Визначення статусу Головного контрольно-ревізійного управління України в системі органів виконавчої влади в контексті адміністративної реформи

Розбіжність у окремих нормативно правових актах України стосовно визначення статусу та підпорядкування Головного контрольно-ревізійне управління України, керівного органу державної контрольно ревізійної служби, уповноваженого на здійснення контролюючих функцій від імені Кабінету Міністрів України, призначення на посаду керівника зазначеного органу і відповідно визначення його місця у механізмі державної влади потребує чіткого врегулювання в контексті адміністративно-правової реформи, запровадження публічної адміністрації та удосконалення системи органів виконавчої влади, пов'язаності з іншими гілками влади системою стримувань і противаг. Ключові слова: державне управління, державний орган, правовий статус, державна контрольно ревізійна служба, механізм державної влади, Головне контрольноревізійне управління України, контроль за використанням державних коштівНесоответствие у отдельных нормативно правовых актах Украины относительно определения статусу та подчинения Главного контрольно ревизионного управления Украины, руководящего органа государственной контрольно ревизионной службы, уполномоченного на осуществление контролирующих функций от имени Кабинета Министров Украины, назначение на должность руководителя указанного органа и соответственно определения его места в механизме государственной власти требует четкого урегулирования в контексте административно правовой реформы, внедрения публичной администрации та усовершенствования системы органов исполнительной власти, связи с другими ветвями власти системой сдерживания та противовесов. Ключевые слова: государственное управление, государственный орган, правовой статус, государственная контрольно ревизионная служба, механизм государственной власти, Главное контрольно ревизионное управление Украины, контроль использования государственных средств.Inconsistency in some normative legal acts of Ukraine as regards determination of the status and subordination of the Main Control and Revision Office of Ukraine, the chief authority of the state control and revision service, entitled for performance of controlling functions on behalf of the Cabinet of Ministers of Ukraine, appointment of the Chairman of the mentioned authority and correspondingly determination of his/her place in the machinery of the government require clear regulation in the context of administrative legal reform, introduction of public administration and improvement of the system of executive authorities, connection with other branches of power by the system of restraints and counterbalances. Key words: public administration, state authority, legal status, the state control and revision service, machinery of the government, the Main Control and Revision Office of Ukraine, control over use of public funds

Integrating workplace exposure databases for occupational medicine services and epidemiologic studies at a former nuclear weapons facility

We outline methods for integrating epidemiologic and industrial hygiene data systems for the purpose of exposure estimation, exposure surveillance, worker notification, and occupational medicine practice. We present examples of these methods from our work at the Rocky Flats Plant?a former nuclear weapons facility that fabricated plutonium triggers for nuclear weapons and is now being decontaminated and decommissioned. The weapons production processes exposed workers to plutonium, gamma photons, neutrons, beryllium, asbestos, and several hazardous chemical agents, including chlorinated hydrocarbons and heavy metals. We developed a job exposure matrix (JEM) for estimating exposures to 10 chemical agents in 20 buildings for 120 different job categories over a production history spanning 34 years. With the JEM, we estimated lifetime chemical exposures for about 12,000 of the 16,000 former production workers. We show how the JEM database is used to estimate cumulative exposures over different time periods for epidemiological studies and to provide notification and determine eligibility for a medical screening program developed for former workers. We designed an industrial hygiene data system for maintaining exposure data for current cleanup workers. We describe how this system can be used for exposure surveillance and linked with the JEM and databases on radiation doses to develop lifetime exposure histories and to determine appropriate medical monitoring tests for current cleanup workers. We also present time-line-based graphical methods for reviewing and correcting exposure estimates and reporting them to individual workers

Non-classical ProIL-1beta activation during mammary gland infection is pathogen-dependent but caspase-1 independent

Infection of the mammary gland with live bacteria elicits a pathogen-specific host inflammatory response. To study these host-pathogen interactions wild type mice, NF-kappaB reporter mice as well as caspase-1 and IL-1beta knockout mice were intramammarily challenged with Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The murine mastitis model allowed to compare the kinetics of the induced cytokine protein profiles and their underlying pathways. In vivo and ex vivo imaging showed that E. coli rapidly induced NF-kappaB inflammatory signaling concomitant with high mammary levels of TNF-alpha, IL-1 alpha and MCP-1 as determined by multiplex analysis. In contrast, an equal number of S. aureus bacteria induced a low NF-kappaB activity concomitant with high mammary levels of the classical IL-1beta fragment. These quantitative and qualitative differences in local inflammatory mediators resulted in an earlier neutrophil influx and in a more extensive alveolar damage post-infection with E. coli compared to S. aureus. Western blot analysis revealed that the inactive proIL-1beta precursor was processed into pathogen-specific IL-1beta fragmentation patterns as confirmed with IL-1beta knockout animals. Additionally, caspase-1 knockout animals allowed to investigate whether IL-1beta maturation depended on the conventional inflammasome pathway. The lack of caspase-1 did not prevent extensive proIL-1beta fragmentation by either of S. aureus or E. coli. These non-classical IL-1beta patterns were likely caused by different proteases and suggest a sentinel function of IL-1beta during mammary gland infection. Thus, a key signaling nodule can be defined in the differential host innate immune defense upon E. coli versus S. aureus mammary gland infection, which is independent of caspase-1

Simvastatin inhibits TLR8 signaling in primary human monocytes and spontaneous TNF production from rheumatoid synovial membrane cultures

Simvastatin has been shown to have anti-inflammatory effects that are independent of its serum cholesterol lowering action, but the mechanisms by which these anti-inflammatory effects are mediated have not been elucidated. To explore the mechanism involved, the effect of simvastatin on Toll-like receptor (TLR) signalling in primary human monocytes was investigated. A short pre-treatment with simvastatin dose-dependently inhibited the production of tumor necrosis factor-α (TNF) in response to TLR8 (but not TLRs 2, 4, or 5) activation. Statins are known inhibitors of the cholesterol biosynthetic pathway, but intriguingly TLR8 inhibition could not be reversed by addition of mevalonate or geranylgeranyl pyrophosphate; downstream products of cholesterol biosynthesis. TLR8 signalling was examined in HEK 293 cells stably expressing TLR8, where simvastatin inhibited IKKα/β phosphorylation and subsequent NF-κB activation without affecting the pathway to AP-1. Since simvastatin has been reported to have anti-inflammatory effects in RA patients and TLR8 signalling contributes to TNF production in human RA synovial tissue in culture, simvastatin was tested in these cultures. Simvastatin significantly inhibited the spontaneous release of TNF in this model which was not reversed by mevalonate. Together, these results demonstrate a hitherto unrecognized mechanism of simvastatin inhibition of TLR8 signalling that may in part explain its beneficial anti-inflammatory effects

Primary and malignant cholangiocytes undergo CD40 mediated Fas dependent Apoptosis, but are insensitive to direct activation with exogenous fas ligand

Introduction Cholangiocarcinoma is a rare malignancy of the biliary tract, the incidence of which is rising, but the pathogenesis of which remains uncertain. No common genetic defects have been described but it is accepted that chronic inflammation is an important contributing factor. We have shown that primary human cholangiocyte and hepatocyte survival is tightly regulated via co-operative interactions between two tumour necrosis family (TNF) receptor family members; CD40 and Fas (CD95). Functional deficiency of CD154, the ligand for CD40, leads to a failure of clearance of biliary tract infections and a predisposition to cholangiocarcinoma implying a direct link between TNF receptor-mediated apoptosis and the development of cholangiocarcinoma. Aims To determine whether malignant cholangiocytes display defects in CD40 mediated apoptosis. By comparing CD40 and Fas-mediated apoptosis and intracellular signalling in primary human cholangiocytes and three cholangiocyte cell lines. Results Primary cholangiocytes and cholangiocyte cell lines were relatively insensitive to direct Fas-mediated killing with exogenous FasL when compared with Jurkat cells, which readily underwent Fas-mediated apoptosis, but were extremely sensitive to CD154 stimulation. The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignant cells and was STAT-3 and AP-1 dependent in both. Conclusions 1) Both primary and malignant cholangiocytes are relatively resistant to Fas–mediated killing but show exquisite sensitivity to CD154, suggesting that the CD40 pathway is intact and fully functional in both primary and malignant cholangiocytes 2) The relative insensitivity of cholangiocytes to Fas activation demonstrates the importance of CD40 augmentation of Fas dependent death in these cells. Agonistic therapies which target CD40 and associated intracellular signalling pathways may be effective in promoting apoptosis of malignant cholangiocytes

Теоретико-методологічні основи розуміння механізму правового регулювання

Метою цієї статті є аналіз напрямів наукових досліджень, що у своїй єдності формують теорію механізму правового регулювання (МПР), розкриття теоретикометодологічних проблем, які мають місце при осмисленні МПР, визначення та систематизація методологічних підходів до розуміння МПР

CD40L Deficiency Attenuates Diet-Induced Adipose Tissue Inflammation by Impairing Immune Cell Accumulation and Production of Pathogenic IgG-Antibodies

BACKGROUND: Adipose tissue inflammation fuels the metabolic syndrome. We recently reported that CD40L--an established marker and mediator of cardiovascular disease--induces inflammatory cytokine production in adipose cells in vitro. Here, we tested the hypothesis that CD40L deficiency modulates adipose tissue inflammation in vivo. METHODOLOGY/PRINCIPAL FINDINGS: WT or CD40L(-/-) mice consumed a high fat diet (HFD) for 20 weeks. Inflammatory cell recruitment was impaired in mice lacking CD40L as shown by a decrease of adipose tissue macrophages, B-cells, and an increase in protective T-regulatory cells. Mechanistically, CD40L-deficient mice expressed significantly lower levels of the pro-inflammatory chemokine MCP-1 both, locally in adipose tissue and systemically in plasma. Moreover, levels of pro-inflammatory IgG-antibodies against oxidized lipids were reduced in CD40L(-/-) mice. Also, circulating low-density lipoproteins and insulin levels were lower in CD40L(-/-) mice. However, CD40L(-/-) mice consuming HFD were not protected from the onset of diet-induced obesity (DIO), insulin resistance, and hepatic steatosis, suggesting that CD40L selectively limits the inflammatory features of diet-induced obesity rather than its metabolic phenotype. Interestingly, CD40L(-/-) mice consuming a low fat diet (LFD) showed both, a favorable inflammatory and metabolic phenotype characterized by diminished weight gain, improved insulin tolerance, and attenuated plasma adipokine levels. CONCLUSION: We present the novel finding that CD40L deficiency limits adipose tissue inflammation in vivo. These findings identify CD40L as a potential mediator at the interface of cardiovascular and metabolic disease

Acute exacerbations of COPD are associated with significant activation of matrix metalloproteinase 9 irrespectively of airway obstruction, emphysema and infection

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are associated with accelerated aggravation of clinical symptoms and deterioration of pulmonary function. The mechanisms by which exacerbations may contribute to airway remodeling and declined lung function are poorly understood. In this study, we investigated if AE-COPD are associated with differential expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in bronchoalveolar lavage (BAL). METHODS: COPD patients undergoing diagnostic bronchoscopy, with either stable disease (n = 53) or AE-COPD (n = 44), matched for their demographics and lung function parameters were included in this study. Protein levels of MMP-2,-9,-12 and of TIMP-1 and -2 in BAL were measured by ELISA. Enzymatic activity of MMP-2 and -9 was assessed by gelatin zymography. RESULTS: We observed that MMP-9, TIMP-1 and TIMP-2 were significantly increased in BAL during AE-COPD. Furthermore, there was a significant negative correlation of MMP-9, TIMP-1 and TIMP-2 with FEV1% predicted and a significant positive correlation of TIMP-1 and TIMP-2 with RV% predicted in AE-COPD. None of MMPs and TIMPs correlated with DLCO% predicted, indicating that they are associated with airway remodeling leading to obstruction rather than emphysema. In AE-COPD the gelatinolytic activity of MMP-2 was increased and furthermore, MMP-9 activation was significantly up-regulated irrespective of lung function, bacterial or viral infections and smoking. CONCLUSIONS: The results of this study indicate that during AE-COPD increased expression of TIMP-1, TIMP-2, and MMP-9 and activation of MMP-9 may be persistent aggravating factors associated with airway remodeling and obstruction, suggesting a pathway connecting frequent exacerbations to lung function decline