Biological evaluation of selected 3,4‐dihydro‐2(1H)‐quinoxalinones and 3,4‐dihydro‐1,4‐benzoxazin‐2‐ones: Molecular docking study

In order to investigate new potential therapeutically active agents, we investigated the biological properties of two small libraries of quinoxalinones and 1,4‐benzoxazin‐2‐ones. The results obtained showed that compounds 5 , 9–11 have good cytotoxic activity against HeLa cells where the lowest IC₅₀ value (10.46 ± 0.82 μM/mL) was measured for compound 10 . Additionally, the most active compounds ( 5 , 9 – 11 ) showed much better selectivity for MRC‐5 cells (up to 17.4) compared to cisplatin. In vitro evaluation of the inhibition of the enzyme α‐glucosidase showed that compounds 10 and 11 exert significant inhibition of the enzyme at 52.54 ± 0.09 and 40.09 ± 0.49 μM, respectively. Competitive experiments with ethidium bromide (EB) indicated that all tested compounds have affinity to displace EB from the EB‐DNA complex through intercalation, suggesting good competition with EB (K_sv = (3.1 ± 0.2), (5.1 ± 0.1), (5.6 ± 0.2), and (6.3 ± 0.2) × 10³ M^?1). A molecular docking study was also performed to better understand the binding modes and to conclude the structure–activity relationships of the synthesized compounds.

     

An updated meta-analysis of the distribution and prevalence of <Emphasis Type="Italic">Borrelia burgdorferi</Emphasis> s.l. in ticks in Europe

Background

The bacteria of the group Borrelia burgdorferi s.l. are the etiological agents of Lyme borreliosis in humans, transmitted by bites of ticks. Improvement of control measures requires a solid framework of the environmental traits driving its prevalence in ticks.

Methods

We updated a previous meta-analysis of the reported prevalence of Borrelia burgdorferi s.l. in questing nymphs of Ixodes ricinus with a literature search from January 2010–June 2017. This resulted in 195 new papers providing the prevalence of Bb for 926 geo-referenced records. Previously obtained data (878 records, years 2000–2010) were appended for modelling. The complete dataset contains data from 82,004 questing nymphs, resulting in 558 records of B. afzelii, 404 of B. burgdorferi s.s. (only 80 after the year 2010), 552 of B. garinii, 78 of B. lusitaniae, 61 of B. spielmanii, and 373 of B. valaisiana. We associated the records with explicit coordinates to environmental conditions and to a categorical definition of European landscapes (LANMAP2) looking for a precise definition of the environmental niche of the most reported species of the pathogen, using models based on different classification methods.

Results

The most commonly reported species are B. afzelii, B. garinii and B. valaisiana largely overlapping across Europe. Prevalence in ticks is associated with portions of the environmental niche. Highest prevalence occurs in areas of 280°–290° (Kelvin) of mean annual temperature experiencing a small amplitude, steady spring slope, together with high mean values and a moderate spring rise of vegetation vigor. Low prevalence occurs in sites with low and a noteworthy annual amplitude of temperature and the Normalized Difference Vegetation Index (colder areas with abrupt annual changes of vegetation). Models based on support vector machines provided a correct classification rate of the habitat and prevalence of 89.5%. These results confirm the association of prevalence of the three most commonly reported species of B. burgdorferi s.l. in Europe to parts of the environmental niche and provide a statistically tractable framework for analyzing trends under scenarios of climate change.

     

Clinical characteristics and functional outcome of patients with West Nile neuroinvasive disease in Serbia

Neurologic manifestations are prominent characteristic of West Nile virus (WNV) infection. The aim of this article was to describe neurological manifestations in patients with WNV neuroinvasive disease and their functional outcome at discharge in the first human outbreak of WNV infection in Serbia. The study enrolled patients treated in the Clinic for Infectious and Tropical Diseases, Clinical Center Serbia in Belgrade, with serological evidence of acute WNV infection who presented with meningitis, encephalitis and/or acute flaccid paralyses (AFP). Functional outcome at discharge was assessed using modified Rankin Scale (mRS) and Barthel index. Fifty-two patients were analysed. Forty-four (84.6 %) patients had encephalitis, eight (15.4 %) had meningitis, and 13 (25 %) had AFP. Among patients with AFP, 12 resembled poliomyelitis and one had clinical and electrodiagnostic findings consistent with polyradiculoneuritis. Among patients with encephalitis, 17 (32.7 %) had clinical signs of rhombencephalitis, and eight (15.4 %) presented with cerebellitis. Respiratory failure with subsequent mechanical ventilation developed in 13 patients with WNE (29.5 %). Nine (17.3 %) patients died, five (9.6 %) were functionally dependent (mRS 3–5), and 38 (73.1 %) were functionally independent at discharge (mRS 0–2). In univariate analysis, the presence of AFP, respiratory failure and consciousness impairment were found to be predictors of fatal outcome in patients with WNV neuroinvasive disease (p < 0.001, p < 0.001, p = 0.018, respectively). The outbreak of human WNV infection in Serbia caused a notable case fatality ratio, especially in patients with AFP, respiratory failure and consciousness impairment. Rhombencephalitis and cerebellitis could be underestimated presentations of WNV neuroinvasive disease.     

Can Different Subsets of Ineffective Esophageal Motility Influence the Outcome of Nissen Fundoplication?

Background

Ineffective esophageal motility (IEM) in patients with gastroesophageal reflux disease includes three different subsets that may affect symptom profiles. Our aim was to assess symptoms and functional outcome in patients with erosive esophagitis according to different subsets of IEM, before and after Nissen fundoplication (NF).

Methodology

A retrospective study with prospective follow-up of 72 patients with reflux esophagitis and IEM in whom open NF was performed. Based on principal manometric esophageal body motility disorder, patients were divided in three groups: predominantly low-amplitude (LAC, N?=?38), non-propulsive (NPC, N?=?18), and simultaneous low-amplitude esophageal contractions (SC, N?=?16). Patients underwent symptomatic questionnaire and stationary esophageal manometry before and 6 months, 1 year, and 3 years after surgery.

Results

Preoperatively, patients in NPC and SC groups had higher mean scores of dysphagia, without statistical significance as opposed to the LAC group (p?=?0.239). Postoperative dysphagia occurred in 36 patients, without statistical significance between groups regarding dysphagia grades (p?=?0.390). A longer duration of postoperative dysphagia was noted in the SC group (p?p?Conclusion Three years after NF, successful symptomatic and functional outcome was achieved in analyzed groups of patients with erosive esophagitis regardless of IEM subtype.     

The hepatoduodenal ligament revisited: cross-sectional imaging spectrum of non-neoplastic conditions

Introduction

The hepatoduodenal ligament is frequently involved by conditions affecting the portal triad and surrounding structures, including a vast array of non-neoplastic conditions. Due its unique location between the retroperitoneum and the peritoneal space, the hepatoduodenal ligament is also targeted by inflammatory conditions involving the retroperitoneum and the liver. Finally, the presence of lymphatics and of the biliary tracts makes the hepatoduodenal ligament a route of spread for a variety of infections. The purpose of this pictorial essay is twofold: to review the cross-sectional radiological anatomy and variants of the structures within the hepatoduodenal ligament, and to illustrate the non-neoplastic conditions that may arise within the hepatoduodenal ligament.

Conclusion

Familiarity with these specific entities and their cross-sectional imaging findings is fundamental for a more accurate diagnosis.

     

The additive prognostic value of restrictive pattern and dipyridamole-induced contractile reserve in idiopathic dilated cardiomyopathy

BACKGROUND: Diastolic dysfunction and lack of contractile reserve are unfavorable prognostic predictors in patients with dilated cardiomyopathy (DCM). AIMS: This study aims to assess whether diastolic dysfunction and lack of dipyridamole-induced contractile reserve were additive predictors of poor outcome in patients with DCM. METHODS: A total of 116 patients with DCM and ejection fraction (EF<35%) were studied by dipyridamole echo (0.84 mg/kg over 10 min). At rest, a restrictive filling pattern was defined as: E/A ratio >2 and an E-wave deceleration time of <140 ms on transmitral flow velocity profile. RESULTS: Rest wall motion score index (WMSI) was 2.2+/-0.3 and decreased to 1.9+/-0.41 after dipyridamole (p<0.001). During follow-up (median 26.5 months), 22 cardiac deaths occurred. At multivariate analysis, dipyridamole-induced contractile reserve yielded significant incremental prognostic value (RR=0.275, p<0.006) over NYHA class (RR=1.971, p<0.03), angiotensin-converting enzyme inhibitor therapy (RR=0.173, p<0.001), and left ventricular end-diastolic diameter (RR=1.131, p<0.001). The worst prognostic combination was the presence of restrictive pattern at rest and the absence of contractile reserve (deltaWMSI<0.15). CONCLUSION: In patients with DCM, the ominous combination of restrictive transmitral flow pattern and lack of contractile reserve during dipyridamole stress predicts an unfavourable outcome.     

High pre-transplant serum nitrate levels predict risk of acute steroid-refractory graft-versus-host disease in the absence of statin therapy

Steroid-refractory graft-versus-host disease is a life-threatening complication after allogeneic stem cell transplantation. Evidence is accumulating that steroid-refractory graft-versus-host disease is associated with endothelial distress. Endothelial cell homeostasis is regulated by nitric oxide, and serum nitrates are derived from nitric oxide synthase activity or dietary sources. In this retrospective study based on 417 patients allografted at our institution we investigated whether quantification of serum nitrates could predict steroid-refractory graft-versus-host disease. Elevated pre-transplant levels of serum nitrates (>26.5 μM) predicted steroid-refractory graft-versus-host disease (P=0.026) and non-relapse mortality (P=0.028), particularly in combination with high pre-transplant angiopoietin-2 levels (P=0.0007 and P=0.021, respectively). Multivariate analyses confirmed serum nitrates as independent predictors of steroid-refractory graft-versus-host disease and non-relapse mortality. Differences in serum nitrate levels did not correlate with serum levels of tumor necrosis factor or C-reactive protein or expression of inducible nitric oxide synthase in blood cells. Patients with high pre-transplant nitrate levels had significantly reduced rates of refractory graft-versus-host disease (P=0.031) when pravastatin was taken. In summary, patients at high risk of developing steroid-refractory graft-versus-host disease could be identified prior to transplantation by serum markers linked to endothelial cell function. Retrospectively, statin medication was associated with a reduced incidence of refractory graft-versus-host disease in this endothelial high-risk cohort.