Synthesis and pharmacological evaluation of pentacyclic 6a,7-dihydrodiindole and 2,3-dihydrodiindole derivatives as novel melatoninergic ligands

The synthesis of novel melatonin analogues 3a and 4a-c designed as melatonin receptor ligands is described. Among the newly synthesized ligands, 2-((S)-2-hydroxymethylindolin-1-ylmethyl)-melatonin 4b displayed the highest affinity for MT(1) receptors (K(i)=9.8 nM) and for MT(2) subtype (K(i)=7.8 nM), whereas the rigid pentacyclic ligand 3 showed the highest selectivity towards the MT(2) receptor subtype (K(i)=319.3 nM for MT(1) and K(i)=65.2 nM for MT(2)).     

Perioperative Duloxetine and Etoricoxibto improve postoperative pain after lumbar Laminectomy: a randomized,double-blind,controlled study

Background

Duloxetine, Etoricoxib and opioid are of the commonly administered drugs in Lumbar laminectomy. The aim of this study is to assess the effect of perioperative use of Duloxetine in combination with Etoricoxib on postoperative pain and opioid requirements.

Methods

One hundred twenty patients with ASA physical status were enrolled with age between 18 and 70 years. Patients were divided randomly into four groups of 30 patients: group P received placebo, group E received etoricoxib 120 mg, group D received duloxetine 60 mg and group D/E received duloxetine 60 mg capsules and etoricoxib 120 mg; 1 h before surgery and 24 h after.

Results

Neither Duloxetine nor etoricoxib individually had effect on pain with movement, while their combination revealed a significant reduction in pain scores over the entire postoperative period at rest and on movement. Etoricoxib showed a significant decrease in pain at all times at rest when compared with group P, while it showed significant pain decrease only at 0, 2 and 4 h when compared with group D. On the other hand duloxetine alone showed significant decrease in pain at rest at 24 h and 48 h when compared with group P. ConcerningMorphine requirement after 24 h.; it wassignificantly lower in the D/E group in comparison with groups P, E and D. It should be noted also that there was a significant decrease morphine requirement in both groups E and D.

Conclusion

The perioperative administration of the combination of etoricoxib and duloxetine improved analgesia and reduced opioid consumption without significant side effects.

Trial registration

ISRCTN48329522. 17 June 2017

     

Analysis of cardiac signals using spatial filling index and time-frequency domain

Background  

Analysis of heart rate variation (HRV) has become a popular noninvasive tool for assessing the activities of the autonomic nervous system (ANS). HRV analysis is based on the concept that fast fluctuations may specifically reflect changes of sympathetic and vagal activity. It shows that the structure generating the signal is not simply linear, but also involves nonlinear contributions. These signals are essentially non-stationary; may contain indicators of current disease, or even warnings about impending diseases. The indicators may be present at all times or may occur at random in the time scale. However, to study and pinpoint abnormalities in voluminous data collected over several hours is strenuous and time consuming.     

Interrelationships of the subgenera of Coryphaenoides (Teleostei: Gadiformes: Macrouridae): synthesis of allozyme,peptide mapping,and DNA sequence data

DNA sequences of the 12s rRNA mitochondrial gene from 12 species key to the question of the monophyly of the deep-sea fish genus Coryphaenoides (Macrouridae) were analyzed phylogenetically using maximum parsimony and maximum likelihood. The results were compared with those of three previous studies in which allozyme, peptide mapping, and DNA sequence data were similarly analyzed. The allozyme and DNA sequence data suggested that the largest subgenus (Coryphaenoides), which contained most of the species inhabiting continental slopes between approximately 600 and 2000m depth, is monophyletic. Two of the three subgenera containing the species inhabiting abyssal ocean basins below approximately 2000m together formed a sister group to subgenus Coryphaenoides. The macrourids of the abyssal basins and those of the continental slopes thus appear to have experienced separate radiations from a common ancestor.     

Synthesis of some pyridine ribosides and their biological activity

A synthesis of 1-(beta-D-ribofuranosyl)-pyridin-2-thiones via reaction of 3-cyanopyridin-2(1H)-thiones with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide under basic conditions, followed by hydrolysis with methanolic ammonia is reported.     

Synthesis and biological activity of modified thiopyrimidine nucleosides

N3-beta-D-glucopyranosyl, galactopyranosyl and xylopyranosyl 6-methyl-2-methylthiouracil and their 5-bromo derivatives have been synthesized by coupling an alpha-acetobromosugar with the corresponding thiouracil. The new modified thiouridine analogues were evaluated for their inhibitory activity against Human Immunodeficiency Virus (HIV) replication in MT-4 cells as well as for their cytotoxicity.     

Periodic health examination, 1999 update: 1. Detection,prevention and treatment of obesity

OBJECTIVES: (1) To evaluate the evidence relating to the effectiveness of methods to prevent and treat obesity, and (2) to provide recommendations for the prevention and treatment of obesity in adults aged 18 to 65 years and for the measurement of the body mass index (BMI) as part of a periodic health examination. OPTIONS: In adults with obesity (BMI greater than 27) management options include weight reduction, prevention of further weight gain or no intervention. OUTCOMES: The long-term (more than 2 years) effectiveness of (a) methods to prevent obesity and (b) methods to treat obesity. EVIDENCE: MEDLINE was searched for articles published from 1966 to April 1998 that related to the prevention and treatment of obesity; additional articles were identified from the bibliographies of review articles and the listings of Current Contents. Selection criteria were used to limit the analysis to prospective studies with at least 2 years'' follow-up. BENEFITS, HARM AND COSTS: Health benefits of weight reduction were evaluated in terms of alleviation of symptoms, improved management of obesity-related diseases and a reduction in major clinical outcomes. The health risk of weight-reduction methods were briefly evaluated in terms of increased mortality and morbidity. VALUES: The recommendations of this report reflect the commitment of the Canadian Task Force on Preventive Health Care to provide a structured, evidence-based appraisal of whether a manoeuvre should be part of a periodic health examination. RECOMMENDATIONS: (1) Prevention: There is insufficient evidence to recommend in favour of or against community-based obesity prevention programs; however, because of considerable health risks associated with obesity and the limited long-term effectiveness of weight-reduction methods, the prevention of obesity should be a high priority for health care providers (grade C recommendation). (2) Treatment: (a) For obese adults without obesity-related diseases, there is insufficient evidence to recommend in favour of or against weight-reduction therapy because of a lack of evidence supporting the long-term effectiveness of weight-reduction methods (grade C recommendation); (b) for obese adults with obesity-related diseases (e.g., diabetes mellitus, hypertension), weight reduction is recommended because it can alleviate symptoms and reduce drug therapy requirements, at least in the short term (grade B recommendation). (3) Detection: (a) for people without obesity-related diseases, there is insufficient evidence to recommend the inclusion or exclusion of BMI measurement as part of a periodic health examination, and therefore BMI measurement is left to the discretion of individual health care providers (grade C recommendation); (b) for people with obesity-related diseases, BMI measurement is recommended because weight reduction should be considered with a BMI of more than 27 (grade B recommendation). VALIDATION: The findings of this analysis were reviewed through an iterative process by the members of the Canadian Task Force on Preventive Health Care. SPONSORS: The Canadian Task Force on Preventive Health Care is funded through a partnership between the Provincial and Territorial Ministries of Health and Health Canada.     

Evolution of transposable elements: an IS10 insertion increases fitness in Escherichia coli

Strains of Escherichia coli carrying Tn10, a transposon consisting of two IS10 insertion sequences flanking a segment encoding for a tetracycline-resistance determinant, gain a competitive advantage in chemostat cultures. All Tn10-bearing strains that increase in frequency during competition have a new IS10 insertion that is found in the same location in the genome of those strains. We mapped, by a gradient of transmission, the position of the new IS10 insertion. We examined 11 isolates whose IS10 insertion was deleted by recombinational crossing- over, and in all cases the competitive fitness of the isolates was decreased. These results show that the IS10-generated insertion increases fitness in chemostat cultures. We named the insertion fit::IS10 and suggest that transposable elements may speed the rate of evolution by promoting nonhomologous recombination between preexisting variations within a genome and thereby generating adaptive variation.      

Soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) Is Elevated in Bronchoalveolar Lavage Fluid of Patients with Acute Respiratory Distress Syndrome

Introduction

Pulmonary vascular endothelial activation has been implicated in acute respiratory distress syndrome (ARDS), yet little is known about the presence and role of endothelial activation markers in the alveolar space in ARDS. We hypothesized that endothelial activation biomarkers would be differentially expressed in bronchoalveolar lavage fluid from patients with ARDS compared with healthy volunteers, and that biomarker concentrations would be associated with ARDS severity.

Methods

We performed a cross-sectional analysis of data from 26 intubated patients with ARDS undergoing evaluation for clinically suspected ventilator-associated pneumonia and five healthy volunteers. Patients underwent bronchoalveolar lavage a median of five days after intubation. Healthy volunteers also underwent bronchoalveolar lavage. Endothelial activation biomarkers (soluble vascular cell adhesion molecule-1 [sVCAM-1], soluble endothelial selectin [sESEL], angiopoietin-1 [Ang-1] and angiopoietin-2 [Ang-2]) were measured in bronchoalveolar lavage fluid. Clinically suspected ventilator-associated pneumonia was confirmed with microbiologic culture data.

Results

Patients with ARDS had significantly higher median sVCAM-1 concentrations in the bronchoalveolar lavage fluid compared with healthy volunteers (985 vs 119 pg/mL, p = 0.03). Additionally, there was a trend toward greater bronchoalveolar lavage fluid sVCAM-1 concentrations among patients with moderate/severe compared to mild ARDS (1395 vs 209 pg/mL, p = 0.06). We did not detect significant differences in bronchoalveolar lavage fluid levels of sESEL, Ang-1 or Ang-2 between patients with ARDS and healthy volunteers. Median bronchoalveolar lavage fluid biomarker levels did not differ between patients with and without microbiologically-confirmed ventilator-associated pneumonia.

Conclusions

sVCAM-1 concentrations were significantly higher in the bronchoalveolar lavage fluid of patients with ARDS compared to healthy controls, and tended to be higher in moderate/severe ARDS compared to mild ARDS. Our findings add to the growing evidence supporting the concept that endothelial activation plays an important mechanistic role in the pathogenesis of ARDS. Further studies are necessary to characterize the role and/or clinical significance of sVCAM-1 and other endothelial activation markers present in the alveolar space in ARDS.