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21.
Dzierba CD Takvorian AG Rafalski M Kasireddy-Polam P Wong H Molski TF Zhang G Li YW Lelas S Peng Y McElroy JF Zaczek RC Taub RA Combs AP Gilligan PJ Trainor GL 《Journal of medicinal chemistry》2004,47(23):5783-5790
Corticotropin releasing factor (CRF) is the primary regulator of the hypothalamus-pituitary-adrenal (HPA) axis, coordinating the endocrine, behavioral, and autonomic responses to stress. It has been postulated that small molecules that can antagonize the binding of CRF1 to its receptor may serve as a treatment for anxiety-related and/or affective disorders. Members within a series of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ones, exemplified by compound 2 (IC50 = 0.70 nM), were found to be very potent antagonists of CRF1. Compound 8w showed high CRF1 receptor binding affinity and was examined further in vivo. The compound was efficacious in a defensive withdrawal model of anxiety in rats and had a long half-life and reasonable oral bioavailability in dog pharmacokinetic studies. 相似文献
22.
De Vries J Rothkrantz-Kos S van Dieijen-Visser MP Drent M 《Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG / World Association of Sarcoidosis and Other Granulomatous Disorders》2004,21(2):127-136
BACKGROUND AND AIM OF THE WORK: Studies on the relationship between fatigue and clinical parameters are sparse. In the present study this relationship was examined in a systematic way. METHODS: Patients with time since diagnosis < or = 2 years, visiting the outpatient clinic of the University Hospital Maastricht (n = 60; 34 untreated, 26 treated) were clinically evaluated and completed the Fatigue Assessment Scale (FAS). A representative sample of the Dutch population (n = 1893) also completed the FAS. Pulmonary disease severity was estimated from lung function test results and measures of metabolic derangement. Acute phase response markers high-sensitivity C-reactive protein (hs-CRP), serum amyloid A (SAA) and sarcoidosis activity parameters, soluble interleukin-2-receptor (sIL2R), and angiotensin-converting enzyme (ACE) were also measured. RESULTS: Only 27% of the sarcoidosis patients were diagnosed as non-fatigued (FAS score < 22), compared to 80% in the control population (n = 1893). In the sarcoidosis patients no sex differences and no differences in fatigue scores between the treated and the untreated groups were found. Patients with fatigue (FAS-score > or = 22) had lower DLCO values (p < 0.05). However, none of the tested clinical or serological parameters appeared to be a significant predictor of fatigue. CONCLUSIONS: In the present study, it was confirmed that fatigue is a major problem in sarcoidosis. The extent of fatigue could not be explained by clinical parameters. Thus, up to now, no clinical or physiological variable seems useful in predicting which patients are fatigued. In this light, the Fatigue Assessment Scale might be considered as a supplementary tool in sarcoidosis. 相似文献
23.
Pittis MG Montalvo AL Miocic S Martini C Deganuto M Candusso M Ciana G Bembi B 《American journal of medical genetics. Part A》2003,(3):225-230
Glycogen storage disease type II (GSDII) is an autosomal recessive disorder due to the deficiency of the lysosomal enzyme acid alpha glucosidase. Four novel mutations (C670T, G989A, G2188T, and Delta 23 nt 828-850) were identified in five Italian patients with the infantile form of the disease. The C670T mutation was present in two unrelated patients in heterozygosity; the effect on enzyme activity was assessed by in vitro expression. COS-1 cells expressing the C670T allele had a twofold higher activity than the negative control cells. The G989A and G2188T point mutations lead to the introduction of premature stop signals that results in truncated forms of alpha glucosidase. The in vitro expression of G2188T allele demonstrated no increment in activity compared to negative control. The frame shifting deletion of nucleotides 828-850 was identified in one patient in heterozygosity. The shift in the reading frame introduces a stop codon 135 nucleotides downstream the deletion junction that results in a truncated protein without catalytic activity. Nested PCR screening showed that the mutation was carried by the mother and was absent in the other members of the family. The four novel severe mutations herein described concerned only infantile onset GSDII patients; the loss of enzyme activity is correlated with the severity of the disease. 相似文献
24.
Govender Thirumala Ehtezazi Touraj Stolnik Snjezana Illum Lisbeth Davis Stanley S. 《Pharmaceutical research》1999,16(7):1125-1131
Purpose. Due to the importance of drug-polymer interactions in, inter alia, drug loading/release, supramolecular assemblies and DNA delivery for gene therapy, the aim of this study was therefore to establish the mechanism of interaction between a model polymer (Polyacrylic acid, PAA) and a model drug (procaine HCl).
Methods. This was performed by studying the effect of salt (KCl) concentration on their heat released values using Isothermal Titration Microcalorimetry (ITM). The integrated released heat data were computer fitted to a one class binding model and the thermodynamic parameters (Kobs, H, and N) were determined.
Results. As the KC1 concentration was increased, Kobs decreased thus establishing the salt dependence of the interaction. The linear variation of Gobs with Sobs indicated that their interaction was entropically driven. The stoichiometry of the interaction was calculated to be one procaine molecule per monomer of PAA. Dissection of the total observed free energy at each KC1 concentration indicated that the contribution of the non-electrostatic attractions to the interaction of PAA with procaine HC1 was greater than those of the electrostatic attractions.
Conclusions. We have shown that the interaction between PAA and procaine HC1 is dependent upon the presence of counterions (monovalent ions) and is mainly entropically driven. The calculated stoichiometry indicated that one procaine HC1 molecule neutralised one carboxylic acid group on PAA. Although electrostatic interactions were necessary for initiating complex formation, the non-electrostatic forces were dominant in stabilising the PAA-procaine HC1 complex. 相似文献
25.
Mangesh C Deshpande Martin C Garnett M Vamvakaki Lindsey Bailey Steven P Armes Snjezana Stolnik 《Journal of controlled release》2002,81(1-2):185-199
The influence of polymer structure on the characteristics of complexes of a phosphorothioate antisense oligonucleotide (ISIS 5132) was studied, using well-defined cationic copolymers based on 2-(dimethylamino) ethyl methacrylate (DMAEMA) and poly(ethylene glycol) (PEG). The three related copolymer structures were: DMAEMA-PEG (a diblock copolymer) DMAEMA-OEGMA 7 (a brush-type copolymer), DMAEMA-stat-PEGMA (a comb-type copolymer); each of these were examined together with DMAEMA homopolymer, which served as a control. The results revealed that all the polymers exhibited good binding ability with the oligonucleotide (ON). Interestingly, the comb-type polymer DMAEMA-stat-PEGMA demonstrated the highest binding ability and DMAEMA homopolymer the lowest, as judged by a dye displacement assay. DMAEMA homopolymer produced large agglomerates of smaller individual complexes as observed by optical density, photon correlation spectroscopy and transmission electron microscopy studies. In contrast, two PEG-block copolymers, DMAEMA-PEG and DMAEMA-OEGMA 7, formed compact complexes of 80-150 nm which had good long-term colloidal stability. This is attributed to the steric stabilisation effect of the PEG chains on the ON-copolymer complexes. These two copolymers are believed to form complexes with ON that have a micellar structure. Comb-type DMAEMA-stat-PEGMA copolymer formed highly soluble complexes with the ON that did not phase separate from the buffer solution. This study clearly demonstrates that varying the copolymer architecture allows access to a range of ON complexes. In vitro cytotoxicity experiments on HepG2 cells showed that all of the tertiary amine methacrylate copolymers displayed lower cytotoxicity than the control poly(L-lysine). 相似文献
26.
I?igo Landa Tihana Ibrahimpasic Laura Boucai Rileen Sinha Jeffrey A. Knauf Ronak H. Shah Snjezana Dogan Julio C. Ricarte-Filho Gnana P. Krishnamoorthy Bin Xu Nikolaus Schultz Michael F. Berger Chris Sander Barry S. Taylor Ronald Ghossein Ian Ganly James A. Fagin 《The Journal of clinical investigation》2016,126(3):1052-1066
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BACKGROUND: Sarcoidosis is a multiorgan inflammatory granulomatous disorder of unknown origin for which adequate markers to monitor disease severity are lacking. The aim of this study was to evaluate the potential clinical usefulness of serologic markers of inflammation [high-sensitivity C-reactive protein (hs-CRP) and serum amyloid A (SAA)], T-cell activation [soluble interleukin-2 receptor (sIL2R)], and granuloma formation [angiotensin-converting enzyme (ACE)] for monitoring of sarcoidosis. METHODS: Of the 185 sarcoidosis patients who visited the Sarcoidosis Management Center between 1999 and 2002, we selected 144 nonsmoking patients: 73 untreated (group I) and 71 treated (group II). Subgroups of the untreated patients [group Ia (nonchronic group with time since diagnosis < or = 2 years) and group Ib (chronic group with time since diagnosis >2 years)] were evaluated separately. ROC curves and logistic regression analyses were used to compare the diagnostic accuracy of different markers to assess disease severity. Pulmonary disease severity was defined by lung function test results. RESULTS: In untreated subgroup Ia and the total untreated group (group I), sIL2R had the largest areas under the curves (AUCs; 0.891 and 0.799, respectively) and the highest sensitivity (82% and 64%), specificity (94% and 88%), and positive (82% and 70%) and negative (94% and 88%) predictive values among the evaluated markers in both untreated groups. Nevertheless, the confidence intervals for sIL2R AUC, sensitivity, and specificity were broad and partly overlapped those of ACE, hs-CRP, and SAA. In the treated group (group II), all four markers appeared to have comparable AUCs, ranging from 0.645 for SAA to 0.711 for sIL2R. CONCLUSION: sIL2R appears to be useful for monitoring respiratory disease severity in sarcoidosis. We recommend sIL2R measurement in the follow-up of patients with sarcoidosis. 相似文献
30.
Buyandelger B Ng KE Miocic S Piotrowska I Gunkel S Ku CH Knöll R 《Pflügers Archiv : European journal of physiology》2011,462(1):135-142
Muscle LIM protein (MLP, also known as cysteine rich protein 3 (CSRP3, CRP3)) is a muscle-specific-expressed LIM-only protein.
It consists of 194 amino-acids and has been described initially as a factor involved in myogenesis (Arber et al. Cell 79:221–231,
1994). MLP soon became an important model for experimental cardiology when it was first demonstrated that MLP deficiency leads
to myocardial hypertrophy followed by a dilated cardiomyopathy and heart failure phenotype (Arber et al. Cell 88:393–403,
1997). At this time, this was the first genetically altered animal model to develop this devastating disease. Interestingly, MLP
was also found to be down-regulated in humans with heart failure (Zolk et al. Circulation 101:2674–2677, 2000) and MLP mutations are able to cause hypertrophic and dilated forms of cardiomyopathy in humans (Bos et al. Mol Genet Metab
88:78–85, 2006; Geier et al. Circulation 107:1390–1395, 2003; Hershberger et al. Clin Transl Sci 1:21–26, 2008; Kn?ll et al. Cell 111:943–955, 2002; Kn?ll et al. Circ Res 106:695–704, 2010; Mohapatra et al. Mol Genet Metab 80:207–215, 2003). Although considerable efforts have been undertaken to unravel the underlying molecular mechanisms—how MLP mutations, either
in model organisms or in the human setting cause these diseases are still unclear. In contrast, only precise knowledge of
the underlying molecular mechanisms will allow the development of novel and innovative therapeutic strategies to combat this
otherwise lethal condition. The focus of this review will be on the function of MLP in cardiac mechanosensation and we shall
point to possible future directions in MLP research. 相似文献