Echocardiographic Reference Ranges of Non-invasive Myocardial Work Indices in Children.

Global myocardial work (GMW) is an emerging method to characterize left ventricle (LV) function with potential advantages over both ejection fraction and global longitudinal strain (GLS). We aimed to determine the feasibility and reproducibility for echocardiographic-derived GMW in a healthy pediatric population; establish normal reference values; and investigate the influence of age, gender, and other clinical factor on normal reference ranges. We prospectively enrolled 212 individuals (median age of 9 years; interquartile range, 6 to 12 years, 112 female). Global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) were measured from LV pressure-strain loops. Quantification of GMW was performed using a GE Vivid E95 system and available software package (Echopac V.203, GE). The mean LV EF was 64 ± 3% with GLS of -21.3 ± 1.5%. GWI was 1688 ± 219 mmHg% with mean GWE of 96.5 ± 1.4%. The GCW was 1959 ± 207 mmHg%, and the mean GWW of 61.1 ± 30.9 mmHg%. No significant difference was found in MW indices across age group and gender (p > 0.05 for all). There were significant correlations between both GWI and GCW with GLS and systolic blood pressure (p < 0.001), but not with GWE and GWW. Linear regression model revealed that GWI and GCW were more closely correlated with systolic blood pressure than GLS. LV MW indices had good intra-observer and inter-observer reproducibility. This study establishes both the feasibility and reference ranges for non-invasive echocardiographic indices of GMW in healthy children. Myocardial work appears to be a complementary modality to assess LV performance in children.

Pre-operative Factors Predicting Mortality in Six Months and Functional Recovery in Elderly Patients with Hip Fractures.

Introduction: This study aimed to determine on-admission and perioperative factors predicting six-month mortality and functional recovery in Vietnamese patients with hip fracture. Materials and methods: Between April 2020 and July 2021, 118 patients participated in this prospective study. Patients' data were collected from medical records. Harris hip score (HHS) was used to evaluate the functional recovery six months after fractures. The obtained data were analysed using a univariate and multivariate model. Results: The mean age of the participants was 79.5±9.4 years and 68.6% of the patients were female. The six-month mortality rate was 5.9% and independently associated with age (odds ratio (OR): 3.512, 95% confidence interval (CI) 1.538 - 8.019; P<0.001, patients aged >80 years vs those aged ≤80 years) and hypoproteinemia (OR: 2.859, 95% CI: 1.001 - 8.166, P=0.049). Among 111 survivors there were 66 (59.5%) of patients with a good functional recovery. Patients aged >80 years had a higher risk of poor functional outcome (OR: 3.167, 95% CI: 1.386 - 7.235, P: 0.006) compared to those aged ≤ 80 years. No significant correlations between other clinical (gender, body mass index, comorbidities, type of fractures or surgery, time until surgery) or laboratory parameters (anaemia, hyperglycemia, marked elevation of C reactive protein level, electrolyte abnormalities, elevated urea) and mortality or functional outcome were found. Conclusion: Advanced age is the most important factor affecting both mortality and functional outcome while hypoproteinemia is associated with a higher risk of mortality in elderly patients with hip fractures.

Ligand-based discovery of new potential acetylcholinesterase inhibitors for Alzheimer's disease treatment.

The enzyme acetylcholinesterase (AChE) is currently a therapeutic target for the treatment of neurodegenerative diseases. These diseases have highly variable causes but irreversible evolutions. Although the treatments are palliative, they help relieve symptoms and allow a better quality of life, so the search for new therapeutic alternatives is the focus of many scientists worldwide. In this study, a QSAR-SVM classification model was developed by using the MATLAB numerical computation system and the molecular descriptors implemented in the Dragon software. The obtained parameters are adequate with accuracy of 88.63% for training set, 81.13% for cross-validation experiment and 81.15% for prediction set. In addition, its application domain was determined to guarantee the reliability of the predictions. Finally, the model was used to predict AChE inhibition by a group of quinazolinones and benzothiadiazine 1,1-dioxides obtained by chemical synthesis, resulting in 14 drug candidates with in silico activity comparable to acetylcholine.

Large renal arteriovenous fistula treated by embolization: a case report.

Renal arteriovenous fistula (RAVF) is an uncommon vascular malformation of the kidney, which can be congenital, acquired or idiopathic. Although most patients are asymptomatic, RAVF can lead to hypertension, heart failure, renal insufficiency, hematuria, and progressive increase in size of renal vessels. Diagnosis is aided by radiological studies, with digital subtraction angiography as a gold standard. Besides, ultrasound with color Doppler and computed tomography angiography are noninvasive imaging techniques and can be useful for planning the treatment. A large fistula are generally treated by nephrectomy. Intervention can ameliorate the hemodynamic effects of high flow and to preserve the renal parenchymal function. Although endovascular therapy may be challenging due to the large size and high flow of fistula, this report describes a case of huge RAVF was successfully treated by embolization instead of surgery.

Sensitive MnFe2O4-Ag hybrid nanoparticles with photothermal and magnetothermal properties for hyperthermia applications.

In this study, we present an experiment showing that designing multifunctional MnFe2O4-Ag nanoparticles to act as a dual hyperthermia agent is an efficient route for enhancing their heating ability. Interestingly, the specific absorption rate of the heteromeric MnFe2O4-Ag nanoparticles increased 2.7 times under simultaneous irradiation of a 100 Oe magnetic field and 0.14 W cm-2 laser compared to the action by the magnetic field alone, and more interestingly, is 30% higher than the sum of the two individual actions. The synergistic benefit of the magneto- and photo-thermal properties of the heteromeric structure can reduce the strengths of the magnetic field and laser intensities as well as their irradiation time to levels lower than those required in their hyperthermia applications individually. In vitro cytotoxicity analysis performed on HepG2 liver cancer and Hela cervical cancer cell lines showed that IC50 values were 83 ± 5.6 µg mL-1 (for HepG2) and 122.6 ± 19.8 µg mL-1 (for Hela cells) after 48 h of incubation, therefore, the nanoparticles are moderately cytotoxic and nontoxic to HepG2 and Hela cells, respectively; which offers the potential of safe therapy.

Correction: Sensitive MnFe2O4-Ag hybrid nanoparticles with photothermal and magnetothermal properties for hyperthermia applications.

[This corrects the article DOI: 10.1039/D1RA03216J.].

Pathological Characterization of an Outbreak of Porcine Reproductive and Respiratory Syndrome in Northern Vietnam.

In 2007, a highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) emerged in Vietnam and spread to nearly all regions of the country by 2010. Ten representative pigs of different age groups, infected naturally with HP-PRRSV in northern Vietnam in 2010, were used to characterize the pathological features of the infection. Infection was confirmed using reverse transcriptase polymerase chain reaction and viral isolation. The clinical signs and gross findings in these pigs included high fever (>40.2°C), red skin, blue ears, anorexia, respiratory distress, diarrhoea, haemorrhagic pleurisy and lymphadenopathy. Reproductive failure was the main clinical feature in sows. PRRSV infection-associated microscopical lung and lymph node lesions were observed frequently, regardless of age of the animals. Lung lesions were characterized by interstitial pneumonia and were occasionally associated with haemorrhage and fluid exudation following alveolar collapse. Lymph nodes exhibited characteristic haemorrhage and apoptosis, lymphocytic depletion and disorganization secondary to fibrosis and capillary formation. Haematoxylin and eosin staining or caspase-3 immunohistochemistry revealed apoptosis induction in various tissues and organs, particularly the lymph nodes and lungs. Primarily haemorrhagic microscopical lesions were observed commonly in other organs including the spleen, liver, heart and kidney. Immunohistochemical examination revealed HP-PRRS antigen in the lung, lymph node, liver and kidney macrophages, and lung and kidney epithelial cells. Pigs infected naturally with HP-PRRS in the field have multisystemic disease characterized by marked apoptotic cell death.

Esters of chlorambucil with 2-substituted 1,4-dihydroxy-9,10-anthraquinones as multifunctional anticancer agents.

Novel twelve esters of chlorambucil with 2-(1-hydroxyalkyl)-1,4-dihydroxy-9,10-anthraquinone were synthesized and tested for their antitumor activity in mice bearing S-180 ascitic cells as well as cytotoxic activity against L1210 cells. Eight of them were highly cytotoxic on L1210 cells (ED(50), <6 microg mL(-1)) and derivatives 1 and 12 (T/C, 200 and 205%) appeared more active in vivo than chlorambucil (T/C, 168%).

2-(1 -hydroxyiminoalkyl)-1 ,4-dimethoxy-9,10-anthraquinones: synthesis and evaluation of cytotoxicity.

A series of 2-(1-hydroxyiminoalkyl)-1,4-dimethoxy-9,10-anthraquinones (oximes) was synthesized and evaluated for cytotoxicity against L1210 cells and A549 cells. These oximes showed a greater cytotoxic activity compared to those of 2-(1-hydroxyalkyl)-1,4-dimethoxy-9,10-anthraquinones as the hydroxyalkyl bioisosteres. The enhanced cytotoxicity assumed to be due to the improved water solubility of the hydroxyimino group. Moreover, it was found that the cytotoxicity of the oximes decreased with elongation of alkyl groups at the side chain. All of the synthesized compounds showed higher cytotoxicity against L1210 cells than A549 cells.

Effect of the aryl substituent on antitumor activity of 2-substituted-1,4-dihydroxy-9,10-anthraquinones and 2-substituted-anthracene-1,4,9,10-tetraones.

2-(1-Aryl-1-hydroxymethyl)- and 2-aroyl-DHAQ derivatives (DHAQ, 1,4-dihydroxy-9,10-anthraquinone), and 2-(1-aryl-1-hydroxymethyl)-ATO derivatives (ATO, anthracene-1,4,9,10-tetraone) were synthesized and their antitumor activities were determined. 2-(1-Aryl-1-hydroxymethyl)-DHAQ derivatives showed a stronger cytotoxicity compared to the series of 2-(1-hydroxyalkyl)-1,4-dihydroxy-9,10-anthraquinone derivatives. It was suggested that the presence of aryl group at the side chain accelerated the bioreductive activation leading to cell death. 2-Aroyl-DHAQ derivatives, despite their higher electrophilicity, revealed smaller cytotoxicity and antitumor activity (expressed by T/C value) than 2-(1-aryl-1-hydroxymethyl)-DHAQ derivatives. Thus, no consistent relationship between the electronic effect on aromatic side chain and the cytotoxicity was observed. ATO series exhibited a higher antitumor activity (T/C, 125 to approximately 218%), though their cytotoxicity was not further improved compared to that of 2-(1-aryl-1-hydroxymethyl)-1,4-dihydroxy-9,10-anthraquinones. They manifested no correlation between the cytotoxicity and the antitumor activity. In case of 2-[1-hydroxy-1-(4-propylphenyl)-methyl]-ATO, the most bioactive one in vivo among the same series, it showed an ED50 value of 10.2 mg/mL and a T/C value of 218%. It is assumed that the anthracene-1,4,9,10-tetraones after uptake into cellular tissues might be transformed to a cytotoxic metabolite(s).

Mechanisms of inactivation of lipoxygenases by phenidone and BW755C.

Inhibition of soybean lipoxygenase (L-1) and potato 5-lipoxygenase (5-PLO) by the pyrazoline derivatives phenidone and BW755C only occurs after oxidation of these compounds by the peroxidase-like activity of the lipoxygenases. There is a clear relationship between this oxidation and the irreversible inactivation of L-1. The final product of phenidone oxidation by L-1, 4,5-didehydrophenidone, is not responsible of this inactivation, but the species derived from a one-electron oxidation of phenidone plays a key role in L-1 inactivation. In the absence of O2, inactivation of 1 mol of L-1 occurs after the oxidation of 34 mol of phenidone and the covalent binding of 0.8 mol of phenidone-derived metabolite(s) to L-1. In the presence of O2, inactivation of 1 mol of L-1 occurs already after oxidation of 11 mol of phenidone and only involves the covalent binding of 0.4 mol of phenidone-derived metabolite(s) to L-1. A mechanism is proposed for L-1 inactivation by phenidone, which involves the irreversible binding of a phenidone metabolite to the protein and the oxidation of an L-1 amino acid residue (in the presence of O2).

Combretoxazolones: synthesis, cytotoxicity and antitumor activity.

Two series of combretoxazolones including 3,4-diaryloxazolones (6) and 4,5-diaryloxazolones (7) were synthesized and evaluated for cytotoxicity and antitumor activity. Both series showed strong cytotoxicities against a variety of tumor cell lines. Compound 6g exhibited a significant antitumor activity in BDF1 mice bearing B16 murine melanoma cells with inhibition rates of 67 and 61% at 100 and 30 mg/kg/day, respectively.

Synthesis and evaluation of the antitumor activity of 2-substituted 1,4-dihydroxy-9,10-anthraquinones.

2-(1-Hydroxyiminoalkyl)-1,4-dimethoxy-9,10-anthraquinones were demethylated to produce 2-(1-hydroxyiminoalkyl)-1,4-dihydroxy-9,10-anthraquinones (1,4-dihydroxy-9,10-anthraquinone, DHAQ), oxime hydroxyl groups were in turn acylated to give the corresponding 2-(1-acyloxyiminoalkyl)-DHAQ derivatives. The anti-proliferative activity of 2-(1-hydroxyiminoalkyl)-DHAQ derivatives was found to be dependent on the size of an alkyl chain. Thus, DHAQ analogues with alkyl chains longer than heptyl had negligible anti-proliferative activity, whilst those compounds possessing shorter chains demonstrated moderate anti-proliferative activity (ED50, 2.73-19.21 microM). However, the antitumor activity as expressed by T/C values did not correlate with the anti-proliferative activity; 2-(1-hydroxyiminononyl)-DHAQ with an ED50 value of more than 20 microM exhibited potent antitumor activity (T/C, 166%). Only four of the 2-(1-hydroxyiminoalkyl)-DHAQ analogues showed good antitumor activity (T/C, > 150%); 2-(1-hydroxyiminobutyl)-DHAQ (T/C, 163%), 2-(1-hydroxyiminopentyl)-DHAQ (T/C, 180%) and 2-(1-hydroxyiminononyl)-DHAQ (T/C, 166%). Acylation of the hydroxyl group of these oximes enhanced the anti-proliferative activity and antitumor effects; 2-(1-propanoyloxyiminopropyl)-DHAQ (ED50, 4.41 microM; T/C, 221%) vs. 2-(1-hydroxyiminopropyl)-DHAQ (ED50, 14.64 microM; T/C, 100%) and 2-(1-propanoyloxyiminobutyl)-DHAQ (ED50, 2.65 microM; T/C, 202%) vs. 2-(1-hydroxyiminobutyl)-DHAQ (ED50, 16.43 microM; T/C, 163%).

Metabolic activation of acetylenes. Covalent binding of [1,2-14C]octyne to protein, DNA and haem in vitro and the protective effects of certain thiol compounds.

[1,2-14C]Oct-l-yne was used to investigate metabolic activation of the ethynyl substituent in vitro. Activation of octyne by liver microsomal cytochrome P-450-dependent enzymes gave intermediate(s) that bound covalently to protein, DNA and to haem. The time course and extent of covalent binding of octyne to haem and to protein were similar. However, two different activating mechanisms are probably involved. Whereas covalent binding to protein or to DNA was inhibited by nucleophiles such as N-acetylcysteine, that to haem was little affected. When N-acetylcysteine was included in the reaction mixtures, two major octyne-N-acetylcysteine adducts were isolated and purified by high-pressure liquid chromatography. G.l.c.-mass spectrometry and n.m.r. suggest that these are the cis-trans isomers of S-3-oxo-oct-1-enyl-N-acetylcysteine. Oct-1-yn-3-one reacted non-enzymically with N-acetylcysteine at pH 7.4 and 37 degrees C with a t1/2 of about 6 s also to yield S-3-oxo-oct-l-enyl-N-acetylcysteine. The same product was formed when microsomal fractions were incubated with oct-1-yn-3-ol, N-acetylcysteine and NAD(P)+. Octyn-3-one did not appear to react with haem or protoporphyrin IX. 5. A mechanism for the metabolic activation of oct-1-yne is proposed, consisting in (a) microsomal hydroxylation of the carbon atom alpha to the acetylenic bond and (b) oxidation to yield octyn-3-one as the reactive species.

Syntheses of certain 3-aryl-2-propenoates and evaluation of their cytotoxicity.

A series of 3-aryl-2-propenoates including cinnamates, (E)-methyl/ethyl 3-[2-(1,4-dimethoxy-5,8-dione)naphthalenyl]-2-propenoates (8ba, 8bb) and (E)-methyl/ethyl 3-[2-(1,4-dihydroxy-9,10-dione)anthracenyl]-2-propenoates (9aa,9ab) was synthesized and evaluated for antitumor cytotoxicity. It was found that the ortho- or para-dihydroxy funtionality on the aryl ring was essential for the cytotoxicity of cinnamates. Compounds 8ba, 8bb and 9aa, 9ab showed potent cytotoxicity against various tumor cell lines.

Hexanal phenylhydrazone is a mechanism-based inactivator of soybean lipoxygenase 1.

Hexanal phenylhydrazone (1; 70:30 E:Z mixture) at micromolar concentration irreversibly inactivates soybean lipoxygenase 1 (L-1) in the presence of dioxygen. L-1 catalyzes the oxidation of 1 into its alpha-azo hydroperoxide 2 [C5H11CH(OOH)N = NC6H5]. 2 is an efficient inactivator of L-1. The aerobic reaction between 1 and L-1 follows a branched pathway leading to the release of 2 into the medium or to L-1 inactivation. The respective parameters corresponding to this inactivation by the (E)-1 and (Z)-1 isomers are Ki = 0.25 and 0.40 microM and kinact = 0.8 and 2.1 min-1. Linoleic acid protection agrees with a mechanism-based inactivation process. The oxidation of a minimum of 13 +/- 3 molar equiv of 1 is required for complete L-1 inactivation, but up to 70 equiv is necessary in the presence of a very large excess of 1. The inactivation is actually the result of two pathways: one is due to a reaction of 2 as soon as it is formed at the active site (20%); the other is due to 2 released into the medium and coming back to the active site (80%). The inactivation is accompanied by the oxidation of 1.8 +/- 0.8 methionine residues of the protein into the corresponding sulfoxide. The inactivated L-1 is electron paramagnetic resonance (EPR) silent with an effective magnetic moment of mu = 5.0 +/- 0.1 Bohr magnetons corresponding to an S = 2 spin state. An inactivation mechanism is proposed on the basis of EPR and magnetic susceptibility data obtained from the anaerobic and aerobic reactions of L-1 with 1 and 2.