Microbiological changes observed over 48 weeks of treatment with inhaled liposomal ciprofloxacin in individuals with non-cystic fibrosis bronchiectasis and chronic Pseudomonas aeruginosa lung infection

ObjectivesNon-cystic fibrosis bronchiectasis (NCFBE) with Pseudomonas aeruginosa has been associated with increased pulmonary exacerbation (PEx) and mortality risk. European Respiratory Society guidelines conditionally recommend inhaled antimicrobials for persons with NCFBE, P aeruginosa and three or more PEx/year. We report microbiological results of two randomized, 48-week placebo-controlled trials of ARD-3150 (inhaled liposomal ciprofloxacin) in individuals with NCFBE with P aeruginosa and PEx history [Lancet Respir Med 2019;7:213–26].MethodsRespiratory secretions from 582 participants receiving up to six 28-day on/off treatment cycles were analysed for sputum P. aeruginosa, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and Escherichia coli densities, P. aeruginosa susceptibilities to ciprofloxacin and nine other antimicrobials, and prevalence of other bacterial opportunists. Associations between PEx risk and sputum density, antimicrobial susceptibility and opportunist prevalence changes were studied.ResultsSputum P. aeruginosa density reductions from baseline after ARD-3150 treatments ranged from 1.77 (95% CI 2.13–1.40) versus 0.54 (95% CI 0.89–0.19) log₁₀ CFU/g for placebo (second period) to 2.07 (95% CI 2.45–1.69) versus 0.70 (95% CI 1.11–0.29) log₁₀ CFU/g for placebo (fourth period) with only modest correlation between density reduction magnitude and PEx benefit. ARD-3150 (but not placebo) treatment was associated with increased P. aeruginosa ciprofloxacin MIC but not emergence of other bacterial opportunists across the study; ciprofloxacin MIC₅₀ increased from 0.5 to 1 mg/L, MIC₉₀ increased from 4 to 16 mg/L. Other antimicrobial MIC were mostly unaffected.ConclusionMicrobiological changes over 48 weeks of ARD-3150 treatment appear modest. Ciprofloxacin susceptibility (but not other antimicrobial susceptibility) decreases were observed that did not appear to preclude PEx risk reduction benefit.     

Intestinal schistosomiasis: a very long-lived tropical parasite

We report a case of intestinal schistosomiasis in a patient who had not travelled outside Europe after migrating 20 years ago. Images of the Schistosoma mansoni eggs are shown that confirm the active nature of the infection.     

Microbiological diagnostics of bloodstream infections in Europe—an ESGBIES survey

ObjectivesHigh-quality diagnosis of bloodstream infections (BSI) is important for successful patient management. As knowledge on current practices of microbiological BSI diagnostics is limited, this project aimed to assess its current state in European microbiological laboratories.MethodsWe performed an online questionnaire-based cross-sectional survey comprising 34 questions on practices of microbiological BSI diagnostics. The ESCMID Study Group for Bloodstream Infections, Endocarditis and Sepsis (ESGBIES) was the primary platform to engage national coordinators who recruited laboratories within their countries.ResultsResponses were received from 209 laboratories in 25 European countries. Although 32.5% (68/209) of laboratories only used the classical processing of positive blood cultures (BC), two-thirds applied rapid technologies. Of laboratories that provided data, 42.2% (78/185) were able to start incubating BC in automated BC incubators around-the-clock, and only 13% (25/192) had established a 24-h service to start immediate processing of positive BC. Only 4.7% (9/190) of laboratories validated and transmitted the results of identification and antimicrobial susceptibility testing (AST) of BC pathogens to clinicians 24 h/day. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry from briefly incubated sub-cultures on solid media was the most commonly used approach to rapid pathogen identification from positive BC, and direct disc diffusion was the most common rapid AST method from positive BC.ConclusionsLaboratories have started to implement novel technologies for rapid identification and AST for positive BC. However, progress is severely compromised by limited operating hours such that current practice of BC diagnostics in Europe complies only partly with the requirements for optimal BSI management.     

Effects of intermittent hypoxia training on leukocyte pyruvate dehydrogenase kinase 1 (PDK-1) mRNA expression and blood insulin level in prediabetes patients

Purpose

Intermittent hypoxia training/treatment (IHT) is an emerging therapeutic approach to alleviate chronic diseases, such as diabetes. The present study investigated the effects of IHT on blood leucocyte pyruvate dehydrogenase kinase 1 (PDK-1) mRNA expression and its relationship with the changes in blood insulin level.

Methods

Seven adult healthy volunteers and 11 prediabetic patients participated in this study. A 3-week course of IHT consisted of a 40-min session of 4 cycles of 5-min 12% O₂ and 5-min room air breathing per day, 3 sessions per week for 3 weeks (i.e., total 9 sessions of IHT). Plasma insulin levels and leukocyte PDK-1 mRNA expression were determined at various time points either under fasting condition or following oral glucose tolerance test (OGTT). Correlation between the IHT-induced changes in PDK-1 mRNA and insulin or glucose levels in the same serological samples was analyzed.

Results

At pre-IHT baseline, PDK-1 mRNA expression was two times higher in prediabetes than control subjects. IHT resulted in significant augmentation in PDK-1 mRNA expression (> twofold) in prediabetes at the end of 3-week IHT and remained elevated 1 month after IHT, which was correlated with a significantly reduced insulin release and lower blood glucose after glucose loading with OGTT.

Conclusion

IHT can trigger beneficial effects in normalizing blood insulin levels in prediabetic patients under oral glucose load, which were closely correlated with an enhanced mRNA expression of PDK-1 in leukocytes. Further clinical trials are warranted to validate the utility of IHT as a non-invasive complementary therapy against diabetes-associated pathologies.

     

Non- Hodgkin lymphoma of the lips: A rare entity

AimTo investigate clinico-pathological features of lymphoma of the lips, and review the literature.Materials and MethodsRetrospective analysis and review of English literature, 1996-2016.ResultsAnalysis included 23 cases, 7 new cases and 16 from literature, 12 M: 11 F, age 7–82 years. Four occurred in children, mean age 10.1; 19 in adults, mean 61.1 years.The lower lip was involved in the majority of cases (16, 69.56%). 14 (60.87%) were isolated to the lips, 8 (34.78%) were multifocal. Nine (39.13%) occurred in association with Sjogren's syndrome, of which one also had Hashimoto thyroiditis. IgG4-related disease and HIV were reported in one case each. The lip salivary glands were involved in most cases (19, 82.6%); 3 (13.6%) showed only cutaneous involvement.The typical presentation was single or multiple nodules (15, 65.21%), with surface ulceration in only two (8.69%). Constituent symptoms were absent in all cases, paresthesia was reported in one (4.34%). The majority (18, 78.26%) was extranodal marginal zone B-cell lymphoma - mucosa-associated lymphoid tissue lymphoma (EMZB-MALT), and one case each was mantle cell, NK-T cell, CD30 positive and plasmablastic lymphoma.ConclusionThe lips seem to have a unique pattern of non-Hodgkin lymphoma dominated by EMZB-MALT lymphoma, rarely other types. In more than half, neither Sjogren's syndrome nor other chronic inflammation was identified. Lesions tend to present as asymptomatic slowly progressing, non-ulcerated submucosal masses. Lymphoma should be considered even in the absence of constituent symptoms, as most cases showed none. Although the number of reported cases is rather small, disease course is usually prolonged and prognosis seems to be good.     

Structural correlates of the orbitofrontal cortex and amygdala and personality in female adolescents

The five‐factor model consists of cognitive‐affective‐behavioral trait dimensions (neuroticism, extraversion, openness to experience, agreeableness, conscientiousness) that are central to models of psychopathology. In adults, individual differences in three of the Big Five traits, neuroticism, extraversion, and conscientiousness, have been linked to structural morphology and connectivity of the orbitofrontal cortex (OFC) and the amygdala, two brain regions critically involved in affective and regulatory processing. It is unclear whether these associations manifest in adolescence, a critical neurodevelopmental period during which many forms of psychiatric illness emerge. A total of 223 adolescent girls (ages 14–16 years) completed a multimodal neuroimaging study that utilized T1‐weighted structural MRI (e.g., cortical thickness and volume) and tractography‐based diffusion tensor imaging (64‐direction). Cortical thickness and volume were extracted from the medial orbitofrontal cortex (mOFC) and amygdala and tractography‐based fractional anisotropy was computed in the uncinate fasciculus (UF; the white matter tract connecting the OFC to the temporal lobe). We found that high neuroticism was associated with less mOFC volume (bilateral), and low conscientiousness was associated with higher white matter integrity in the UF, more amygdala volume, and less mOFC thickness (right hemisphere). Extraversion was not observed to share associations with OFC markers. These OFC‐amygdala structural correlations to personality do not match those reported in adult samples. Multimodal neuroimaging techniques can help to clarify the underpinnings of personality development between adolescence and adulthood.     

Developmental origins of murine γδ T-cell subsets

Murine γδ T cells display diverse responses to pathogens and tumours through early provision of pro-inflammatory cytokines such as interleukin-17A (IL-17) and interferon-γ (IFN-γ). Although it is now clear that acquisition of these cytokine-secreting effector fates is to a great extent developmentally pre-programmed in the thymus, the stages through which γδ progenitor cells transition, and the underlying mechanistic processes that govern these commitment events, are still largely unclear. Here, we review recent progress in the field, with particular consideration of how TCR-γδ signalling impacts on developmental programmes initiated before TCR-γδ expression.     

Intraductal carcinoma of the prostate in the absence of high-grade invasive carcinoma represents a molecularly distinct type of in situ carcinoma enriched with oncogenic driver mutations

Intraductal carcinoma of the prostate (IDC-P) most often appears associated with high-grade invasive prostate carcinoma (PCa), where it is believed to represent retrograde spread. However, IDC-P rarely occurs as an isolated finding at radical prostatectomy or with concurrent low-grade (Grade Group 1) invasive carcinoma. We hypothesized that isolated IDC-P (iIDC-P) in these unusual cases may represent a distinct in situ lesion and molecularly profiled 15 cases. iIDC-P was characterized by copy number alteration (CNA) profiling and targeted next generation sequencing in cases with sufficient tissue (n = 7). Immunohistochemistry for PTEN and ERG was performed on the total cohort (n = 15), where areas of iIDC-P and associated invasive disease were evaluated separately (n = 9). By copy number profiling, iIDC-P alterations were similar to those previously described in high-grade invasive PCa (PTEN, RB1, and CHD1 loss; MYC gain). However, in four cases, targeted sequencing revealed a striking number of activating oncogenic driver mutations in MAPK and PI3K pathway genes, which are extraordinarily rare in conventional PCa. In addition, pathogenic mutations in DNA repair genes were found in two cases of iIDC-P (BRCA2, CHEK2, CDK12) and other known PCa-associated mutations (FOXA1, SPOP) in two cases. Overall, ERG was expressed in 7% (1/15) of the iIDC-P lesions and PTEN was lost in 53% (8/15). Discordance for ERG or PTEN status between IDC-P and the low-grade PCa was observed in five of nine cases, with intact PTEN in the invasive tumor and PTEN loss in IDC-P in four. Despite a CNA profile similar to conventional PCa, iIDC-P is enriched with potentially targetable oncogenic driver mutations in MAPK/PI3K genes. Based on PTEN and ERG status, iIDC-P is not likely a precursor to the associated low-grade invasive PCa, but represents a molecularly unique in situ tumor of unclear clinical significance. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.