Clinical and operational value of the extensively drug-resistant tuberculosis definition.

Currently, no information is available on the effect of resistance/susceptibility to first-line drugs different from isoniazid and rifampicin in determining the outcome of extensively drug-resistant tuberculosis (XDR-TB) patients, and whether being XDR-TB is a more accurate indicator of poor clinical outcome than being resistant to all first-line anti-tuberculosis (TB) drugs. To investigate this issue, a large series of multidrug-resistant TB (MDR-TB) and XDR-TB cases diagnosed in Estonia, Germany, Italy and the Russian Federation during the period 1999-2006 were analysed. Drug-susceptibility testing for first- and second-line anti-TB drugs, quality assurance and treatment delivery was performed according to World Health Organization recommendations in all study sites. Out of 4,583 culture-positive TB cases analysed, 361 (7.9%) were MDR and 64 (1.4%) were XDR. XDR-TB cases had a relative risk (RR) of 1.58 to have an unfavourable outcome compared with MDR-TB cases resistant to all first-line drugs (isoniazid, rifampicin ethambutol, streptomycin and, when tested, pyrazinamide), and an RR of 2.61 compared with "other" MDR-TB cases (those susceptible to at least one first-line anti-TB drug among ethambutol, pyrazinamide and streptomycin, regardless of resistance to the second-line drugs not defining XDR-TB). The emergence of extensively drug-resistant tuberculosis confirms that problems in tuberculosis management are still present in Europe. While waiting for new tools which will facilitate management of extensively drug-resistant tuberculosis, accessibility to quality diagnostic and treatment services should be urgently ensured and adequate public health policies should be rapidly implemented to prevent further development of drug resistance

Choice of Bacterial Growth Medium Alters the Transcriptome and Phenotype of Salmonella enterica Serovar Typhimurium

The type of bacterial culture medium is an important consideration during design of any experimental protocol. The aim of this study was to understand the impact of medium choice on bacterial gene expression and physiology by comparing the transcriptome of Salmonella enterica SL1344 after growth in the widely used LB broth or the rationally designed MOPS minimal medium. Transcriptomics showed that after growth in MOPS minimal media, compared to LB, there was increased expression of 42 genes involved in amino acid synthesis and 23 genes coding for ABC transporters. Seven flagellar genes had decreased expression after growth in MOPS minimal medium and this correlated with a decreased motility. In both MOPS minimal medium and MEM expression of genes from SPI-2 was increased and the adhesion of S. Typhimurium to intestinal epithelial cells was higher compared to the levels after growth in LB. However, SL1344 invasion was not significantly altered by growth in either MOPs minimal media or MEM. Expression of SPI-2 was also measured using chromosomal GFP reporter fusions followed by flow cytometry which showed, for the first time, that the reduction in SPI-2 transcript after growth in different media related to a reduction in the proportion of the bacterial population expressing SPI-2. These data highlight the profound differences in the global transcriptome after in vitro growth in different media and show that choice of medium should be considered carefully during experimental design, particularly when virulence related phenotypes are being measured

Tackling TB in migrants arriving at Europe’s southern border

Over a quarter of the individuals diagnosed with tuberculosis [TB] in the European Union region are born outside of the area and the proportion has been increasing steadily. Italy is a low TB incidence country with over 50% of TB cases in the foreign-born population primarily due to the high numbers of migrants entering the country via land or sea. As a case study to evaluate the value of screening in newly arrived migrants, the EDETECT-TB project in Italy implemented and evaluated active TB screening in the migrant population at first reception centres to ensure early diagnosis to avoid further spread. Based on a cost-effectiveness analysis from a program provider perspective, a decision tree model allowed the assessment of the value for money of case finding by estimating the cost per case of active TB detected compared with the status quo of no screening. The analysis confirmed that early case detection is a cost-effective intervention in areas with migrants arriving from high TB risk settings. Targeted post-arrival early screening of high TB risk vulnerable new entrants to Italy has a potential role in reducing the spread of TB among migrants

Nicotinic receptors

Regulation of normal or abnormal behaviour is critically controlled by the central serotonergic systems. Recent evidence has suggested that serotonin (5-HT) neurotransmission dysfunction contributes to a variety of pathological conditions, including depression, anxiety, schizophrenia and Parkinson’s disorders. There is also a great amount of evidence indicating that 5-HT signalling may affect the reinforcing properties of drugs of abuse by the interaction and modulation of dopamine (DA) function. This chapter is focused on one of the more addictive drugs, nicotine. It is widely recognised that the effects of nicotine are strongly associated with the stimulatory action it exhibits on mesolimbic DAergic function. We outline the role of 5-HT and its plethora of receptors, focusing on 5-HT2 subtypes with relation to their involvement in the neurobiology of nicotine addiction. We also explore the novel pharmacological approaches using 5-HT agents for the treatment of nicotine dependence. Compelling evidence shows that 5-HT2C receptor agonists may be possible therapeutic targets for smoking cessation, although further investigation is required.peer-reviewe

The Tuberculosis Network European Trials group (TBnet) ERS Clinical Research Collaboration: addressing drug-resistant tuberculosis through European cooperation

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Tocolytic effect of a selective FP receptor antagonist in rodent models reveals an innovative approach to the treatment of preterm labor

<p>Abstract</p> <p>Background</p> <p>Management of preterm labor by tocolysis remains an unmet medical need. Prostaglandins play a major role in regulation of uterine activity and in molecular mechanisms of human labor and parturition. There is some circumstantial evidence that prostaglandin F2α by action through the prostaglandin receptor subtype FP is effective in key events during labor uterine contraction, rupture of membranes and cervical dilation. This role of FP is briefly reviewed. In this study, we tested the hypothesis that an orally active and selective FP antagonist may arrest labor and delay parturition in animal models.</p> <p>Methods</p> <p>We examined the effects of a small molecule selective antagonist of the FP receptor (AS604872) in inhibition of spontaneous uterine contraction in pregnant rat near term. We tested AS604872 for its ability to delay preterm birth in a mouse model in which the anti-progestin agent RU486 triggered parturition.</p> <p>Results</p> <p>By oral or intravenous dosing AS604872 reduced markedly and dose-dependently the spontaneous uterine contractions in late-term pregnant rats at gestational days 19–21. In pregnant mice, AS604872 delayed the preterm birth caused by RU486 administration. The effect was dose-dependent with a significant increase in the mean delivery time of 16 and 33 hours at oral doses of 30 mg/kg and 100 mg/kg, respectively, in the case of labor triggered at gestational day 14. In both models AS604872 appeared more effective than the β-agonist ritodrine.</p> <p>Conclusion</p> <p>The tocolytic activity displayed by a selective FP receptor antagonist supports a key role for the FP receptor in the pathophysiology of premature birth and demonstrates the therapeutic potential of an FP antagonist for the treatment of preterm labor cases in which uterine hyperactivity plays a dominant role.</p

Emerging roles of ATF2 and the dynamic AP1 network in cancer

Cooperation among transcription factors is central for their ability to execute specific transcriptional programmes. The AP1 complex exemplifies a network of transcription factors that function in unison under normal circumstances and during the course of tumour development and progression. This Perspective summarizes our current understanding of the changes in members of the AP1 complex and the role of ATF2 as part of this complex in tumorigenesis.Fil: Lopez Bergami, Pablo Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Lau, Eric . Burnham Institute for Medical Research; Estados UnidosFil: Ronai, Zeev . Burnham Institute for Medical Research; Estados Unido

App-based symptoms screening with Xpert MTB/RIF Ultra assay used for active tuberculosis detection in migrants at point of arrivals in Italy: The E-DETECT TB intervention analysis

BACKGROUND: From 2014 to 2017, the number of migrants who came to Italy via the Mediterranean route has reached an unprecedented level. The majority of refugees and migrants were rescued in the Central Mediterranean and disembarked at ports in the Sicily region. Rapid on-spot active TB screening intervention at the point of arrival will cover most migrants arriving in EU and by detecting TB prevalent cases will limit further transmission of the disease. // MATERIAL AND METHODS: Between November 2016 and December 2017 newly arrived migrants at point of arrivals in Sicily, were screened for active Tuberculosis using a smartphone application, followed in symptomatic individuals by fast molecular test, Xpert MTB/RIF Ultra, on collected sputum samples. // RESULTS: In the study period 3787 migrants received a medical evaluation. Eight hundred and ninety-one (23.5%) reported at least one protocol-defined Tuberculosis symptom. Fifteen (2.7%) were positive to at least one microbiological test revealing a post-entry screening prevalence rate of 396 per 100.000 individuals screened (95% CI: 2.22-6.53). In logistic regression analysis, those with cough and at least one other symptom had an increased probability of testing positive compared to persons with symptoms other than cough. Whole-genome-sequencing demonstrate two separate cases of transmission. // DISCUSSION: To our knowledge this study reports first-time results of an active TB case finding strategy based on on-spot symptom screening using a smartphone application, followed by fast molecular test on collected sputum samples. Our preliminary findings reveal a post-entry screening prevalence rate of 396 per 100.000 individuals screened (95% CI: 2.22-6.53)