Assessment of the genotoxic and carcinogenic potentials of 3‐aminothiophene derivatives using in vitro and in silico methodologies

Thiophene derivatives, a class of compounds widely used in products such as pharmaceuticals, agrochemicals or dyestuffs, represent chemicals of concern. Indeed, the thiophene ring is often considered as a structural moiety that may be involved in toxic effects in humans. We primarily focus on the genotoxic/mutagenic and carcinogenic potentials of the methyl 3‐amino‐4‐methylthiophene‐2‐carboxylate (1), a precursor of the articaine local anesthetic (4) which falls within the scope of the European REACH (Registration, Evaluation, Authorisation and restriction of CHemicals) legislation. To discern some structure–toxicity relationships, we also studied two related compounds, namely the 3‐amino 4‐methylthiophene (2) and the 2‐acetyl 4‐chlorothiophene (3). Techniques employed to assess mutagenic and DNA‐damaging effects involved the Salmonella mutagenicity assay (or Ames test) and the single‐cell gel electrophoresis assay (or Comet assay). In the range of tested doses, none of these derivatives led to a positive response in the Ames tests and DNA damage was only observed in the Comet assay after high concentration exposure of 2. The study of their carcinogenic potential using the in vitro SHE (Syrian Hamster Embryo) cell transformation assay (CTA) highlighted the activity of compound 2. A combination of experimental data with in silico predictions of the reactivity of thiophene derivatives towards cytochrome P450 (CYP450), enabled us to hypothesize possible pathways leading to these toxicological profiles. Copyright © 2013 John Wiley & Sons, Ltd.     

Mayaro Virus Infects Human Brain Cells and Induces a Potent Antiviral Response in Human Astrocytes

Mayaro virus (MAYV) and chikungunya virus (CHIKV) are known for their arthrotropism, but accumulating evidence shows that CHIKV infections are occasionally associated with serious neurological complications. However, little is known about the capacity of MAYV to invade the central nervous system (CNS). We show that human neural progenitors (hNPCs), pericytes and astrocytes are susceptible to MAYV infection, resulting in the production of infectious viral particles. In primary astrocytes, MAYV, and to a lesser extent CHIKV, elicited a strong antiviral response, as demonstrated by an increased expression of several interferon-stimulated genes, including ISG15, MX1 and OAS2. Infection with either virus led to an enhanced expression of inflammatory chemokines, such as CCL5, CXCL10 and CXCL11, whereas MAYV induced higher levels of IL-6, IL-12 and IL-15 in these cells. Moreover, MAYV was more susceptible than CHIKV to the antiviral effects of both type I and type II interferons. Taken together, this study shows that although MAYV and CHIKV are phylogenetically related, they induce different types of antiviral responses in astrocytes. This work is the first to evaluate the potential neurotropism of MAYV and shows that brain cells and particularly astrocytes and hNPCs are permissive to MAYV, which, consequently, could lead to MAYV-induced neuropathology.     

Suppurative mediastinitis secondary to Burkholderia cepacia in a patient with cystic fibrosis

Burkholderia cepacia is an important opportunistic pathogen among patients with cystic fibrosis (CF); it is associated with deterioration of lung function, poor outcome following lung transplantation and increased mortality. Fever, an elevated white blood cell count, weight loss and an often fatal deterioration in pulmonary function characterize a particular clinical course, termed ‘Cepacia syndrome’. The present case report describes a 40-year-old man with CF who developed Cepacia syndrome complicated by suppurative mediastinitis, from which B cepacia was isolated. Despite optimal medical and surgical therapy, this patient succumbed to his illness. Those caring for patients with CF should be aware of this potentially catastrophic complication of B cepacia infection, especially in the setting of Cepacia syndrome.     

Precise evaluation of liver histology by computerized morphometry shows that steatosis influences liver stiffness measured by transient elastography in chronic hepatitis C

Background

Liver stiffness evaluation (LSE) by Fibroscan is now widely used to assess liver fibrosis in chronic hepatitis C. Liver steatosis is a common lesion in chronic hepatitis C as in other chronic liver diseases, but its influence on LSE remains unclear. We aimed to precisely determine the influence of steatosis on LSE by using quantitative and precise morphometric measurements of liver histology.

Methods

650 patients with chronic hepatitis C, liver biopsy, and LSE were included. Liver specimens were evaluated by optical analysis (Metavir F and A, steatosis grading) and by computerized morphometry to determine the area (%, reflecting quantity) and fractal dimension (FD, reflecting architecture) of liver fibrosis and steatosis.

Results

The relationships between LSE and liver histology were better described using morphometry. LSE median was independently linked to fibrosis (area or FD), steatosis (area or FD), activity (serum AST), and IQR/LSE median. Steatosis area ≥4.0 % induced a 50 % increase in LSE result in patients with fibrosis area <9 %. In patients with IQR/LSE median ≤0.30, the rate of F0/1 patients misclassified as F ≥ 2 by Fibroscan was, respectively for steatosis area <4.0 and ≥4.0 %: 12.6 vs 32.4 % (p = 0.003). Steatosis level did not influence LSE median when fibrosis area was ≥9 %, and consequently did not increase the rate of F ≤ 3 patients misclassified as cirrhotic.

Conclusion

A precise evaluation of liver histology by computerized morphometry shows that liver stiffness measured by Fibroscan is linked to liver fibrosis, activity, and also steatosis. High level of steatosis induces misevaluation of liver fibrosis by Fibroscan.     

Islet of Langerhans isolation from pediatric and juvenile donor pancreases

Islet grafts isolated from young donors allow superior functional outcomes but are often associated with poor islet isolation yields. The objective of this study was to comparatively analyze the outcomes of islet isolation between young and older donors. We retrospectively analyzed 564 pancreas isolations performed at our institution. Isolation outcomes were compared between donors aged ≤20 years (n = 42, YD) and >20 years (n = 522, OD). Isolation procedure was identical in both groups. Prepurification percentage of embedded islets was higher in YD (44.3 ± 22.7% vs. 24.9 ± 20.9%, P < 0.001). This led to a lower recovery rate in YD (48% vs. 76%, P = 0.002) and hence lower postpurification IEQ/g pancreas in YD (2 412 ± 1 789 IEQ/g vs. 3 194 ± 1 892 IEQ/g, P = 0.01). Final yield was 180 982 ± 128 073 IEQ in YD and 244 167 ± 134 137 IEQ in OD, (P = 0.006). In vitro function was markedly, albeit nonsignificantly, higher in YD (SI: 4.5 ± 5.1 vs. 3.0 ± 5.7, P = 0.350). Proportion of transplanted preparations was similar in both groups, 38% (16/42) in YD vs. 43% (224/522) in OD, P = 0.628. In spite of isolation and purification difficulties, pancreases from young donors allowed similar islet transplantation rates as older donors. Efforts should be directed at improving islet extraction in these donors to realize their full potential for islet transplantation.     

Do greater rates of body heat storage precede the accelerated reduction of self-paced exercise intensity in the heat?

Aim

To reevaluate the previous hypothesis that greater reductions in self-paced exercise intensity in the heat are mediated by early differences in the rate of body heat storage (S).

Methods

Eight trained volunteers cycled in 19 °C/1.8 kPa (COOL), 25 °C/1.2 kPa (NORM), and 34 °C/1.6 kPa (HOT), while maintaining an RPE of 16. Potential differences in S following the onset of exercise were assessed by comparing rates of esophageal temperature change (ΔT _es/Δt); and estimated S values using a traditional two-compartment thermometric model (S _therm) of changes in rectal (T _re) and skin (T _sk) temperature, and partitional calorimetry (S _cal).

Results

After 15 min of exercise, workload decreased more in HOT vs. COOL (P = 0.03), resulting in a shorter time (HOT: 40.7 ± 14.9 min; COOL: 53.5 ± 18.7 min; P = 0.04) to 70 % of initial workload. However, there were no preceding differences in ΔT _es/Δt between conditions (P = 0.18). S _therm values were different between HOT and COOL during the first 5 min of exercise (P < 0.05), primarily due to negative S _therm values (?32 ± 15 kJ min^?1) in COOL, which according to partitional calorimetric measurements, required improbably high (~56 kJ min^?1) rates of evaporation when no sweating on the back and thigh was observed until after 7.6 ± 1.5 min and 4.8 ± 1.7 min of exercise, respectively. S _cal values in the first 5 min of exercise confirmed S was actually positive in COOL (+21 ± 8 kJ min^?1) and not negative. Different S _therm values following the onset of exercise at different environmental temperatures are simply due to transient differences in the rate of change in T _sk.

Conclusion

Reductions in self-paced exercise intensity in the heat are not mediated by early differences in S following the onset of exercise.     

Observation of Traditional Caregiver-Infant Feeding Behaviours and Porridge and Energy Intakes during One Meal to Define Key Messages for Promoting Responsive Feeding in the Amparafaravola District,Rural Madagascar

Undernutrition is highly prevalent in young children in Madagascar and insufficient intake per meal could be one of the main causes. A cross-sectional survey of infant feeding practices including video-recorded meal observations was carried out with 101 caregiver–infant pairs in the Amparafaravola district, Northeast Madagascar. The objective was to quantify the porridge/energy intake of 9–11-month-old children and assess its association with the caregiver–infant feeding behaviours. Then, key messages for promoting responsive feeding (RF) were developed and tested through focus group discussions. The mean porridge intake was 12.8 ± 7.5 g/kg body weight (BW)/meal, corresponding to hardly one-third of the 300 kcal recommended from complementary foods for 9–11-month-old children. Analysis of meal videos suggested that mothers practiced the five positive feeding behaviours (self-feeding, responsive, active, social, and distraction), and rarely the negative ones. Only 6.9% of mothers used positive RF “very frequently”, although it was associated with higher intakes (p < 0.05), with mean intake reaching 21 g/kg BW. In focus groups, caregivers approved the six RF messages and related counselling cards. They suggested some modifications to improve their understanding, and counselling cards were revised accordingly. The long-term impact of RF-promoting card use on the meal intakes and the nutritional status of young children must now be assessed.