОЗЛ та ожиріння, яке є складовою метаболічного синдрому (МС) і стало проблемою нашого часу. Зв'язок між МС та ХОЗЛ спостерігається в декількох довготривалих і одномоментних дослідженнях, а також синдром був визначений як незалежний фактор ризику для погіршення респіраторних симптомів, збільшення порушення функції легень, легеневої гіпертензії та бронхіальної астми [3]. 50% пацієнтів з ХОЗЛ мають один або декілька компонентів МС [2]. Одним із актуальних аспектів проблеми поєднання ХОЗЛ та МС є розроблення обґрунтованої патогенетичної терапії. Залишається відкритим питання про лікування ХОЗЛ на тлі МС (глюкокортикостероїдні гормони сприяють підвищенню артеріального тиску та рівня глюкози в крові) [16, 44]. Є дані про сприятливу дію на рівень глюкози інгібітору фосфодіестерази-4 [ФДЕ-4] — рофлуміласту [9]. Встановлено, що даний препарат зменшує вираженість порушення толерантності до глюкози [34]. На тлі лікування рофлуміластом, відзначається зниження маси тіла у пацієнтів з ожирінням, поліпшення глікемічного профілю у хворих на цукровий діабет 2-го типу [70]. За даними подвійного сліпого, рандомізованого дослідження [17] лікування рофлуміластом призводило до значного зниження ваги (-2.0 кг з рофлуміластом, проти 0,1 кг з плацебо), індексу маси тіла (ІМТ) (-0,73 кг/м² з рофлуміластом, проти 0,03 кг/м² з плацебо). Застосування рофлуміласту покращує показники oб’єму фoрсoванoгo видиху за першу секунду (ОФВ1) та позитивно впливає на інші показники функції легень у порівнянні з плацебо [7]. Позитивна дія рофлуміласту на функцію легень пов'язана зі значним зменшенням ваги пацієнтів, в першу чергу за рахунок втрати жирової маси [6]. Мета нашої роботи дослідити ефективність рофлуміласту у хворих на хронічне обструктивне захворювання легень із ожирінням

Performance deficits of NK1 receptor knockout mice in the 5 choice serial reaction time task: effects of d Amphetamine, stress and time of day.

Background The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon. Methods and Results The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning. Conclusion In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies

Evaluating an integrated neighbourhood approach to improve well-being of frail elderly in a Dutch community: a study protocol

<p>Abstract</p> <p>Background</p> <p>An important condition for independent living is having a well-functioning social network to provide support. An Integrated Neighbourhood Approach (INA) creates a supportive environment for the frail elderly, offering them tailored care in their local context that allows them to improve self-management abilities and well-being. The purpose of our research is to investigate how an INA can contribute to outcomes of frail elderly and the cost-effectiveness of such a program. The first central study question is: To what extent does INA contribute to (a) continuous, demand-driven, coordinated care and support for the independently- living frail elderly; (b) improvement of their well-being and self-management abilities; and (c) reinforcement of their neighbourhood networks. The second central research question is: is the INA a cost-effective method to support the frail, independently- living elderly?</p> <p>Methods</p> <p>We investigate a Dutch INA. This transition experiment aims to facilitate the independently-living frail elderly (70+) to live the life they wish to live and improve their well-being. The study population consists of independently-living frail elderly persons in Rotterdam. The transition experiment starts in two Rotterdam districts and is later extended to two other districts. We propose a concurrent mixed methods design, that is, a combination of qualitative and quantitative research methods to evaluate processes, effects and costs of INA. Such a design will provide insight into an on-going INA and demonstrate which of its elements are potentially (cost)-effective for the frail elderly.</p> <p>Discussion</p> <p>We embrace a wide range of scientific methodologies to evaluate the INA project and obtain information on mechanisms and contexts that will be valuable for decision making on local and national levels. The study will lead to a better understanding of how to provide support via social networks for the frail elderly and add to the knowledge on the feasibility and cost-effectiveness of the program in maintaining or improving their well-being. Last, the study will highlight the factors that determine the program's success or failure.</p

Cerebral Accumulation of Dietary Derivable Plant Sterols does not Interfere with Memory and Anxiety Related Behavior in Abcg5−/− Mice

Plant sterols such as sitosterol and campesterol are frequently applied as functional food in the prevention of atherosclerosis. Recently, it became clear that plasma derived plant sterols accumulate in murine brains. We questioned whether plant sterols in the brain are associated with alterations in brain cholesterol homeostasis and subsequently with brain functions. ATP binding cassette (Abc)g5−/− mice, a phytosterolemia model, were compared to Abcg5+/+ mice for serum and brain plant sterol accumulation and behavioral and cognitive performance. Serum and brain plant sterol concentrations were respectively 35–70-fold and 5–12-fold increased in Abcg5−/− mice (P < 0.001). Plant sterol accumulation resulted in decreased levels of desmosterol (P < 0.01) and 24(S)-hydroxycholesterol (P < 0.01) in the hippocampus, the brain region important for learning and memory functions, and increased lanosterol levels (P < 0.01) in the cortex. However, Abcg5−/− and Abcg5+/+ displayed no differences in memory functions or in anxiety and mood related behavior. The swimming speed of the Abcg5−/− mice was slightly higher compared to Abcg5+/+ mice (P < 0.001). In conclusion, plant sterols in the brains of Abcg5−/− mice did have consequences for brain cholesterol metabolism, but did not lead to an overt phenotype of memory or anxiety related behavior. Thus, our data provide no contra-indication for nutritional intake of plant sterol enriched nutrition

Epithelial-immune cell interplay in primary Sjogren syndrome salivary gland pathogenesis

In primary Sjogren syndrome (pSS), the function of the salivary glands is often considerably reduced. Multiple innate immune pathways are likely dysregulated in the salivary gland epithelium in pSS, including the nuclear factor-kappa B pathway, the inflammasome and interferon signalling. The ductal cells of the salivary gland in pSS are characteristically surrounded by a CD4(+) T cell-rich and B cell-rich infiltrate, implying a degree of communication between epithelial cells and immune cells. B cell infiltrates within the ducts can initiate the development of lymphoepithelial lesions, including basal ductal cell hyperplasia. Vice versa, the epithelium provides chronic activation signals to the glandular B cell fraction. This continuous stimulation might ultimately drive the development of mucosa-associated lymphoid tissue lymphoma. This Review discusses changes in the cells of the salivary gland epithelium in pSS (including acinar, ductal and progenitor cells), and the proposed interplay of these cells with environmental stimuli and the immune system. Current therapeutic options are insufficient to address both lymphocytic infiltration and salivary gland dysfunction. Successful rescue of salivary gland function in pSS will probably demand a multimodal therapeutic approach and an appreciation of the complicity of the salivary gland epithelium in the development of pSS. Salivary gland dysfunction is an important characteristic of primary Sjogren syndrome (pSS). In this Review, the authors discuss various epithelial abnormalities in pSS and the mechanisms by which epithelial cell-immune cell interactions contribute to disease development and progression

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer's disease, about the therapeutic strategies in Alzheimer's research

Experimental models that faithfully mimic the developmental pathology of sporadic Alzheimer's disease (sAD) in humans are important for testing the novel therapeutic approaches in sAD treatment. Widely used transgenic mice AD models have provided valuable insights into the molecular mechanisms underlying the memory decline but, due to the particular β-amyloid-related gene manipulation, they resemble the familial but not the sporadic AD form, and are, therefore, inappropriate for this purpose. In line with the recent findings of sAD being recognised as an insulin resistant brains state (IRBS), a new, non-transgenic, animal model has been proposed as a representative model of sAD, developed by intracerebroventricular application of the betacytotoxic drug streptozotocin (STZ-icv). The STZ-icv-treated animals (mostly rats and mice) develop IRBS associated with memory impairment and progressive cholinergic deficits, glucose hypometabolism, oxidative stress and neurodegeneration that share many features in common with sAD in humans. The therapeutic strategies (acetylcholinesterase inhibitors, antioxidants and many other drugs) that have been tested until now on the STZ-icv animal model have been reviewed and the comparability of the drugs' efficacy in this non-transgenic sAD model and the results from clinical trials on sAD patients, evaluated

Multi-laboratory study of the analysis and kinetics of stanozolol and its metabolites in treated calves.

The European Union banned the use of anabolic steroids for cattle fattening in 1988. Analytical techniques able to detect trace amounts of the parent drugs and their metabolites are mandatory for the control of abuse. Stanozolol (Stan) is an anabolic steroid that is often found in injection sites and cocktails. However, it has never been detected in tissues (kidney fat, meat) or excreta (urine, faeces) taken during regulatory inspection. The difference between the structure of Stan and the ether steroids (a pyrazole ring fused to the androstane ring system) is probably the cause of this phenomenon. In the multi-laboratory study described here, veal calves were treated with intramuscular doses of Stan. In the excreta of these calves the presence, absence and/or concentration of Stan and of its major metabolites 16β-hydroxystanozolol and 3'-hydroxystanozolol were determined. For the determination of these analytes the different laboratories used different extraction and clean-up procedures and also evaluated different analytical techniques such as GC-MS (negative chemical ionization) and LC-MS-MS. The aim of this investigation was to explore which analyte should be validated for veterinary inspection purposes