Search

This study explores the role of porosity in the impact deposition of a ceramic-reinforced metal-matrix (i.e., Al/B4C) composite coating fabricated via cold spraying. The Johnson–Holmquist–Beissel constitutive law and the modified Gurson–Tvergaard–Needleman model were used to describe the high strain-rate behavior of the boron carbide and the aluminum metal matrix during impact deposition, respectively. Within a finite element model framework, the Arbitrary Lagrangian–Eulerian technique is implemented to explore the roles of reinforcement particle size and velocity, and pore size and depth in particle retention by examining the post-impact crater morphology, penetration depth, and localized plastic deformation of the aluminum substrate. Results reveal that some degree of matrix porosity may improve particle retention. In particular, porosity near the surface facilitates particle retention at lower impact velocities, while kinetic energy dominates particle retention at higher deposition velocities. Altogether, these results provide insights into the effect of deposition variables (i.e., particle size, impact velocity, pore size, and pore depth) on particle retention that improves coating quality.

Thermal spray deposition techniques have been well-established, owing to their flexibility in addressing degradation due to wear and corrosion issues faced due to extreme environmental conditions. With the adoption of these techniques, a broad spectrum of industries is experiencing continuous improvement in resolving these issues. To increase industrial-level implementation, state-of-the-art advanced materials are required. High-entropy alloys (HEAs) have recently gained considerable attention within the scientific community as advanced materials, mainly due to their exceptional properties and desirable microstructural features. Unlike traditional material systems, high-entropy alloys are composed of multi-component elements (at least five elements) with equimolar or nearly equimolar concentrations. This allows for a stable microstructure that is associated with high configurational entropy. This review article provides a critical assessment of different strengthening mechanisms observed in various high-entropy alloys developed by means of deposition techniques. The wear, corrosion, and oxidation responses of these alloys are reviewed in detail and correlated to microstructural and mechanical properties and behavior. In addition, the review focused on material design principles for developing next-generation HEAs that can significantly benefit the aerospace, marine, oil and gas, nuclear sector, etc. Despite having shown exceptional mechanical properties, the article describes the need to further evaluate the tribological behavior of these HEAs in order to show proof-of-concept perspectives for several industrial applications in extreme environments.

This study investigated the effect of stress on the microstructure evolution of austenitic stainless steels (316L SS and 304 SS) subjected to cavitation erosion and cavitation erosion-corrosion. Results show that continuous accumulation of stress of austenitic stainless steels at the early stage of cavitation erosion was observed from the samples tested in deionised water (DIW) but not in artificial seawater (ASW), which is due to stress release induced by ASW. In addition, a stress-induced phase transformation from austenite to martensite during the cavitation erosion tests in both DIW and ASW was observed in 304 SS, but not in 316 SS. Furthermore, primary cavitation craters formed during the cavitation erosion were not expanded directly but shrank first and then expanded due to re-accumulation of stress. More importantly, this study reports for the first time that pre-existing pores are not initiation points of cavitation erosion damage, possibly because of the ductility of austenitic stainless steels, which resulted in continuous shrinkage of the pores caused by the accumulated stress. Our findings provide new insights into understanding the failure mechanisms of austenitic stainless steels subjected to cavitation erosion, which will inform the development of high-performance cavitation erosion-resistant materials.

Objectives: Our objectives were to identify Shigella isolates in the United States with decreased susceptibility to azithromycin (DSA) and characterize the genetic mechanisms responsible for this resistance. Methods: The National Antimicrobial Resistance Monitoring System (NARMS) at the US Centers for Disease Control and Prevention (CDC) collects and conducts broth microdilution antimicrobial susceptibility testing on Shigella to determine minimum inhibitory concentrations (MICs) for up to 15 drugs, including azithromycin. Isolates with decreased susceptibility to azithromycin were subjected to molecular methods (e.g., polymerase chain reaction [PCR], whole-genome sequencing, and plasmid typing/transformation) to identify the genetic mechanisms of resistance. Results: A total of 118 isolates with decreased susceptibility to azithromycin were tested—65 (55%) isolates contained only mphA, 1 (

Nanostructured materials are being actively developed, while it remains an open question how to rapidly scale them up to bulk engineering materials for broad industrial applications. This study propose an industrial approach to rapidly fabricate high-strength large-size nanostructured metal matrix composites and attempts to investigate and optimize the deposition process and strengthening mechanism. Here, advanced nanocrystalline aluminum matrix composites (nanoAMCs) were assembled for the first time by a novel nano-additive manufacturing method that was guided by numerical simulations (i.e. the in-flight particle model and the porefree deposition model). The present nanoAMC with a mean grain size

We examined outbreak investigations conducted around the world from 1988 to 1999 by the Centers for Disease Control and Prevention’s Epidemic Intelligence Service. In 44 (4.0%) of 1,099 investigations, identified causative agents had bioterrorism potential. In six investigations, intentional use of infectious agents was considered. Healthcare providers reported 270 (24.6%) outbreaks and infection control practitioners reported 129 (11.7%); together they reported 399 (36.3%) of the outbreaks. Health departments reported 335 (30.5%) outbreaks. For six outbreaks in which bioterrorism or intentional contamination was possible, reporting was delayed for up to 26 days. We confirmed that the most critical component for bioterrorism outbreak detection and reporting is the frontline healthcare profession and the local health departments. Bioterrorism preparedness should emphasize education and support of this frontline as well as methods to shorten the time between outbreak and reporting.

TIGIT is an alternative checkpoint receptor (CR) whose inhibition promotes Graft-versus-Leukemia effects of NK cells. Given the significant immune-permissiveness of NK cells circulating in acute myeloid leukemia (AML) patients, we asked whether adoptive transfer of activated NK cells would benefit from additional TIGIT-blockade. Hence, we characterized cytokine-induced memory-like (CIML)-NK cells and NK cell lines for the expression of inhibitory CRs. In addition, we analyzed the transcription of CR ligands in AML patients (CCLE and Beat AML 2.0 cohort) in silico and evaluated the efficacy of CR blockade using in vitro cytotoxicity assays, CD69, CD107a and IFN-γ expression. Alternative but not classical CRs were abundantly expressed on healthy donor NK cells and even further upregulated on CIML-NK cells. In line with our finding that CD155, one important TIGIT-ligand, is reliably expressed on AMLs, we show improved killing of CD155 + -AML blasts by NK-92 but interestingly not CIML-NK cells in the presence of TIGIT-blockade. Additionally, our in silico data (n = 671) show that poor prognosis AML patients rather displayed a CD86 low CD112/CD155 high phenotype, whereas patients with a better outcome rather exhibited a CD86 high CD112/CD155 low phenotype. Collectively, our data evidence that the complex CR ligand expression profile on AML blasts may be one explanation for the intrinsic NK cell exhaustion observed in AML patients which might be overcome with adoptive NK-92 transfer in combination with TIGIT-blockade., (© 2024. The Author(s).)

Background and Aims: To evaluate the effect of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus on the function and metabolic changes, as well as the relationship of the virus with blood groups. Methods and Results: This cross-sectional study included a matched sample of adult individuals with coronavirus disease 2019 (COVID-19) ( n  = 114) or without (controls; n  = 236). Blood samples were collected and processed for triglycerides (TGs), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, and blood typing analysis. The results showed that subjects with COVID-19 had higher TG and lower HDL-C levels compared with the control group. As for blood typing, the risk of COVID-19 was higher in subjects with blood group A than in those with blood group B and in those with other blood groups. In addition, an association of COVID-19 with blood type and Rh A- was observed. When related to the severity of COVID-19 symptoms, blood type A was more protective against moderate/severe symptoms compared with blood type O. In addition, individuals with blood type O were 2.90 times more likely to have symptoms moderate/severe symptoms of COVID-19 than those with other blood groups and individuals with type A blood were less likely to have severe/moderate symptoms of COVID-19 compared with individuals without type A blood. Conclusion: The results suggest that blood type may play a role in susceptibility to SARS-CoV-2 infection and add evidence that infection with the novel coronavirus may be associated with changes in lipid metabolism.

The impact of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic on pediatric intensive care units (PICUs) is difficult to quantify. We conducted an observational study in all eight Swiss PICUs between 02/24/2020 and 06/15/2020 to characterize the logistical and medical aspects of the pandemic and their impact on the management of the Swiss PICUs. The nine patients admitted to Swiss PICUs during the study period suffering from pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and constituting 14% (9/63) of all SARS-CoV-2 positive hospitalized patients in Swiss children's hospitals caused a higher workload [total Nine Equivalents of nursing Manpower use Score (NEMS) points, p = 0.0008] and were classified to higher workload categories ( p < 0.0001) than regular PICU patients ( n = 4,881) admitted in 2019. The comparison of the characteristics of the eight Swiss PICUs shows that they were confronted by different organizational issues arising from temporary regulations put in place by the federal council. These general regulations had different consequences for the eight individual PICUs due to the differences between the PICUs. In addition, the temporal relationship of these different regulations influenced the available PICU resources, dependent on the characteristics of the individual PICUs. As pandemic continues, reflecting and learning from experience is essential to reduce workload, optimize bed occupancy and manage resources in each individual PICU. In a small country as Switzerland, with a relatively decentralized health care local differences between PICUs are considerable and should be taken into account when making policy decisions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Soomann, Wendel-Garcia, Kaufmann, Grazioli, Perez, Hilty, André and Brotschi.)

Reports on accidental intravenous epinephrine overdose in children are extremely rare, although medication errors in the management of pediatric anaphylaxis seem to be frequent. We report a case of a 12-year-old boy presenting with a long-lasting skin rash and dyspnea who was incorrectly diagnosed with early anaphylactic shock and was treated with 10-fold the recommended dose administered by the wrong route (intravenous instead of intramuscular). He reacted with acute loss of consciousness and acute cardiorespiratory failure due to arterial hypotension, ischemic heart failure, and severe pulmonary edema. He responded rapidly to mechanical ventilation, treatment with diuretics, and low-dose inotropes and recovered without sequelae. Despite this ultimately favorable outcome, we report this case to remind the scientific community that inadvertent and accidental epinephrine overdosing is probably an underrecognized event, which can result in potentially lethal complications. Heightening the awareness of the personnel, implementing safety precautions for the dosage and the route of administration, stocking of prefilled intramuscular dose syringes for emergency use in anaphylaxis and, ideally, introducing a standardized drug order form should reduce potential risks and facilitate proper and optimal treatment for all acutely ill children.

Competing Interests: There are no conflicts of interest.

The treatment of leukemia/lymphoma by chimeric antigen receptor (CAR) redirected T cells with specificity for CD19 induced complete remissions in the majority of patients, with a realistic hope for cure. However, recent follow-up data revealed a substantial risk of relapse through leukemic cells that lack the CAR targeted antigen. In this situation, a bispecific CAR with binding domains for CD19 and CD20 is aimed at recognizing leukemic cells with only one cognate antigen. The anti-CD20-CD19 bispecific CAR induced a full T-cell response upon engagement of CD19 or CD20 on target cells showing a true "OR" gate recognition in redirecting T-cell activation. T cells with the anti-CD20-CD19 CAR efficiently killed patients' chronic lymphocytic leukemia cells in vitro. The bispecific CAR T cells cleared pediatric acute lymphocytic leukemia with a mixed CD19 + CD20 + /CD20 - phenotype from the blood and bone marrow of transplanted mice, while anti-CD20 CAR T cells left CD20 - leukemic cells behind without curing the disease. Data indicate the superior anti-leukemic activity in the control of leukemia, implying that the anti-CD20-CD19 bispecific CAR T cells may reduce the risk of relapse through antigen-loss leukemic cells in the long term.

NK cells are functionally controlled by the killer immunoglobulin-like receptor (KIR) family that comprises inhibitory (iKIR) and activating (aKIR) members. Genetic association studies suggest that donors expressing aKIRs next to iKIRs will be superior donors in the setting of hematopoietic stem cell transplantation of patients with leukemia. However, contrary evidence states that aKIR expression may be irrelevant or even detrimental. Using a complex methodology incorporating KIR-Q-PCR, double fluorescence and viSNE analysis, we characterized subset distribution patterns and functionality in haplotype A donors which lack aKIRs and haplotype B donors that express a variety of B-specific genes. Here, we show that the alloreactive KIR2DS1+ NK cell subset in HLA-C1/C2 donors is highly responsive towards C2-expressing targets but quantitatively small and as such does not significantly contribute to cytotoxicity. Thus, we fail to find a direct link between haplotype allocation status and NK cell cytotoxicity at least in HLA-C1/C2 heterozygous donors., (© The Japanese Society for Immunology. 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Exposure and response prevention (ERP) is an effective treatment for individuals with obsessive-compulsive disorder (OCD), yet a substantial number of individuals with OCD do not fully respond to this intervention. Based on emerging experimental and clinical research on acceptance, this study sought to explore whether willingness to experience unpleasant thoughts, emotions, and bodily sensations during ERP was associated with improved treatment response., Methods: Two hundred eighty-eight adults with OCD receiving residential ERP provided self-rated willingness and other exposure-related variables during each daily coached ERP session. Obsessive-compulsive and depressive symptom severity was assessed every week. Multilevel modeling was used to study the impact of willingness on treatment outcome during the first 6 weeks of residential care., Results: Data indicated that individuals with higher willingness during ERP reported faster symptom reduction during residential treatment, even when controlling for length of stay, psychopharmacological intervention, depression, adherence, and rituals performed during ERP. These results appear to have both statistical and clinical significance., Conclusions: Willingness to fully experience unpleasant and unwanted thoughts, emotions, and bodily sensations during exposures appears to be a marker of successful exposure therapy in adults with OCD. Future research should examine how willingness may enhance extinction learning during ERP., (© 2017 Wiley Periodicals, Inc.)

Fascinating earlier evidence suggests an intrinsic capacity of human natural killer (NK) cells to acquire adaptive immune features in the context of cytomegalovirus (CMV) infection or pro-inflammatory cytokine stimulation. Since the role of memory NK cells in cancer has so far remained elusive and adoptive NK cell transfer in relapsing pediatric acute B cell precursor leukemia (BCP-ALL) patients awaits improvement, we asked the question whether tumor-priming could promote the generation of memory NK cells with enhanced graft-vs.-leukemia (GvL) reactivity. Here, we provide substantial evidence that priming of naive human NK cells with pediatric acute B cell leukemia or acute myeloid leukemia specimens induces a functional conversion to tumor-induced memory-like (TIML)-NK cells displaying a heightened tumor-specific cytotoxicity and enhanced perforin synthesis. Cell cycles analyses reveal that tumor-priming sustainably alters the balance between NK cell activation and apoptosis in favor of survival. In addition, gene expression patterns differ between TIML- and cytokine-induced memory-like (CIML)-NK cells with the magnitude of regulated genes being distinctly higher in TIML-NK cells. As such, the tumor-induced conversion of NK cells triggers the emergence of a so far unacknowledged NK cell differentiation stage that might promote GvL effects in the context of adoptive cell transfer.

Antibody-dependent cellular cytotoxicity (ADCC) of natural killer (NK) cells largely contributes to the success of monoclonal antibody (mAb) treatment in cancer. As no antibodies are clinically available for immunotherapy of myeloid leukemias (MLs), we aimed to develop an Fc-optimized CD133 mAb for induction of NK ADCC against MLs. When comparing different available CD133 mAbs, no difference was observed with regard to binding to primary chronic myeloid leukemia cells. However, clone 293C3 recognized acute myeloid leukemia (AML) cells in a substantially higher percentage of patient cases and was thus chosen to generate chimeric mAbs with either wild-type Fc part (293C3-WT) or a variant containing amino-acid exchanges (S239D/I332E) to enhance affinity to CD16 on NK cells (293C3-SDIE). In vitro, treatment with 293C3-SDIE significantly enhanced activation, degranulation and lysis of primary CD133-positive AML cells by allogeneic and autologous NK cells as compared with its wild-type counterpart. In line with the observed lower expression levels of CD133 on healthy cells compared with malignant hematopoietic cells, 293C3-SDIE caused no relevant toxicity towards committed hematopoietic progenitor cells. In a NOD.Cg-PrkdcscidIL2rgtmWjl/Sz xenotransplantation model, 293C3-SDIE facilitated elimination of patient AML cells by human NK cells. Thus, 293C3-SDIE constitutes an attractive immunotherapeutic compound, in particular for elimination of minimal residual disease in the context of allogeneic stem cell transplantation in AML.

Natural killer (NK) cells play an important role in surveillance and elimination of malignant cells. Their spontaneous cytotoxicity was first demonstrated in vitro against leukemia cell lines, and NK cells might play a crucial role in the therapy of leukemia. NK cell activity is controlled by an array of germ line-encoded activating and inhibitory receptors, as well as modulating coreceptors. This biologic feature can be exploited in allogeneic cell therapy, and the recognition of "missing-self" on target cells is crucial for promoting NK cell-mediated graft-versus-leukemia effects. In this regard, NK cells that express an inhibitory killer immunoglobulin-like receptor (iKIR) for which the respective major histocompatibility complex class I ligand is absent on leukemic target cells can exert alloreactivity in vitro and in vivo. Several models regarding potential donor-patient constellations have been described that have demonstrated the clinical benefit of such alloreactivity of the donor-derived NK cell system in patients with adult acute myeloid leukemia and pediatric B-cell precursor acute lymphoblastic leukemia after allogeneic stem cell transplantation. Moreover, adoptive transfer of mature allogeneic NK cells in the nontransplant or transplant setting has been shown to be safe and feasible, whereas its effectivity needs further evaluation. NK cell therapy can be further improved by optimal donor selection based on phenotypic and genotypic properties, by adoptive transfer of NK cells with ex vivo or in vivo cytokine stimulation, by the use of antibodies to induce antibody-dependent cellular cytotoxicity or to block iKIRs, or by transduction of chimeric antigen receptors., (© 2016 by The American Society of Hematology.)

This cross-sectional study, performed in an oncology hospital in Goiania, aimed to characterize the prevalence of oral colonization and antimicrobial susceptibility of Pseudomonas spp. isolated from the saliva of healthcare workers. Microorganisms were subjected to biochemical tests, susceptibility profile, and phenotypic detection. Of 76 participants colonized with Gram negative bacilli, 12 (15.8%) harbored Pseudomonas spp. Of all isolates, P. aeruginosa (75.0%), P. stutzeri (16.7%), and P. fluorescens (8.3%), were resistant to cefoxitin, and therefore likely to be AmpC producers. The results are clinically relevant and emphasize the importance of surveillance to minimize bacterial dissemination and multiresistance.

Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease with poor outcome. Adequate model systems are required for preclinical studies to improve understanding of AML biology and to develop novel, rational treatment approaches. Xenografts in immunodeficient mice allow performing functional studies on patient-derived AML cells. We have established an improved model system that integrates serial retransplantation of patient-derived xenograft (PDX) cells in mice, genetic manipulation by lentiviral transduction, and essential quality controls by immunophenotyping and targeted resequencing of driver genes. 17/29 samples showed primary engraftment, 10/17 samples could be retransplanted and some of them allowed virtually indefinite serial transplantation. 5/6 samples were successfully transduced using lentiviruses. Neither serial transplantation nor genetic engineering markedly altered sample characteristics analyzed. Transgene expression was stable in PDX AML cells. Example given, recombinant luciferase enabled bioluminescence in vivo imaging and highly sensitive and reliable disease monitoring; imaging visualized minimal disease at 1 PDX cell in 10000 mouse bone marrow cells and facilitated quantifying leukemia initiating cells. We conclude that serial expansion, genetic engineering and imaging represent valuable tools to improve the individualized xenograft mouse model of AML. Prospectively, these advancements enable repetitive, clinically relevant studies on AML biology and preclinical treatment trials on genetically defined and heterogeneous subgroups.

Recruitment of Fc-receptor-bearing effector cells, such as natural killer (NK) cells, is a feature critical for the therapeutic success of antitumor antibodies and can be improved by the modifications of an antibody's Fc part. The various ligands of the activating immunoreceptor NKG2D, NKG2DL) are selectively expressed on malignant cells including leukemia. We here took advantage of the tumor-associated expression of NKG2DL for targeting leukemic cells by NKG2D-immunoglobulin G (IgG)1 fusion proteins containing modified Fc parts. Compared to NKG2D-Fc containing a wild-type Fc part (NKG2D-Fc-WT), our mutants (S239D/I332E and E233P/L234V/L235A/ΔG236/A327G/A330S) displayed highly enhanced (NKG2D-Fc-ADCC) and abrogated (NKG2D-Fc-KO) affinity to the NK cell Fc receptor, respectively. Functional analyses with allogenic as well as autologous NK cells and primary malignant cells of leukemia patients revealed that NKG2D-Fc-KO significantly reduced NK reactivity by blocking immunostimulatory NKG2D-NKG2DL interaction. NKG2D-Fc-WT already enhanced antileukemia reactivity by inducing antibody-dependent cellular cytotoxicity (ADCC) with NKG2D-Fc-ADCC mediating significantly stronger effects. Parallel application of NKG2D-Fc-ADCC with Rituximab caused additive effects in lymphoid leukemia. In line with the tumor-associated expression of NKG2DL, no NK cell ADCC against resting healthy blood cells was induced. Thus, NKG2D-Fc-ADCC potently enhances NK antileukemia reactivity despite the inevitable reduction of activating signals upon binding to NKG2DL and may constitute an attractive means for immunotherapy of leukemia., (© 2014 UICC.)

Therapeutic natural killer (NK)-cell-mediated alloreactivity toward acute myeloid leukemia has largely been attributed to mismatches between killer immunoglobulin-like receptors (KIRs) on NK cells and their ligands, HLA class I molecules, on target cells. While adult acute B-cell precursor leukemia (BCP-ALL) appears to be resistant to NK-cell-mediated lysis, recent data indicate that pediatric BCP-ALL might yet be a target of NK cells. In this study, we demonstrate in a donor-patient-specific NOD.Cg-Prkdc(scid) IL2rg(tmWjl)/Sz (NSG) xenotransplantation model that NK cells mediate considerable alloreactivity toward pediatric BCP-ALL in vivo. Notably, both adoptively transferred mature KIR(+) NK cells and immature KIR(-) NK cells arising early posttransplantation in humanized NSG mice exerted substantial antileukemic activity. Low-dose and long-term treatment of humanized NSG mice with the DNA-demethylating agent 5-aza-cytidine distinctly enhanced the antitumor response, interestingly without inducing common inhibitory KIR expression but rather by promoting the differentiation of various NK-cell precursor subsets. Collectively, these data indicate that the future design of innovative therapy protocols should consider further exploitation of NK-cell-mediated immune responses for poor prognosis pediatric BCP-ALL patients., (© 2014 by The American Society of Hematology.)

The aim of the study was to analyze epidemiological and microbiological aspects of oral colonization by methicillin-resistant Staphylococcus of health care workers in a cancer hospital. Interview and saliva sampling were performed with 149 health care workers. Antimicrobial resistance was determined by disk diffusion and minimum inhibitory concentration. Polymerase Chain Reaction, Internal Transcribed Spacer-Polymerase Chain Reaction and Pulsed Field Gel Electrophoresis were performed for genotypic characterization of methicillin-resistant Staphylococcus. Risk factors were determined by logistic regression. Methicillin-resistant Staphylococcus colonization prevalence was 19.5%, denture wearing (p = 0.03), habit of nail biting (p = 0.04) and preparation and administration of antimicrobial (p = 0.04) were risk factors identified. All methicillin-resistant Staphylococcus were S. epidermidis, 94.4% of them had mecA gene. Closely related and indistinguishable methicillin-resistant S. epidermidis were detected. These results highlight that HCWs which have contact with patient at high risk for developing infections were identified as colonized by MRSE in the oral cavity, reinforcing this cavity as a reservoir of these bacteria and the risk to themselves and patients safety, because these microorganisms may be spread by coughing and talking.

Background: Nasal colonization with coagulase-negative Staphylococcus (CoNS) has been described as a risk factor for subsequent systemic infection. In this study, we evaluated the genetic profile of CoNS isolates colonizing the nares of children admitted to a neonatal intensive care unit (NICU)., Methods: We assessed CoNS carriage at admittance and discharge among newborns admitted to a NICU from July 2007 through May 2008 in one of the major municipalities of Brazil. Isolates were screened on mannitol salt agar and tryptic soy broth and tested for susceptibility to antimicrobials using the disc diffusion method. Polymerase chain reaction (PCR) was used to determine the species, the presence of the mecA gene, and to perform SCCmec typing. S. epidermidis and S. haemolyticus isolated from the same child at both admission and discharge were characterized by PFGE., Results: Among 429 neonates admitted to the NICU, 392 (91.4%) had nasal swabs collected at both admission and discharge. The incidence of CoNS during the hospitalization period was 55.9% (95% confidence interval [CI]: 50.9-60.7). The most frequently isolated species were S. haemolyticus (38.3%) and S.epidermidis (38.0%). Multidrug resistance (MDR) was detected in 2.2% and 29.9% of the CoNS isolates, respectively at admittance and discharge (p = 0.053). The mecA gene was more prevalent among strains isolated at discharge (83.6%) than those isolated at admission (60%); overall, SCCmec type I was isolated most frequently. The length of hospitalization was associated with colonization by MDR isolates (p < 0.005). Great genetic diversity was observed among S. epidermidis and S. haemolyticus., Conclusions: NICU represents an environment of risk for colonization by MDR CoNS. Neonates admitted to the NICU can become a reservoir of CoNS strains with the potential to spread MDR strains into the community.

Although immortalized cell lines have been extensively used to optimize treatment strategies in cancer, the usefulness of such in vitro systems to recapitulate primary disease is limited. Therefore, the design of in vivo models ideally utilizing patient-derived material is of critical importance. In this regard, NOD.Cg-Prkdc(scid) IL2rg(tmWjl) /Sz (NSG) mice have been reported to provide superior engraftment rates. However, limited data exist on the validity of such a model to constitute a surrogate marker for clinical parameters. We studied primary and serial engraftment on more than 200 NSG mice with 54 primary pediatric B cell precursor acute lymphatic leukemia (B-ALL), myeloid leukemia (AML) and T cell leukemia (T-ALL) samples, characterized the leukemogenic profile and correlated engraftment kinetics with clinical outcome. Median time to engraftment was 7-10 weeks and 90% of the mice engrafted. Male recipients conferred significantly higher engraftment levels than female recipients (p ≤ 0.004). PCR-based minimal residual disease marker expression and fluorescence in situ hybridization confirmed the presence of patient-specific genetic aberrations in mice. Transcriptome cluster analysis of genes known to be important in the leukemogenesis of all three diseases revealed that well-known tumor-regulating genes were expressed to a comparable extent in mice and men. The extent of engraftment and overall survival of NSG mice highly correlated with the individual prognosis of B-ALL, AML and T-ALL patients. Thus, we propose an in vivo model that provides a valuable preclinical tool to explore the heterogeneity of leukemic disease and exploit patient-tailored leukemia-targeting strategies within multivariate analyses., (© 2013 UICC.)

Unlabelled: Polymorphonuclear neutrophil granulocytes (neutrophils) are tightly controlled by an incompletely understood homeostatic feedback loop adjusting the marrow's supply to peripheral needs. Although it has long been known that marrow cellularity is inversely correlated with G-CSF levels, the mechanism linking peripheral clearance to production remains unknown. Herein, the feedback response to antibody induced neutropenia is characterized to consist of G-CSF–dependent shifts of marrow hematopoietic progenitor populations including expansion of the lin-/Sca-1/c-kit (LSK) and granulocyte macrophage progenitor (GMP) compartments at the expense of thrombopoietic and red cell precursors. Evidence is provided that positive feedback regulation is independent from commensal germs as well as T, B, and NK cells. However, in vivo feedback is impaired in TLR4-/- and TRIF-/-, but not MyD88-/- animals. In conclusion, steady-state neutrophil homeostasis is G-CSF–dependent and regulated through pattern-recognition receptors,thereby directly linking TLR-triggering to granulopoiesis., Key Points: Steady-state and emergency granulopoiesis are both dependent on TLR signaling.

The transcriptional regulator ecotropic viral integration site-1 (EVI-1) has mainly been studied for its role in myeloid malignancies, in which high EVI-1 levels are associated with particularly aggressive disease. The role of EVI-1 in lymphoid cells, however, is largely unknown. Here we show that EVI-1 is indeed expressed in lymphoid malignancies such as acute lymphoblastic leukemia (ALL) and a subset of chronic lymphocytic leukemia. Expression data from pediatric ALL further suggest that high EVI-1 levels are associated with poor prognosis. Suppression of EVI-1 expression by RNA interference reduces cell growth and enhances apoptosis sensitivity in response to various stimuli in lymphoblastic leukemia cells. At the molecular level, EVI-1 modulates expression of several apoptosis-related genes (such as BCL2, BCL-x, XIAP, NOXA, PUMA, TRAIL-R1). Furthermore, EVI-1 knockdown strongly impairs in vivo engraftment of lymphoblastic leukemia cells upon transplantation in immune-permissive NOD/SCID/IL2Rγ(null) mice, conferring a survival benefit when compared with mice transplanted with control cells. Thus, our data show that EVI-1 is expressed not only in myeloid but also in lymphoid leukemias, and contributes to the leukemogenic potential and apoptosis resistance of ALL cells.

Background: There is no consensus on the standard treatment options for female pattern androgenetic alopecia (AGA). Efficacy of finasteride in women is controversial. The purpose of this study was to evaluate the clinical efficacy and safety of 5 mg/day oral finasteride in normoandrogenic postmenopausal woman., Materials and Methods: A total of 40 normoandrogenic postmenopausal women with AGA was enrolled in this study. They were treated with oral finasteride 5 mg/day for 18 months. Efficacy was evaluated by patient's satisfaction and global photograph assessment. All the 40 patients completed 18 months of finasteride treatment schedule., Results: After 6 months, 22 patients referred significant improvement, 12 moderate improvement, and 6 no improvement. Regarding to global photo assessment, 8 patients showed no improvement, 16 showed moderate improvement and 16 showed significant improvements at the 6(th) month. A slight improvement was observed over time from 6 to 12 and 18 months observation. Maintained libido reduction was referred by four patients and liver enzymes increase was observed in one patient. Older patients were more prone to worse response., Discussion: Finasteride 5 mg/day is effective and safe for the treatment of female AGA in postmenopausal women in the absence of clinical or laboratory signs of hyper-androgenism.

Cytotoxic T cells are important effectors for robust antitumor immune responses. However, tumor-infiltrating CD8 T cells are often functionally impaired. Insufficient antitumor activity of CD8 T cells can be due to a lack of costimulatory signals. NKG2D is such a costimulatory receptor on CD8 T cells that facilitates immunorecognition of stressed and malignant cells, promotes tumor rejection by NK and CD8 T cells and contributes to immunosurveillance of spontaneous malignancies. Previous reports suggested an involvement of NKG2D in establishing CD8 T cell-mediated antitumor memory. However, the significance of NKG2D for the generation and effector phase of memory CD8 T cell responses is largely unknown. To address these issues, we made use of a transgenic mouse model (H2-K(b)-MICA mice) where the human NKG2D ligand MICA is ubiquitously and constitutively expressed resulting in a severe dysfunction of NKG2D. Both, ovalbumin (OVA)-specific (H2-K(b)/OVA(257-264)) memory CD8 T cells arisen from the endogenous T cell pool and adoptively transferred OVA-specific OT-I memory cells were unable to control growth of an OVA-expressing lymphoma in H2-K(b)-MICA mice. While expansion of memory T cells in these mice on antigen challenge was not different from controls, CD8 memory T cells of H2-K(b)-MICA mice did not effectively eliminate tumor cells in vivo. Altogether, our data suggest that NKG2D has no major role in the generation and expansion of memory CD8 T cells, but rather substantially enhances the cytolytic effector responses of reactivated memory T cells and thereby contributes to an efficacious tumor rejection., (Copyright © 2011 UICC.)

The zebrafish has become a powerful vertebrate model for genetic studies of embryonic development and organogenesis and increasingly for studies in cancer biology. Zebrafish facilitate the performance of reverse and forward genetic approaches, including mutagenesis and small molecule screens. Moreover, several studies report the feasibility of xenotransplanting human cells into zebrafish embryos and adult fish. This model provides a unique opportunity to monitor tumor-induced angiogenesis, invasiveness, and response to a range of treatments in vivo and in real time. Despite the high conservation of gene function between fish and humans, concern remains that potential differences in zebrafish tissue niches and/or missing microenvironmental cues could limit the relevance and translational utility of data obtained from zebrafish human cancer cell xenograft models. Here, we summarize current data on xenotransplantation of human cells into zebrafish, highlighting the advantages and limitations of this model in comparison to classical murine models of xenotransplantation., (© 2012 New York Academy of Sciences.)

Septic diseases are characterized by an initial systemic, proinflammatory phase, followed by a period of anti-inflammation. In the context of the latter, monocytes have been described to display altered functions, including reduced TNF secretion and T cell-stimulating capacities in response to recall antigens. This hyporesponsiveness is supposed to be detrimental for coping with secondary infections. We here characterize bacterially reprogrammed PBMC-derived monocytes with special focus on their phagocytic activity. Hence, we have implemented a surrogate model of the early, postinflammatory period by exposing PBMCs to Escherichia coli on d0 and rechallenging them with bacteria on d2. This induced the emergence of a distinct monocytic phenotype with profound phagocytic impairments but a preserved ability for naïve T cell stimulation. The compromising effects on phagocytosis required the presence of bacteria and were not mimicked by TLR4 ligation or exposure to isolated cytokines alone. Moreover, the impairments were specific for the engulfment of bacteria and were coupled to a selective down-regulation of FcγR and SR expression. Intriguingly, this monocytic phenotype contributed to the stimulation of a T(H)17-polarized adaptive immune response in the context of secondary infection. Our findings extend the current knowledge of monocytic reprogramming and identify the phagocytic capacity of monocytes as a putative sepsis biomarker.

Trials of immune-modulating drugs in septic patients have mostly failed to demonstrate clinical efficacy. Thus, we sought to generate a surrogate model of myelomonocytic lineage differentiation that would potentially allow sepsis induction and preclinical testing of anti-inflammatory drugs. Comparing transplantation of cord blood-derived stem cells in neonatal NOD/SCID/IL2Rγ(null) (neonatal huNSG) mice with transplantation of adult peripheral mobilized stem cells into adult NSG (adult huNSG) recipients, we demonstrate that myelomonocytic lineage differentiation in neonatal huNSG mice is retarded and monocytes are phenotypically immature with respect to HLA-DR expression and the emergence of CD80(+)CD86(+) monocytes. Functionally, neonatal huNSG mice were less sensitive toward interferon-γ-induced upregulation of CD86 and exhibited a reduced T-cell stimulating capacity when compared with adult huNSG mice, whereas the phagocytic activity and the ability for cytokine secretion were mature. However, comparison of these data with data obtained from human neonates indicate that absence of the CD80(+)CD86(+) population and the reduced T-cell stimulating capacity of neonatal huNSG monocytes resemble functional immaturities observed in human neonatal monocytes. Thus, these two mouse models might well serve as 2 independent surrogate models for studying the neonatal myelomonocytic lineage differentiation or for testing the efficacy of immunomodulatory drugs on functionally mature monocytes., (Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

People with Williams syndrome (WS) have been consistently described as showing heightened sociability, gregariousness, and interest in people, in conjunction with an uneven cognitive profile and mild to moderate intellectual or learning disability. To explore the mechanisms underlying this unusual social-behavioral phenotype, we investigated whether individuals with WS show an atypical appraisal style and autonomic responsiveness to emotionally laden images with social or nonsocial content. Adolescents and adults with WS were compared to chronological age-matched and nonverbal mental age-matched groups in their responses to positive and negative images with or without social content, using measures of self-selected viewing time (SSVT), autonomic arousal reflected in pupil dilation measures, and likeability ratings. The participants with WS looked significantly longer at the social images compared to images without social content and had reduced arousal to the negative social images compared to the control groups. In contrast to the comparison groups, the explicit ratings of likeability in the WS group did not correlate with their SSVT; instead, they reflected an appraisal style of more extreme ratings. This distinctive pattern of viewing interest, likeability ratings, and autonomic arousal to images with social content in the WS group suggests that their heightened social drive may be related to atypical functioning of reward-related brain systems reflected in SSVT and autonomic reactivity measures, but not in explicit ratings.

Cutaneous leiomyosarcoma is a relatively uncommon tumor that accounts for 7% of all soft tissue sarcomas. It occurs more frequently in males between 50-70 years and only 10-15% of cases are located on the trunk. Radiotherapy and previous trauma have been implied as risk factors. We report the case of a 57 year-old male with an eight-month history of a hard painless erythematous-violaceous tumor on the presternal region. Histopathology evidenced a malignant spindle cell tumor, "cigar" shaped, with pleomorphic nuclei and a high mitotic index that occupied the entire dermal thickness. Immunohistochemical staining of the tumor cells was positive for smooth muscle actin, desmin and vimentin and negative for S-100 protein and pan-cytokeratin, which supported the diagnosis of dermal leiomyosarcoma. Radical surgery was performed to remove the tumor.

Churg-Strauss syndrome (CSS) is an infrequent vasculitis that affects small to medium-sized vessels. We describe a 51 year-old-female admitted to our inpatient unit with bullae on her right foot and forearm with pain, paresthesias and impotence of the foot. There was rapid clinical deterioration with lost of gait and peripheral eosinophilia. Histopathology showed many extravascular eosinophils. Bone marrow had an increased number of eosinophils and their precursors with no neoplastic cells infiltration. Electromyogram revealed mononeuritis multiplex with bilateral sciatic and right femoral nerve involvement. She fulfilled the eligibility criteria of American College of Rheumatology (ACR) and Chapell Hill Conference Consensus (CHCC) of CSS so corticosteroids and cyclophosphamide and rehabilitation program were begun with good clinical and laboratorial response. This report illustrates the importance of identifying atypical cutaneous features of CSS for the early diagnosis of this rare condition and the role of a multidisciplinary team in this multissystemic disease.

Epidermal Langerhans cells (LC) are potent APCs surveying the skin. They are crucial regulators of T cell activation in the context of inflammatory skin disease and graft-versus-host disease (GVHD). In contrast to other dendritic cell subtypes, murine LC are able to reconstitute after local depletion without the need of peripheral blood-derived precursors. In this study, we introduce an experimental model of human skin grafted to NOD-SCID IL2Rγ(null) mice. In this model, we demonstrate that xenografting leads to the transient loss of LC from the human skin grafts. Despite the lack of a human hematopoietic system, human LC repopulated the xenografts 6 to 9 wk after transplantation. By staining of LC with the proliferation marker Ki67, we show that one third of the replenishing LC exhibit proliferative activity in vivo. We further used the skin xenograft as an in vivo model for human GVHD. HLA-disparate third-party T cells stimulated with skin donor-derived dendritic cells were injected intravenously into NOD-SCID IL2Rγ(null) mice that had been transplanted with human skin. The application of alloreactive T cells led to erythema and was associated with histological signs of GVHD limited to the transplanted human skin. The inflammation also led to the depletion of LC from the epidermis. In summary, we provide evidence that human LC are able to repopulate the skin independent of blood-derived precursor cells and that this at least partly relates to their proliferative capacity. Our data also propose xeno-transplantation of human skin as a model system for studying the role of skin dendritic cells in the efferent arm of GVHD.

Basal Cell Carcinoma is the most common skin cancer. We describe a single-staged technique for correction of nasal ala defect after the excision of a basal cell carcinoma. This technique allows correction of surgical defects of the ala rebuilding the original anatomy, maintaining cosmetic units, without need for a graft.