Antibiotics have made it possible to treat bacterial infections such as meningitis and bacteraemia that, prior to their introduction, were untreatable and consequently fatal. Unfortunately, in recent decades overuse and misuse of antibiotics as well as social and economic factors have accelerated the spread of antibiotic-resistant bacteria, making drug treatment ineffective. Currently, at least 700,000 people worldwide die each year due to antimicrobial resistance (AMR). Without new and better treatments, the World Health Organization (WHO) predicts that this number could rise to 10 million by 2050, highlighting a health concern not of secondary importance. In February 2017, in light of increasing antibiotic resistance, the WHO published a list of pathogens that includes the pathogens designated by the acronym ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) to which were given the highest “priority status” since they represent the great threat to humans. Understanding the resistance mechanisms of these bacteria is a key step in the development of new antimicrobial drugs to tackle drug-resistant bacteria. In this review, both the mode of action and the mechanisms of resistance of commonly used antimicrobials will be examined. It also discusses the current state of AMR in the most critical resistant bacteria as determined by the WHO’s global priority pathogens list.

Although type I interferons (IFN-a/b) have been traditionally associated with antiviral responses, their importance in host defense against bacterial pathogens is being increasingly appreciated. Little is known, however, about the occurrence and functional role of IFN-a/b production in response to pathogenic yeasts. Here, we found that conventional DCs, but not macrophages nor plasmacytoid DCs, mounted IFN-b responses after in vitro stimulation with Candida spp. or Saccharomyces cerevisiae. These responses absolutely required MyD88, a Toll-like receptor (TLR) adaptor molecule, and were partially dependent on TLR9 and TLR7. Moreover, Candida DNA, as well as RNA, could recapitulate the IFN-b response. After intravenous challenge with Candida albicans, most mice lacking the IFN-a/b receptor died from their inability to control fungal growth, whereas all WT controls survived. These data suggest that recognition of yeast nucleic acids by TLR7 and TLR9 triggers a host-protective IFN-a/b response.Key words: Candida albicans . Cytokines . DCs . Fungal infections . Macrophages Supporting Information available online IntroductionCandida albicans (C. albicans) is, among fungi, the most common pathogen of humans. Although they are normally harmless commensals of the intestinal and urinary tract, C. albicans and other Candida species can cause recurrent mucosal infections in otherwise healthy subjects and life-threatening conditions in hospitalized or immunocompromised patients [1]. In recent years, C. albicans has become the fourth most common cause of bloodstream infections, with an incidence of between 1 and 24 cases per 100 000 and a mortality rate of 30-50% [2]. Since the host immune status is the major factor that determines the transition of C. albicans from commensalism to pathogenicity, elucidating the mechanisms underlying immune response initiation, particularly those underlying recognition of fungal components, is crucial to developing new and more effective strategies to combat these infections. In fact, despite the availability of new classes of antifungal drugs, current available therapies are only partially effective and are associated with significant side effects.Antimicrobial responses are initiated by the activation of germ-line-encoded receptors (pattern-recognition receptors, PRRs) expressed by cells of the innate immune system, mainly by macrophages and DCs, which monitor potential portals of pathogen entry. Each PRR binds directly or indirectly to one or more evolutionary conserved microbial molecules (pathogenassociated molecular patterns, PAMPs) and triggers intracellular signal transduction cascades culminating in distinctive transcriptional and nontranscriptional responses. By this mechanism, PRRs link microbial recognition with the selective activation of specific arms of the innate immune system [3].Ã These authors have contributed equally to this study. Eur. J. Immunol. 2011. 41: 1969-1979 DOI 10.1002 Immunity to infection 1969Considerable progress has been recently made in the identification ...

BACKGROUND AND PURPOSE3-Iodothyronamine (T1AM), an endogenous derivative of thyroid hormones, is regarded as a rapid modulator of behaviour and metabolism. To determine whether brain thyroid hormone levels contribute to these effects, we investigated the effect of central administration of T1AM on learning and pain threshold of mice either untreated or pretreated with clorgyline (2.5 mg·kg -1 , i.p.), an inhibitor of amine oxidative metabolism. EXPERIMENTAL APPROACHT1AM (0.13, 0.4, 1.32 and 4 mg·kg -1 ) or vehicle was injected i.c.v. into male mice, and after 30 min their effects on memory acquisition capacity, pain threshold and curiosity were evaluated by the following tests: passive avoidance, licking latency on the hot plate and movements on the hole-board platform. Plasma glycaemia was measured using a glucorefractometer. Brain levels of triiodothyroxine (T3), thyroxine (T4) and T1AM were measured by HPLC coupled to tandem MS. ERK1/2 activation and c-fos expression in different brain regions were evaluated by Western blot analysis. RESULTST1AM improved learning capacity, decreased pain threshold to hot stimuli, enhanced curiosity and raised plasma glycaemia in a dose-dependent way, without modifying T3 and T4 brain concentrations. T1AM effects on learning and pain were abolished or significantly affected by clorgyline, suggesting a role for some metabolite(s), or that T1AM interacts at the rapid desensitizing target(s). T1AM activated ERK in different brain areas at lower doses than those effective on behaviour. CONCLUSIONS AND IMPLICATIONST1AM is a novel memory enhancer. This feature might have important implications for the treatment of endocrine and neurodegenerative-induced memory disorders. AbbreviationsCREB, cyclic AMP-responsive element binding; PBST, PBS plus Tween; T1AM, 3-iodothyronamine; T3, triiodothyroxine; T4, thyroxine; TA1 receptor, trace amine-associated receptor 1

Cryptosporidium is a protozoan that infects a wide variety of vertebrates, including humans, causing acute gastroenteritis. The disease manifests with abdominal pain and diarrhea similar to that of choleric infection. In the immunocompromised hosts, the parasite causes prolonged infections that can also be fatal. For this reason, cryptosporidiosis is considered one of riskiest opportunistic infections for patients with acquired immunodeficiency syndrome. The best way to control the infection in these patients is setting up sensitive and specific diagnostic tests for epidemiological surveillance and morbidity reduction. Here, we summarized the general aspects of Cryptosporidium infection focusing on available diagnostic tools used for the diagnosis of cryptosporidiosis. Molecular methods currently available for its detection and progress in the development of new diagnostics for cryptosporidiosis are also discussed.

Although treatment of stroke patients with mild hypothermia is a promising therapeutic approach, chemicals inducing prompt and safe reduction of body temperature are an unmet need. We measured the effects of the transient receptor potential vanilloid-1 (TRPV1) agonist rinvanil on thermoregulation and ischemic brain injury in mice. Intraperitoneal or intracerebroventricular injection of rinvanil induces mild hypothermia that is prevented by the receptor antagonist capsazepine. Both intraischemic and postischemic treatments provide permanent neuroprotection in animals subjected to transient middle cerebral artery occlusion (MCAo), an effect lost in mice artificially kept normothermic. Data indicate that TRPV1 receptor agonists are promising candidates for hypothermic treatment of stroke.