Sion Lewis

Clinical trial comparing nicotine replacement therapy (NRT) plus brief counselling, brief counselling alone, and minimal intervention on smoking cessation in hospital inpatients

Background: Guidelines recommend that smoking cessation interventions are offered in all clinical settings to all smokers willing to make a quit attempt. Since the effectiveness of routine provision of behavioural counselling and nicotine replacement therapy (NRT) to smokers admitted to hospital has not been established, a randomised controlled trial of these interventions given together compared with counselling alone or minimal intervention was performed in hospital inpatients. Methods: Medical and surgical inpatients who were current smokers at the time of admission were randomised to receive either usual care (no additional advice at admission), counselling alone (20 minute intervention with written materials), or NRT plus counselling (counselling intervention with a 6 week course of NRT). Continuous and point prevalence abstinence from smoking (validated by exhaled carbon monoxide <10 ppm) was measured at discharge from hospital and at 3 and 12 months, and self-reported reduction in cigarette consumption in smokers was assessed at 3 and 12 months. Results: 274 inpatient smokers were enrolled. Abstinence was higher in the NRT plus counselling group (n=91) than in the counselling alone (n=91) or usual care (n=92) groups. The difference between the groups was significant for validated point prevalence abstinence at discharge (55%, 43%, 37% respectively, p=0.045) and at 12 months (17%, 6%, 8%, p=0.03). The respective differences in continuous validated abstinence at 12 months were 11%, 4%, 8% (p=0.25). There was no significant difference between counselling alone and usual care, or in reduction in cigarette consumption between the treatment groups. Conclusions: NRT given with brief counselling to hospital inpatients is an effective routine smoking cessation intervention.

Increased distribution and expression of CD64 on blood polymorphonuclear cells from patients with the systemic inflammatory response syndrome (SIRS)

Evidence is growing to suggest that the multiple organ damage of the systemic inflammatory response syndrome (SIRS) arises from the untoward activity of blood polymorphonuclear cells (PMNs), which upon activation acquire the IgG high affinity receptor, CD64. In the current study, flow cytometry was used to assess the prevalence of CD64‐bearing PMNs and the intensity of expression of CD64 in whole blood samples from 32 SIRS patients, 11 healthy normal subjects and from eight non‐SIRS patients in the intensive care unit (ICU). The percentage of PMNs expressing CD64 was higher in SIRS patients (mean 65%) than in non‐SIRS patients (mean 42%; Pu2003<u20030·02) and in healthy controls (mean 19%; Pu2003<u20030·001) and was particularly evident in patients with SIRS and sepsis (mean 71%; Pu2003<u20030·02) as opposed to SIRS alone (mean 55%). There were more CD64 molecules expressed on PMNs from patients with SIRS (median 1331 molecules/cell) in comparison with PMNs from healthy subjects (median 678 molecules/cell; Pu2003<u20030·01). The highest intensity of CD64 expression was associated with PMNs from patients with both SIRS and sepsis. Functional studies revealed that the supranormal binding of PMNs from patients with SIRS to endothelial monolayers treated with TNFα was impeded by anti‐CD64 antibodies (mean 24% inhibition; Pu2003<u20030·01). Monitoring the distribution of CD64+ PMNs and their level of CD64 expression could be of assistance in the rapid discrimination of patients with SIRS from other ICU patients and in the identification of PMNs which are likely to participate in the pathological manifestations of the disease.

Ligation of the adhesion-GPCR EMR2 regulates human neutrophil function

At present, ~150 different members of the adhesion‐G protein‐coupled receptor (GPCR) family have been identified in metazoans. Surprisingly, very little is known about their function, although they all possess large extracellular domains coupled to a seven‐transmembrane domain, suggesting a potential role in cell adhesion and signaling. Here, we demonstrate how the human‐restricted adhesion‐GPCR, EMR2 (epidermal growth factor‐like module‐containing mucin‐like hormone receptor), regulates neutrophil responses by potentiating the effects of a number of proinflamma‐tory mediators and show that the transmembrane region is critical for adhesion‐GPCR function. Using an anti‐EMR2 antibody, ligation of EMR2 increases neu‐trophil adhesion and migration, and augments superoxide production and proteolytic enzyme degranulation. On neutrophil activation, EMR2 is rapidly translocated to membrane ruffles and the leading edge of the cell. Further supporting the role in neutrophil activation, EMR2 expression on circulating neutrophils is significantly increased in patients with systemic inflammation. These data illustrate a definitive function for a human adhesion‐GPCR within the innate immune system and suggest an important role in potentiating the inflammatory response. Ligation of the adhesion‐GPCR EMR2 regulates human neutrophil function.—Yona S., Lin, H.‐H., Dri, P., Davies, J. Q., Hayhoe, R. P. G., Lewis, S. M., Heinsbroek, S. E. M., Brown, K. A., Perretti, M., Hamann, J., Treacher, D. F., Gordon S., Stacey M. Ligation of the adhesion‐GPCR EMR2 regulates human neutrophil function. FASEB J. 22, 741–751 (2008)

Leucodepletion and the interaction of polymorphonuclear cells with endothelium in systemic inflammatory response syndrome

The abnormal interaction of polymorphonuclear cells (PMNs) with blood vessel walls is considered to underlie the multiple organ failure of systemic inflammatory response syndrome (SIRS). This consideration is supported by the present finding that PMNs from patients with SIRS are activated, as assessed by an increased distribution of cells bearing CD64, enhanced expression of CD11b and decreased expression of CD62L, and are highly adhesive to endothelial monolayers. Passage of SIRS blood through leucodepletion filters in a laboratory-designed extracorporeal circuit resulted in a marked depletion of PMNs. Of the PMNs that remained in the blood, far fewer cells bound to cultured endothelial cells in comparison with PMNs prior to leucofiltration. We propose that leucofiltration of SIRS blood will limit the number of PMNs available for binding to blood vessel walls and, hence, reduce the pathological manifestations associated with this disorder.

The diagnostic and prognostic significance of monitoring blood levels of immature neutrophils in patients with systemic inflammation.

IntroductionIn this cohort study, we investigated whether monitoring blood levels of immature neutrophils (myelocytes, metamyelocytes and band cells) differentiated patients with sepsis from those with the non-infectious (N-I) systemic inflammatory response syndrome (SIRS). We also ascertained if the appearance of circulating immature neutrophils was related to adverse outcome.MethodsBlood samples were routinely taken from 136 critically ill patients within 48xa0hours of ICU entry and from 20 healthy control subjects. Clinical and laboratory staff were blinded to each other’s results, and patients were retrospectively characterised into those with SIRS (nu2009=u2009122) and those without SIRS (nu2009=u200914). The patients with SIRS were further subdivided into categories of definite sepsis (nu2009=u200951), possible sepsis (nu2009=u200932) and N-I SIRS (nu2009=u200939). Two established criteria were used for monitoring immature white blood cells (WBCs): one where band cells >10% WBCs and the other where >10% of all forms of immature neutrophils were included but with a normal WBC count. Immature neutrophils in blood smears were identified according to nuclear morphology and cytoplasmic staining.ResultsWith the first criterion, band cells were present in most patients with SIRS (meanu2009=u200966%) when compared with no SIRS (meanu2009=u200929%; P <0.01) and with healthy subjects (0%). The prevalence of band cells was higher in definite sepsis (meanu2009=u200982%) than in patients with possible sepsis (meanu2009=u200963%; P <0.05) or with N-I SIRS (meanu2009=u200939%; P <0.001), and they had a sensitivity of 84% and a specificity of 71% for the detection of definite sepsis. With the second criterion (that is, patients with normal WBC counts), we noted that immature neutrophils did not differentiate any of the patient groups from one another. Patients who died within 1xa0week of blood sample provision had higher levels of myelocytes and metamyelocytes (medianu2009=u20099%; P <0.05) than patients who died at 2 to 4xa0weeks (median =0.5%).ConclusionsRaised blood levels of band cells have diagnostic significance for sepsis, provided that measurements are not confined to patients with normal WBC counts, whereas an increased prevalence of myelocytes and metamyelocytes may have prognostic application.

Plasma from Patients with Sepsis Up-Regulates the Expression of CD49d and CD64 on Blood Neutrophils

An excessive interaction of blood neutrophils with microvascular walls may underlie the organ failure of sepsis. In this study, flow cytometric analysis was used to investigate whether plasma from 22 patients with sepsis altered the expression of the adhesion molecules (CD11a, CD11b, CD49d, and CD62L) on normal blood neutrophils and enhanced their binding to cultured endothelium. Most of the plasma samples from patients with sepsis increased the percentage of neutrophils bearing CD49d (86% samples versus 22% normal plasma samples; P < 0.001) and CD64 (69% samples versus 17% normal plasma samples; P < 0.001). This effect was not seen with plasma from patients with community-acquired infections who did not develop sepsis, nor with plasma from patients with acute or chronic inflammation who had no evidence of infection. A direct association was noted between the percentage of neutrophils expressing CD64 in the blood of patients with sepsis and the ability of plasma from these patients to up-regulate CD64 on normal neutrophils. Although CD62L was present on the majority of neutrophils after incubation with sepsis plasma, it was less apparent when the cells were cultured with normal plasma. The patients plasma had no effect on neutrophils expressing CD11a and CD11b. High levels of TNF-alpha, IL-6, IL-8, and IL-10 were detected in the patients blood, but incubation of the recombinant forms of these cytokines with neutrophils, even in the presence of LPS, did not increase CD49d and CD64 expression. The sepsis plasma also enhanced the attachment of neutrophils to untreated and TNF-alpha-treated endothelium, and this binding was impeded by anti-CD49d and anti-CD64 antibodies. We suggest that changes in the phenotype of neutrophils by circulating factors may facilitate their attachment to endothelium, which may be an important factor in the induction of organ dysfunction in severe sepsis.

Expression of CD11c and EMR2 on neutrophils: Potential diagnostic biomarkers for sepsis and systemic inflammation

There is a need for cellular biomarkers to differentiate patients with sepsis from those with the non‐infectious systemic inflammatory response syndrome (SIRS). In this double‐blind study we determined whether the expression of known (CD11a/b/c, CD62L) and putative adhesion molecules [CD64, CD97 and epidermal growth factor (EGF)‐like molecule containing mucin‐like hormone receptor (EMR2)] on blood neutrophils could serve as useful biomarkers of infection and of non‐infectious SIRS in critically ill patients. We studied 103 patients with SIRS, 83 of whom had sepsis, and 50 healthy normal subjects, using flow cytometry to characterize neutrophils phenotypically in whole blood samples. Patients with SIRS had an increased prevalence of neutrophils expressing CD11c, CD64 and EMR2 in comparison with healthy subjects (Pu2009<u20090·001), but normal expression of CD11a, CD11b, CD62L and CD97. An increase in the percentage of neutrophils bearing CD11c was associated with sepsis, EMR2 with SIRS and CD64 with sepsis and SIRS. Neutrophils expressing CD11c had the highest sensitivity (81%) and specificity (80%) for the detection of sepsis, and there was an association between the percentage of neutrophils expressing EMR2 and the extent of organ failure (Pu2009<u20090·05). Contrary to other reports, we did not observe an abnormal expression of CD11b or CD62L on neutrophils from patients with SIRS, and suggest that this discrepancy is due to differences in cell processing protocols. We propose that blood neutrophils expressing CD11c and EMR2 be considered as potential biomarkers for sepsis and SIRS, respectively.

Depletion of blood neutrophils from patients with sepsis: treatment for the future?

Organ failure arising from severe sepsis accounts for nearly 6 million deaths worldwide per annum. At present there are no specific pharmacological agents available for its treatment and identifying a suitable therapeutic target is urgently needed. Neutrophils appear to be contributing directly to pulmonary damage in severe forms of lung injury and indirectly to the failure of other organs. Blood neutrophils from patients with sepsis possess a phenotype that is indicative of activation and our results show that neutrophils isolated from patients with sepsis exhibit a supranormal adherence to endothelial monolayers treated with pro-inflammatory cytokines. Additional studies reveal that the patients cells are highly efficient at releasing IL-8. We also demonstrate that organ function is improved upon removing neutrophils from the circulation. In this article we propose that in severe sepsis there is a subpopulation of neutrophils which is actively engaged in pathological insult. The phenotypic characterisation of this subset may provide a novel therapeutic strategy for sepsis that could lead to patient benefit.

Targeting cytokines as a treatment for patients with sepsis: A lost cause or a strategy still worthy of pursuit?

Despite often knowing the aetiology of sepsis and its clinical course there has not been the anticipated advances in treatment strategies. Cytokines are influential mediators of immune/inflammatory reactions and in patients with sepsis high circulating levels are implicated in the onset and perpetuation of organ failure. Antagonising the activities of pro-inflammatory cytokines enhances survival in animal models of sepsis but, so far, such a therapeutic strategy has not improved patient outcome. This article addresses the questions of why encouraging laboratory findings have failed to be translated into successful treatments of critically ill patients and whether modifying cytokine activity still remains a promising avenue for therapeutic advance in severe sepsis. In pursuing this task we have selected reports that we believe provide an incisive, critical and balanced view of the topic.

Lower prevalence of pre-morbid neurological illness in African-Caribbean than White psychotic patients in England

BACKGROUNDnIt has been suggested that the increased incidence of psychosis in African-Caribbeans living in England may be due to illnesses in which social stress plays an important aetiological role. If this is the case, the prevalence of factors associated with psychosis that predate illness onset such as obstetric complications, pre-morbid neurological illness and poor childhood social adjustment may be expected to be lower in African-Caribbean than Whites psychotic patients.nnnMETHODnDetails of obstetric complications, pre-morbid neurological illness, and pre-morbid social adjustment were obtained for 337 psychotic patients by patient interview, interviews of mothers and chart review. The proportions of patients with each risk factor in the African-Caribbean (N = 103) and White (N = 184) groups were compared using regression analysis; age, sex, social class, diagnosis and referral status were possible explanatory variables.nnnRESULTSnAfrican-Caribbean patients were less likely to have suffered a pre-morbid neurological disorder than their White counterparts (odds ratio 0.19, 95% CI 0.06-0.61). There was no significant difference in pre-morbid social adjustment or obstetric complications between the two groups, though fewer obstetric complications were reported in the African-Caribbean group (21.5%) than the White group (30.9%).nnnCONCLUSIONSnAfrican-Caribbean patients with psychosis have experienced less pre-morbid neurological illness.