Transfer of trace metals by trophic chain of plankton - filter-feeding bivalves in the brackish-water lagoon lakes on the Japan Sea coast

Content of the metals Fe, Mn, Ni, Pb, Zn, Cd, and Cu was determined in the water, suspended matter, plankton organisms and bivalves collected in the brackish-water lagoon lakes on the coast of the Japan Sea in July 2011-2012, August 2013, and July 2014. The lakes are located in the sparsely populated area of eastern Sikhote-Alin including the Sikhote-Alin biosphere nature reserve. The content of Fe, Mn, Ni, and Pb has a tendency to decrease along the trophic chain that is conditioned by prevalence of their suspended forms over dissolved ones in the water and decreasing of the surface : weight ratio with size of living organisms. On the contrary, the content of Cu, Zn and Cd is rather stable along the food chain because of prevalence of their dissolved forms and low content in the suspended organic matter

Nod1 signaling overcomes resistance of S. pneumoniae to opsonophagocytic killing

Airway infection by the Gram-positive pathogen Streptococcus pneumoniae (Sp) leads to recruitment of neutrophils but limited bacterial killing by these cells. Co-colonization by Sp and a Gram-negative species, Haemophilus influenzae (Hi), provides sufficient stimulus to induce neutrophil and complement-mediated clearance of Sp from the mucosal surface in a murine model. Products from Hi, but not Sp, also promote killing of Sp by ex vivo neutrophil-enriched peritoneal exudate cells. Here we identify the stimulus from Hi as its peptidoglycan. Enhancement of opsonophagocytic killing was facilitated by signaling through nucleotide-binding oligomerization domain-1 (Nod1), which is involved in recognition of γ-D-glutamyl-meso-diaminopimelic acid (meso-DAP) contained in cell walls of Hi but not Sp. Neutrophils from mice treated with Hi or compounds containing meso-DAP, including synthetic peptidoglycan fragments, showed increased Sp killing in a Nod1-dependent manner. Moreover, Nod1-/- mice showed reduced Hi-induced clearance of Sp during co-colonization. These observations offer insight into mechanisms of microbial competition and demonstrate the importance of Nod1 in neutrophil-mediated clearance of bacteria in vivo

Hydrochemical and biogeochemical features of freshwater and brackish lakes in eastern Sikhote-Alin

Concentration of major ions and trace metals dissolved and suspended in water and trace metals in plankton of freshwater (Vaskovskoye, Golubichnoye, Yaponskoye) and brackish (Dukhovskoye, Krugloye, Mramornoye, Blagodati) lakes of eastern Sikhote-Alin is determined in July 2011-2012. The Lakes Golubichnoye and Blagodati are included in the Sikhote-Alin State Natural Biosphere Reserve. Anions are detected by the liquid chromatography (Shimadzu LC-10AVP), cations and metals are analyzed by the atomic absorption spectrophotometry (AAS Shimadzu 6800), and carbon concentration is measured by the method of thermocatalytic oxidation with infrared registration (TOC-VCPN, Shimadzu). The freshwater lakes of eastern Sikhote-Alin are distinguished by heightened concentrations of chlorides, sulfates, and sodium as compared with lakes of East-European Plain, mainly because of aerial transfer of ions from the sea. The ions concentration in brackish lakes is determined by direct penetration of seawater. Difference of the heavy metals concentration between freshwater and brackish lakes is negligible, except the manganese with higher concentration in the freshwater lakes. Lakes with wetlands in their drainage area have high concentrations of dissolved organic carbon, iron and manganese, which are depended on water regime. Concentrations of trace metals in the lakes water are low because of its pluvial origin (rainwater transforms slightly in the process of filtration through effusive rocks), with exception of Lake Vaskovskoe located in the area of mining and processing the polymetallic and borosilicate ores, close to the lead smeltery in Rudnaya Pristan stopped in 2009: the lead concentration in the water of this lake is heightened, both in dissolved and suspended forms, though does not exceed the maximal permissible concentration for drinking water. Accumulation of metals by plankton is determined mainly by biological need of the plankton in these elements and practically doesn’t depend on their concentration in water

Effect of dopants on laser-induced damage threshold of ZnGeP2

The effect of doping Mg, Se, and Ca by diffusion into ZnGeP2 on the optical damage threshold at a wavelength of 2.1 μm has been studied. It has been shown that diffusion-doping with Mg and Se leads to an increase in the laser-induced damage threshold (LIDT) of a single crystal (monocrystal), ZnGeP2; upon annealing at a temperature of 750 °C, the damage threshold of samples doped with Mg and Se increases by 31% and 21% from 2.2 ± 0.1 J/cm2 to 2.9 ± 0.1 and 2.7 ± 0.1 J/cm2, respectively. When ZnGeP2 is doped with Ca, the opposite trend is observed. It has been suggested that the changes in the LIDT depending on the introduced impurity by diffusion can be explained by the creation of additional energy dissipation channels due to the processes of radiative and fast non-radiative relaxation through impurity energy levels, which further requires experimental confirmation

Treatment of atopic dermatitis with upadacitinib: adcare single center experience

IntroductionThe role of upadacitinib in the management of moderate to severe atopic dermatitis seems promising, but more data on its efficacy and safety are needed. This study endeavors to assess the practical impact and safety of upadacitinib in patients with moderate to severe atopic dermatitis. The study aims to evaluate the efficacy and safety of upadacitinib in the treatment of moderate to severe atopic dermatitis, focusing on analyzing patient responses to the treatment.MethodsIn this study, adult patients diagnosed with moderate to severe atopic dermatitis received upadacitinib at daily doses of 15 mg or 30 mg, as prescribed by their attending physicians. The therapeutic efficacy of upadacitinib was meticulously assessed using established clinical metrics. Simultaneously, a comprehensive safety assessment was conducted through monthly monitoring, including the evaluation of potential effects of upadacitinib intake on hepatic function, lipid profile, and hematopoiesis using the pertinent laboratory tests.ResultsSixteen participants were enrolled in the study. At 1month follow-up, there was a significant reduction in the mean Eczema Area and Severity Index (EASI) score to 18.8 points, which further increased to 24 points at the 4-month mark. Additionally, 9 participants (56%) demonstrated an EASI-50 response after 1 month of treatment, with this response increasing to 9 participants (90%) after 4 months. Furthermore, enhanced therapeutic responses were observed at 4 months, with 6 patients (38%) achieving an EASI-75 response at 1month and 8 patients (80%) achieving this milestone at the 4-month follow-up. This study highlights the potential of upadacitinib as an effective treatment option for moderate to severe atopic dermatitis. While it demonstrates improved symptom management, close monitoring for potential adverse events, particularly infections and the known risks of Janus kinase inhibitors, is essential. Further research is essential to determine the long-term safety and efficacy of upadacitinib

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Early Bacterial Colonization Induces Toll-Like Receptor-Dependent Transforming Growth Factor β Signaling in the Epithelium▿

Colonization of the upper respiratory tract is an initial step that may lead to disease for many pathogens. To prevent compromise of the epithelial barrier, the host must monitor and tightly control bacterial levels on the mucosa. Here we show that innate immune functions of respiratory epithelial cells control colonization by Streptococcus pneumoniae and Haemophilus influenzae in a Toll-like receptor (TLR)-dependent manner. Activation of inflammatory pathways, including mitogen-activated protein kinase signaling, in respiratory epithelial cells was accompanied by the induction of the transforming growth factor β signaling cascade during early colonization. Thus, colonization resulted in upregulation of factors involved in a proinflammatory response (e.g., interleukin-6) as well as factors known to modulate the epithelial barrier (e.g., Snail-1). These in vivo data provided a link between inflammation control and maintenance of the mucosal barrier function during infection and emphasized the importance of TLR-dependent inflammatory responses of the respiratory epithelium

Host and Bacterial Factors Contributing to the Clearance of Colonization by Streptococcus pneumoniae

Nasopharyngeal colonization is the first step in the interaction between Streptococcus pneumoniae (the pneumococcus) and its human host. Factors that contribute to clearance of colonization are likely to affect the spread of the pneumococcus and the rate of pneumococcal disease in the population. To identify host and bacterial factors contributing to this process, we examined the time course of colonization using genetically modified mice and pneumococci. Severe combined immunodeficient mice remained persistently colonized (>6 weeks). Major histocompatibility complex II-deficient mice, but not μMT mice, were unable to clear colonization and showed a diminished T helper 1 response. Thus, CD4(+) T cells, rather than the generation of specific antibody, appear to be required for effective Th1-mediated clearance. In addition, the microbial pattern recognition receptor toll-like receptor 2 (TLR2), but not TLR4, was necessary for efficient clearance of colonization. In contrast, no role of complement component 3, inducible nitric oxide synthetase, interleukin 12 (IL-12), or IL-4 could be demonstrated. Expression of the pneumococcal toxin pneumolysin enhanced acute localized inflammatory responses and promoted clearance of colonization in a TLR4-independent manner. We conclude that both innate and CD4(+) T-cell-mediated immunity and proinflammatory bacterial factors, rather than a humoral adaptive immune response, are important for clearance of S. pneumoniae from the murine nasopharynx

The role of innate immune responses in the outcome of interspecies competition for colonization of mucosal surfaces. PLoS Pathog 1: e1

Since mucosal surfaces may be simultaneously colonized by multiple species, the success of an organism may be determined by its ability to compete with co-inhabitants of its niche. To explore the contribution of host factors to polymicrobial competition, a murine model was used to study the initiation of colonization by Haemophilus influenzae and Streptococcus pneumoniae. Both bacterial species, which occupy a similar microenvironment within the nasopharynx, persisted during colonization when given individually. Co-colonization, however, resulted in rapid clearance of S. pneumoniae from the upper respiratory tract, associated with increased recruitment of neutrophils into paranasal spaces. Systemic depletion of either neutrophil-like cells or complement was sufficient to eliminate this competitive effect, indicating that clearance was likely due to enhanced opsonophagocytic killing. The hypothesis that modulation of opsonophagocytic activity was responsible for host-mediated competition was tested using in vitro killing assays with elicited neutrophil-like cells. Components of H. influenzae (but not S. pneumoniae) stimulated complement-dependent phagocytic killing of S. pneumoniae. Thus, the recruitment and activation of neutrophils through selective microbial pattern recognition may underlie the H. influenzae–induced clearance of S. pneumoniae. This study demonstrates how innate immune responses may mediate competitive interactions between species and dictate the composition of the colonizing flora. Citation: Lysenko ES, Ratner AJ, Nelson AL, Weiser JN (2005) The role of innate immune responses in the outcome of interspecies competition for colonization of mucosa