Genetic Control of the Variable Innate Immune Response to Asymptomatic Bacteriuria

The severity of urinary tract infection (UTI) reflects the quality and magnitude of the host response. While strong local and systemic innate immune activation occurs in patients with acute pyelonephritis, the response to asymptomatic bacteriuria (ABU) is low. The immune response repertoire in ABU has not been characterized, due to the inherent problem to distinguish bacterial differences from host-determined variation. In this study, we investigated the host response to ABU and genetic variants affecting innate immune signaling and UTI susceptibility. Patients were subjected to therapeutic urinary tract inoculation with E. coli 83972 to ensure that they were exposed to the same E. coli strain. The innate immune response repertoire was characterized in urine samples, collected from each patient before and after inoculation with bacteria or PBS, if during the placebo arm of the study. Long-term E. coli 83972 ABU was established in 23 participants, who were followed for up to twelve months and the innate immune response was quantified in 233 urine samples. Neutrophil numbers increased in all but two patients and in an extended urine cytokine/chemokine analysis (31 proteins), the chemoattractants IL-8 and GRO-α, RANTES, Eotaxin-1 and MCP-1, the T cell chemoattractant and antibacterial peptide IP-10, inflammatory regulators IL-1-α and sIL-1RA and the T lymphocyte/dendritic cell product sIL-2Rα were detected and variably increased, compared to sterile samples. IL-6, which is associated with symptomatic UTI, remained low and numerous specific immune mediators were not detected. The patients were also genotyped for UTI-associated IRF3 and TLR4 promoter polymorphisms. Patients with ABU associated TLR4 polymorphisms had low neutrophil numbers, IL-6, IP-10, MCP-1 and sIL-2Rα concentrations. Patients with the ABU-associated IRF3 genotype had lower neutrophils, IL-6 and MCP-1 responses than the remaining group. The results suggest that the host-specific, low immune response to ABU mainly includes innate immune mediators and that host genetics directly influence the magnitude of this response

Climate Impacts in Europe - The JRC PESETA II Project

The objective of the JRC PESETA II project is to gain insights into the sectoral and regional patterns of climate change impacts in Europe by the end of this century. The study uses a large set of climate model runs and impact categories (ten impacts: agriculture, energy, river floods, droughts, forest fires, transport infrastructure, coasts, tourism, habitat suitability of forest tree species and human health). The project integrates biophysical direct climate impacts into a macroeconomic economic model, which enables the comparison of the different impacts based on common metrics (household welfare and economic activity). Under the reference simulation the annual total damages would be around €190 billion/year, almost 2% of EU GDP. The geographical distribution of the climate damages is very asymmetric with a clear bias towards the southern European regions. More than half of the overall annual EU damages are estimated to be due to the additional premature mortality (€120 billion). Moving to a 2°C world would reduce annual climate damages by €60 billion, to €120 billion (1.2% of GDP)

Functional evidence that ATP or a related purine is an inhibitory NANC neurotransmitter in the mouse jejunum: study on the identity of P2X and P2Y purinoceptors involved

1. Conflicting views exist on whether ATP is a neurotransmitter in the enteric nervous system. We investigated the role of ATP in enteric transmission in circular muscle strips of the mouse jejunum. 2. On PGF(2α)-precontracted muscle strips and in the presence of atropine and guanethidine, electrical field stimulation (EFS, 1–8 Hz) of nonadrenergic noncholinergic (NANC) nerves induced transient relaxations that were abolished by the nerve-conductance blocker tetrodotoxin. The NO synthase blocker L-nitroarginine (L-NOARG) partially inhibited the NANC relaxations to EFS, but fast-twitch relaxations to EFS were still observed in the presence of L-NOARG. 3. In the presence of L-NOARG, ATP, the P2X receptor agonist αβMeATP and the P2Y receptor agonist ADPβS relaxed jejunal muscle strips. Tetrodotoxin did not affect the relaxation to ATP and ADPβS, but inhibited that to αβMeATP. 4. The L-NOARG-resistant NANC relaxations to EFS were almost abolished by apamin, a blocker of small-conductance Ca(2+) activated K(+) channels, and by suramin and PPADS, blockers of P2 purinoceptors. Relaxations to ATP were almost abolished by apamin and suramin but not affected by PPADS. 5. Desensitisation of αβMeATP-sensitive P2X receptors, the P2X receptor blocker Evans blue and the P2X(1,2,3) receptor blocker NF 279 inhibited the L-NOARG-resistant NANC relaxations to EFS and that to αβMeATP without affecting the relaxation to ADPβS. Brilliant blue G, a P2X(2,5,7) receptor blocker, did not affect the relaxations to EFS. 6. Desensitisation of P2Y receptors and MRS 2179, a P2Y(1) receptor blocker, virtually abolished the L-NOARG-resistant NANC relaxations to EFS and the relaxation to ADPβS without affecting the relaxation to αβMeATP. 7. Dipyridamole, an adenosine uptake inhibitor, or theophylline and 8-phenyltheophylline, blockers of P1 and A1 purinoceptors, respectively, did not affect the purinergic NANC relaxations to EFS. 8. Our results suggest that ATP or a related purine acts as an inhibitory NANC neurotransmitter in the mouse jejunum, activating P2 but not P1 purinoceptors. Relaxations to the purinergic NANC neurotransmitter mainly involve P2Y receptors of the P2Y(1) subtype that are located postjunctionally. Purinergic NANC neurotransmission also involves P2X receptors, most likely of the P2X(1) and P2X(3) subtype, located pre- and/or postjunctionally

Regulation of basal tone, relaxation and contraction of the lower oesophageal sphincter. Relevance to drug discovery for oesophageal disorders

The lower oesophageal sphincter (LOS) is a specialized region of the oesophageal circular smooth muscle that allows the passage of a swallowed bolus to the stomach and prevents the reflux of gastric contents into the oesophagus. The anatomical arrangement of the LOS includes semicircular clasp fibres adjacent to the lesser gastric curvature and sling fibres following the greater gastric curvature. Such anatomical arrangement together with an asymmetric intrinsic innervation and distinct proportion of neurotransmitters in both regions produces an asymmetric pressure profile. The LOS tone is myogenic in origin and depends on smooth muscle properties that lead to opening of L-type Ca2+ channels; however it can be modulated by enteric motor neurons, the parasympathetic and sympathetic extrinsic nervous system and several neurohumoral substances. Nitric oxide synthesized by neuronal NOS is the main inhibitory neurotransmitter involved in LOS relaxation. Different putative neurotransmitters have been proposed to play a role together with NO. So far, only ATP or related purines have shown to be co-transmitters with NO. Acetylcholine and tachykinins are involved in the LOS contraction acting through acetylcholine M3 and tachykinin NK2 receptors. Nitric oxide can also be involved in the regulation of LOS contraction. The understanding of the mechanisms that originate and modulate LOS tone, relaxation and contraction and the characterization of neurotransmitters and receptors involved in LOS function are important to develop new pharmacological tools to treat primary oesophageal motor disorders and gastro-oesophageal reflux disease