Pseudomonas aeruginosa is a frequent cause of respiratory exacerbations in individuals with cystic fibrosis. An important virulence determinant of this pathogen is its type III protein secretion system. In this study, the type III secretion properties of 435 P. aeruginosa respiratory isolates from 56 chronically infected individuals with cystic fibrosis were investigated. Although it had been previously reported that 75 to 90% of P. aeruginosa isolates from patients with hospital-acquired pneumonia secreted type III proteins, only 12% of isolates from cystic fibrosis patients did so, with nearly all of these isolates secreting ExoS and ExoT but not ExoU. Despite the low overall prevalence of type III protein-secreting isolates, at least one secreting isolate was cultured from one-third of cystic fibrosis patients. Interestingly, the fraction of cystic fibrosis patient isolates capable of secreting type III proteins decreased with duration of infection. Although 90% of isolates from the environment, the presumed reservoir for the majority of P. aeruginosa strains that infect patients with cystic fibrosis, secreted type III proteins, only 49% of isolates from newly infected children, 18% of isolates from chronically infected children, and 4% of isolates from chronically infected adults with cystic fibrosis secreted these proteins. Within individual patients, isolates of clonal origin differed in their secretion phenotypes, indicating that as strains persisted in cystic fibrosis patient airways, their type III protein secretion properties changed. Together, these findings indicate that following infection of cystic fibrosis patient airways, P. aeruginosa strains gradually change from a type III protein secretion-positive phenotype to a secretion-negative phenotype.

Disease overview POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome. Diagnosis: The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. Risk stratification: Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. The number of clinical criteria is not prognostic, but the extent of the plasma cell disorder is. Those patients with an iliac crest bone marrow biopsy that does not reveal a plasma cell clone are candidates for local radiation therapy; those with a more extensive or disseminated clone will be candidates for systemic therapy. Risk‐adapted therapy: For those patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3 to 6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. The benefit of anti‐VEGF antibodies is conflicting. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes. Am. J. Hematol. 86:592–601, 2011. © 2011 Wiley‐Liss, Inc.

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Pseudomonas aeruginosa (PA) from acute and chronic (e.g. cystic fibrosis [CF]) infections differ in several respects though they can worsen prognosis in each context. Factors that facilitate conversion from an acute to chronic phenotype are poorly understood. Type III (T3) secretion proteins are virulence factors associated with poorer outcomes in acute infections, but little is known about their role in CF. We wished to characterize T3 secretion in CF PA isolates and examine its role in clinical outcomes. One-hundred fourteen CF subjects were divided into 3 cohorts: 1 st infected individuals, chronically infected (CI) children, and adults. Serial respiratory cultures were analyzed for T3 secretion. Serial spirometry and exacerbation data were prospectively collected. In 1 st infection, 45.2% +/− 9.1% of PA isolates secreted T3 proteins compared to 29.1% +/− 4.2% and 11.5% +/− 3.0% in CI children and CI adults, respectively (p<0.001). There was an inverse correlation between duration of PA infection and percent T3 positive isolates (r=−0.32, p<0.001). Overall there was no association between T3 secretion and pulmonary outcomes, but in the subgroup of subjects who had at least one T3 positive organism, T3 secretion was inversely correlated with FEV 1 decline (r=−0.35, p=0.02). In 1 st infection, 82% of cultures grew either all or no T3 positive organisms. In these patients, T3 secretion was associated with greater risk of subsequent PA isolation (p<0.001). In CF, PA T3 secretion decreases with residence time in lung, may predict FEV 1 decline in patients who have detectable T3 organisms, and may facilitate persistence following 1 st infection.

Rationale Aminoglycoside (AG) resistance by Pseudomonas aeruginosa in Cystic Fibrosis is associated with poorer clinical outcomes and is usually due to overexpression of the efflux pump MexXY. MexXY is regulated by mexZ, one of the most commonly mutated genes in CF P. aeruginosa isolates. Little is known about the evolutionary relationship between AG resistance, MexXY expression and mexZ mutations. Objectives To test the hypothesis that AG resistance in P. aeruginosa develops in parallel with higher MexXY expression and mexZ mutations. Methods CF P. aeruginosa isolates were compared for chronically infected (CI) adults, CI children, and children with new infection. Measurements One P. aeruginosa isolate from each patient was analyzed for mexZ mutations, mexY mRNA expression, and amikacin resistance. Main Results Fifty-six CF patients were enrolled: 21 children with new P. aeruginosa infection, 18 CI children, and 17 CI adults. Amikacin resistance and mexY mRNA expression were higher in cohorts with longer P. aeruginosa infection. The prevalence of non-conservative mexZ mutations was 0%, 33%, and 65% in children with new infection, CI children, and CI adults, respectively. The same trend was seen in the ratio of non-conservative to non-synonymous mexZ mutations. Of isolates with non-conservative mexZ mutations, 59% were amikacin- resistant compared to 18% of isolates with non-synonymous mutations. The doubling rate for amikacin resistance and non-conservative mexZ mutations was approximately 5 years. Conclusion P. aeruginosa mexZ mutations undergo positive selection resulting in increased mexY mRNA expression and amikacin resistance and likely play a role in bacterial adaption in the CF lung.

The 2004 National Action Plan for Tobacco Cessation recommended that the US Department of Health and Human Services convene a diverse group of experts to ensure that competency in tobacco dependence interventions be a core graduation requirement for all new physicians and other key health care professionals. Core competencies would guide the design of new modules and explicitly outline the learning objectives for all graduating medical students. In 2002, the National Cancer Institute funded a consortium to develop, test, and integrate tobacco curricula at 12 US medical schools. Because there was neither an explicit set of tobacco competencies for medical schools nor a process to develop them, one of the consortium's tasks was to articulate competencies and learning objectives.

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