3D Imaging of a Dislocation Loop at the Onset of Plasticity in an Indented Nanocrystal.

Structural quality and stability of nanocrystals are fundamental problems that bear important consequences for the performances of small-scale devices. Indeed, at the nanoscale, their functional properties are largely influenced by elastic strain and depend critically on the presence of crystal defects. It is thus of prime importance to be able to monitor, by noninvasive means, the stability of the microstructure of nano-objects against external stimuli such as mechanical load. Here we demonstrate the potential of Bragg coherent diffraction imaging for such measurements, by imaging in 3D the evolution of the microstructure of a nanocrystal exposed to in situ mechanical loading. Not only could we observe the evolution of the internal strain field after successive loadings, but we also evidenced a transient microstructure hosting a stable dislocation loop. The latter is fully characterized from its characteristic displacement field. The mechanical behavior of this small crystal is clearly at odds with what happens in bulk materials where many dislocations interact. Moreover, this original in situ experiment opens interesting possibilities for the investigation of plastic deformation at the nanoscale.

Vichy Thermal Spring Water (VTSW), a cosmetic ingredient of potential interest in the frame of skin ageing exposome: an in vitro study.

OBJECTIVE: To study the effects of the very high minerality Vichy Thermal Spring Water (VTSW) on human keratinocytes grown in vitro. METHODS: The effect of VTSW was monitored by full genome transcriptomic technology and immunofluorescence microscopy. RESULTS: In the presence of 50% VTSW, the expression of a number of skin homoeostasis-related genes is increased, specifically with respect to dermal-epidermal junction, epidermal cohesion and communication, keratinocyte proliferation-differentiation balance, antioxidant mechanisms and DNA repair. CONCLUSION: This work suggests that VTSW could be considered as an ingredient of potential interest to address some of the deleterious effects of skin ageing exposome.

Population Pharmacokinetics of Posaconazole Tablets and Monte Carlo Simulations To Determine whether All Patients Should Receive the Same Dose.

Posaconazole is extensively used for prophylaxis for invasive fungal infections. The gastro-resistant tablet formulation has allowed the bioavailability issues encountered with the oral suspension to be overcome. However, overexposure is now frequent. This study aimed to (i) describe the pharmacokinetics of posaconazole tablets in a real-life cohort of patients with hematological malignancies and (ii) perform Monte Carlo simulations to assess the possibility that the daily dose can be reduced while keeping a sufficient exposure. Forty-nine consecutive inpatients were prospectively included in the study. Posaconazole trough concentrations (TC) were measured once a week, and biological and demographic data were collected. The concentrations were analyzed by compartmental modeling, and Monte Carlo simulations were performed using estimated parameters to assess the rate of attainment of the target TC after dose reduction. The pharmacokinetics of posaconazole were well described using a one-compartment model with first-order absorption and elimination. The values of the parameters (interindividual variabilities) were as follows: the absorption constant (ka ) was 0.588 h-1 (fixed), the volume of distribution (V/F) was 420 liters (28.2%), and clearance (CL/F) was 7.3 liters/h (24.2%) with 31.9% interoccasion variability. Forty-nine percent of the simulated patients had TC at steady state of ≥1.5 µg/ml and maintained a TC above 1 µg/ml after a reduction of the dose to 200 mg daily. A third of these patients eligible for a dose reduction had TC of ≥1.5 µg/ml as soon as 48 h of treatment. Though posaconazole tablets were less impacted by bioavailability issues than the oral suspension, the pharmacokinetics of posaconazole tablets remain highly variable. Simulations showed that approximately half of the patients would benefit from a reduction of the dose from 300 mg to 200 mg while keeping the TC above the minimal recommended target of 0.7 µg/ml, resulting in a 33% savings in the cost of this very expensive drug.

Socioeconomic inequalities in knee pain, knee osteoarthritis, and health-related quality of life: a population-based cohort study in southern Sweden.

OBJECTIVES: To determine socioeconomic inequalities in frequent knee pain (FKP), knee osteoarthritis (OA), and associated health-related quality of life (HRQoL) in Sweden. METHOD: In 2007 a postal questionnaire about knee pain was sent to a random sample of 10 000 residents of Malmö, Sweden (7402 individuals responded). Subjects reporting pain with duration ≥ 4 weeks in one or both knees in the past 12 months were classified as having FKP. A random sample of 1527 subjects with and without FKP attended a clinical and radiographic knee examination and responded to generic and disease-specific HRQoL questionnaires. We used the individuals' level of education and occupation as socioeconomic status (SES) measures, and we calculated the relative index of inequality (RII) using Poisson regression with robust standard errors adjusted for age and gender. We applied weighting to account for a possible selection bias that might arise from non-responses in the study. RESULTS: With education, the RIIs for FKP and knee OA were 0.71 [95% confidence interval (CI) 0.61-0.84] and 0.56 (95% CI 0.34-0.93), respectively. With occupation, the corresponding figures were 0.70 (95% CI 0.60-0.82) and 0.59 (95% CI 0.37-0.94), respectively. There were socioeconomic gradients in HRQoL in favour of people with better SES. RIIs for FKP and HRQoL but not knee OA were essentially similar after additional adjustment for mediators. CONCLUSIONS: In Sweden there are socioeconomic gradients related to both FKP and knee OA as well as HRQoL in favour of people with better SES. SES should be taken into account in health resource allocation pertaining to knee-related disorders.

Seasonal and geographic variations in the incidence of asthma exacerbations in the United States.

BACKGROUND: Exacerbations drive the burden of asthma and lead to significant morbidity and consumption of health care resources. Many prior studies of the epidemiology of asthma exacerbations have relied upon data from hospital care. OBJECTIVE: The objective of this study was to determine US patterns of geographic and seasonal variations of asthma exacerbations being defined as asthma episodes requiring hospital care and/or a prescription for oral steroid. METHODS: The study was a retrospective observational cohort study using administrative claims data for insured individuals from the HealthCore Integrated Research Database, including around 43 million members in the United States. Analyses examined 3 age groups, 6-17, 18-64, and ≥65 years and four US regions, Northeast, Southeast, Central, and Western. RESULTS: Monthly rates of asthma exacerbations showed the greatest variation over the year in children, less so in adults and in the elderly. Clinically important differences in rates of asthma exacerbation were observed between regions with the Western Region having the lowest in all three age groups followed by the Northeast, Central, and Southeast regions. Peaks in children occurred in the early fall following troughs in the summer months, and peaks at year-end occurred in adults, particularly in those over 65 years. CONCLUSIONS: There is a striking seasonal variation in asthma exacerbations in the United States. Substantial differences between regions of the United States in asthma exacerbation rates cannot readily be explained and invite further investigation.

CD28 deletion improves obesity-induced liver steatosis but increases adiposity in mice.

BACKGROUND/OBJECTIVES: Lymphocytes have a critical role in visceral adipose tissue (AT) inflammation. The CD28 costimulatory molecule is required for lymphocyte activation and for the development of a functional regulatory T cells (Tregs) compartment; however, its role during obesity is unknown. METHODS: During diet-induced obesity, we investigated the effects of selective interference with CD28 signaling using knockout mice (Cd28KO) and a CTLA4-Ig fusion protein inhibiting CD28-B7 interactions. RESULTS: Cd28 deficiency decreased pathogenic T cells and Treg content within AT without changing the macrophages number. Cd28KO epididymal but not subcutaneous fat was characterized by enlarged adipocytes, reduced levels of inflammatory cytokines and increased Glut4, adiponectin and lipogenic enzyme mRNA levels. This was associated with reduced inflammation, fat accumulation and enhanced glucose metabolism in liver. Weight gain and fasting glucose tolerance were not affected. CTLA4-Ig injections reduced the number of T cells in epididymal AT (epiAT) but not the inflammatory cytokines levels and failed to improve liver fat accumulation. CONCLUSIONS: Deletion of CD28 creates a new pro/anti-inflammatory balance in epiAT and liver and exerts a protective effect against hepatic steatosis.

Lack of drug interaction between cyclosporine and telaprevir in a liver transplant recipient.

Telaprevir is a novel NS3A/4A protease inhibitor approved in combination with ribavirin and peg-interferon alfa for the treatment of genotype-1 chronic hepatitis C. This drug is also known to be a potent cytochrome P450 3A and drug efflux protein ATP-binding cassette B1 (also called P-glycoprotein) inhibitor, and could therefore interact with immunosuppressive drugs. For this reason, a decrease in cyclosporine (CsA) dosage has been proposed when combining this drug with telaprevir. We report herein the case of an unpredictable lack of interaction between CsA and telaprevir in a liver transplant recipient. The decrease in CsA dosage, conducted as recommended in the literature, did not result in stable CsA concentrations but decreased them. However, the decrease in CsA exposure could have been unseen without the measurement of CsA concentrations 2 h after the administration (C2 ) of the drug, because it mainly resulted from the decrease in CsA peak. The mechanism leading to this lack of drug interaction in this patient has not been fully elucidated yet, but is likely to affect the absorption phase. Therapeutic drug monitoring using only CsA trough concentrations could be falsely reassuring, and the addition of the measurement of the C2 may add useful information to adapt CsA dosage in patients co-treated with telaprevir.

Sound and light from fractures in scintillators.

Prompted by intriguing events observed in certain particle-physics searches for rare events, we study light and acoustic emission simultaneously in some inorganic scintillators subject to mechanical stress. We observe mechanoluminescence in Bi4Ge3O12, CdWO4, and ZnWO4, in various mechanical configurations at room temperature and ambient pressure. We analyze the temporal and amplitude correlations between the light emission and the acoustic emission during fracture. A novel application of the precise energy calibration of Bi4Ge3O12 provided by radioactive sources allows us to deduce that the fraction of elastic energy converted to light is at least 3×10(-5).

Total desmosines in plasma and urine correlate with lung function.

The aim of the present study was to evaluate the relationship between the matrix degradation biomarkers, desmosine and isodesmosine (desmosines), and lung function. Plasma and creatinine-corrected urinary total desmosines (P- and U-desmosines, respectively), lung function and diffusing capacity of the lung for carbon monoxide (D(L,CO)) were measured in a cohort of subjects from the Swedish Twin Registry. Concentrations of U- and P-desmosines were measured in 349 and 318 subjects, respectively; approximately one-third of subjects had chronic obstructive pulmonary disease (COPD). Age, female sex, body mass index (BMI) and smoking were significantly associated with U-desmosines in a multiple linear regression analysis. In the overall population, after adjustments for age, sex, height, BMI and smoking, concentrations of U-desmosines were significantly correlated with all lung function measures, and P-desmosines with forced expiratory volume in 1 s and D(L,CO) (p<0.05). With the exception of residual volume versus P-desmosines, relationships between concentrations of desmosines and lung function measures were markedly stronger in subjects with COPD compared with those without COPD. These cross-sectional data showing associations between desmosines and several lung function variables suggest that desmosines, particularly U-desmosines, could be a useful biomarker of COPD status.

In situ three-dimensional reciprocal-space mapping during mechanical deformation.

Mechanical deformation of a SiGe island epitaxically grown on Si(001) was studied by a specially adapted atomic force microscope and nanofocused X-ray diffraction. The deformation was monitored during in situ mechanical loading by recording three-dimensional reciprocal-space maps around a selected Bragg peak. Scanning the energy of the incident beam instead of rocking the sample allowed the safe and reliable measurement of the reciprocal-space maps without removal of the mechanical load. The crystal truncation rods originating from the island side facets rotate to steeper angles with increasing mechanical load. Simulations of the displacement field and the intensity distribution, based on the finite-element method, reveal that the change in orientation of the side facets of about 25° corresponds to an applied pressure of 2-3 GPa on the island top plane.

[Landscape components favouring the occurrence of anthrax in the Flooding Pampa grasslands (Buenos Aires province, Argentina)]. / Componentes del paisaje que favorecen la aparición de carbunco en la Pampa Deprimida (provincia de Buenos Aires, Argentina).

The authors studied the landscape components that favour the occurrence of anthrax in the Flooding Pampa grasslands (Buenos Aires province, Argentina). They made spatial locations of anthrax outbreaks diagnosed by registered veterinary laboratories in the study area's zone of influence. As variables for study, they differentiated areas that are flooded for 20% of the time or more from primary and secondary runoff channels. They also identified areas with low-productivity pasture. Logistic regression analysis of farm populations revealed that landscape components favouring the occurrence of anthrax outbreaks are shared runoff channels (odds ratio (OR) = 2.3; confidence interval (CI) = 1.2; 4.7) and > or = 40% low-productivity pasture (OR = 5.4; CI = 3.5; 8.3). Contrary to initial assumptions, susceptibility to flooding was not a significant variable (OR = 1.1; CI = 0.5; 2.1). The authors concluded that the first step in decision-making and ensuring more efficient implementation of future anthrax control and eradication plans was to identify risk variables.

Efficacy of generic meropenem products in combination with colistin in carbapenemase-producing Klebsiella pneumoniae experimental osteomyelitis.

Guidelines for the management of carbapenemase-producing Enterobacterales (CPE) infections recommend a combination of two active agents, including meropenem if the minimum inhibitory concentration (MIC) is ≤8 mg/L. The therapeutic equivalence of meropenem generics has been challenged. We compared the bactericidal activity of meropenem innovator (AstraZeneca) and four generic products (Actavis, Kabi, Mylan and Panpharma), both in vitro and in vivo, in association with colistin. In vitro time-kill studies were performed at 4 × MIC. An experimental model of KPC-producing Klebsiella pneumoniae osteomyelitis was induced in rabbits by tibial injection of a sclerosing agent followed by 2 × 108 CFU of K. pneumoniae KPC-99YC (meropenem MIC = 4 mg/L; colistin MIC = 1 mg/L). At 14 days after inoculation, treatment for 7 days started in seven groups of ≥10 rabbits, including a control group, a colistin group, and one group for each meropenem product (i.e. the innovator and four generics), in combination with colistin. In vitro, meropenem + colistin was bactericidal with no viable bacteria after 6 h, and this effect was similar with all meropenem products. In the osteomyelitis model, there was no significant difference between meropenem generics and the innovator when combined with colistin. Colistin-resistant strains were detected after treatment with colistin + meropenem innovator (n = 3) and generics (n = 3). The efficacy of four meropenem generics did not differ from the innovator in vitro and in an experimental rabbit model of KPC-producing K. pneumoniae osteomyelitis in terms of bactericidal activity and the emergence of resistance.

The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes.

AIMS/HYPOTHESIS: Obesity is associated with adipose tissue inflammation. The CD40 molecule, TNF receptor superfamily member 5 (CD40)/CD40 ligand (CD40L) pathway plays a role in the onset and maintenance of the inflammatory reaction, but has not been studied in human adipose tissue. Our aim was to examine CD40 expression by human adipocytes and its participation in adipose tissue inflammation. METHODS: CD40 expression was investigated in human whole adipose tissue and during adipocyte differentiation by real-time PCR, Western blot and immunohistochemistry. The CD40/CD40L pathway was studied using recombinant CD40L (rCD40L) in adipocyte culture and neutralising antibodies in lymphocyte/adipocyte co-culture. RESULTS: CD40 mRNA levels in subcutaneous adipose tissue were higher in the adipocyte than in the stromal-vascular fraction. CD40 expression was upregulated during adipocyte differentiation. Addition of rCD40L to adipocytes induced mitogen activated protein kinase (MAPK) activation, stimulated inflammatory adipocytokine production, and decreased insulin-induced glucose transport in parallel with a downregulation of IRS1 and GLUT4 (also known as SCL2A4). rCD40L decreased the expression of lipogenic genes and increased lipolysis. CD40 mRNA levels were significantly higher in subcutaneous adipose tissue than in visceral adipose tissue of obese patients and were positively correlated with BMI, and with IL6 and leptin mRNA levels. Lymphocyte/adipocyte co-culture led to an upregulation of proinflammatory adipocytokines and a downregulation of leptin and adiponectin. Physical separation of the two cell types attenuated these effects, suggesting the involvement of a cell-cell contact. Blocking the CD40/CD40L interaction with neutralising antibodies reduced IL-6 secretion from adipocytes. CONCLUSIONS/INTERPRETATION: Adipocyte CD40 may contribute to obesity-related inflammation and insulin resistance. T lymphocytes regulate adipocytokine production through both the release of soluble factor(s) and heterotypic contact with adipocytes involving CD40.

Incidence of severe knee and hip osteoarthritis in relation to different measures of body mass: a population-based prospective cohort study.

OBJECTIVE: To determine in a prospective population-based cohort study relationships between different measures of body mass and the incidence of severe knee and hip osteoarthritis defined as arthroplasty of knee or hip due to osteoarthritis. MATERIALS AND METHODS: Body mass index (BMI), waist circumference, waist-hip ratio (WHR), weight and percentage of body fat (BF%) were measured at baseline in 11,026 men and 16,934 women from the general population. The incidence of osteoarthritis over 11 years was monitored by linkage with the Swedish hospital discharge register. RESULTS: 471 individuals had knee osteoarthritis and 551 had hip osteoarthritis. After adjustment for age, sex, smoking and physical activity, the relative risks (RR) of knee osteoarthritis (fourth vs first quartile) were 8.1 (95% CI 5.3 to 12.4) for BMI, 6.7 (4.5 to 9.9) for waist circumference, 6.5 (4.6 to 9.43) for weight, 3.6 (2.6 to 5.0) for BF% and 2.2 (1.7 to 3.0) for WHR. Corresponding RR for hip osteoarthritis were 2.6 (2.0 to 3.4) for BMI, 3.0 (2.3 to 4.0) for weight, 2.5 (1.9 to 3.3) for waist, 1.3 (0.99 to 1.6) for WHR and 1.5 (1.2 to 2.0) for BF%. CONCLUSION: All measures of overweight were associated with the incidence of knee osteoarthritis, with the strongest relative risk gradient observed for BMI. The incidence of hip osteoarthritis showed smaller but significant differences between normal weight and obesity. Our results support a major link between overweight and biomechanics in increasing the risk of knee and hip osteoarthritis in men and women.

C-reactive protein, metabolic syndrome and incidence of severe hip and knee osteoarthritis. A population-based cohort study.

OBJECTIVE: To explore the relationships between C-reactive protein (CRP), metabolic syndrome (MetS) and incidence of severe knee or hip osteoarthritis (OA) in a prospective study. METHODS: A population-based cohort (n=5171, mean age 57.5+/-5.9 years) was examined between 1991 and 1994. Data was collected on lifestyle habits, measures of overweight, blood pressure as well as high-density lipoprotein (HDL) cholesterol, triglycerides, glucose and CRP measured with high-sensitive methods. Incidence of severe OA, defined as arthroplasty due to knee or hip OA, was monitored over 12 years of follow-up, in relation to CRP levels and presence of the MetS according to the adult treatment panel III-national cholesterol education program (ATPIII-NCEP) definition. RESULTS: A total of 120 participants had severe hip OA and 89 had knee OA during the follow-up. After adjustment for age, sex, smoking, physical activity and CRP, presence of MetS was associated with significantly increased risk of knee OA (relative risk [RR]: 2.1, 95% confidence interval [CI]: 1.3-3.3). However, this relationship was attenuated and non-significant after adjustment for body mass index (BMI) (RR: 1.1, 95% CI: 0.7-1.8). MetS was not significantly associated with incidence of hip OA. In women, CRP was associated with knee OA in the age-adjusted analysis. However, there was no significant relationship between CRP and incidence of knee or hip OA after risk factor adjustments. CONCLUSION: The increased incidence of knee OA in participants with the MetS was largely explained by increased BMI. CRP was not associated with incidence of knee or hip OA when possible confounding factors were taken into account.

Moxifloxacin-rifampicin combination for the treatment of non-staphylococcal Gram-positive orthopedic implant-related infections.

OBJECTIVE: We aimed to describe the effectiveness and safety of the moxifloxacin-rifampicin combination in non-staphylococcal Gram-positive orthopedic implant-related infections. METHODS: Patients treated with the moxifloxacin-rifampicin combination for an implant-related infection from November 2014 to November 2016 were retrospectively identified from the database of the referral centers for bone and joint infections in Western France. RESULTS: Twenty-three cases of infection due to Streptococcus spp. (n=12), Cutibacteriumacnes (n=6), and Enterococcus faecalis (n=5) were included. Ten patients with hip prosthesis were included. Infection was polymicrobial in 11 cases. According to the MIC, moxifloxacin was 1.5 to 11.7 times as active as levofloxacin against non-staphylococcal Gram-positive bacteria. We reported an 81.8% success rate, and no severe adverse effect. CONCLUSION: The moxifloxacin-rifampicin combination is a valuable alternative for the treatment of non-staphylococcal Gram-positive implant-related infections because of the good activity of moxifloxacin against these bacteria and the potential activity on the biofilm.

Colistin-containing cement spacer for treatment of experimental carbapenemase-producing Klebsiella pneumoniae prosthetic joint infection.

Carbapenemase-producing Enterobacteriaceae (CPE) are emerging multidrug-resistant bacteria responsible for invasive infections, including prosthetic joint infections (PJIs). Local administration of colistin may provide bactericidal concentrations in situ. This study evaluated the efficacy of a colistin-impregnated cement spacer, alone and in combination with systemic antibiotics, in a rabbit model of CPE-PJI. Elution of 3 MIU of colistimethate sodium (CMS) in 40 g of poly(methyl methacrylate) cement was studied in vitro. In vivo, 5 × 108 CFU of KPC-producing Klebsiella pneumoniae (colistin and meropenem MICs of 1 mg/L and 4 mg/L, respectively) were injected close to a prosthetic knee. Surgical debridement and prosthesis removal were performed 7 days later, and rabbits were assigned to six treatment groups (11-13 rabbits each): drug-free spacer; colistin-loaded spacer; colistin intramuscular (i.m.); colistin i.m. + colistin spacer; colistin i.m. + meropenem subcutaneous (s.c.); and colistin i.m. + meropenem s.c. + colistin spacer. Systemic treatment was administered at doses targeting pharmacokinetics in humans, and rabbits were euthanised 7 days later to evaluate bacterial counts in infected bones. In vitro, CMS elution was low (<0.1% at 24 h) but reached a local concentration of ≥20 mg/L (>20 × MIC). In vivo, combinations of local and systemic colistin, with or without meropenem, were the only regimens superior to the control group (P ≤ 0.05) in terms of viable bacterial counts and the proportion of rabbits with sterile bone, with no emergence of colistin-resistant strains. Colistin-loaded cement spacer in combination with systemic antibiotics were the most effective regimens in this CPE-PJI model.

Safety study and therapeutic drug monitoring of the oral tablet formulation of posaconazole in patients with haematological malignancies.

PURPOSE: Posaconazole is a triazole antifungal widely used for prophylaxis of invasive fungal disease (IFI). Posaconazole tablets allow reaching higher plasma levels than the oral suspension, but safety data with this formulation in real life are scarce. This study aimed at evaluating the safety profile, the pharmacokinetic variability, and the concentration-toxicity relationship of posaconazole tablets in patients with haematological malignancies. METHODS: Sixty neutropenic patients treated with posaconazole tablets for prophylaxis of IFI were prospectively included in the study. Adverse drug reactions (ADR) were recorded and analyzed by the Regional Pharmacovigilance Centre to assess posaconazole implication. Blood samples were drawn once a week and plasma trough concentrations (C min) were assayed by LC-MS/MS. The rates of ADR by quartile of C min were compared. RESULTS: Eighteen patients (30%) experienced at least one ADR attributed to posaconazole. Liver function test (LFT) abnormalities were encountered in 20% of patients and resulted in four (6.7%) treatment discontinuations. Posaconazole median (range) C min was 1.36 (< 0.1-3.44) µg/mL (inter-patient CV = 43.9%). During follow-up, 28.6% of patients had at least one concentration < 0.7 µg/mL, and 35.7% had at least one concentration > 2 µg/mL. Rates of ADR by quartile of C min were not different. CONCLUSIONS: Posaconazole was well tolerated; however, LFT abnormalities were frequent. ADR occurrence was not linked to posaconazole exposure. Because posaconazole concentrations were highly variable, TDM can be helpful to avoid underexposure to the drug and increase its efficacy in preventing IFI. Conversely, a large proportion of patients was overexposed and might have benefited of a dose reduction.

Chronic plasminogen activator inhibitor-1 (PAI-1) overexpression dampens CD25+ lymphocyte recruitment after lipopolysaccharide endotoxemia in mouse lung.

BACKGROUND: Plasma plasminogen activator inhibitor-1 (PAI-1) level rises during sepsis and confers a worse prognosis. PAI-1 participation to sepsis has been poorly documented and was mainly associated with fibrin deposits. Beside fibrin deposits, increased tissue PAI-1 expression may contribute to the poor outcome of endotoxemia through other mechanisms. OBJECTIVE AND METHODS: During lipopolysaccharide (LPS) challenge, the role of PAI-1 in the early phase of inflammation was examined in the lungs of transgenic mice that either overexpress or lack the PAI-1 gene (PAI-1Tg or PAI-1(-/-)). RESULTS: Analysis of leukocytes revealed that neutrophil and macrophage infiltrations did not differ for PAI-1Tg and wild-type (WT) mice. Remarkably, CD25+ lymphocyte infiltration was totally blunted in PAI-1Tg lungs and inversely correlated with fibrin depositions. In parallel, mRNA levels of the regulatory T cell (Treg) markers FoxP3, CTLA-4, and GITR were significantly lower in PAI-1Tg than in WT lungs after LPS challenge. These data are supported by opposite results in PAI-1(-/-) lungs. The systemic compartments (spleen and peripheral blood) showed no decrease in CD25+, CD4+ CD25+ lymphocytes, and Treg markers in PAI-1Tg mice after LPS injection compared with WT mice. In addition, plasma and lung concentrations of interleukin-6 (IL-6) and macrophage inflammatory protein-1alpha (MIP-1alpha) were significantly higher in PAI-1Tg mice than WT mice. CONCLUSION: Our results suggest that chronic tissue PAI-1 overexpression influences the early phase of the inflammatory response during endotoxemia through the control of T lymphocyte traffic.

Identifying Defects with Guided Algorithms in Bragg Coherent Diffractive Imaging.

Crystallographic defects such as dislocations can significantly alter material properties and functionality. However, imaging these imperfections during operation remains challenging due to the short length scales involved and the reactive environments of interest. Bragg coherent diffractive imaging (BCDI) has emerged as a powerful tool capable of identifying dislocations, twin domains, and other defects in 3D detail with nanometer spatial resolution within nanocrystals and grains in reactive environments. However, BCDI relies on phase retrieval algorithms that can fail to accurately reconstruct the defect network. Here, we use numerical simulations to explore different guided phase retrieval algorithms for imaging defective crystals using BCDI. We explore different defect types, defect densities, Bragg peaks, and guided algorithm fitness metrics as a function of signal-to-noise ratio. Based on these results, we offer a general prescription for phasing of defective crystals with no a priori knowledge.