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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]

We describe the use of abraded bivalve shells by the shellback crabs Hypoconcha arcuata Stimpson, 1858 and H. parasitica (Linnaeus, 1763) in southeastern Brazil. Shells from four species of bivalves were associated with the crabs: Eucallista purpurata (Lamarck, 1818), Chionopsis crenata (Gmelin, 1791), and Tivela zonaria (Lamarck, 1818) (Veneridae), and, most frequently (50%), Dallocardia delicatula (E.A. Smith, 1915) (Cardiidae). This was the first documented record of shellback crabs using valves of veneriid bivalves, as well as the first report of a crab-shell association for Hypoconcha in the South Atlantic Ocean. The relationship between the increase in size of shellback crabs and the size of the chosen shell was discussed. [ABSTRACT FROM AUTHOR]

Home oxygen therapy (HOT) burns carry high morbidity and mortality. Many patients are active smokers, which is the most frequent cause of oxygen ignition. We conducted a retrospective review at our institution to characterize demographics and outcomes in this patient population. An IRB-approved single-institution retrospective review was conducted for home oxygen therapy burn patients between July 2016 and January 2021. Demographic and clinical outcome data were compared between groups. We identified 100 patients with oxygen therapy burns. Mean age was 66.6 years with a male to female ratio of 1.3:1 and median burn surface area of 1%. In these patients, 97% were on oxygen for COPD and smoking caused 83% of burns. Thirteen were discharged from the emergency department, 35 observed for less than 24 hours, and 52 admitted. For admitted patients, 69.2% were admitted to the ICU, 37% required intubation, and 11.5% required debridement and grafting. Inhalational injury was found in 26.9% of patients, 3.9% underwent tracheostomy, and 17.3% experienced hospital complications. In-hospital mortality was 9.6% and 7.7% were discharged to hospice. 13.5% required readmission within 30 days. Admitted patients had significantly higher rates of admission to the ICU, intubation, and inhalational injury compared to those that were not admitted (P < .01). Most HOT-related burns are caused by smoking and can result in significant morbidity and mortality. Efforts to educate and encourage smoking cessation with more judicious HOT allocation would assist in preventing these unnecessary highly morbid injuries. [ABSTRACT FROM AUTHOR]

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]

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]

We document the current status of the enigmatic bright-red anchialine shrimps in Tiniguiban Islet in the western Visayas region of the Philippines. A second epigeal anchialine pool was discovered in nearby Hinlaran Islet, and two shrimp species were recorded in the pools, the large barbouriid Parhippolyte uveae Borradaile, 1900 as previously reported and a much smaller atyid Antecaridina lauensis (Edmondson, 1935). The shrimps move in and out of the pools with tidal fluctuations, since both pools completely dry out at low tide. The shrimps remain very abundant in Tiniguiban despite extensive modifications made by its owners and an apparent decrease in dissolved oxygen levels. Magico-religious beliefs regarding these unusual red shrimps persist, yet a subtle shift in values is noted, particularly with the growing popularity of the Tiniguiban pool with local tourists. Further modernization and coastal development may rapidly threaten these rare shrimp populations. Our study provides baseline data for systematic study and future protection of these rare pools and their shrimps that uniquely dwell at the interface of cave and marine habitats. [ABSTRACT FROM AUTHOR]

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]

Background: Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from monocytic or dendritic cell lineage. Whereas the genomic features for Langerhans cell histiocytosis and Erdheim‐Chester disease have been well described, other less common and often aggressive tumors in this broad category remain poorly characterized, and comparison studies across the World Health Organization diagnostic categories are lacking. Methods: Tumor samples from a total of 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs), underwent hybridization capture with analysis of up to 406 cancer‐related genes. Results: Among the entire cohort of 102 patients, CDKN2A mutations were most frequent across subtypes and made up 32% of cases, followed by TP53 mutations (22%). Mitogen‐activated protein kinase (MAPK) pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCS (72% vs. 0%; p <.0001). In contrast, NF‐κB pathway mutations were frequent in FDCSs but rare in M group histiocytoses (61% vs. 12%; p <.0001). Tumor mutational burden was significantly higher in M group histiocytoses as compared with FDCSs (median 4.0/Mb vs. 2.4/Mb; p =.012). We also describe a pediatric patient with recurrent secondary histiocytic sarcoma treated with targeted therapy and interrogated by molecular analysis to identify mechanisms of therapeutic resistance. Conclusion: A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies. Our findings highlight the potential value of molecular testing to enable precise tumor classification, identify candidate oncogenic drivers, and define personalized therapeutic options for patients with these aggressive tumors. Implications for Practice: This study presents comprehensive genomic profiling results on 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs). MAPK pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCSs. In contrast, NF‐κB pathway mutations were frequent in FDCSs but rare in M group histiocytosis. A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies. Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from the monocytic or dendritic cell lineage. This article presents the molecular characteristics of the four major subtypes of malignant histiocytic and dendritic cell neoplasms, focusing on genomic alterations that could represent therapeutic targets. [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]

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]

Summary: Coal burning power plants are a frequent target of regulatory programmes because of their emission of chemicals that are known precursors to the formation of ambient particulate air pollution. Health impact assessments of emissions from coal power plants typically rely on assumed causal relationships between emissions, ambient pollution and health, many of which have never been empirically verified. We offer a novel statistical evaluation of some of these presumed causal relationships, integrating the formality of causal inference methods with repurposed tools from atmospheric science to accommodate the central challenge of long‐range pollution transport of emissions from power plants to exposed populations. The statistical approach follows recent work on Bayesian methods for deploying principal stratification and causal mediation analysis in tandem to characterize the extent to which decreased sulphur dioxide emissions from 410 power plants across the USA impact mortality and hospitalization outcomes across Medicare beneficiaries residing across 12370 locations in a manner that is mediated through reductions of ambient fine particulate pollution. The result is the first epidemiological investigation integrating causal inference methodology with direct measurements of coal emissions, pollution transport, ambient pollution and human health in a single analysis, indicating the potential for data science at the intersection of statistics, epidemiology and atmospheric science. [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]

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]

Intersexuality in a gonochoric palaemonid shrimp is reported for the first time in a wild population of Macrobrachium amazonicum (Heller, 1862). This phenomenon was confirmed based on an investigation of anatomic and morphometric traits and the ultrastructure of gonopores. The intersex had both reproductive organs despite the absence of vitellogenic oocytes and spermatozoa. This individual had a vestigial male gonopore complex and female gonopores. The intersexuality was related to a genetic mutation and/or hormonal disruption because there was no detection of chemicals in the water or parasites in the samples. Non-functional hermaphroditism is a very rare event (0.06%) in M. amazonicum, indicating that this species is gonochoric, and intersex individuals are not reproductively viable. [ABSTRACT FROM AUTHOR]

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: Use of synthetic cathinones, which are designer stimulants found in “bath salts,” has increased dramatically in recent years. Following governmental bans of methylenedioxypyrovalerone, mephedrone, and methylone, a second generation of synthetic cathinones with unknown abuse liability has emerged as replacements. Methods: Using a discrete trials current intensity threshold intracranial self-stimulation procedure, the present study assessed the effects of 2 common second-generation synthetic cathinones, α‐pyrrolidinopentiophenone (0.1–5mg/kg) and 4-methyl-N-ethcathinone (1–100mg/kg) on brain reward function. Methamphetamine (0.1–3mg/kg) was also tested for comparison purposes. Results: Results revealed both α‐pyrrolidinopentiophenone and 4-methyl-N-ethcathinone produced significant intracranial self-stimulation threshold reductions similar to that of methamphetamine. α‐Pyrrolidinopentiophenone (1 mg/kg) produced a significant maximal reduction in intracranial self-stimulation thresholds (~19%) most similar to maximal reductions produced by methamphetamine (1 mg/kg, ~20%). Maximal reductions in intracranial self-stimulation thresholds produced by 4-methyl-N-ethcathinone were observed at 30 mg/kg (~15%) and were comparable with those observed with methamphetamine and α‐pyrrolidinopentiophenone tested at the 0.3-mg/kg dose (~14%). Additional analysis of the ED50 values from log-transformed data revealed the rank order potency of these drugs as methamphetamine ≈ α‐pyrrolidinopentiophenone>4-methyl-N-ethcathinone. Conclusions: These data suggest that the newer second-generation synthetic cathinones activate the brain reward circuitry and thus may possess a similar degree of abuse potential as prototypical illicit psychostimulants such as methamphetamine as well as the first generation synthetic cathinone methylenedioxypyrovalerone, as previously reported. [ABSTRACT FROM AUTHOR]

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]

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]