Chronic pain can develop in response to conditions such as inflammatory arthritis. The central mechanisms underlying the development and maintenance of chronic pain in humans are not well elucidated although there is evidence for a role of microglia and astrocytes. However in pre-clinical models of pain, including models of inflammatory arthritis, there is a wealth of evidence indicating roles for pathological glial reactivity within the CNS. In the spinal dorsal horn of rats with painful inflammatory arthritis we found both a significant increase in CD11b microglia-like cells and GFAP astrocytes associated with blood vessels, and the number of activated blood vessels expressing the adhesion molecule ICAM-1, indicating potential glio-vascular activation. Using pharmacological interventions targeting VEGFR2 in arthritic rats, to inhibit endothelial cell activation, the number of dorsal horn ICAM-1 blood vessels, CD11b microglia and the development of secondary mechanical allodynia, an indicator of central sensitization, were all prevented. Targeting endothelial VEGFR2 by inducible Tie2-specific VEGFR2 knock-out also prevented secondary allodynia in mice and glio-vascular activation in the dorsal horn in response to inflammatory arthritis. Inhibition of VEGFR2 in vitro significantly blocked ICAM-1-dependent monocyte adhesion to brain microvascular endothelial cells, when stimulated with inflammatory mediators TNF-α and VEGF-Aa. Taken together our findings suggest that a novel VEGFR2-mediated spinal cord glio-vascular mechanism may promote peripheral CD11b circulating cell transmigration into the CNS parenchyma and contribute to the development of chronic pain in inflammatory arthritis. We hypothesise that preventing this glio-vascular activation and circulating cell translocation into the spinal cord could be a new therapeutic strategy for pain caused by rheumatoid arthritis.

Descending controls on spinal nociceptive processing play a pivotal role in shaping the pain experience after tissue injury. Secondary hypersensitivity develops within undamaged tissue adjacent and distant to damaged sites. Spinal neuronal pools innervating regions of secondary hypersensitivity are dominated by descending facilitation that amplifies spinal inputs from unsensitized peripheral nociceptors. Cyclooxygenase-prostaglandin (PG) E 2 signaling within the ventrolateral periaqueductal gray (vlPAG) is pronociceptive in naive and acutely inflamed animals, but its contributions in more prolonged inflammation and, importantly, secondary hypersensitivity remain unknown. In naive rats, PG EP3 receptor (EP3R) antagonism in vlPAG modulated noxious withdrawal reflex (EMG) thresholds to preferential C-nociceptor, but not A-nociceptor, activation and raised thermal withdrawal thresholds in awake animals. In rats with inflammatory arthritis, secondary mechanical and thermal hypersensitivity of the hindpaw developed and was associated with spinal sensitization to A-nociceptor inputs alone. In arthritic rats, blockade of vlPAG EP3R raised EMG thresholds to C-nociceptor activation in the area of secondary hypersensitivity to a degree equivalent to that evoked by the same manipulation in naive rats. Importantly, vlPAG EP3R blockade also affected responses to A-nociceptor activation, but only in arthritic animals. We conclude that vlPAG EP3R activity exerts an equivalent facilitation on the spinal processing of C-nociceptor inputs in naive and arthritic animals, but gains in effects on spinal A-nociceptor processing from a region of secondary hypersensitivity. Therefore, the spinal sensitization to A-nociceptor inputs associated with secondary hypersensitivity is likely to be at least partly dependent on descending prostanergic facilitation from the vlPAG.

Introduction: Ventilator-associated pneumonia (VAP) caused by multidrug-resistant Acinetobacter baumannii (MDR-AB) is common in hospitals and impacts patient survival. We determined the incidence of MDR-AB VAP in critical care units and examined the predictors of 14-day mortality in these patients. Methodology: A retrospective case series study was conducted at a tertiary referral teaching hospital in north Jordan. A list of patients with a positive culture of A. baumannii between January 2007 and June 2013 was retrieved using computerized hospital databases. Medical records of all these patients were reviewed, and cases of VAP infected with MDR-AB were identified. Predictors of 14-day mortality were determined using multivariable logistic regression adjusted for possible confounders. Results: Out of 121 A. baumannii-VAP cases, 119 (98.3%) were caused by MDR-AB. The incidence rate of MDR-AB VAP was 1.59 cases per 100 critical care unit admissions. The mortality of A. baumannii-VAP cases in critical care units was 42% (50/119). Being prescribed two or more definitive antibiotics (prescribed based on susceptibility data) (OR = 0.075, 95% CI = 0.017-0.340, p = 0.001) and ipratropium/salbutamol during mechanical ventilation (OR = 0.140, 95% CI = 0.028-0.705, p = 0.017) were independently associated with lower hospital mortality. Conclusions: Our results suggest incidence of MDR-AB VAP in critical care units is high and that prescription of antibiotics based on antibiotic susceptibility and use of bronchodilators is associated with lower mortality in this population. Larger prospective studies are needed to explore whether these findings can be replicated in different clinical settings.

The implementation of clinical pharmacy services in this setting was successful and should positively impact patient care.