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The effect of a saccharin-based artificial sweetener was tested on animal performance measures and on the microbial communities associated with the rumen content and with the rumen epithelium during heat stress. Ten cannulated Holstein-Friesian milking dairy cattle were supplemented with 2 g of saccharin-based sweetener per day, top-dressed into individual feeders for a 7-day adaptation period followed by a 14-day heat stress period. A control group of ten additional cows subjected to the same environmental conditions but not supplemented with sweetener were included for comparison. 16S rRNA gene amplicon sequencing was performed on rumen content and rumen epithelium samples from all animals, and comparisons of rumen content microbiota and rumen epithelial microbiota were made between supplemented and control populations. Supplementation of the saccharin-based sweetener did not affect the rumen content microbiota, but differences in the rumen epithelial microbiota beta-diversity (PERMANOVA, P = 0.003, R 2 = 0.12) and alpha-diversity (Chao species richness, P = 0.06 and Shannon diversity, P = 0.034) were detected between the supplemented and control experimental groups. Despite the changes detected in the microbial community, animal performance metrics including feed intake, milk yield, and short-chain fatty acid (acetic, propionic, and butyric acid) concentrations were not different between experimental groups. Thus, under the conditions applied, supplementation with a saccharin-based sweetener does not appear to affect animal performance under heat stress. Additionally, we detected differences in the rumen epithelial microbiota due to heat stress when comparing initial, prestressed microbial communities to the communities after heat stress. Importantly, the changes occurring in the rumen epithelial microbiota may have implications on barrier integrity, oxygen scavenging, and urease activity. This research adds insight into the impact of saccharin-based sweeteners on the rumen microbiota and the responsivity of the rumen epithelial microbiota to different stimuli, providing novel hypotheses for future research. [ABSTRACT FROM AUTHOR]

The benefits of living in groups drive the evolution of sociality, and these benefits could vary across a life-cycle. However, there may be experimental problems in linking group size at one time in a life-cycle to benefits that only become apparent later on when group size has changed, leading to what we call "temporal dissonance". In the only known social colletid bee, Amphylaeus morosus , parasite pressures arise at various times throughout the life-cycle from different parasitoid species. Amphylaeus morosus is impacted by eight different parasitoid species operating at different host-colony phenology phases, including five species of Gasteruption wasps, a bombyliid fly and two mutillid wasp species. We found that, as the reproductive season progressed, the number of host adults in a nest declined, often to zero, but the presence of even one adult host female during late brood-rearing stages appeared to offer substantial brood protection against mutillids. We propose that the apparent benefits of colony size at one point in time may not reflect the benefits that become apparent at a later point in the season, leading to a temporal dissonance between group size and its later fitness benefits. We also show that A. morosus is strongly protogynous, with variation in parasitoid pressure across the reproductive phenology distorting operational sex ratios away from initial investment ratios. Combined, our data suggest that seasonal variation in parasitoid pressure may have major consequences for understanding social evolution, but these kinds of consequences are largely unexplored in current studies of insect social evolution. [ABSTRACT FROM AUTHOR]

An unusual feature of the opportunistic pathogen Candida albicans is its ability to switch stochastically between two distinct, heritable cell types called white and opaque. Here, we show that only opaque cells, in response to environmental signals, massively upregulate a specific group of secreted proteases and peptide transporters, allowing exceptionally efficient use of proteins as sources of nitrogen. We identify the specific proteases [members of the secreted aspartyl protease (SAP) family] needed for opaque cells to proliferate under these conditions, and we identify four transcriptional regulators of this specialized proteolysis and uptake program. We also show that, in mixed cultures, opaque cells enable white cells to also proliferate efficiently when proteins are the sole nitrogen source. Based on these observations, we suggest that one role of white-opaque switching is to create mixed populations where the different phenotypes derived from a single genome are shared between two distinct cell types. [ABSTRACT FROM AUTHOR]

The fungal species Candida albicans is both a member of the human microbiome and a fungal pathogen. C. albicans undergoes several different morphological transitions, including one called white-opaque switching. Here, cells reversibly switch between two states, "white" and "opaque," and each state is heritable through many cell generations. Each cell type has a distinct cellular and colony morphology and they differ in many other properties including mating, nutritional specialization, and interactions with the innate immune system. Previous genetic screens to gain insight into white-opaque switching have focused on certain classes of genes (for example transcriptional regulators or chromatin modifying enzymes). In this paper, we examined 172 deletion mutants covering a broad range of cell functions. We identified 28 deletion mutants with at least a fivefold effect on switching frequencies; these cover a wide variety of functions ranging from membrane sensors to kinases to proteins of unknown function. In agreement with previous reports, we found that components of the pheromone signaling cascade affect white-to-opaque switching; however, our results suggest that the major effect of Cek1 on white-opaque switching occurs through the cell wall damage response pathway. Most of the genes we identified have not been previously implicated in white-opaque switching and serve as entry points to understand new aspects of this morphological transition. [ABSTRACT FROM AUTHOR]

Cystic fibrosis gastrointestinal disease includes nutrient malabsorption and intestinal inflammation. We show that the abundances of Escherichia coli in fecal microbiota were significantly higher in young children with cystic fibrosis than in controls and correlated with fecal measures of nutrient malabsorption and inflammation, suggesting that E. coli could contribute to cystic fibrosis gastrointestinal dysfunction. [ABSTRACT FROM PUBLISHER]

The increasing prevalence of immune-related diseases, including multiple sclerosis, may be partly explained by reduced microbial burden during childhood. Within a multi-centre case-control study population, we examined: (i) the co-morbid immune diseases profile of adults with a first clinical diagnosis of central nervous system demyelination ( FCD) and (ii) sibship structure in relation to an autoimmune ( FCD) and an allergic (asthma) disease. FCD cases ( n = 282) were aged 18-59 years; controls ( n = 558) were matched on age, sex and region. Measures include: history of doctor-diagnosed asthma; sibling profile (number; dates of birth); and regular childcare attendance. FCD cases did not differ from controls with regard to personal or family history of allergy, but had a greater likelihood of chronic fatigue syndrome [odds ratio ( OR) = 3·11; 95% confidence interval ( CI) 1·11, 8·71]. Having any younger siblings showed reduced odds of FCD ( OR = 0·68; 95% CI: 0·49, 0·95) but not asthma ( OR = 1·47; 95% CI: 0·91, 2·38). In contrast, an increasing number of older siblings was associated with reduced risk of asthma ( P trend = 0·04) but not FCD ( P trend = 0·66). Allergies were not over-represented among people presenting with FCD. Sibship characteristics influence both FCD and asthma risk but the underlying mechanisms differ, possibly due to the timing of the putative 'sibling effect'. [ABSTRACT FROM AUTHOR]

Observational studies suggest that people with a high serum 25-hydroxyvitamin D (25(OH)D) concentration may have reduced risk of chronic diseases such as osteoporosis, multiple sclerosis, type 1 diabetes, cardiovascular disease, and some cancers. The AusD Study (A Quantitative Assessment of Solar UV Exposure for Vitamin D Synthesis in Australian Adults) was conducted to clarify the relationships between ultraviolet (UV) radiation exposure, dietary intake of vitamin D, and serum 25(OH)D concentration among Australian adults residing in Townsville (19.3°S), Brisbane (27.5°S), Canberra (35.3°S), and Hobart (42.8°S). Participants aged 18–75 years were recruited from the Australian Electoral Roll between 2009 and 2010. Measurements were made of height, weight, waist:hip ratio, skin, hair, and eye color, blood pressure, and grip strength. Participants completed a questionnaire on sun exposure and vitamin D intake, together with 10 days of personal UV dosimetry and an associated sun-exposure and physical-activity diary that was temporally linked to a blood test for measurement of 25(OH)D concentration. Ambient solar UV radiation was also monitored at all study sites. We collected comprehensive, high-quality data from 1,002 participants (459 males, 543 females) assessed simultaneously across a range of latitudes and through all seasons. Here we describe the scientific and methodological issues considered in designing the AusD Study. [ABSTRACT FROM PUBLISHER]

Inconsistent evidence exists regarding the association between work-related factors and risk of multiple sclerosis (MS). We examined the association between occupational exposures and risk of a first clinical diagnosis of central nervous system demyelination (FCD), which is strongly associated with progression to MS, in a matched case-control study of 276 FCD cases and 538 controls conducted in Australia (2003–2006). Using a personal residence and work calendar, information on occupational history and exposure to chemicals and animals was collected through face-to-face interviews. Few case-control differences were noted. Fewer cases had worked as professionals (≥6 years) than controls (adjusted odds ratio (AOR) = 0.60, 95% confidence interval (CI): 0.37, 0.96). After further adjustment for number of children, cases were more likely to have ever been exposed to livestock than controls (AOR = 1.54, 95% CI: 1.03, 2.29). Among women, there was an increase in FCD risk associated with 10 or more years of exposure to livestock (AOR = 2.78, 95% CI: 1.22, 6.33) or 6 or more years of farming (AOR = 2.00, 95% CI: 1.23, 3.25; also adjusted for number of children). Similar findings were not evident among men. Thus, farming and exposure to livestock may be important factors in the development of FCD among women, with this finding further revealed after the confounding effect of parity or number of children is considered. [ABSTRACT FROM PUBLISHER]

Aims: To determine the activity of enterocin AS-48 against ropy-forming Bacillus licheniformis from cider. Methods and Results: Enterocin AS-48 was tested on B. licheniformis LMG 19409 from ropy cider in MRS-G broth, fresh-made apple juice and in two commercial apple ciders (A and B). Bacillus licheniformis was rapidly inactivated in MRS-G by 0·5 μg ml−1AS-48 and in fresh-made apple juice by 3 μg ml−1. Concentration-dependent inactivation of this bacterium in two commercial apple ciders (A and B) stored at 4, 15 and 30°C for 15 days was also demonstrated. Counts from heat-activated endospores in cider A plus AS-48 decreased very slowly. Application of combined treatments of heat (95°C) and enterocin AS-48 reduced the time required to achieved complete inactivation of intact spores in cider A to 4 min for 6 μg ml−1 and to 1 min for 12 μg ml−1. D and z values also decreased as the bacteriocin concentration increased. Conclusion: Enterocin AS-48 can inhibit ropy-forming B. licheniformis in apple cider and increase the heat sensitivity of spores. Significance and Impact of the Study: Results from this study support the potential use of enterocin AS-48 to control B. licheniformis in apple cider. [ABSTRACT FROM AUTHOR]

mª.t. garcía, r. lucas, h. abriouel, n. ben omar, r. pérez, mª.j. grande, m. martínez-cañamero and a. gálvez. 2004.Activity of the bacteriocin EJ97 produced byEnterococcus faecalisEJ97 against strains of‘ Bacillus macroides/B. maroccanus’ isolated from spoiled zucchini purée was investigated.The influence of several factors like bacteriocin concentration, incubation temperature, pH, growth medium and chemical perservatives on bacteriocin activity was investigated. Enterocin EJ97 [2 arbitrary units (AU) per millilitre] had a marked bactericidal effect on strain INRA P53-2 after 4 h of incubation at 37°C, 24 h at 15°C or 48 h at 4°C. Activity was markedly reduced at pH values of 5·0 and 9·0, but was potentiated by sodium nitrite, sodium benzoate, sodium lactate and sodium tripolyphosphate. Inhibition of strain INRA P53-2 in a commercial vegetable purée required a 10-fold higher bacteriocin concentration. Strain EJ97 was able to grow and produce bacteriocin on vegetable purée, but no inhibition of strain INRA P53-2 was detected.The concentration-dependent bactericidal activity of enterocin EJ97 against strain INRA P53-2 was higher at 37°C and neutral pH, and was potentiated by chemical preservatives. Although enterocin EJ97 was less active in vegetable purée, the concentrations providing bactericidal activity in this food matrix are practical for commercial use.Enterocin EJ97 may have a potential for use in the prevention of food spoilage caused by‘ B. macroides/B. maroccanus’. [ABSTRACT FROM AUTHOR]

The swine industry is comprised of highly productive and healthy sows capable of weaning large litters for multiple parities. This prolificacy has resulted in greater metabolic demands during lactation due to increased capacity and demand for milk production. Modern sows also have increased genetic merit for leanness which has altered the amount of energy reserves available for mobilization to support the growing demands of lactation. Together, these factors may render modern sows more vulnerable to metabolic disorders such as postpartum dysgalactia syndrome (PDS) or mastitis-metritis-agalactia (MMA). Described as a metabolic and hormonal disturbance, a hallmark of PDS is a reduction (dysgalactia) or cessation (agalactia) in milk production after farrowing. Insufficient milk production by the sow leads to increased piglet mortality, causing substantial economic losses, reducing sow welfare, and resulting in premature removal of sows from the herd. Our prior reports have shown differences in circulating analytes and inflammatory markers between healthy sows and sows affected with PDS following parturition. However, very few differences were observed before clinical signs were evident, rendering these analytes ineffective in early detection of PDS. Therefore, the objective of the current study was to utilize gas-chromatography mass-spectrometry (GC-MS) to further characterize the biological conditions and metabolic pathways contributing to PDS in sows. Through this, we aimed to identify small molecules in circulation with the potential for use as a biomarker to aid in early detection of PDS. To accomplish this, a study was conducted on a commercial sow farm with a history of poor lactation performance. Sows (n = 36) with clinical signs of PDS were matched by parity and day of lactation with healthy control (CON) sows (n = 36) that remained unaffected. Blood samples collected at farrowing (timepoint 1) and at onset of clinical PDS (timepoint 2) were subjected to GC-MS. As expected, piglets from PDS sows had decreased (P < 0.01) average daily gain and greater mortality than piglets from control sows. Following GC-MS analysis, 16 and 41 molecules were identified as significantly different between CON and PDS sows at timepoint 1 and timepoint 2, respectively (P < 0.10). A difference in 2-hydroxybutyric acid, an early marker for insulin resistance and impaired glucose regulation, was observed at timepoint 1. Additional molecules identified as significantly different at timepoint 1 include D-pinitol, D-glucose, inositol (3,6)-bisphosphate, and others. These differentially abundant molecules at timepoint 1 represent potential biomarkers for early detection of PDS. [ABSTRACT FROM AUTHOR]

Aims Gut microbiota have been linked to blood lipid levels and cardiovascular diseases (CVDs). The composition and abundance of gut microbiota trophic networks differ between ethnicities. We aim to evaluate the relationship between gut microbiotal trophic networks and CVD phenotypes. Methods and results We included cross-sectional data from 3860 individuals without CVD history from 6 ethnicities living in the Amsterdam region participating in the prospective Healthy Life in Urban Setting (HELIUS) study. Genetic variants were genotyped, faecal gut microbiota were profiled, and blood and anthropometric parameters were measured. A machine learning approach was used to assess the relationship between CVD risk (Framingham score) and gut microbiota stratified by ethnicity. Potential causal relationships between gut microbiota composition and CVD were inferred by performing two-sample Mendelian randomization with hard CVD events from the Pan-UK Biobank and microbiome genome-wide association studies summary data from a subset of the HELIUS cohort (n = 4117). Microbial taxa identified to be associated with CVD by machine learning and Mendelian randomization were often ethnic-specific, but some concordance across ethnicities was found. The microbes Akkermansia muciniphila and Ruminococcaceae UCG-002 were protective against ischaemic heart disease in African-Surinamese and Moroccans, respectively. We identified a strong inverse association between blood lipids, CVD risk, and the combined abundance of the correlated microbes Christensenellaceae–Methanobrevibacter–Ruminococcaceae (CMR). The CMR cluster was also identified in two independent cohorts and the association with triglycerides was replicated. Conclusion Certain gut microbes can have a potentially causal relationship with CVD events, with possible ethnic-specific effects. We identified a trophic network centred around Christensenellaceae , Methanobrevibacter, and various Ruminococcaceae , frequently lacking in South-Asian Surinamese, to be protective against CVD risk and associated with low triglyceride levels. [ABSTRACT FROM AUTHOR]

Examines all breast carcinomas diagnosed using the Advanced Breast Biopsy Instrumentation (ABBI) procedure that were subsequently treated with surgery. Breast biopsy system's enabling of the excision of suspicious, impalpable, breast lesions under local anesthesia; Determination of a way to predict the complete absence of tumor in the remaining breast that might make reoperation unnecessary.

Circulating T and B lymphocytes contribute to the pathogenesis of the neuroinflammatory autoimmune disease, multiple sclerosis (MS). Further progress in the development of MS treatments is dependent upon a greater understanding of the immunological disturbances that underlie the disease. Analyses of circulating immune cells by flow cytometry have revealed MS-associated alterations in the composition and function of T and B cell subsets, including temporal changes associated with disease activity. Disturbances in circulating immune populations reflect those observed in the central nervous system and include skewing towards proinflammatory CD4+ and CD8+ T cells and B cells, greater proportions of follicular T helper cells and functional defects in the corresponding T and B regulatory subsets. Utilizing the analytical power of modern flow cytometers, researchers are now well positioned to monitor immunological changes associated with disease activity or intervention, describe immunological signatures with predictive value and identify targets for therapeutic drug development. This review discusses the contribution of various T and B lymphocyte subsets to MS pathogenesis, provides current and relevant phenotypical descriptions to assist in experimental design and highlights areas of future research. [ABSTRACT FROM AUTHOR]

The article discusses research which examined the results the James Lind Alliance's (JLA) National Institute for Health Research's method of qualitative research, Priority Setting Partnership (PSP). Topics discussed include the aim of the PSP to identify the therapeutic uncertainties on dermatological conditions and some of the ichthyosis therapeutic uncertainties are long-term side-effects of oral retinoids and best topical keratolytic agent.

Background Pulmonary exacerbations (PEx) in people with cystic fibrosis (PwCF) are associated with significant morbidity. While standard PEx treatment for PwCF with Pseudomonas aeruginosa infection includes two IV antipseudomonal antibiotics, little evidence exists to recommend this approach. This study aimed to compare clinical outcomes of single versus double antipseudomonal antibiotic use for PEx treatment. Methods Retrospective cohort study using the linked CF Foundation Patient Registry-Pediatric Health Information System dataset. PwCF were included if hospitalized between 2007 and 2018 and 6–21 years of age. Regression modeling accounting for repeated measures was used to compare lung function outcomes between single versus double IV antipseudomonal antibiotic regimens using propensity-score weighting to adjust for relevant confounding factors. Results Among 10,660 PwCF in the dataset, we analyzed 2,578 PEx from 1,080 PwCF, of which 455 and 2,123 PEx were treated with 1 versus 2 IV antipseudomonal antibiotics, respectively. We identified no significant differences between PEx treated with 1 versus 2 IV antipseudomonal antibiotics either in change between pre- and post-PEx percent predicted forced expiratory volume in one second (ppFEV1) (–0.84%, [95% CI –2.25, 0.56]; P = 0.24), odds of returning to ≥90% of baseline ppFEV1 within 3 months following PEx (Odds Ratio 0.83, [95% CI 0.61, 1.13]; P = 0.24) or time to next PEx requiring IV antibiotics (Hazard Ratio 1.04, [95% CI 0.87, 1.24]; P = 0.69). Conclusions Use of 2 IV antipseudomonal antibiotics for PEx treatment in young PwCF was not associated with greater improvements in measured respiratory and clinical outcomes compared to treatment with 1 IV antipseudomonal antibiotic. [ABSTRACT FROM AUTHOR]

Aims: To characterize bacteriocin production, antimicrobial spectrum and plasmid content in bacteriocinogenic enterococci from foods. Methods and Results: Bacteriocinogenic Enterococcus faecium (14 isolates) and Enterococcus faecalis (three isolates) showed two different patterns of bacteriocin production in liquid broth: exponential-phase and stationary-phase production. Bacteriocin concentrates from all enterococci were inactivated by trypsin, but seldom by heat (100–117°C), extremes of pH (2·0 to 9·0) or reducing agents (such as dithiothreitol). All bacteriocin concentrates were active against Listeria innocua and Listeria monocytogenes, and most were also active against many Ent. faecalis and Ent. faecium isolates. Enterococci clustered in three main groups according to their plasmid content (which included plasmids from 2·0 to 53 kb). Several isolates from different foods showed almost identical plasmid profiles. The enterocin P structural gene ( entP) was detected by hybridization on plasmids of c. 19, 26 and/or 35–38 kb. Conclusions: Enterococci from food show different patterns of bacteriocin production and different plasmid content in spite of carrying similar bacteriocin-encoding genes. Significance and Impact of the Study: This study provides information on the diversity of bacteriocinogenic enterococci from food sources carrying apparently similar enterocin genes. [ABSTRACT FROM AUTHOR]

Background: Bacteria adapt to survive and grow in different environments. Genetic mutations that promote bacterial survival under harsh conditions can also restrict growth. The causes and consequences of these adaptations have important implications for diagnosis, pathogenesis, and therapy.Objectives: We describe the isolation and characterization of an antibiotic-dependent, temperature-sensitive Pseudomonas aeruginosa mutant chronically infecting the respiratory tract of a cystic fibrosis (CF) patient, underscoring the clinical challenges bacterial adaptations can present.Methods: Respiratory samples collected from a CF patient during routine care were cultured for standard pathogens. P. aeruginosa isolates recovered from samples were analysed for in vitro growth characteristics, antibiotic susceptibility, clonality, and membrane phospholipid and lipid A composition. Genetic mutations were identified by whole genome sequencing.Results: P. aeruginosa isolates collected over 5 years from respiratory samples of a CF patient frequently harboured a mutation in phosphatidylserine decarboxylase (psd), encoding an enzyme responsible for phospholipid synthesis. This mutant could only grow at 37°C when in the presence of supplemented magnesium, glycerol, or, surprisingly, the antibiotic sulfamethoxazole, which the source patient had repeatedly received. Of concern, this mutant was not detectable on standard selective medium at 37°C. This growth defect correlated with alterations in membrane phospholipid and lipid A content.Conclusions: A P. aeruginosa mutant chronically infecting a CF patient exhibited dependence on sulphonamides and would likely evade detection using standard clinical laboratory methods. The diagnostic and therapeutic challenges presented by this mutant highlight the complex interplay between bacterial adaptation, antibiotics, and laboratory practices, during chronic bacterial infections. [ABSTRACT FROM AUTHOR]

Summary: Background: Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer‐prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders. Objectives: To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC. Methods: We conducted RNA‐Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies. Results: Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA‐Seq data. In addition, enzyme‐linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB. Conclusions: Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury‐sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What's already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development.Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix‐synthetic capacity.This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor‐β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention.It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB. Linked Comment: Has. Br J Dermatol 2019; 181:440–441. Plain language summary available online [ABSTRACT FROM AUTHOR]

Focuses on the treatment of AIDS-associated prurigo nodularis (PN) with thalidomide. Characteristics of PN; Other therapeutic functions of thalidomide.

We measured in vitro phenotypes of early Pseudomonas aeruginosa isolates from children with cystic fibrosis in an antibiotic eradication therapy trial. Isolates frequently exhibited phenotypes associated with chronic adaptation. Two phenotypes were correlated with failure to eradicate, representing promising candidate markers.Background. Pseudomonas aeruginosa is a key respiratory pathogen in people with cystic fibrosis (CF). Due to its association with lung disease progression, initial detection of P. aeruginosa in CF respiratory cultures usually results in antibiotic treatment with the goal of eradication. Pseudomonas aeruginosa exhibits many different phenotypes in vitro that could serve as useful prognostic markers, but the relative relationships between these phenotypes and failure to eradicate P. aeruginosa have not been well characterized.Methods. We measured 22 easily assayed in vitro phenotypes among the baseline P. aeruginosa isolates collected from 194 participants in the 18-month EPIC clinical trial, which assessed outcomes after antibiotic eradication therapy for newly identified P. aeruginosa. We then evaluated the associations between these baseline isolate phenotypes and subsequent outcomes during the trial, including failure to eradicate after antipseudomonal therapy, emergence of mucoidy, and occurrence of an exacerbation.Results. Baseline P. aeruginosa isolates frequently exhibited phenotypes thought to represent chronic adaptation, including mucoidy. Wrinkly colony surface and irregular colony edges were both associated with increased risk of eradication failure (hazard ratios [95% confidence intervals], 1.99 [1.03–3.83] and 2.14 [1.32–3.47], respectively). Phenotypes reflecting defective quorum sensing were significantly associated with subsequent mucoidy, but no phenotype was significantly associated with subsequent exacerbations during the trial.Conclusions. Pseudomonas aeruginosa phenotypes commonly considered to reflect chronic adaptation were observed frequently among isolates at early detection. We found that 2 easily assayed colony phenotypes were associated with failure to eradicate after antipseudomonal therapy, both of which have been previously associated with altered biofilm formation and defective quorum sensing. [ABSTRACT FROM AUTHOR]

Few clinical laboratories currently culture for slow-growing, antibiotic-resistant mutants of Staphylococcus aureus known as small-colony variants (SCVs). We found that SCVs commonly infect children with cystic fibrosis lung disease. SCV infection was independently associated with significantly worse lung disease.Background. Cystic fibrosis (CF) lung disease is associated with diverse bacteria chronically infecting the airways. Slow-growing, antibiotic-resistant mutants of Staphylococcus aureus known as small-colony variants (SCVs) have been isolated from respiratory secretions from European adults and children with CF lung disease using specific but infrequently used culture techniques. Staphylococcus aureus SCVs can be selected either by exposure to specific antibiotics or by growth with another CF pathogen, Pseudomonas aeruginosa. We sought to determine the prevalence, clinical significance, and likely mechanisms of selection of S. aureus SCVs among a US cohort of children with CF.Methods. We performed a 2-year study of 100 children with CF using culture techniques sensitive for S. aureus SCVs, and evaluated associations with clinical characteristics using multivariable regression models.Results. Staphylococcus aureus SCV infection was detected among 24% of participants and was significantly associated with a greater drop in lung function during the study (P = .007, adjusted for age and lung function at enrollment). This association persisted after adjusting for infection with other known CF pathogens, including P. aeruginosa and methicillin-resistant S. aureus. Evidence indicated that S. aureus SCVs were likely selected in vivo by treatment with the antibiotic trimethoprim-sulfamethoxazole and possibly by coinfection with P. aeruginosa.Conclusions. Infection with SCV S. aureus was independently associated with worse CF respiratory outcomes in this pediatric cohort. As many clinical microbiology laboratories do not specifically detect S. aureus SCVs, validation and extension of these findings would require widespread changes in the usual laboratory and clinical approaches to these bacteria. [ABSTRACT FROM AUTHOR]

Summary Background Basal epidermolysis bullosa simplex (EBS) is a group of blistering genodermatoses mostly caused by mutations in the keratin genes, KRT5 and KRT14. Recessive mutations represent about 5% of all EBS mutations, being common and specific in populations with high consanguinity, where affected patients show severe phenotypes. Objectives To accomplish the first mutational analysis in patients of Spanish origin with EBS and to delineate a comprehensive genotype-phenotype correlation. Methods Twenty-one EBS families were analysed. Immunofluorescence mapping at the dermoepidermal junction level was performed on skin biopsies from patients. Mutation screening of the entire coding sequences of KRT5 and KRT14 in genomic DNA was assessed by polymerase chain reaction and direct sequencing. Results KRT5 or KRT14 causative mutations were identified in 18 of the 21 EBS families. A total of 14 different mutations were disclosed, of which 12 were dominant missense mutations and two truncating recessive mutations. Five of the 14 mutations were novel including three dominant in KRT5 (p.V186E, p.T321P and p.A428T) and two recessive in KRT14 (p.K116X and p.K250RfsX8). The two patients with EBS carrying homozygous recessive mutations were affected by severe phenotypes and belonged to consanguineous families. All five families with the EBS Dowling-Meara subtype carried recurrent mutations affecting the highly conserved ends of the α-helical rod domain of K5 and K14. The seven mutations associated with the localized EBS subtype were widely distributed along the KRT5 and KRT14 genes. Two families with mottled pigmentation carried the P25L mutation in KRT5, commonly associated with this subtype. Conclusions This study further confirms the genotype-phenotype correlation established for EBS in other ethnic groups, and is the first in a Mediterranean country (excluding Israel). This study adds two novel recessive mutations to the worldwide record to date, which includes a total of 14 mutations. As in previous reports, the recessive mutations resulted in a lack of keratin K14, giving rise to a generalized and severe presentation. [ABSTRACT FROM AUTHOR]

Summary: 隐性营养不良性大疱性表皮松解症(RDEB)、Kindler综合征 (KS) 和 C 组着色性干皮病(XPC) 是三种令患者发生癌症风险增加的遗传性皮肤疾病(遗传性皮肤病) 。仍未充分了解在这些疾病中导致癌症的事件, 包括在皮肤水平发生的事件, 尽管已对它们进行了深入调查。为了加深对于这些罕见病的认识,最终发现新的治疗, 西班牙研究小组调查了来自 RDEB、KS 和 XPC 患者的一种称为真皮纤维母细胞的皮肤细胞的基因表达谱 (标签) 。研究者们发现, 来自这三种遗传皮肤病的纤维母细胞都有大量以相同方式异常(错误)表达的基因。它们反过来转化成一种活化表型, 导致真皮 (一层皮肤) 硬度变化和氧化还原 (一种化学反应)状态失衡。这一重叠标签似乎不依赖于导致缺乏缺陷 (即 VII 型胶原、kindlin‐1 或 XPC 的丢失) 的原发疾病,而是尚未充分了解的常见损伤‐反应性事件的结果。总而言之, 该研究为真皮纤维母细胞在 RDEB、XPC 和 KS 中所扮演角色添加了最新认识, 并强调了可能的新治疗靶点。 Linked Article: Chacón‐Solano et al. Br J Dermatol 2019; 181:512–522 [ABSTRACT FROM AUTHOR]

Summary: Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and Xeroderma pigmentosum C (XPC) are three genetic skin diseases (i.e. genodermatoses) in which patients are at increased risk of developing cancer. The events leading to cancer in these diseases, including those taking place at the level of the skin, are still not well understood even though they are under intense investigation. To deepen the knowledge of these rare diseases with the ultimate goal of finding new treatments, the Spanish research group investigated the gene expression profile (signature) of a type of skin cell called dermal fibroblasts from patients with RDEB, KS and XPC. The researchers found that the fibroblasts from three genodermatoses share a large number of genes aberrantly (wrongly) expressed in a similar fashion. That in turn translates into what is defined as an activated phenotype and leads to changes in dermal (a skin layer) stiffness and an imbalance of the redox (a type of chemical reaction) status. This overlapping signature seems not to depend on the primary disease‐causing deficiency defect (i.e. loss of type VII collagen, kindlin‐1 or XPC) but rather the consequence of a common injury‐responsive event not yet fully understood. In conclusion, this study adds to the current knowledge about the role played by dermal fibroblasts in RDEB, XPC and KS and highlights new targets for possible treatments. Linked Article: Chacón‐Solano et al. Br J Dermatol 2019; 181:512–522 [ABSTRACT FROM AUTHOR]

Presents a letter to the editor on the possible relationship between linear lichen planus and lichen striatus.