S100A4-neutralizing monoclonal antibody 6B12 counteracts the established experimental skin fibrosis induced by bleomycin.

OBJECTIVES: Our previous studies have demonstrated that the Damage Associated Molecular Pattern (DAMP) protein, S100A4, is overexpressed in the involved skin and peripheral blood of patients with SSc. It is associated with skin and lung involvement, and disease activity. By contrast, lack of S100A4 prevented the development of experimental dermal fibrosis. Herein we aimed to evaluate the effect of murine anti-S100A4 mAb 6B12 in the treatment of preestablished experimental dermal fibrosis. METHODS: The effects of 6B12 were assessed at therapeutic dosages in a modified bleomycin-induced dermal fibrosis mouse model by evaluating fibrotic (dermal thickness, proliferation of myofibroblasts, hydroxyproline content, phosphorylated Smad3-positive cell count) and inflammatory (leukocytes infiltrating the lesional skin, systemic levels of selected cytokines and chemokines) outcomes, and transcriptional profiling (RNA sequencing). RESULTS: Treatment with 7.5 mg/kg 6B12 attenuated and might even reduce pre-existing dermal fibrosis induced by bleomycin as evidenced by reduction in dermal thickness, myofibroblast count and collagen content. These antifibrotic effects were mediated by the downregulation of TGF-ß/Smad signalling and partially by reducing the number of leukocytes infiltrating the lesional skin and decrease in the systemic levels of IL-1α, eotaxin, CCL2 and CCL5. Moreover, transcriptional profiling demonstrated that 7.5 mg/kg 6B12 also modulated several profibrotic and proinflammatory processes relevant to the pathogenesis of SSc. CONCLUSION: Targeting S100A4 by the 6B12 mAb demonstrated potent antifibrotic and anti-inflammatory effects on bleomycin-induced dermal fibrosis and provided further evidence for the vital role of S100A4 in the pathophysiology of SSc.

Effect of Anti-S100A4 Monoclonal Antibody Treatment on Experimental Skin Fibrosis and Systemic Sclerosis-Specific Transcriptional Signatures in Human Skin.

OBJECTIVE: S100A4 is a DAMP protein. S100A4 is overexpressed in patients with systemic sclerosis (SSc), and levels correlate with organ involvement and disease activity. S100A4-/- mice are protected from fibrosis. The aim of this study was to assess the antifibrotic effects of anti-S100A4 monoclonal antibody (mAb) in murine models of SSc and in precision cut skin slices of patients with SSc. METHODS: The effects of anti-S100A4 mAbs were evaluated in a bleomycin-induced skin fibrosis model and in Tsk-1 mice with a therapeutic dosing regimen. In addition, the effects of anti-S100A4 mAbs on precision cut SSc skin slices were analyzed by RNA sequencing. RESULTS: Inhibition of S100A4 was effective in the treatment of pre-established bleomycin-induced skin fibrosis and in regression of pre-established fibrosis with reduced dermal thickening, myofibroblast counts, and collagen accumulation. Transcriptional profiling demonstrated targeting of multiple profibrotic and proinflammatory processes relevant to the pathogenesis of SSc on targeted S100A4 inhibition in a bleomycin-induced skin fibrosis model. Moreover, targeted S100A4 inhibition also modulated inflammation- and fibrosis-relevant gene sets in precision cut SSc skin slices in an ex vivo trial approach. Selected downstream targets of S100A4, such as AMP-activated protein kinase, calsequestrin-1, and phosphorylated STAT3, were validated on the protein level, and STAT3 inhibition was shown to prevent the profibrotic effects of S100A4 on fibroblasts in human skin. CONCLUSION: Inhibition of S100A4 confers dual targeting of inflammatory and fibrotic pathways in complementary mouse models of fibrosis and in SSc skin. These effects support the further development of anti-S100A4 mAbs as disease-modifying targeted therapies for SSc.

Clinical and pathogenic significance of S100A4 overexpression in systemic sclerosis.

OBJECTIVES: We have studied the damage-associated molecular pattern protein S100A4 as a driver of fibroblast activation in systemic sclerosis (SSc). METHODS: S100A4 protein concentration was measured by ELISA in serum of SSc (n=94) and healthy controls (n=15). Protein expression in skin fibroblast cultures from diffuse cutaneous SSc (SScF, n=6) and healthy controls (normal fibroblasts (NF), n=6) was assessed. Recombinant S100A4 and a high affinity anti-S100A4 neutralising monoclonal antibody (AX-202) were tested on SScF and NF. RESULTS: Median (range) S100A4 (ng/mL) was higher in serum of SSc (89.9 (15.0-240.0)) than healthy controls (71.4 (7.9-131.8); p=0.027). There was association with SSc-interstitial lung disease (p=0.025, n=55), scleroderma renal crisis (p=0.026, n=4). Median (range) S100A4 (ng/mL) was higher in culture supernatants of SScF (4.19 (0.52-8.42)) than NF controls (0.28 (0.02-3.29); p<0.0001). AX-202 reduced the constitutive profibrotic gene and protein expression phenotype of SScF. Genome-wide RNA sequencing analysis identified an S100A4 activated signature in NF overlapping the hallmark gene expression signature of SScF. Thus, 464 differentially expressed genes (false discovery rate (FDR) <0.001 and fold change (FC) >1.5) induced in NF by S100A4 were also constitutively overexpressed, and downregulated by AX-202, in SScF. Pathway mapping of these S100A4 dependent genes in SSc showed the most significant enriched Kegg pathways (FDR <0.001) were regulation of stem cell pluripotency (4.6-fold) and metabolic pathways (1.9-fold). CONCLUSION: Our findings provide compelling evidence for a profibrotic role for S100A4 in SSc and suggest that serum level may be a biomarker of major organ manifestations and disease severity. This study supports examining the therapeutic potential of targeting S100A4 in SSc.

Outcomes with sacubitril/valsartan in outpatients with heart failure and reduced ejection fraction: The ARIADNE registry.

AIMS: ARIADNE aimed to assess the association between effects of sacubitril/valsartan and no sacubitril/valsartan treatment and clinical characteristics, functional capacity, and clinical outcomes (cause-specific mortality and hospitalizations) in outpatients with heart failure (HF) with reduced ejection fraction (HFrEF). METHODS: ARIADNE was a prospective European registry of 9069 patients with HFrEF treated by office-based cardiologists or selected primary care physicians. Of the 8787 eligible for analysis, 4173 patients were on conventional HF treatment (non-S/V group), whereas 4614 patients were either on sacubitril/valsartan treatment at enrolment or started sacubitril/valsartan within 1 month of enrolment (S/V group). We also generated a restricted analysis set (rS/V) including only those 2108 patients who started sacubitril/valsartan treatment within the month prior to or after enrolment. RESULTS: At the baseline, average age of patients enrolled in the study was 68 years, and 23.9% (2099/8787) were female. At the baseline, the proportions of patients with New York Heart Association (NYHA) Class III symptoms were 30.9 (1288/4173), 42.8 (1974/4614), and 48.2% (1015/2108), in non-S/V, S/V, and rS/V groups, respectively. After 12 months of treatment, the proportion of patients with NYHA Class III at baseline who improved to Class II was 32.0% (290/907) in the non-S/V group vs. 46.3% (648/1399) in S/V group and 48.7% (349/717) in rS/V group. The overall mortality rate was 5.0 per 100 patient-years. Rates of HF hospitalizations were high (20.9, 20.3, and 21.2 per 100 patient-years in the non-S/V, S/V, and rS/V groups, respectively). Emergency room visits without hospitalization occurred in 3.9, 3.2, and 3.9% of patients in the non-S/V, S/V, and rS/V groups, respectively. CONCLUSIONS: This large HFrEF European registry provides a contemporary outcome profile of outpatients with HFrEF treated with or without sacubitril/valsartan. In a real-world setting, sacubitril/valsartan was associated with an improvement of symptoms in patients with HFrEF compared with the conventional HFrEF treatment.

Utilization of sacubitril/valsartan in patients with heart failure with reduced ejection fraction: real-world data from the ARIADNE registry.

AIMS: To compare baseline characteristics of patients with heart failure with reduced ejection fraction (HFrEF) initiated on sacubitril/valsartan compared with patients continued on conventional heart failure (HF)-treatment in a European out-patient setting. METHODS AND RESULTS: Between July 2016 and July 2019, ARIADNE enrolled 8787 outpatients aged ≥18 years with HFrEF from 17 European countries. Choice of therapy was solely at the investigators' discretion. In total, 4173 patients were on conventional HF-treatment (non-S/V group), while 4614 patients were on sacubitril/valsartan either at enrolment or started sacubitril/valsartan within 1 month of enrolment (S/V group). Of these, 2108 patients started sacubitril/valsartan treatment ±1 month around enrolment [restricted S/V (rS/V) group]. The average age of the patients was 68 years. Patients on S/V were more likely to have New York Heart Association (NYHA) class III or IV symptoms (50.3%, 44.6%, 32.1% in rS/V, S/V, and non-S/V, respectively) and had lower left ventricular ejection fraction (LVEF; 32.3%, 32.7%, and 35.4% in rS/V, S/V, and non-S/V, respectively; P < 0.0001). The most frequently received HF treatments were angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB; ∼84% in non-S/V), followed by ß-blockers (∼80%) and mineralocorticoid receptor antagonists (MRAs; 53%). The use of triple HF therapy (ACEI/ARB/angiotensin receptor neprilysin inhibitor with ß-blockers and MRA) was higher in the S/V groups than non-S/V group (48.2%, 48.2%, and 40.2% in rS/V, S/V, and non-S/V, respectively). CONCLUSION: In this large multinational HFrEF registry, patients receiving sacubitril/valsartan tended to be younger with lower LVEF and higher NYHA class. Fewer than half of the patients received triple HF therapy.

PRospective Evaluation of natriuretic peptide-based reFERral of patients with chronic heart failure in primary care (PREFER): a real-world study.

OBJECTIVE: To assess current management practice of heart failure with reduced ejection fraction (HFrEF) in multinational primary care (PC) and determine whether N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP)-guided referral of HFrEF patients from PC to a cardiologist could improve care, defined as adherence to European Society of Cardiology (ESC) guideline-recommended pharmacotherapy. METHODS: PRospective Evaluation of natriuretic peptide-based reFERral of patients with chronic HF in PC (PREFER) study enrolled HFrEF patients from PC considered clinically stable and those with NT-pro-BNP ≥600 pg/mL were referred to a cardiologist for optimisation of HF treatment. The primary outcome of adherence to ESC HF guidelines after referral to specialist was assessed at the second visit within 4 weeks of cardiologist's referral and no later than 6 months after the baseline visit. Based on futility interim analysis, the study was terminated early. RESULTS: In total, 1415 HFrEF patients from 223 PCs from 18 countries in Europe were enrolled. Of these, 1324 (96.9%) were considered clinically stable and 920 (65.0%) had NT-pro-BNP ≥600 pg/mL (mean: 2631 pg/mL). In total, 861 (60.8%) patients fulfilled both criteria and were referred to a cardiologist. Before cardiologist consultation, 10.1% of patients were on ESC guideline-recommended HFrEF medications and 2.7% were on recommended dosages of HFrEF medication (defined as ≥50% of ESC guideline-recommended dose). Postreferral, prescribed HFrEF drugs remained largely unchanged except for an increase in diuretics (+4.6%) and mineralocorticoid receptor antagonists (+7.9%). No significant increase in patients' adherence to guideline-defined drug combinations (11.2% post-referral vs 10.1% baseline) or drug combinations and dosages (3.3% postreferral vs 2.7% baseline) was observed after cardiologist consultation. CONCLUSIONS: PREFER demonstrates substantial suboptimal treatment of HFrEF patients in the real world. Referral of patients with elevated NT-pro-BNP levels from PC to cardiologist did not result in meaningful treatment optimisation for treatments with known mortality and morbidity benefit.

Sacubitril/valsartan ameliorates cardiac hypertrophy and preserves diastolic function in cardiac pressure overload.

AIMS: Sacubitril/valsartan (sac/val) has shown superior effect compared with blockade of the renin-angiotensin-aldosterone system in heart failure with reduced ejection fraction. We aimed to investigate effects of sac/val compared with valsartan in a pressure overload model of heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Sprague-Dawley rats underwent aortic banding or sham (n = 16) surgery and were randomized to sac/val (n = 28), valsartan (n = 29), or vehicle (n = 26) treatment for 8 weeks. Sac/val reduced left ventricular weight by 11% compared with vehicle (P = 0.01) and 9% compared with valsartan alone (P = 0.04). Only valsartan reduced blood pressure compared with sham (P = 0.02). Longitudinal early diastolic strain rate was preserved in sac/val compared with sham, while it was reduced by 23% in vehicle (P = 0.03) and 24% in valsartan (P = 0.02). Diastolic dysfunction, measured by E/e'SR, increased by 68% in vehicle (P < 0.01) and 80% in valsartan alone (P < 0.001), while sac/val showed no increase. Neither sac/val nor valsartan prevented interstitial fibrosis. Although ejection fraction was preserved, we observed mild systolic dysfunction, with vehicle showing a 28% decrease in longitudinal strain (P < 0.01). Neither sac/val nor valsartan treatment improved this dysfunction. CONCLUSIONS: In a model of HFpEF induced by cardiac pressure overload, sac/val reduced hypertrophy compared with valsartan alone and ameliorated diastolic dysfunction. These effects were independent of blood pressure. Early systolic dysfunction was not affected, supporting the notion that sac/val has the largest potential in conditions characterized by reduced ejection fraction. Observed anti-hypertrophic effects in preserved ejection fraction implicate potential benefit of sac/val in the clinical setting of hypertrophic remodelling and impaired diastolic function.

OUTSTEP-HF: randomised controlled trial comparing short-term effects of sacubitril/valsartan versus enalapril on daily physical activity in patients with chronic heart failure with reduced ejection fraction.

AIMS: OUTSTEP-HF compared the effect of sacubitril/valsartan vs. enalapril on 6-min walk test (6MWT) distance, non-sedentary daytime physical activity and heart failure (HF) symptoms in patients with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Ambulatory patients (n = 621) with stable symptomatic HFrEF were randomised 1:1 to sacubitril/valsartan (n = 310) or enalapril (n = 311). Changes in physical activity and mean daily non-sedentary daytime activity from baseline to Week 12 were measured using 6MWT and a wrist-worn accelerometer device, respectively. After 12 weeks, 6MWT improved by 35.09 m with sacubitril/valsartan [97.5% confidence interval (CI) 27.85, 42.32] and by 26.11 m with enalapril (97.5% CI 18.78, 33.43); however, there was no significant difference between groups [least squares means treatment difference: 8.98 m (97.5% CI -1.31, 19.27); P = 0.0503]. Mean daily non-sedentary daytime activity decreased by 27 min with sacubitril/valsartan and by 21 min with enalapril [least squares means treatment difference: -6 min (97.5% CI -25.7, 13.4), P = 0.4769] after 12 weeks. 6MWT improved by ≥30 m in 51% of patients in the sacubitril/valsartan group vs. 44% of patients treated with enalapril (odds ratio 1.251, 95% CI 0.895, 1.748). At Week 4, non-sedentary daytime activity increased by ≥10% in 58% of patients treated with sacubitril/valsartan vs. 64% with enalapril; 58% of patients treated with sacubitril/valsartan reported improved HF symptoms as assessed by patient global assessment vs. 43% with enalapril. However, these differences did not persist at Week 12. CONCLUSION: After 12 weeks of treatment, there was no significant benefit of sacubitril/valsartan on either 6MWT or daytime physical activity measured by actigraphy compared with enalapril.

Rationale and study design of OUTSTEP-HF: a randomised controlled study to assess the effect of sacubitril/valsartan and enalapril on physical activity measured by accelerometry in patients with heart failure with reduced ejection fraction.

AIM: In PARADIGM-HF, sacubitril/valsartan demonstrated superiority to enalapril in reducing mortality and morbidity in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Several patient-centred outcomes like improved physical activity and quality of life have been emphasised as important treatment goals in HF management. OUTSTEP-HF has been designed to evaluate the effect of sacubitril/valsartan compared with enalapril on non-sedentary daytime physical activity in patients with HFrEF. METHODS: OUTSTEP-HF is a randomised, actively controlled, double-blind, double-dummy study that plans to enrol 600 ambulatory patients with symptomatic HFrEF in 19 European countries. Patients will be randomised 1:1 to receive sacubitril/valsartan 97/103 mg bid or enalapril 10 mg bid. The primary objective of the study is to assess changes from baseline (Week 0) to Week 12 in exercise capacity measured by the 6-min walk test and in daily non-sedentary daytime activity. Physical activity and objective sleep parameters will be measured by accelerometry using a wrist-worn device, worn continuously from screening (Week -2) until the end of study (Week 12). As a co-primary outcome, changes from baseline in sub-maximal exercise capacity will be assessed by the 6-min walk test. Patient- and physician-reported questionnaires will be used to assess quality of life, changes in signs and symptoms of HF and sleep parameters. CONCLUSION: OUTSTEP-HF will be the largest randomised trial in HF to date to use non-invasive accelerometry to assess whether treatment with sacubitril/valsartan improves patients' daily physical activity and exercise capacity compared with enalapril.

Biferrocenyl Schiff bases as efficient corrosion inhibitors for an aluminium alloy in HCl solution: a combined experimental and theoretical study.

The corrosion inhibitive capabilities of some ferrocene-based Schiff bases on aluminium alloy AA2219-T6 in acidic medium were investigated using Tafel polarization, electrochemical impedance spectroscopy (EIS), weight loss measurement, FT-IR spectroscopy and scanning electron microscopic (SEM) techniques. The influence of molecular configuration on the corrosion inhibition behavior has been explored by quantum chemical calculation. Ferrocenyl Schiff bases 4,4'-((((ethane-1,2-diylbis(oxy))bis(4,1-phenylene))bis(methaneylylidene))bis(azaneylylidene))bisferrocene (Fcua), 4,4'-((((ethane-1,2-diylbis(oxy))bis(2-methoxy-1,4-phenylene))bis(methaneylylidene))bis(azaneylylidene))bisferrocene (Fcub) and 4,4'-((((ethane-1,2-diylbis(oxy))bis(2-ethoxy-1,4-phenylene))bis(methaneylylidene))bis(azaneylylidene))bisferrocene (Fcuc) have been synthesized and characterized by FT-IR, 1H and 13C NMR spectroscopic studies. These compounds showed a substantial corrosion inhibition against aluminium alloy in 0.1 M of HCl at 298 K. Fcub and Fcuc showed better anticorrosion efficiency as compared with Fcua due to the electron donating methoxy and ethoxy group substitutions, respectively. Polarization curves also indicated that the studied biferrocenyl Schiff bases were mixed type anticorrosive materials. The inhibition of the aluminium alloy surface by biferrocenyl Schiff bases was evidenced through scanning electron microscopy (SEM) studies. Semi-empirical quantum mechanical studies revealed a correlation between corrosion inhibition efficiency and structural functionalities.

Therapeutic inertia amongst general practitioners with interest in diabetes.

INTRODUCTION: As the therapeutic options in the management of type 2 diabetes increase, there is an increase confusion among health care professionals, thus leading to the phenomenon of therapeutic inertia. This is the failure to escalate or de-escalate treatment when the clinical need for this is required. It has been studied extensively in various settings, however, it has never been reported in any studies focusing solely on primary care physicians with an interest in diabetes. This group is increasingly becoming the focus of managing complex diabetes care in the community, albeit with the support from specialists. METHODS: In this retrospective audit, we assessed the prevalence of the phenomenon of therapeutic inertia amongst primary care physicians with an interest in diabetes in UK. We also assessed the predictive abilities of various patient level characteristics on therapeutic inertia amongst this group of clinicians. RESULTS: Out of the 240 patients reported on, therapeutic inertia was judged to have occurred in 53 (22.1%) of patients. The full model containing all the selected variables was not statistically significant, p=0.59. So the model was not able to distinguish between situations in which therapeutic inertia occurred and when it did not occur. None of the patient level characteristics on its own was predictive of therapeutic inertia. CONCLUSION: Therapeutic inertia was present only in about a fifth of patient patients with diabetes being managed by primary care physicians with an interest in diabetes.

CaMKII in addition to MLCK contributes to phosphorylation of regulatory light chain in cardiomyocytes.

The aim was to identify kinase activities involved in the phosphorylation of regulatory light chain (RLC) in situ in cardiomyocytes. In electrically stimulated rat cardiomyocytes, phosphatase inhibition by calyculin A unmasked kinase activities evoking an increase of phosphorylated RLC (P-RLC) from about 16% to about 80% after 80 min. The phosphorylation rate in cardiomyocytes was reduced by about 40% by the myosin light chain kinase (MLCK) inhibitor, ML-7. In rat ventricular muscle strips, calyculin A induced a positive inotropic effect that correlated with P-RLC levels. The inotropic effect and P-RLC elevation were abolished by ML-7 treatment. The kinase activities phosphorylating RLC in cardiomyocytes were reduced by about 60% by the non-selective kinase inhibitor staurosporine and by about 50% by the calmodulin antagonist W7. W7 eliminated the inhibitory effect of ML-7, suggesting that the cardiac MLCK is Ca(2+)/calmodulin (CaM)-dependent. The CaM-dependent kinase II (CaMKII) inhibitor KN-93 attenuated the calyculin A-induced RLC phosphorylation by about 40%, indicating a contribution from CaMKII. The residual phosphorylation in the presence of W7 indicated that also CaM-independent kinase activities might contribute. RLC phosphorylation was insensitive to protein kinase C inhibition. In conclusion, in addition to MLCK, CaMKII phosphorylates RLC in cardiomyocytes. Involvement of other kinases cannot be excluded.

Non-classical regulation of ß1- and ß 2-adrenoceptor-mediated inotropic responses in rat heart ventricle by the G protein Gi.

Studies suggest that increased activity of Gi contributes to the reduced ß-adrenoceptor-mediated inotropic response (ßAR-IR) in failing cardiomyocytes and that ß2AR-IR but not ß1AR-IR is blunted by dual coupling to Gs and Gi. We aimed to clarify the role of Gi upon the ß1AR-IR and ß2AR-IR in Sham and failing myocardium by directly measuring contractile force and cAMP accumulation. Contractility was measured ex vivo in left ventricular strips and cAMP accumulation in cardiomyocytes from rats with post-infarction heart failure (HF) or sham operates (Sham). The ß2AR-IR in Sham and HF was small and was amplified by simultaneously inhibiting phosphodiesterases 3 and 4 (PDE3&4). In HF, the inotropic response and cAMP accumulation evoked by ß1AR- or ß2AR-stimulation were reduced. Inactivation of Gi with pertussis toxin (PTX) did not restore the ß1AR-IR or ß2AR-IR in HF to Sham levels but did enhance the maximal ß2AR-IR. PTX increased both ß1AR- and ß2AR-evoked cAMP accumulation more in Sham than that in HF, and HF levels approached those in untreated Sham. The potency of agonists at ß1 and at ß2ARs (only under PDE3&4 inhibition) was increased in HF and by PTX in both HF and Sham. Without PDE3&4 inhibition, PTX increased only the maximal ß2AR-IR, not potency. We conclude that Gi regulates both ß1AR- and ß2AR-IR independent of receptor coupling with Gi. Gi together with PDE3&4 tonically restrict the ß2AR-IR. Gi inhibition did not restore the ßAR-IR in HF despite increasing cAMP levels, suggesting that the mechanism of impairment resides downstream to cAMP signalling.

Solvothermal preparation of ZnO nanorods as anode material for improved cycle life Zn/AgO batteries.

Nano materials with high surface area increase the kinetics and extent of the redox reactions, thus resulting in high power and energy densities. In this study high surface area zinc oxide nanorods have been synthesized by surfactant free ethylene glycol assisted solvothermal method. The nanorods thus prepared have diameters in the submicron range (300 ~ 500 nm) with high aspect ratio. They have uniform geometry and well aligned direction. These nanorods are characterized by XRD, SEM, Specific Surface Area Analysis, solubility in alkaline medium, EDX analysis and galvanostatic charge/discharge studies in Zn/AgO batteries. The prepared zinc oxide nanorods have low solubility in alkaline medium with higher structural stability, which imparts the improved cycle life stability to Zn/AgO cells.

N,N'-Bis(4-hy-droxy-phen-yl)pyridine-2,6-dicarboxamide di-methyl-formamide monosolvate.

The mol-ecular structure of the pyridine derivative, C19H15N3O4·C3H7NO, shows almost planar geometry with dihedral angles of 6.9 (1) and 13.4 (1)° between the pyridine ring and the two benzene rings. This conformation is stabilized by two intra-molecular N-H⋯N(pyridine) bonds. In the crystal, strong O-H⋯O(carboxamide) and N-H⋯O(hy-droxy-phen-yl) hydrogen bonds link the mol-ecules, forming a three-dimensional structure. The di-methyl-formamide solvent mol-ecules are not involved in the hydrogen bonding. The structure shows pseudosymmetry, but refinement in the space group Pbcn leads to significantly worse results and a disordered di-methyl-formamide mol-ecule.

Triethyl-ammonium 4-(3,5-dinitro-benzamido)-N-(3,5-dinitro-benzo-yl)benzene-sulfonamidate.

The mol-ecular structure of the title salt, C6H16N(+)·C20H11N6O12S(-), shows a planar geometry of the benzamido-phen-yl-sulfonyl moiety, with a dihedral angle of 1.59 (9)° between the aromatic ring planes. The central ring and the aromatic ring of the other dinitro-benzamide group are nearly perpendicular, making a dihedral angle of 89.55 (9)°. All nitro groups lie almost in plane with the associated aromatic rings, the O-N-C-C torsion angles ranging from 9.2 (2) to 24.3 (2)°. In the crystal, strong anion-anion N-H⋯O and anion-cation hydrogen bonds form inversion dimers stacked along the a axis. Less prominent anion-anion C-H⋯O inter-actions lead to the formation of a three-dimensional network including anion-anion dimers as well as anion-anion chains along [100?].

N,N'-Bis(4-bromo-phen-yl)pyridine-2,6-dicarboxamide.

The mol-ecule of the title compound, C19H13Br2N3O2, lies about a twofold rotation axis. The benzene ring makes dihedral angles of 8.9 (2) and 16.4 (2)° with the central pyridine ring and the second benzene ring, respectively. An intra-molecular N-H⋯N contact occurs. In the crystal, mol-ecules are connected by pairs of N-H⋯O hydrogen bonds into chains along the c axis.

PDE3, but not PDE4, reduces ß1 - and ß2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients.

BACKGROUND AND PURPOSE: PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1 µM) or PDE4 inhibitor rolipram (1-10 µM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium. EXPERIMENTAL APPROACH: Right and left ventricular trabeculae from freshly explanted hearts of 5 non-ß-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through ß1 adrenoceptors (ß2 adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through ß2 adrenoceptors (ß1 adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from -logEC50s. KEY RESULTS: Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-ß-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients. CONCLUSIONS AND IMPLICATIONS: Metoprolol induces a control by PDE3 of ventricular effects mediated through both ß1 and ß2 adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through ß2 adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle.

Antimicrobial and pilling evaluation of the modified cellulosic fabrics using polyurethane acrylate copolymers.

Polyurethane acrylate copolymers (PACs) were synthesized by three step synthesis process via emulsion polymerization using toluene-2,4-diisocyanate, hydroxy terminated poly (caprolactone) diol (PCL), 2-hydroxyethylacrylate (HEA) and butyl acrylate (BuA). The proposed structure of the synthesized polyurethane acrylate copolymer (PAC) was confirmed using Fourier transform infrared (FTIR) spectrophotometer. The pilling characteristic and antimicrobial activities of the plain weave poly-cotton grey, white, printed and dyed fabric swatches after application of PAC were evaluated. The results revealed that by increasing the molecular weight of PCL in the synthesized PAC samples, the antimicrobial activities increased and this behavior was interpreted in term of increasing hydrophilic character. An increase in pilling ratings of the treated samples has been observed by increasing the molecular weight of the polycaprolactone diols in the synthesized PAC samples.

N,N-Dicyclo-hexyl-3,5-dinitro-benzamide.

In the title compound, C(19)H(25)N(3)O(5), the benzene ring is not coplanar with the amide group [dihedral angle = 61.90 (5)°]. The cyclo-hexyl rings are in chair conformations. There is a strong inter-molecular inter-action between the C=O group of the amide group and the nitro group of an adjoining mol-ecule, with a short O⋯N distance of 2.7862 (17) Å. In the crystal, C-H⋯O inter-actions occur along the [100] direction.