Further consideration of the clonal nature of Salmonella typhi: evaluation of molecular and clinical characteristics of strains from Indonesia and Peru.

We examined envelope protein profiles, chromosomal restriction endonuclease digest patterns, and immune responses to envelope proteins for collections of Salmonella typhi strains isolated in Peru and Indonesia. Only minor differences in envelope protein patterns were apparent among strains. Strains from 7 of 20 Indonesian patients had a distinct chromosomal digest pattern compared with patterns of Peruvian and other Indonesian strains. Strains with this pattern carried the gene for the j flagellar antigen (H1-j); differences in response to envelope proteins of j and d strains were noted on immunoblot analysis. Our data suggest that there are genotypic and phenotypic differences among S. typhi strains. The clinical importance of these differences remains to be fully evaluated; however, in this study it was not possible to show a clear correlation between strain characteristics and disease severity.     

Toxicokinetics and toxicodynamics of gonyautoxins after an oral toxin dose in cats.

Although the action of Gonyautoxins (GTXs) and Saxitoxin (STX) mechanisms is well known at the molecular level, there are still many unresolved questions associated with the intoxication syndrome in mammals. For example, how are these toxins absorbed in the digestive system? Where are they absorbed? What is the absorption rate? What is the maximal concentration in plasma (C(max)) and the time taken to reach this C(max) (T(max)) in the case of oral toxin administration? These questions are addressed in this paper, which describes an experimental design which allowed us to follow the toxicokinetics and toxicodynamics of GTX 2/3 epimers poisoning in vivo, when an oral dose of toxin was administered to an anaesthetized cat permanently coupled to an artificial ventilator. The GTX 2/3 epimers was orally administered with a dose of 70 microg/kg, then urine and blood samples were collected during a 5 h experimental period. The toxins were quantified using a post column derivatisation high performance liquid chromatography method. Procedure of extraction, clean up and detection of GTX 2/3 epimers are described. The arterial pressure of the cats was continuously monitored. The GTX 2/3 epimers oral dose was completely absorbed at intestinal level. This dose was sufficient to decrease arterial pressure and to produce death within the experimental time. However, with the intravenous (i.v.) administration of 2.5 microg/min kg of dobutamine, hemodynamic parameters were restored which allowed the animal to overcome the cardiovascular shock. The renal clearance of GTX 2/3 epimers measured in the cats was 4.6 ml/min kg, indicating that like STX, in cats with normal cardiovascular parameters and diuresis, the GTX 2/3 excretion mainly involves glomerular filtration. Oral doses of 35 microg/kg of GTX 2/3 epimers and plasma level of 36 ng/ml are lethal limits for cats. This is the first report that shows the effects of the GTX 2/3 epimers at different plasmatic levels and their relationship to their toxic effects when they are administered orally, resembling the intoxication illness in mammals.     

Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma

Purpose

Anaplastic thyroid carcinoma (ATC) is an aggressive, chemo-resistant malignancy. Chemo-resistance is often associated with changes in activity of the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways and/or a high expression of ATP binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). To assess the therapeutic efficacy in ATC of a combination of the dual mTOR kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX), we generated a new cell line (Rho-) via the selection of human thyroid carcinoma 8505C cells that exhibit a low accumulation of rhodamine 123, which serves as a P-gp and BCRP substrate.

Methods

Immunohistochemistry was used for P-gp and BCRP expression analyses in primary ATC patient samples. Spheroid formation and immunodeficient NSG mice were used for performing in vitro and in vivo tumorigenicity assays, respectively. MTT, flow-cytometry, fluorescent microscopy, cell death and proliferation assays, as well as migration, invasion and gelatin degradation assays, were used to assess the potential of AZD2014 to enhance the effects of PTX. ATC xenografts in SCID mice were used for evaluating in vivo treatment efficacies.

Results

Rho- cells were found to be 10-fold more resistant to PTX than 8505C cells and, in addition, to be more tumorigenic. We also found that AZD2014 sensitized Rho- cells to PTX by inhibiting proliferation and by inducing autophagy. The combined use of AZD2014 and PTX efficiently inhibited in vitro ATC cell migration and invasion. Subsequent in vivo xenograft studies indicated that the AZD2014 and PTX combination effectively suppressed ATC tumor growth.

Conclusions

Our data support results from recent phase I clinical trials using combinations of AZD2014 and PTX for the treatment of solid tumors. Such combinations may also be employed for the design of novel targeted ATC treatment strategies.

     

Current state and future of pediatric allergology in Europe: A road map

The history of pediatric allergology (PA) in Europe is relatively youthful, dating back to 1984, when a small group of pediatricians founded the European Working Group on Pediatric Allergy and Immunology—later giving rise to ESPACI (European Society on Pediatric Allergology and Clinical Immunology). In 1990, the first dedicated journal, Pediatric Allergy and Immunology (PAI), was founded. There are striking differences across Europe, and even within European countries, in relation to the training pathways for doctors seeing children with allergic disease(s). In 2016, the EAACIClemens von Pirquet Foundation (CvP) organized and sponsored a workshop with the European Academy of Allergy and Clinical Immunology (EAACI) Pediatric Section. This collaboration focussed on the future of PA and specifically on education, research, and networking/ advocacy. The delegates representing many countries across Europe have endorsed the concept that optimal care of children with allergic diseases is delivered by pediatricians who have received dedicated training in allergy, or allergists who have received dedicated training in pediatrics. In order to meet the needs of children and families with allergic disease(s), the pediatric allergist is highly encouraged to develop several networks. Our challenge is to reinforce a clear strategic approach to scientific excellence to across our member base and to ensure and enhance the relevance of European pediatric research in allergy. With research opportunities in basic, translational, clinical, and epidemiologic trials, more trainees and trained specialists are needed and it is an exciting time to be a pediatric allergologist.     

Pediatric infection due to multiresistant Salmonella enterica serotype Infantis in Honduras

We report the case of a pediatric patient with a Salmonella enterica serotype Infantis infection. Detailed microbiological investigation revealed that this isolate carries four beta-lactamase genes (bla(TEM-1b) variant, bla(SHV-5), bla(CTX-M-15), and bla(CMY-2)) conferring resistance to all beta-lactams but imipenem. This is the first report of a Salmonella isolate with CTX-M and AmpC enzymes on the American continent, the first report of bla(CMY-2) in Salmonella serotype Infantis, and the first report of bla(CTX-M-15) in the genus Salmonella.     

Differences in metabolic parameters and cardiovascular risk between American Diabetes Association and World Health Organization definition of impaired fasting glucose in European Caucasian subjects: a cross-sectional study

Introduction

The American Diabetes Association (ADA) defines impaired fasting glucose (IFG) as fasting plasma glucose concentration of 100–125 mg/dl, whereas the World Health Organization (WHO) and the International Diabetes Federation (IDF) define IFG as fasting plasma glucose levels of 110–125 mg/dl. We identified differences in metabolic parameters and cardiovascular disease (CVD) risk according to the ADA or WHO/IDF definition of IFG.

Material and methods

Healthy drug-naive Caucasian (Greek) subjects (n = 396; age 55 ±12 years) participated in this cross-sectional study.

Results

Diastolic blood pressure (DBP) and uric acid levels were higher in the subjects with glucose 100–109 mg/dl compared with those with glucose < 100 mg/dl (87 ±9 mm Hg vs. 84 ±11 mm Hg, p = 0.004 for DBP, 5.6 ±1.5 mg/dl vs. 5.0 ±1.0 mg/dl, p = 0.002 for uric acid), whereas triglyceride levels were lower in subjects with glucose 100–109 mg/dl compared with those with glucose ≥ 110 mg/dl (169 mg/dl (interquartile range (IQR) = 102–186) vs. 186 mg/dl (IQR = 115–242), p = 0.002). Only the ADA definition recognized subjects with significantly increased 10-year CVD risk estimation (SCORE risk calculation) compared with their respective controls (5.4% (IQR = 0.9–7.3) vs. 4.1% (IQR = 0.7–5.8), p = 0.002).

Conclusions

The ADA IFG definition recognized more subjects with significantly increased CVD risk (SCORE model) compared with the WHO/IDF definition.