Exhaled Pneumocystis jirovecii output and detection of asymptomatic exhalation by facemask sampling in HIV-uninfected, immunocompromised patients.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) transmission is poorly defined. Previous studies have sampled air of rooms occupied by HIV-infected patients with PJP, while natural and direct exhalations of HIV-uninfected subjects remain under-investigated. Here, clinical facemasks were used to examine and quantify potential P. jirovecii exhalations from HIV-uninfected patients with suspected PJP and to determine whether pathogen exhalation was definable clinically or radiologically. METHODS: Forty-five patients in Leicester (England), highly suspected of having PJP based on European Conference on Infections in Leukaemia (ECIL-5) guidelines, each wore one facemask carrying a gelatine/PVA sampling matrix for 1 h while respiring normally. Mask contamination with P. jirovecii was assessed using a modified quantitative polymerase chain reaction targeting mitochondrial large subunit (MtLSU). Radiological findings on chest X-ray (CXR) and computed tomography (CT) were graded and analysed for correlation with P. jirovecii signals alongside relevant clinical and laboratory findings. RESULTS: P. jirovecii was detected in seven of 20 patients diagnosed with PJP and three of 19 patients with suspected but undiagnosed PJP. The median captured signal was 8.59 × 104 MtLSU copies/mask (interquartile range (IQR) = 3.01 × 105-1.81 × 104). Blood ß-D-glucan test results correlated with the mask detection data (r = 0.65; P<0.0001) but other clinical indices and radiological features did not. Five of the 10 P. jirovecii-exhalers exhibited normal CXR with a median exhalation burden 1.28 × 105 copies/mask (IQR = 1.51 × 105-2.27 × 104). Two P. jirovecii-exhalers (7.64 × 104 copies/mask) were asymptomatic. CONCLUSION: P. jirovecii was exhaled sufficiently during normal respiration to be detectable in facemasks worn by HIV-uninfected patients. Neither clinical nor radiological features correlated with P. jirovecii exhalation.

An evolutionary perspective on the immunomodulatory role of hydrogen sulphide.

Most preclinical studies on endogenous hydrogen sulphide signalling have given little consideration to the fact that the human body contains more bacterial cells than human cells, and that evolution provides the context for all biology. Whether hydrogen sulphide is pro or anti-inflammatory is heavily debated within the literature, yet researchers have not fully considered that invasive bacteria produce hydrogen sulphide, often at levels far above the endogenous levels of the host. Here I argue that if hydrogen sulphide is an endogenous signalling molecule with immunomodulatory functions, then it must have evolved in the presence of virulent bacteria which produce hydrogen sulphide. This context leads to two competing theories about the evolution of endogenous hydrogen sulphide signalling. The detectable emission theory proposes that bacteria produce hydrogen sulphide as part of normal metabolism and hosts which evolved to detect and respond to this hydrogen sulphide would gain a selective survival advantage. This predicts that the endogenous production of hydrogen sulphide is a mechanism which amplifies the bacterial hydrogen sulphide signal. The opposing protective agent theory predicts that bacterial hydrogen sulphide is an effective defence against the bactericidal mechanisms of the host's immune response. In this case, endogenous hydrogen sulphide production is either at inconsequential levels to alter the immune response, or is involved in the inflammation resolution process. Evidence suggests that the direct interactions of hydrogen sulphide with the bactericidal mechanisms of the innate immune system are most congruent with the protective agent theory. Therefore, I argue that if hydrogen sulphide is an immunomodulatory endogenous signalling molecule its effects are most likely anti-inflammatory.

The cannabinoid CB2 receptor agonist GW405833 does not ameliorate brain damage induced by hypoxia-ischemia in rats.

The cannabinoid CB2 receptor has been under investigation as a potential target for neuroprotection with the suppression of neuroinflammation as the proposed mechanism of action. Several studies have now reported that CB2 agonists are neuroprotective in models of cerebral ischemia. However, these studies have tended to measure brain infarctions in rodents 1-3 days after drug administration and have not assessed behavioral outcomes. As it has been shown that apparent protection soon after injury is not necessarily correlated with improved outcome after several weeks, we tested the CB2 selective agonist GW405833 in a model of cerebral hypoxia-ischemia, and assessed histological and behavioral outcomes 15 days after injury. Many putatively neuroprotective drugs have failed to translate from promising preclinical results to clinical success. We designed our experiments to not only stringently test CB2 mediated neuroprotection, but also to test several drug administration regimens to maximize the chance of detecting any therapeutic effect. However, GW405833 failed to provide neuroprotection in any of our experiments. These results challenge how far the results of earlier studies into CB2 mediated neuroprotection as measured at early time points may be extrapolated to later time points or to other models.