Cadiolide analogues and their precursors as new inhibitors of bacterial quorum sensing and biofilm formation.

Bacterial quorum sensing (QS) and biofilm formation are promising targets for developing new therapies to treat chronic infections. Herein, we report the stereoselective synthesis of 18 new analogs of natural cadiolides. Among the new compounds, substances 8b, 8f, 8i, 9a, 9b and 9e completely inhibited the biofilm formation of Escherichia coli RP347 in vitro. In addition, compound 8b interfered acyl-homoserine lactone (AHL) mediated QS, while 9e interrupted the QS via autoinducer-2 (AI-2). Biological assays also revealed that synthetic intermediates alkynones are potent inhibitors of AI-2 and AHL-mediated QS. These results indicate that cadiolides and alkynones are good candidates for further structural modification for a new generation of more potent antimicrobial agents.

Definition of Reference Range for the Immature Granulocytes Parameter Provided by a Hematology Analyzer.

BACKGROUND: Some pathologies or physiological changes may show forms of granulocytes in peripheral blood. Hematology analyzers have brought new parameters such as the detection of immature granulocytes (IG), which may be useful biomarkers. The objective of this study was determined the IG count in a control group to establish the reference range. METHODS: A group of healthy donors was used to obtain the reference value of IG in the laboratory of the Hospital de Clínicas de Porto Alegre. RESULTS: The reference range of IG (n = 115) was 0 - 0.06 x 109/L and 0 - 0.63%. This reference interval was similar to that of previous studies. CONCLUSIONS: The determination of the specific reference interval for each region is an important tool in the direct application of biomarkers in clinical laboratory routines. The use of reference values is essential so that the true positive cases for microscopic review are detected without a large number of false positives, which would impair laboratory efficiency.

Natural product-inspired profluorophores for imaging NQO1 activity in tumour tissues.

Herein we designed a collection of trimethyl-lock quinone profluorophores as activity-based probes for imaging NAD(P)H:quinone oxidoreductase (NQO1) in cancer cells and tumour tissues. Profluorophores were prepared via synthetic routes from naturally-occurring quinones and characterised in vitro using recombinant enzymes, to be further validated in cells and fresh frozen canine tumour tissues as potential new tools for cancer detection and imaging.

Factors associated with the emotional health of children: high family income as a protective factor.

Anxiety and depressive symptoms have adverse effects on children's development. The present study investigates the associations of socioeconomic factors as well as maternal emotional health with children's emotional health status. The data were collected between 2011 and 2015 in the LIFE Child study, a population-based cohort study in Leipzig, Germany. The emotional health status of 1093 children (2.5-11.9 years old) was investigated using the subscale 'emotional problems' of the Strengths and Difficulties Questionnaire. Associations of maternal emotional health, family status, and socioeconomic status (SES) with the emotional health status of children were estimated via regression analyses. 21.13% of the participating children were assigned to the 'risk' group for emotional problems. The results furthermore revealed that children of mothers reporting more depressive symptoms, children living in single-parent families, and children of families with lower SES scored higher in the emotional problems scale. When considering the different indicators of SES (parental education, occupational status, and monthly net income) separately, only income showed significant associations with children's emotional health status. The prevalence of emotional problems in children in Leipzig, a city in East Germany, appears to be higher than the previously reported German average. Maternal depressive symptoms, single-parent families, lower SES, and especially lower income can be seen as risk factors for children's emotional health.

Synthesis of Selenium-Quinone Hybrid Compounds with Potential Antitumor Activity via Rh-Catalyzed C-H Bond Activation and Click Reactions.

In continuation of our quest for new redox-modulating catalytic antitumor molecules, selenium-containing quinone-based 1,2,3-triazoles were synthesized using rhodium-catalyzed C-H bond activation and click reactions. All compounds were evaluated against five types of cancer cell lines: HL-60 (human promyelocytic leukemia cells), HCT-116 (human colon carcinoma cells), SF295 (human glioblastoma cells), NCIH-460 (human lung cells) and PC3 (human prostate cancer cells). Some compounds showed good activity with IC50 values below 1 µM. The cytotoxic potential of the naphthoquinoidal derivatives was also evaluated in non-tumor cells, exemplified by L929 cells. Overall, these compounds represent promising new lead derivatives and stand for a new class of chalcogenium-containing derivatives with potential antitumor activity.

Imidazoles from nitroallylic acetates and α-bromonitroalkenes with amidines: synthesis and trypanocidal activity studies.

Cascade reactions of amidines with nitroallylic acetates and α-bromonitroalkenes provide potentially bioactive imidazoles in good to excellent yields in most cases. While 2,4-disubstituted imidazol-5-yl acetates are formed in the first case, 2,4-disubstituted imidazoles, bearing no substituent at position 5, are the products in the second case. These two series of imidazoles, viz. 2,4,5-trisubstituted and 2,4-disubstituted, were screened for their activity against the protozoan parasite Trypanosoma cruzi which is responsible for Chagas disease. As many as three compounds were as active as the standard benznidazole and two others were 2-3-fold more active highlighting the potential of substituted imidazoles, easily accessible from nitroalkenes, as possible anti-parasitic agents.

Synthesis of imidazoles via cascade reaction of nitroallylic acetates with amidines and studies on their trypanocidal activity.

A one-pot, two step synthesis of highly substituted imidazoles has been carried out in good to excellent yields for the first time via a cascade intermolecular aza-SN2'-intramolecular aza-Michael addition involving a variety of Morita-Baylis-Hillman acetates of nitroalkenes and amidines in the presence of DABCO at room temperature. The synthetic and biological utility of the products has been demonstrated. In particular, some of the imidazoles exhibited potent activity against T. cruzi, the etiological agent of Chagas disease.

1,2,3-triazole-, arylamino- and thio-substituted 1,4-naphthoquinones: potent antitumor activity, electrochemical aspects, and bioisosteric replacement of C-ring-modified lapachones.

1,2,3-Triazole-, arylamino- and thio-substituted naphthoquinones (24, 8, and 2 representatives, respectively) were synthesized in moderate yields and evaluated against several human cancer cell lines (blood, ovarian, breast, central nervous system, colon, and prostate cancers and melanoma), showing, for some of them, IC50 values below 2 µM. The cytotoxic potential of the tested naphthoquinones was also assayed on non-tumor cells such as human peripheral blood mononucluear cells (PBMC) and two murine fibroblast lines (L929 and V79 cells). α-Lapachone- and nor-α-lapachone-based 1,2,3-triazoles and arylamino-substituted naphthoquinones showed potent cytotoxicity against different cancer cell lines. The compounds may represent promising new lead derivatives for anticancer drug development. The electrochemical properties of selected compounds were evaluated in an attempt to correlate them with antitumor activity.

Short-term morbidities in moderate and late preterm infants.

OBJECTIVE: To determine (1) the association between neonatal morbidity and gestational age and (2) the impact of pre-existing maternal medical conditions, pregnancy and birth complications on neonatal outcome in moderate and late preterm infants (32-36 completed weeks). METHODS: Retrospective single-centre cohort study including all moderate and late preterm infants without congenital anomalies born at the Children's and Maternity Hospital Linz, Austria, between January 2007 and June 2010. Stepwise regression analysis was used to determine significant associations between morbidities, maternal and perinatal complications and the gestational age. RESULTS: Of 870 infants included the incidence of neonatal morbidities increased from 24% at 36 weeks to 43% at 35 weeks', 55% at 34 weeks', 75% at 33 weeks' and 93% at 32 weeks' gestation. Infants at 32 weeks had a 4-fold (RR: 3.88; 95% CI: 1.87-8.06) increased risk compared with those at 36 weeks, and infants of 32 weeks were 16 times (RR: 16.01; 95% CI: 9.82-26.09) more likely to be admitted to the NICU than infants of 36 weeks'. Hyperbilirubinemia (29%) and respiratory morbidity (14.3%) were the most common neonatal diagnoses. Intrauterine growth restriction, preeclampsia, preterm premature rupture of the membranes, lack of antenatal steroid administration, antepartum hemorrhage, multiple pregnancy and male gender were all associated with any kind of neonatal morbidity, admission rate to the NICU and length of hospital stay (p<0.05). CONCLUSION: Nearly half of all infants suffered from any morbidity, and several risk factors were identified being significantly associated with NICU admission rate and length of hospitalization.

Active in-database processing to support ambient assisted living systems.

As an alternative to the existing software architectures that underpin the development of smart homes and ambient assisted living (AAL) systems, this work presents a database-centric architecture that takes advantage of active databases and in-database processing. Current platforms supporting AAL systems use database management systems (DBMSs) exclusively for data storage. Active databases employ database triggers to detect and react to events taking place inside or outside of the database. DBMSs can be extended with stored procedures and functions that enable in-database processing. This means that the data processing is integrated and performed within the DBMS. The feasibility and flexibility of the proposed approach were demonstrated with the implementation of three distinct AAL services. The active database was used to detect bed-exits and to discover common room transitions and deviations during the night. In-database machine learning methods were used to model early night behaviors. Consequently, active in-database processing avoids transferring sensitive data outside the database, and this improves performance, security and privacy. Furthermore, centralizing the computation into the DBMS facilitates code reuse, adaptation and maintenance. These are important system properties that take into account the evolving heterogeneity of users, their needs and the devices that are characteristic of smart homes and AAL systems. Therefore, DBMSs can provide capabilities to address requirements for scalability, security, privacy, dependability and personalization in applications of smart environments in healthcare.

[Electrical myostimulation: improvement of quality of life, oxygen uptake and left ventricular function in chronic heart failure]. / Elektromyostimulation: Verbesserung von Lebensqualität, Sauerstoffaufnahme und linksventrikulärer Funktion bei chronischer Herzinsuffizienz.

AIM OF THE STUDY: Regular physical activity has found to be a strategy to increase exercise capacity in patients with chronic heart failure (CHF). Next to endurance training also electromyostimulation (EMS) of thigh and gluteal muscles results in an increased capacity in CHF patients. EMS therapy was either done by stimulating 8 major muscle groups involving also trunk and arm muscles (extended electromyostimulation (exEMS)) in comparison to EMS therapy limited to gluteal and leg muscles (limEMS). METHODS: 31 individuals completed the EMS training program. Stable CHF patients (NYHA class II-III) received either exEMS (18 patients, 11 males, mean age 59.8±13.8 years) or limEMS (13 patients, 10 males, 63.6±9.4 years). Training was performed for 10 weeks twice weekly for 20 min, the level of daily activity remained unchanged. Effects on exercise capacity, left ventricular function (EF - ejection fraction) and QoL (quality of life) were evaluated. RESULTS: QoL was found to be improved in all domains of the SF-36 questionnaire. In the exEMS group there was a significant improvement in the domain physical functioning (54.09±29.9 to 75.45±15.6, p=0.48) and emotional role (63.63±45.8 to 93.93±20.1 p=0.048). LimEMS group showed significant improvement in the domain vitality (37.5±6.9 to 52.8±12.5, p=0.02).There was a significant increase of oxygen uptake at aerobic threshold in all groups (exEMS: +29.6%, p<0.001; limEMS +17.5%, p<0.001). EF -increased from 36.94±8.6 to 42.36±9.1% (+14.7%, p=0.003) in the exEMS group (limEMS 37.7±3.6 to 40.3±5.9% [+6.9%, p=0.18]). CONCLUSION: EMS contributes to an improved quality of life and can improve oxygen uptake and EF in CHF. It may be an alternative therapy in CHF patients who are otherwise unable to undertake conventional forms of exercise training.

Synthesis and anti-Trypanosoma cruzi activity of naphthoquinone-containing triazoles: electrochemical studies on the effects of the quinoidal moiety.

In our continued search for novel trypanocidal compounds, twenty-six derivatives of para- and ortho-naphthoquinones coupled to 1,2,3-triazoles were synthesized. These compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Compounds 17-24, 28-30 and 36-38 are described herein for the first time. Three of these novel compounds (28-30) were found to be more potent than the standard drug benznidazole, with IC50/24h values between 6.8 and 80.8µM. Analysis of the toxicity to heart muscle cells led to LC50/24h of <125, 63.1 and 281.6µM for 28, 29 and 30, respectively. Displaying a selectivity index of 34.3, compound 30 will be further evaluated in vivo. The electrochemical properties of selected compounds were evaluated in an attempt to find correlations with trypanocidal activity, and it was observed that more electrophilic quinones were generally more potent.

Heme oxygenase-1 end-products carbon monoxide and biliverdin ameliorate murine collagen induced arthritis.

OBJECTIVES: Heme oxygenase-1 (HO-1) which degrades Heme to free iron, biliverdin and carbon monoxide (CO) plays an important role in inflammation. There are, however, conflicting data concerning the role of HO-1 in rheumatoid arthritis (RA) and the therapeutic potential of individual heme degradation products remains to be determined. We therefore investigated the effect of CO and biliverdin upon therapeutic administration in the murine collagen induced arthritis (CIA) model of RA. METHODS: CIA was induced in DBA/1 mice. Anti-CII antibody levels were determined by ELISA. Mice were scored for paw swelling and grip strength. After the first clinical signs of arthritis one group of animals was treated with biliverdin, the second group was treated with CO. After 60 days all animals were sacrificed and analysed for histomorphological signs of arthritis. RESULTS: All animals immunised with CII developed serum anti-CII antibodies. Antibody levels were decreased in the CO-treated group. Both, Biliverdin and the CO-treated animals, showed an improvement in clinical disease activity. Histological analysis revealed significantly less inflammation, erosion and reduced numbers of osteoclasts in CO-treated animals only, whereas cartilage degradation was prevented in both biliverdin and CO-treated animals. CONCLUSIONS: Our data demonstrate a beneficial effect of CO, in particular, and biliverdin, on inflammation and bone destruction in the CIA mouse model.

Three-dimensional vision enhances task performance independently of the surgical method.

BACKGROUND: Within the next few years, the medical industry will launch increasingly affordable three-dimensional (3D) vision systems for the operating room (OR). This study aimed to evaluate the effect of two-dimensional (2D) and 3D visualization on surgical skills and task performance. METHODS: In this study, 34 individuals with varying laparoscopic experience (18 inexperienced individuals) performed three tasks to test spatial relationships, grasping and positioning, dexterity, precision, and hand-eye and hand-hand coordination. Each task was performed in 3D using binocular vision for open performance, the Viking 3Di Vision System for laparoscopic performance, and the DaVinci robotic system. The same tasks were repeated in 2D using an eye patch for monocular vision, conventional laparoscopy, and the DaVinci robotic system. RESULTS: Loss of 3D vision significantly increased the perceived difficulty of a task and the time required to perform it, independently of the approach (P < 0.0001-0.02). Simple tasks took 25 % to 30 % longer to complete and more complex tasks took 75 % longer with 2D than with 3D vision. Only the difficult task was performed faster with the robot than with laparoscopy (P = 0.005). In every case, 3D robotic performance was superior to conventional laparoscopy (2D) (P < 0.001-0.015). CONCLUSIONS: The more complex the task, the more 3D vision accelerates task completion compared with 2D vision. The gain in task performance is independent of the surgical method.

Myeloperoxidase levels predict executive function.

The main purpose of the study was to investigate whether baseline myeloperoxidase (MPO) levels are associated with executive cognitive function in individuals with high physical activity. Baseline serum MPO levels of 56 elderly marathon runners and 58 controls were assessed by ELISA. Standardized tests were applied to survey domain-specific cognitive functions. Changes in brain morphology were visualized by magnetic resonance imaging (MRI). High baseline serum MPO levels correlated with worse outcome in tests assessing executive cognitive function in athletes but not in the control group (NAI maze test p<0.05, Trail Making Test ratio p<0.01). In control participants, subcortical white matter hyperintensities were associated with higher scores on the Geriatric Depression Scale (p<0.05), whereas athletes seem to be protected from this effect. During strenuous exercising, MPO as well as its educts may be elevated due to increased oxygen intake and excretion of pro-inflammatory mediators inducing host tissue damage via oxidative stress. This outweighs the potential benefits of physical activity on cognitive function.

Systematic review and meta-analysis of laparoscopic Nissen fundoplication with or without division of the short gastric vessels.

BACKGROUND: The aim of this meta-analysis was to provide a pooled analysis of individual trials comparing clinical outcome following laparoscopic Nissen fundoplication with or without division of the short gastric vessels (SGVs). METHODS: Primary outcome measures were the requirement for reoperation, and the presence of postoperative gastro-oesophageal reflux and postoperative dysphagia. Secondary outcome measures were duration of operation, length of hospital stay, postoperative complications (within 30 days of surgery), postoperative gas bloat syndrome, lower oesophageal sphincter resting pressure and DeMeester score. Pooled odds ratios were calculated for categorical outcomes, and weighted mean differences for secondary continuous outcomes, using random-effects models for meta-analysis. RESULTS: Five randomized trials were included in the analysis. There was no statistically significant effect on the requirement for reoperation, or presence of postoperative dysphagia or reflux. SGV division was associated with a longer duration of operation and a reduced postoperative lower oesophageal sphincter pressure. There was no statistically significant difference in length of hospital stay, postoperative complications, postoperative gas bloat syndrome or DeMeester score. CONCLUSION: This meta-analysis has demonstrated that clinical outcome following laparoscopic Nissen fundoplication appears to be similar regardless of whether the short gastric vessels are divided. However, it is not possible to exclude many potentially important clinical differences and further studies are needed.

It takes two to tango: synthesis of cytotoxic quinones containing two redox active centers with potential antitumor activity.

We report the synthesis of 47 new quinone-based derivatives via click chemistry and their subsequent evaluation against cancer cell lines and the control L929 murine fibroblast cell line. These compounds combine two redox centers, such as an ortho-quinone/para-quinone or quinones/selenium with the 1,2,3-triazole nucleus. Several of these compounds present IC50 values below 0.5 µM in cancer cell lines with significantly lower cytotoxicity in the control cell line L929 and good selectivity index. Hence, our study confirms the use of a complete and very diverse range of quinone compounds with potential application against certain cancer cell lines.

Synthesis of quinone imine and sulphur-containing compounds with antitumor and trypanocidal activities: redox and biological implications.

Ortho-Quinones represent a special class of redox active compounds associated with a spectrum of pronounced biological activities, including selective cytotoxicity and antimicrobial actions. The modification of the quinone ring by simple nitrogen and sulphur substitutions leads to several new classes of compounds with their own, distinct redox behaviour and equally distinct activities against cancer cell lines and Trypanosoma cruzi. Some of the compounds investigated show activity against T. cruzi at concentrations of 24.3 and 65.6 µM with a selectivity index of around 1. These results demonstrate that simple chemical modifications on the ortho-quinone ring system, in particular, by heteroatoms such as nitrogen and sulphur, transform these simple redox molecules into powerful cytotoxic agents with considerable "potential", not only in synthesis and electrochemistry, but also, in a broader sense, in health sciences.

Sex differences in the association between albumin and all-cause and vascular mortality.

BACKGROUND: Low serum albumin levels are associated with cardiovascular disease and mortality risk. This study evaluated the predictive value of low serum albumin for all-cause-mortality in a large Viennese patient cohort and investigated sex differences in the association between serum albumin and mortality. MATERIALS AND METHODS: Serum albumin concentrations of 285 930 patients, who attended the General Hospital Vienna between 1992 and 2002, were evaluated and linked with the Austrian Death Registry. The median observation period was 7.4 +/- 4.0 years and the death rate was 16.8%. For Cox regression analysis, albumin levels were divided into deciles, the highest category served as reference value. To analyse associations between albumin and mortality independent of liver function, results were adjusted for cholinesterase, which indicates protein synthesis capacity of the liver. RESULTS: Hazard ratios for all-cause-mortality increased linearly with decreasing albumin levels from 1.05 in the 9th to 2.98 in the 1st decile. Adjusted for cholinesterase, the relative risk for mortality was still 1.91 in the lowest category. Compared with women, men had an average 50% increased risk of death in almost every decile, adjusting for cholinesterase reduced the sex difference to a 10-20% higher mortality risk for men. In critically ill patients, hazard ratios for all-cause-mortality ranged from 4.5 in the 9th decile to 9.5 in the lowest albumin category. CONCLUSION: This study demonstrates a strong inverse association between serum albumin and mortality in a large patient cohort. The predictive value of low albumin was remarkably higher in men than in women.

Persistent arterial stiffness and endothelial dysfunction following successful pancreas-kidney transplantation in Type 1 diabetes.

OBJECTIVE: Successful simultaneous pancreas-kidney transplantation (SPK) in Type 1 diabetic (T1DM) patients results in improved cardiovascular outcome and survival. However, it is doubtful whether the impairment of cardiovascular and endothelial function in T1DM can be completely reversed. METHODS: Pulse-wave velocity, stroke volume, heart rate, serological markers of endothelial dysfunction (soluble intercellular, vascular cell-adhesion molecules, E-selectin, and plasminogen-activator-inhibitor-1) were measured in 10 T1DM patients after SPK with non-diabetic glucose levels, 10 T1DM patients with poor [T1DM>8; glycated haemoglobin (HbA1c)>8%], and 10 with good glucose control (T1DM<7, HbA1c<7%), in 6 non-diabetic patients after kidney transplantation (KT) and 9 non-diabetic control subjects (CON), matching for major anthropometric characteristics. RESULTS: Pulse-wave velocity was increased in SPK (P < 0.02 vs. CON, KT, T1DM<7) and in T1DM>8 (P < 0.02 vs. T1DM<7). Systolic blood pressure was increased in SPK (P < 0.05 vs. CON). Stroke volume was reduced in SPK, T1DM>8 and T1DM<7 and KT (P < 0.01 vs. CON). Heart rate was elevated in SPK and in T1DM>8 (P < 0.0003 vs. CON and T1DM<7). In SPK, soluble intercellular and vascular cell-adhesion molecules were 100% and 44% higher (P < 0.03 vs. CON), respectively, while plasminogen-activator-inhibitor-1 was decreased in SPK (P < 0.02 vs. CON). CONCLUSION: T1DM patients after SPK experience arterial stiffness, a higher heart-rate and blood pressure, reduced stroke volume and serological signs of endothelial dysfunction. Thus, functional and structural cardiovascular alterations as a result of glucotoxicity, uraemia and hypertension in T1DM might not be completely resolved by SPK.