Presence Of MPA Research Articles

Correlating computed tomographic angiography of pulmonary circulation with clinical course and disease burden in patients with tetralogy of Fallot and pulmonary atresia

PurposeTo determine the type of pulmonary circulation (PC) in patients with tetralogy of Fallot (TOF) and pulmonary atresia (TOF-PA) with the use of computed tomographic angiography (CTA), and describe their clinical courses, corrective surgery and disease burden. Methods145 patients (median age 4 years, interquartile range: IQR2-8 years) were analyzed for PC which divided into 5 CTA-types and 11 subtypes based on presence of main pulmonary trunk (MPA) and confluent pulmonary arteries (confluence-PAs), presence of ductus arteriosus or major aortopulmonary collateral arteries (MAPCAs), respectively. Pulmonary arteries (PAs) were assessed by McGoon ratio and arborization. Corrective surgery or palliative management was recorded by type of PC. Disease burden was calculated as the sum of CTA, diagnostic angiography, and palliative management. ResultsThe most common (N = 77, 53 %) PC was the presence of MPA with confluent-PAs (type-1) which was encountered mostly in TOF patients, followed by the presence of confluent-PAs with atretic MPA (type-2) (N = 47, 32 %) which found mainly in TOF-PA. McGoon ratio in type-1 (2.44 ± 0.84) was significantly larger than type-2 (1.61 ± 0.61) (median difference 0.84, 95 %CI 0.56–1.11, p < 0.001). Almost 2/3 of patients in type-1 (71 %) and 1/3 of patients in type-2 (34 %) achieved corrective surgery. There was no significant difference in amount of disease burden among the different PC, with the median value of 3 (IQR1-4). ConclusionsTypes of PC allow suggestions for size and arborization of PAs and successful surgical correction with an inverse relationship with the numbers of MAPCAs. There is no significant difference in amount of disease burden among the types of PC.

Minor Physical Anomalies, Neurological Soft Signs, and Neurocognitive Dysfunction in Patients with Schizophrenia, Bipolar Disorder and Their Respective Normal Siblings– a Cross-Sectional Case Control Study

Aim : To assess the presence of Minor physical anomalies, Neurological soft signs, and neurocognitive dysfunction in patients with schizophrenia and bipolar disorder and their respective siblings and to assess the difference if any and their clinical relevance. Study Design: cross-sectional case control study. Materials And Methods: Socio demographic details as per Performa collected from cases and controls. Complete physical examination including detailed Neurological evaluation done. Afterwards MPA scale, NES scale and neuropsychological tests were applied to both patients and their healthy siblings separately. Likewise 30 subjects were tested in 4 each groups. Statistical Design: Measures of central tendency and dispersion, tests of significance. Results: The presence of MPA in schizophrenia patients (63.3%) compared to bipolar illness (50%) was not significantly higher. There is significantly higher presence of NSS between schizophrenia, bipolar patients and their siblings. On Neuroconitive dysfunction, there is a significantly higher prevalence of visual memory impairment, executive dysfunction among schizophrenia patients, bipolar patients compared to their siblings. Verbal memory was impaired in significantly higher proportion in schizophrenia patients compared to other groups. Conclusion : NSS, MPAs and neurocognitive dysfunction, may help for understanding etiopathogenesis, symptom dimension and treatment response of both illness. This will help in identifying high risk individuals and possible intervention may be imitated early to prevent the occurrence of illness.

Titanium surface bio-functionalization using osteogenic peptides: Surface chemistry, biocompatibility, corrosion and tribocorrosion aspects.

Titanium (Ti) is widely used in biomedical devices due to its recognized biocompatibility. However, implant failures and subsequent clinical side effects are still recurrent. In this context, improvements can be achieved by designing biomaterials where the bulk and the surface of Ti are independently tailored. The conjugation of biomolecules onto the Ti surface can improve its bioactivity, thus accelerating the osteointegration process. Ti was modified with TiO2, two different spacers, 3-(4-aminophenyl) propionic acid (APPA) or 3-mercaptopropionic acid (MPA) and dentin matrix protein 1 (DMP1) peptides. X-ray photoelectron spectroscopy analysis revealed the presence of carbon and nitrogen for all samples, indicating a success in the functionalization process. Furthermore, DMP1 peptides showed an improved coverage area for the samples with APPA and MPA spacers. Biological tests indicated that the peptides could modulate cell affinity, proliferation, and differentiation. Enhanced results were observed in the presence of MPA. Moreover, the immobilization of DMP1 peptides through the spacers led to the formation of calcium phosphate minerals with a Ca/P ratio near to that of hydroxyapatite. Corrosion and tribocorrosion results indicated an increased resistance to corrosion and lower mass loss in the functionalized materials, showing that this new type of functional material has attractive properties for biomaterials application.

Functionalization of ZnO nanoparticles by 3-mercaptopropionic acid for aqueous curcumin delivery: Synthesis, characterization, and anticancer assessment

Inherent biocompatibility and stability of zinc oxide nanoparticles (ZnO-NPs) and their biomedical potentials make them an emerging candidate for drug delivery. The aim of this study was to develop and assess a simple procedure for surface functionalization of ZnO-NPs by 3-mercaptopropionic acid (MPA) for water-soluble curcumin delivery. Carboxyl-terminated ZnO nanoparticles were successfully made using ZnCl2 and NaOH in the presence of MPA. The functional groups were activated by 1,1′-carbonyldiimidazole (CDI) and the curcumin bonding was carried out at room temperature for 24h. The core-shell nanocomposite had a significant better solubility versus free curcumin, as characterized by XRD, FTIR, UV–Vis spectrophotometry, DLS, and TEM, p<0.005. In addition, MTT cytotoxicity assessment on MDA-MB-231 breast cancer cells revealed a drop of IC50 values from 5μg/mL to 3.3μg/mL for free curcumin and ZnO-MPA-curcumin complex, respectively. This result showed an augmented cancer-inhibitory effect of nanoconjugate complex. In conclusion, the presented improved solubility and elevated functionality of novel ZnO-MPA-curcumin nanoformula is promising, and could be considered for new therapeutic endeavors.

Mono- and binuclear copper(II) complexes of the bipyridine ligand: Structural, electrochemical and biological studies

The copper(II) complexes [Cu(bpy)2(ClO4)](ClO4) (1), [Cu(bpy)2(Cl)](ClO4) (2), [Cu(bpy)2(CH3COO)](ClO4) (3), [Cu2(bpy)2(μ-OH)2(μ-ClO4)2] (4) and [Cu2(bpy)2(μ-OH)(μ-H2O)(μ-CH3COO)](ClO4)2 (5) (where bpy=2,2′-bipyridine) have been synthesized and characterized by single crystal analysis, elemental analysis and spectroscopic methods. Complexes 2 and 4 crystallize in the monoclinic P21/n and C2/m space groups respectively, and the other complexes crystallize in the triclinic P1¯ space group. The molecular Hirshfeld surfaces and fingerprint plots of the complexes were investigated. Complexes 1–3 exhibit one quasi-reversible and complexes 4 and 5 exhibit two quasi-reversible redox cyclic voltammetric responses near the cathodic region in DMF. Binding studies of the complexes with BSA and ctDNA showed good binding affinity. Cleavage of pBR322 DNA by the complexes shows efficient oxidative cleavage in the presence of MPA through the formation of singlet oxygen. The complexes were also screened for their antimicrobial activities, which indicated that the complexes exhibit a zone of inhibition like that of standard drugs.

Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratio via AIB1 or SMRT recruitment to the CCND1 and MYC promoters.

There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)-resistant murine carcinomas antiprogestin responsiveness was restored by re-expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH-6 cells), and the other expressing only PRA (T47D-YA) or PRB (T47D-YB), MFP selectively inhibited the growth of PRA-overexpressing tumors and stimulated IBH-6-PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB-dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that antiprogestins are therapeutic tools that selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters.

Mycophenolic acid affects basic functions of human keratinocytes in the IMPDH-dependent manner

Clinical studies suggest that the immunosuppressant MPA is associated with impaired wound healing. It is believed that the main cause of impairment is the inhibition of inflammatory response. However, it is unknown whether MPA may directly affect epidermal cells. The aim of our study was to examine the direct influence of mycophenolic acid, the selective blocker of de novo purine synthesis, on human epidermal keratinocyte morphology, proliferation, motile activity, and differentiation in in vitro culture. The number of keratinocytes cultured in the presence of MPA was counted and cell motility was measured by a time-lapse computer-aided method. Cell morphology was determined by flow and image cytometry methods. Real-time RT-PCR analysis was employed to investigate the expression of markers of differentiation. We showed that MPA induces irreversible inhibition of cell proliferation, causes cell enlargement and impairs cell locomotion in a time-dependent manner. The level of expression of differentiation markers was significantly reduced by MPA treatment. All these effects were reversed by the addition of guanine. Our results indicated that MPA impairs basic functions of human skin keratinocytes via intracellular guanosine nucleotide depletion, which may be directly reflected in wound healing problems in patients treated with this immunosuppressant.

Abstract 449: Progesterone-induced immunosuppression thwarts immunosurveillance to tumors and promotes lung metastasis in a breast cancer model.

Abstract Exposure to sexual hormones is one of the strongest risk factors for breast cancer. Increased risk is entwined with a greater number of reproductive cycles and the use of progestin-containing hormone replacement therapy. In addition, the importance of progesterone in dampening immune response was illustrated in several models of infection and pregnancy. Based on the tolerogenic properties of progesterone (Pg) and its promoting role in breast cancer, in this work we investigated whether progesterone may thwart immunosurveillance and promote tumor metastasis by fostering an immunosuppressive microenvironment in breast cancer. Exogenously added Pg: (10−8M) or its synthetic analogue medroxiprogesterone acetate (MPA: 10−8M) induced the expression of the immunosuppressive protein galectin-1 (Gal1) in the hormone-dependent human breast cancer cell lines T47D and MCF-7 and in the mouse mammary adenocarcinoma C4HD. This effect was abrogated by pre-treatment with RU486 (10−7M) indicating that the progesterone receptor (PR) was involved. Interestingly, in vitro MPA treatment of human PBMC or mouse splenocytes controlled the expansion of regulatory T cells (Tregs) (CD4+CD25+Foxp3+) and skewed the balance toward a Th2-type cytokine profile. Furthermore, differentiation from naive T-cells to Tregs cells was enhanced in the presence of MPA, IL-2 and suboptimal concentrations of TGF-β. In addition, in vivo treatment with MPA (15mg 30-day release depot) of C4HD tumor-bearing mice increased both the expression of Gal1 and the frequency of Treg cells in tumor-draining lymph nodes and the tumor microenvironment. While the increase in Treg cell frequency was associated with an effect on Treg cell SMAD4 expression that potentiates TGF-β signalling, homing of Treg cells to tumor sites was supported through the induction of tumor-derived CCL22. Finally, we used a PR negative breast tumor model (4T1) to evaluate the effect of MPA on the tumor microenvironment and the consequences of this effect on tumor progression. In vivo treatment with MPA promoted lung metastasis by inducing an invasive phenotype in breast cancer cells. Co-culture of Treg cells differentiated in vivo in the presence of MPA with 4T1 cells promoted its invasive activity and modulate several genes associated with EMT, including SNAIL. In summary, these results demonstrate that progesterone hierarchically fosters an immunosuppressive tumor microenvironment that promotes metastasis by co-ordinately regulating Gal1 expression, stimulating the TGF-β pathway and augmenting the frequency of Treg cells. Our findings provide new insights into the role of progesterone in breast cancer as a crucial promoter of tumor-immune escape. Citation Format: Mariana Salatino, Tomás Dalotto, Diego O. Croci, Santiago P. Mendez Huergo, Sebastian L. Dergan Dylon, Juan P. Cerliani, Marta A. Toscano, Gabriel A. Rabinovich. Progesterone-induced immunosuppression thwarts immunosurveillance to tumors and promotes lung metastasis in a breast cancer model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 449. doi:10.1158/1538-7445.AM2013-449

S48 Mucoidy and the microbiome: community composition in relation to the presence of culturable, mucoid Pseudomonas aeruginosa

<h3>Introduction and Objectives</h3> Cystic fibrosis (CF) and non-cystic fibrosis bronchiectasis (BX) are chronic airway diseases with significant microbial involvement. The presence of mucoid <i>Pseudomonas aeruginosa</i> (mPA) is associated with worse outcomes in these patients. We hypothesised that the presence of this organism would also influence the microbial community structure. We used high throughput sequencing to identify microorganisms present in sputum from these patients, and to associate culture data of mPA with this analysis. <h3>Methods</h3> Expectorated sputum was collected from 16 patients (9 CF, 7 BX) and DNA extracted using standard protocols. PCR of the bacterial 16S rRNA gene and subsequent sequencing using a Roche 454 GS Junior sequencer was compared with standard clinical culture. Non-parametric t test was used to identify significant differential abundance of taxa in the molecular data (Bonferonni-corrected). <h3>Results</h3> In the pilot study, 35 000 high quality 16S rRNA sequences were generated and could be assigned to 240 different bacterial taxa. Both CF and BX samples were dominated by the γ-proteobacteria. The presence of culturable <i>P aeruginosa</i> in a sample had no significant effect on either community composition or structure. However, Principal Coordinate Analysis indicated that the presence of mPA in clinical culture was associated with a different community structure. Though there were no significant differences between the diversity of mPA positive samples (p&gt;0.15), there were significant differences in the abundance of particular species; <i>Achromobacter</i> spp. and <i>Pseudomonas</i> spp. increased in relative abundance (p&lt;0.001 in each case) and <i>Haemophilus</i> spp., <i>Stenotrophomonas</i> spp. and <i>Staphylococcus</i> spp. decreased in mPA positive vs mPA negative samples (p&lt;0.001 in each case). <h3>Conclusions</h3> Deep sequencing of sputum samples from CF and BX patients revealed a relationship between culture positivity for mPA and the presence of other known pathogens such as <i>Achromobacter</i> spp., suggesting an alternative mechanism for worse outcomes in these patients. This pilot has been extended to a larger cohort of 120 patients in order to confirm the result and data will be presented at the meeting.

Secondary metabolite profiles and mating populations of Fusariumspecies in section Liseola associated with bakanae disease of rice

A total of 25 strains of Fusarium species that belong to F. fujikuroi (a pathogen of bakanae disease), F. proliferatum, F.sacchari, F. subglutinans and F. verticillioides were isolated from rice plants showing typical bakanae symptoms in Malaysia and Indonesia and screened for their secondary metabolites. The objectives of the studies were to determine the physiological variability based on production of moniliformin (MON), fumonisin (FB1), gibberellic acid (GA3) and fusaric acid(FA) as well as to ascertain the mating populations (MPs) within the Gibberella fujikuroi species complex based on their ability to produce perithecia and viable ascospores. Production of GA3 could be used to separate F. fujikuroi that belongs to MP-C from other species. In crosses with seven standard testers of MPs, 76% of strains could be assigned to at least one of the G. fujikuroi species complex namely MP-A (G.moniliformis), MP-B (G. sacchari), MP-C (G. fujikuroi) and MP-D (G.intermedia). Single strain (M3237P) that was assigned as MP-C, and has also been identified morphologically as F. fujikuroi was also crossed-fertile with MP-D tester. The secondary metabolites profiles and the presence of MP-A, MP-B, MP-C and MP-D strains on samples of bakanae-infected rice plants are new records in Malaysia.

Foetal echocardiographic assessment of tetralogy of Fallot and post-natal outcome

Outcome of foetuses diagnosed with tetralogy of Fallot (TOF) or pulmonary atresia with ventricular septal defect (PA-VSD) and the reliability of foetal echocardiography to predict post-natal surgical outcome. Outcome of 218 foetuses having been diagnosed with TOF (n = 153) or PA-VSD (n = 65) was reviewed. Abnormal karyotyping, 22q11 deletion, and extracardiac anomalies were found, respectively, in 11, 18, and 46%. Pregnancy was terminated in 75 cases (34%), and in three cases foetuses died in utero. Presence or absence and confluence of PA branches were confirmed after birth or pregnancy termination in all but five (5%) cases. Main pulmonary trunk (MPA) was incorrectly described in 11 (10%) cases and major aorto-pulmonary collateral arteries in 16 (13%) cases. Among live born infants, 110 (88%) were operated and 92 (74%) underwent complete repair in the first year of life. Size of confluent PAs and presence of MPA were related to the probability of having a complete repair in the first year of life. Foetal diagnosis of TOF and PA-VSD has a major impact on pregnancy outcome, as associated anomalies are frequently found. Pre-natally determined size of PA branches and presence of MPA are good predictors of complete repair in the first year of life.

Synthetic analogue approach for the functional domains of copper(ii) bleomycins and its DNA cleavage activity

The dicopper(II) complex [Cu2(R'SSR)2(SO4)2] (1), where R'SSR is a Schiff base, has been prepared from the reaction of CuSO4.5H2O with the Schiff base N,N'-1,1'-dithiobis(ethylenesalicylaldimine)(H2RSSR) and structurally characterized by X-ray crystallography. The crystal structure of 1 shows two {Cu(R'SSR)}2+ units linked by two sulfate ligands each showing a eta3,mu2-binding mode. The Cu...Cu distance is 4.562(2)A with each copper having a square pyramidal (4 + 1) CuNO4 coordination geometry. The monoanionic Schiff base R'SSR has a pendant cationic amine -SCH2CH2NH3+ group which is presumably formed from the hydrolysis of one imine bond of H2RSSR. Complex 1 models the N- and C-terminus domains of bleomycins. The metal centers in 1 are essentially magnetically non-interacting giving a -2J value of 3 cm(-1) with the singlet as the ground state. Using complex 1 as a precursor, ternary copper(II) complexes [Cu(R'SSR)B(SO4)] (2-4)- are prepared, characterized and their DNA binding and cleavage properties studied (B: kanamycin A, 2; 2,2'-bipyridine, 3; 1,10-phenanthroline, 4). IR spectral data suggest a square pyramidal (4 + 1) geometry for the one-electron paramagnetic ternary complexes with the sulfate bound to copper. The complexes are non-conducting in DMF but show conductivity in aqueous medium due to dissociation of the sulfate ligand. They bind to calf thymus DNA in the minor groove giving the relative order: 4 > 2 > 1 approximately 3 (Kapp= 5.4 x 10(5) M(-1) for 4). The precursor complex 1 does not show any apparent chemical nuclease activity when treated with supercoiled (SC) DNA in the presence of 3-mercaptopropionic acid (MPA). The kanamycin A and phen adducts as such or generated under in situ reaction conditions using 1 nd the ligand display efficient chemical nuclease activity in the presence of MPA, while the bpy species shows poor cleavage activity. The ternary kanamycin A complex presents the first synthetic model for three functional domains of bleomycins.

New tetraazamacrocyclic ligand with neutral pendent groups 1,4,7,10-tetrakis(2-cyanoethyl)-1,4,7,10-tetraazacyclododecane (L) and its cobalt(II), nickel(II) and copper(II) complexes: synthesis, structural characterization and antitumor activity

A new tetraazamacrocyclic ligand (L) with four neutral 2-cyanoethyl pendent groups, and its divalent transition-metal complexes [Co(L)(NO 3)]NO 3·H 2O ( 1), [Ni(L)(NO 3)]NO 3·3H 2O ( 2) and [Cu(L)(H 2O)](NO 3) 2 ( 3) have been synthesized. The crystal structures of 1 and 3 have been determined by X-ray analysis. In complex 1 the cobalt atom is coordinated by four nitrogen atoms and two oxygen atoms of a nitrate anion, which define a distorted octahedron. The other nitrate ion lies in the lattice as a counter ion. Complex 3 is five-coordinated by four nitrogen atoms and an axial aqua ligand, which form a tetragonal pyramid. In complex 3 the two nitrate anions exist as counter ions. Pharmaceutical tests showed that all three metal complexes exhibit antitumor activity against HL-60 and BEL-7404 tumor cell lines in vitro, even at a concentration of 10 −8 mol l −1. Complex 1 can partially cleave supercoiled pBR 322 DNA to form nicked DNA in aerobic solution, and complex 3 can convert double strand DNA into nicked DNA completely in the presence of MPA. Complex 3 causes perturbation to K562 tumor cell lines in the G 1 phase.

A new trinuclear copper complex and its reactions with plasmid DNA

A novel trinuclear copper(II) complex with a new trinucleating ligand has been synthesized and structurally characterized, and its reactivity with the plasmid pBR322 has been investigated. The ligand, L, is based on tris(2-aminoethyl)amine, in which the primary amine groups are each substituted with two 2-pyridylmethyl groups. The trinuclear complex, [Cu3(L)(NO3)2(H2O)3](NO3)4·5H2O (C42H64N16O26Cu3) crystallizes in the monoclinic P21c space group with a = 19.357(5) Å, b = 12.548(4) Å, c = 23.765(5) Å, β = 102.46°, V = 5636(2) Å3, and Z = 4. While the three copper(II) ions in [Cu3(L)(NO3)2(H2O)3]4+ each bind to a tridentate N3 moiety of L, the structure is unsymmetrical owing to the coordination of the ‘central’ alkylamine nitrogen to a single copper(II) ion. Furthermore, the remaining two copper(II) ions coordinate different exogenous ligands; one copper(II) ion coordinates two water molecules, while the second binds two nitrate ions. Interestingly, one nitrate coordinates in a monodentate fashion while the other binds to the same copper(II) atom in an anisobidentate geometry. The trinuclear complex, which is formulated as [Cu3II(L)(H2O)n(OH)6−n]n+ in aqueous solution, is observed to cleave the plasmid pBR322 efficiently, in the presence of hydrogen peroxide or 3-mercaptopropionic acid (MPA). The reaction in the presence of MPA is shown to be O2-dependent, and is not inhibited by hydroxyl radical scavengers (dimethylsulfoxide or d-mannitol), or superoxide dismutase. However, catalase completely inhibits the reaction indicating a requirement for H2O2. Cleavage of pBR322 by [Cu3II(L)(H2O)n(OH)6−n]n+ is equally efficient in the presence of H2O2 or MPA, and is comparable to that observed by the well-known footprinting reagent [Cu(op)2]2+ (op = 1,10-phenanthroline). However, the reaction of [Cu(op)2]2+ with pBR322 in the presence of MPA is much more vigorous indicating that the reaction mechanisms for the two complexes may be different. [Cu3II(L)(H2O)n(OH)6−n]n+ is also observed to cleave pBR322 in a slower process, in the absence of H2O2 or MPA, and in a pH dependent manner.

Medroxyprogesterone acetate and tamoxifen do not decrease aggressive behavior in CF-1 male mice

Intact CF-1 male mice were given daily injections of either medroxyprogesterone acetate (MPA, an antiandrogen), tamoxifen (TAM, an antiestrogen), or the two drugs in combination and tested for aggressive behavior toward bulbectomized stimulus males. None of the treatments decreased fighting behavior over a 20-day test period and the presence of TAM led to increased aggression even in the presence of MPA. Testis weight was reduced by MPA while both compounds decreased seminal vesicle weight. The mechanisms involved in the observed effects are considered as well as the implications of the results for the clinical use of these compounds as modulators of testosterone-facilitated behaviors.