Targeting glutathione by dimethylfumarate protects against experimental malaria by enhancing erythrocyte cell membrane scrambling.
The balance between GSH-levels and oxidative stress is critical for cell survival. The GSH-levels of erythrocytes are dramatically decreased during infection with Plasmodium spp. We therefore investigated the consequences of targeting GSH for erythrocyte and Plasmodium survival in vitro and in vivo using dimethylfumarate (DMF) at therapeutically established dosage. We first show that noninfected red blood cells (RBC) exposed to DMF undergo changes typical of apoptosis or eryptosis, such as cell shrinkage and cell membrane scrambling with subsequent phosphatidylserine (PS) exposure. DMF did not induce appreciable hemolysis. DMF-triggered PS exposure was mediated by intracellular GSH depletion and reversed by the antioxidative N-acetyl-l-cysteine. DMF treatment controlled intraerythrocyte DNA amplification and in vitro parasitemia of Plasmodium falciparum-infected RBC. In vivo, DMF treatment had no effect on RBC count or GSH levels in noninfected mice. Consistent with its effects on infected RBC, DMF treatment abrogated parasitemia and enhanced the survival of mice infected with Plasmodium berghei from 0% to 60%. In conclusion, DMF sensitizes the erythrocytes to the effect of Plasmodium infection on PS exposure, thus accelerating the clearance of infected erythrocytes. Accordingly, DMF treatment favorably influences the clinical course of malaria. As DMF targets mechanisms within the host cell, it is not likely to generate resistance of the pathogen.


Increased Frequency of CD4+ Follicular Helper T and CD8+ Follicular T Cells in Human Lymph Node Biopsies during the Earliest Stages of Rheumatoid Arthritis.
Follicular T helper cells (Tfh cells) provide key B-cell help and are essential in germinal center formation and (auto) antibody generation. To gain more insight into their role during the earliest phase of rheumatoid arthritis (RA), we analyzed their frequencies, phenotypes, and cytokine profiles in peripheral blood and lymph node biopsies of healthy controls (HCs), autoantibody-positive individuals at risk for developing RA (RA-risk individuals), and early RA patients. Subsequently, we confirmed their presence in lymph nodes and synovial tissue of RA patients using immunofluorescence microscopy. In the blood, the frequency of Tfh cells did not differ between study groups. In lymphoid and synovial tissues, Tfh cells were localized in B-cell areas, and their frequency correlated with the frequency of CD19+ B cells. Compared to lymphoid tissues of healthy controls, those of RA patients and RA-risk individuals showed more CD19+ B cells, CD4+CXCR5+ follicular helper T cells, and CD8+CXCR5+ follicular T cells. These Tfh cells produced less IL-21 upon ex vivo stimulation. These findings suggest that Tfh cells may present a novel rationale for therapeutic targeting during the preclinical stage of RA to prevent further disease progression.


Is 27 a big number? Correlational and causal connections among numerical categorization, number line estimation, and numerical magnitude comparison.
This study examined the generality of the logarithmic to linear transition in children's representations of numerical magnitudes and the role of subjective categorization of numbers in the acquisition of more advanced understanding. Experiment 1 (49 girls and 41 boys, ages 5-8 years) suggested parallel transitions from kindergarten to second grade in the representations used to perform number line estimation, numerical categorization, and numerical magnitude comparison tasks. Individual differences within each grade in proficiency for the three tasks were strongly related. Experiment 2 (27 girls and 13 boys, ages 5-6 years) replicated results from Experiment 1 and demonstrated a causal role of changes in categorization in eliciting changes in number line estimation. Reasons were proposed for the parallel developmental changes across tasks, the consistent individual differences, and the relation between improved categorization of numbers and increasingly linear representations.


Expression of metallothionein and nuclear size in discrimination of malignancy in mucinous ovarian tumors.
Metallothioneins (MTs) are low molecular weight proteins that control cell proliferation via their metalloregulatory function. Several studies in various tumors have shown their influence in determining response to chemotherapy and prognosis. Because there has been no such study pertaining to ovarian tumors, we investigated MT expression and nuclear size in mucinous ovarian neoplasms (12 benign, 6 borderline, and 8 malignant). The percentage of MT-positive stained cells was significantly higher in the borderline than in the benign tumors, but lower than in the malignant tumors. Single layers of cells in the borderline tumors showed mild immunostaining in 50% of the cells and moderate staining in the remaining 50%, while 83.3% of cells within multilayered epithelium showed moderate to strong immunostaining. In the carcinomas, 87.5% of tumors showed moderate to strong staining in single-layered epithelium and moderate to strong staining of all the cells in multilayered epithelium. Morphometry measurements showed that the mean nuclear area of cells in the carcinomas was significantly larger than in the borderline or benign tumors. The nuclear area of cells in the carcinomas with early recurrence or metastasis was also significantly larger than in carcinomas without recurrence or metastasis. It is concluded that MT protein expression and nuclear size are possible markers for the evaluation of the progression of malignancy in mucinous ovarian tumors.


The impact of cesarean delivery on transmission of infectious agents to the neonate.
The rate of cesarean deliveries has increased dramatically over the past decade. Studies to date have highlighted a number of factors on the part of the treating physician and the expectant mother contributing to this increase. Maternal infections are not a major cause of this increase. There are a limited number of infections in a pregnant woman that warrant cesarean delivery to prevent perinatal transmission. This article outlines those infections known to be transmitted perinatally through the infected birth canal and details the current recommendations for cesarean delivery. Pregnant women with active genital herpes lesions or with known herpes simplex virus infection and a prodromal illness consistent with recurrence at the time of presentation in labor should undergo cesarean delivery. Pregnant women who are HIV infected and have detectable viremia (>1000 copies/mL) should be counseled regarding the potential benefits of cesarean delivery as an adjunct to antiretroviral therapy. Hepatitis C virus (HCV) can be transmitted intrapartum, but prevention of HCV transmission by cesarean delivery has not been proved effective and is not generally indicated. A limited number of other infectious agents can be transmitted through the birth canal but do not constitute an indication for cesarean delivery.


The spread of scientific information: insights from the web usage statistics in PLoS article-level metrics.
The presence of web-based communities is a distinctive signature of Web 2.0. The web-based feature means that information propagation within each community is highly facilitated, promoting complex collective dynamics in view of information exchange. In this work, we focus on a community of scientists and study, in particular, how the awareness of a scientific paper is spread. Our work is based on the web usage statistics obtained from the PLoS Article Level Metrics dataset compiled by PLoS. The cumulative number of HTML views was found to follow a long tail distribution which is reasonably well-fitted by a lognormal one. We modeled the diffusion of information by a random multiplicative process, and thus extracted the rates of information spread at different stages after the publication of a paper. We found that the spread of information displays two distinct decay regimes: a rapid downfall in the first month after publication, and a gradual power law decay afterwards. We identified these two regimes with two distinct driving processes: a short-term behavior driven by the fame of a paper, and a long-term behavior consistent with citation statistics. The patterns of information spread were found to be remarkably similar in data from different journals, but there are intrinsic differences for different types of web usage (HTML views and PDF downloads versus XML). These similarities and differences shed light on the theoretical understanding of different complex systems, as well as a better design of the corresponding web applications that is of high potential marketing impact.


Design characteristics and statistical methods used in interrupted time series studies evaluating public health interventions: a review.
Interrupted time series (ITS) designs are frequently used in public health to examine whether an intervention or exposure has influenced health outcomes. Few reviews have been undertaken to examine the design characteristics, statistical methods, and completeness of reporting of published ITS studies. We used stratified random sampling to identify 200 ITS studies that evaluated public health interventions or exposures from PubMed (2013-2017). Study characteristics, details of statistical models and estimation methods used, effect metrics, and parameter estimates were extracted. From the 200 studies, 230 time series were examined. Common statistical methods used were linear regression (31%, 72/230) and autoregressive integrated moving average (19%, 43/230). In 17% (40/230) of the series, we could not determine the statistical method used. Autocorrelation was acknowledged in 63% (145/230) of the series. An estimate of the autocorrelation coefficient was given for only 1% of the series (3/230). Measures of precision were reported for 63% of effect measures (541/852). Many aspects of the design, methods, analysis, and reporting of ITS studies can be improved, particularly description of the statistical methods and approaches to adjust for and estimate autocorrelation. More guidance on the conduct and reporting of ITS studies is needed to improve this study design.


Effect of gamma irradiation on elimination of aflatoxins produced by apple mycoflora in apple fruits.
The influence of ionizing radiation on the growth of apple mycoflora and the aflatoxins production was investigated. Four strains of fungal isolates, Aspergillus flavus, A. fumigatuis, A. niger, Penicillium expansum, were used. Four doses of gamma radiation were applied (0.5, 1.0, 1.5 and 2.0 KGy). The elimination of aflatoxins under selected conditions was detected by using HPLC techniques. Doses of 0.5 KGy stimulated the production of aflatoxins by all fungi tested while 1.0-2.0 KGy reduced the aflatoxins production. The studies were also carried out to investigate the effect of pre- and post-inoculation of both irradiated and non-irradiated fungal spores on irradiated and non-irradiated apples. The results showed the necessity of irradiation of fresh apple fruits followed by good preservation conditions. The results showed also that the effect of radiation is influences on the apple mycoflora producing aflatoxins and not the apple itself.


Novel spirocyclic phosphazene-based epoxy resin for halogen-free fire resistance: synthesis, curing behaviors, and flammability characteristics.
A novel halogen-free fire resistant epoxy resin with pendent spiro-cyclotriphosphazene groups was designed and synthesized via a three-step synthetic pathway. The chemical structures and compositions of spiro-cyclotriphosphazene precursors and final product were confirmed by (1)H, (13)C, and (31)P NMR spectroscopy, mass spectroscopy, elemental analysis, and Fourier transform infrared spectroscopy. The thermal curing behaviors of the synthesized epoxy resin with 4,4'-diamino-diphenylmethane, 4,4'-diamino-diphenyl sulfone, and novolac as hardeners were investigated by differential scanning calorimetry (DSC), and the curing kinetics were also studied under a nonisothermal condition. The evaluation of the thermal properties demonstrated that these thermosets achieved a good thermal resistance due to their high glass transition temperatures more than 150 °C, and also gained high thermal stabilities with high char yields. The flammability characteristics of the spirocyclic phosphazene-based epoxy thermosets cured with these three hardeners were investigated on the basis of the results obtained from the limiting oxygen index (LOI) and UL-94 vertical burning experiments as well as the analysis of the residual chars collected from the vertical burning tests. The high LOI values and UL-94 V-0 classification of these epoxy thermosets indicated that the incorporation of phosphazene rings into the backbone chain imparts nonflammability to the epoxy resin owing to the unique combination of phosphorus and nitrogen following by a synergistic effect on flame retardancy. The epoxy resin obtained in this study is a green functional polymer and will become a potential candidate for fire- and heat-resistant applications in electronic and microelectronic fields with more safety and excellent performance.


Laboratory testing for von Willebrand's disease: an assessment of current diagnostic practice and efficacy by means of a multi-laboratory survey. RCPA Quality Assurance Program (QAP) in Haematology Haemostasis Scientific Advisory Panel.
We report an evaluation of current laboratory practice for the diagnosis of von Willebrand's disease (VWD) by means of a multilaboratory survey. This assessment was undertaken with the RCPA Quality Assurance Program (QAP) in Haematology, which covers a wide geographic area encompassing Australia, New Zealand and Asia. A total of 25 laboratories actively involved in testing for VWD were selected to participate in a sample testing assessment exercise. Samples comprised 10 plasmas: (i) a normal plasma pool (in duplicate), (ii) this pool diluted to 50% (in duplicate), (iii) a normal individual (X1), (iv) severe Type 1 VWD (X1), (v) Type 2B VWD (x2 unrelated donors), (vi) Type 3 VWD (x1), (vii) Type 2A VWD (x1). Laboratories were asked to perform all tests available to them in order to establish a laboratory diagnosis of VWD, and then to comment on the possibility or otherwise of VWD. Overall findings indicated a wide variation in test practice, in the effectiveness of various test procedures in detecting VWD, and in the ability of various composite test panels to identify type 2 VWD subtypes. Firstly, while all laboratories (n = 25) performed tests for FVIII:C activity, von Willebrand factor 'antigen' (VWF:Ag) and a functional VWF assay [using the ristocetin cofactor assay (VWF:RCo; n = 23) and/or the collagen binding assay (VWF:CBA; n = 12)], only three laboratories carried out VWF:Multimer analysis. Secondly, for the three quantitative VWF assays, 10/25 (40%) laboratories performed all three, whereas 15/25 (60%) performed only two [VWF:Ag and VWF:RCo (n = 13); VWF:Ag and VWF:CBA (n = 2)]. Thirdly, a variety of assay methodologies were evident for VWF:Ag [ELISA, electro-immuno diffusion (EID), latex immuno-assay (LIA), and VIDAS assay] and VWF:RCo (platelet agglutination/'aggregometry' and a 'functional VWF:RCo-alternative' ELISA assay). Between method analysis for the quantitative VWF assays showed that the VWF:RCo yielded the greatest degree of inter-laboratory assay variation, and had the poorest overall performance with respect to sensitivity to low levels of VWF. The VWF:CBA also performed better than the VWF:RCo in terms of ability to detect functional VWF 'discordance' (i.e. Type 2 VWD). Within VWF:Ag method analysis showed that the EID assay procedure was associated with the greatest variation in assay results, while the EID and LIA test methods showed poorer sensitivity at low VWF levels compared to the ELISA method. Within the VWF:RCo assay procedure, greatest variation in assay results and poorest sensitivity to low VWF levels was obtained using the agglutination method; however, the agglutination procedure showed better performance than the 'functional VWF:RCo-alternative' ELISA assay in identifying Type 2 VWD plasma samples. Finally, despite identified variations, most laboratories appeared to understand the complexities involved in the VWD-diagnostic process, and made appropriate diagnostic predictions regarding tested samples. From a total possible 246 interpretation events, laboratories in most cases correctly identified normal samples as normal (67/75 events = 89%), and VWD samples as derived from individuals with VWD (117/121 events = 97%). Moreover, when VWD was suggested by laboratory findings, laboratories usually correctly predicted the general subtype of VWD present (96/109 events = 88%). When 'misinterpretations' occurred, these could often be linked to the test panels utilised by laboratories. That is, laboratories using the VWF:Ag and VWF:RCo combination were more likely to incorrectly identify samples derived from Type 2 VWD patients as being Type 1, Type 1 VWD patients as being Type 2, and normal plasma samples as potentially derived from patients with VWD, compared to those using the VWF:Ag and VWF:CBA.


CTX-m-3 beta-lactamase-producing Escherichia coli from Greece.
An Escherichia coli clinical strain resistant to all beta-lactams except carbapenems was isolated in a Greek hospital. Analysis of beta-lactamase content by isoelectric focusing, PCR assays specific for various bla genes, and DNA sequencing showed that the strain produced TEM-1, a Citrobacter freundii AmpC-related cephalosporinase, and CTX-M-3. The blaCTX.M-3 gene was carried by a 120-kb plasmid that was readily transferable to a susceptible E. coli host.


[Method of recording isotonic blood clot retraction].
The method and the device for photometric registration of blood clot isotonic retraction when the preset constant force is applied to the blood clot are described. The mathematic model enabling one to derive kinetic and energy parameters of the considered process is built. These parameters include: a velocity constant, a half-period of fibrinosis, a latent period, phase durations of contraction and tension, a specific working capacity, velocity constants of clot retraction and relaxation. The method may be useful in clinical diagnostic practice and in research work to evaluate hemocoagulation process and functional properties of blood cells.


Sport training and the growth and pubertal maturation of young athletes.
Growth and pubertal maturation of youth athletes are overwhelmingly within the broad range of normal variability. These include many successful male athletes who mature earlier than average, and many successful female athletes, especially in the "aesthetic" sports (artistic gymnastics, ice-skating, ballet) and distance running, who mature later than average. Artistic gymnasts generally receive the most attention, but their growth and maturation characteristics fall largely within the physiologic range and are indistinguishable from short, late maturing girls. It is difficult to ascribe causality to intensive training for sport as a factor in the later pubertal maturation of heavily training athletes. The alterations in hypothalamic-pituitary function for the GH/IGF-I and gonadal axes are likely appropriate for the stage of adolescent maturation. The selection and sorting processes for elite sport, including ballet, need critical evaluation. If intensive training is a factor affecting growth and pubertal maturation, its effects must be partitioned from (a) other factors known to influence these biological processes, and (b) other components of the overall sport training environment before causality can be established. Other factors which play an indeterminate role include: genetics/epigenetics, stress, psychosocial interactions, family environment and caloric intake, among others. These factors together with the energy expenditure of intensive training may influence the growth and pubertal maturation of some adolescent athletes. The effect is not necessarily attributable to training per se; rather, it is likely embedded in the elite sport training environment which is essentially an adult dominated enterprise.


Enamel remineralization: how to explain it to patients.
The term remineralization of initial enamel caries is frequently used, but mainly at research conferences and in lecture rooms. Clinicians avoid discussing remineralization and white-spot enamel lesion formation with patients because details of the processes are complex. Patients, therefore, incorrectly assume that cavitation occurs right at the onset of caries and that a restoration must be placed to halt further progression of the lesion. Although laboratory and clinical studies have shown that initial white-spot enamel lesions can remineralize, patients have little or no access to this information. The schematic diagrams in this paper explain the diffusion of organic acids from plaque between enamel crystals, the partial loss of mineral from enamel crystals, and subsequent demineralization and remineralization that produces the white-spot lesion. Further, these diagrams may help clinicians explain remineralization as simply as possible to patients who present with white-spot enamel lesions.


The influence of mini-BAL cultures on patient outcomes: implications for the antibiotic management of ventilator-associated pneumonia.
To determine the influence of mini-BAL culture results on subsequent changes in antibiotic therapy and patient outcomes. Prospective, single-center, cohort study. Medical ICU of Barnes-Jewish Hospital, St. Louis, a university-affiliated teaching hospital. One hundred thirty mechanically ventilated patients undergoing mini-BAL for suspected ventilator-associated pneumonia (VAP). Mini-BAL, prospective patient surveillance, and data collection. Sixty (46.2%) patients had mini-BAL cultures that yielded at least one pathogen potentially accounting for the clinically suspected episode of VAP (64 bacterial, 3 viral, 2 fungal). Among the 60 patients with microbiologically positive mini-BAL cultures, 44 (73.3%) were classified as receiving inadequate antibiotic therapy (ie, identification of a microorganism resistant to the prescribed antibiotic regimen). Prior antibiotic administration or its absence remained unchanged in 51 (39.2%) patients based on the mini-BAL culture results, while in another 51 (39.2%) patients, antibiotic therapy was either begun (n=7) or the existing antibiotic regimen was changed (n=44), and in the remaining 28 (21.6%) patients, antibiotic therapy was discontinued altogether. The hospital mortality rates of these three groups were statistically different: 33.3%, 60.8%, and 14.3%, respectively (p<0.001). The most common pattern of antibiotic resistance resulting in an antibiotic change following mini-BAL was the identification of a Gram-negative bacteria resistant to a prescribed third-generation cephalosporin in 23 of 44 (52.3%) patients. Twenty-one of these 23 patients (91.3%) received prior therapy with a cephalosporin class antibiotic during the same hospitalization. Having an immunocompromised state (adjusted odds ratio [OR]=2.45; 95% confidence interval, 1.56 to 3.85; p=0.047) and the presence of a pathogen in the mini-BAL culture resistant to the empirically prescribed antibiotic regimen (adjusted OR=3.28; 95% confidence interval, 2.12 to 5.06; p=0.006) were identified as risk factors independently associated with hospital mortality by logistic regression analysis. These data suggest that antibiotic selection prior to obtaining the results of lower airway cultures is an important determinant of outcome for patients with suspected VAP. A delay in initiating adequate antibiotic therapy was associated with a greater mortality. Therefore, the initial selection of antibiotics for the empiric treatment of VAP should be broad enough to cover all likely pathogens, including antibiotic-resistant bacteria. This appears to be especially important in patients having received prior antibiotics.


Thin foil proton recoil spectrometer performance study for application in DT plasma measurements.
The Thin foil Proton Recoil (TPR) technique has previously been used for deuterium-tritium fusion neutron diagnostics [N. P. Hawkes et al., Rev. Sci. Instrum. 70, 1134 (1999)] and is one of the candidates put forward for use in ITER as part of the high resolution neutron spectrometer (HRNS) system [E. A. Sundén et al., Nucl. Instrum. Methods Phys. Res., Sect. A 701, 62 (2013)]. For ITER, the neutron spectrometer's main purposes are to determine the fuel ion density ratio as well as the ion temperature in DT plasma. This work focuses on testing the capability of a proton telescope detector intended for use as part of the TPR spectrometer. The proton telescope has been tested using proton energies in the range of 3-8 MeV. The experimental results cover energy calibration, resolution estimation, and testing the spectrometer's capability to perform background separation using ΔE - E energy cuts. In addition, spectrometer performance in terms of signal to background ratios for ITER-like DT plasma conditions is estimated using Monte-Carlo simulations. Results show that the TPR spectrometer geometry dominates in determining the energy resolution and the ΔE - E energy cuts will significantly reduce the background. In addition, the estimated spectrometer count rates in ITER-like conditions fall below 20 kHz per detector segment.


Antibody response, recurrence patterns and subsequent herpes simplex virus type 2 (HSV-2) re-infection following initial HSV-2 infection of guinea-pigs: effects of acyclovir.
The production of antibody to specific herpes simplex virus type 2 (HSV-2) polypeptides, the recurrence patterns and the susceptibility to re-infection were studied in the guinea-pig model of genital HSV-2 infection. Further, we defined the effects of acyclovir (ACV) therapy on these parameters of infection. Treatment with ACV reduced the clinical severity of the initial disease but did not affect vaginal viral shedding. Production of neutralizing antibody as well as antibody to the nucleocapsid protein, and glycoproteins B, D and G were all delayed in ACV recipients. ACV treatment of initial infection did not significantly alter the pattern of subsequent recurrence although by several criteria treated animals tended towards decreased recurrences. Re-inoculation with a second strain of HSV-2 resulted in a local cervicovaginal infection but, except for one ACV-treated animal, neural tissue was protected from re-infection.


A 20-channel magnetoencephalography system based on optically pumped magnetometers.
We describe a multichannel magnetoencephalography (MEG) system that uses optically pumped magnetometers (OPMs) to sense the magnetic fields of the human brain. The system consists of an array of 20 OPM channels conforming to the human subject's head, a person-sized magnetic shield containing the array and the human subject, a laser system to drive the OPM array, and various control and data acquisition systems. We conducted two MEG experiments: auditory evoked magnetic field and somatosensory evoked magnetic field, on three healthy male subjects, using both our OPM array and a 306-channel Elekta-Neuromag superconducting quantum interference device (SQUID) MEG system. The described OPM array measures the tangential components of the magnetic field as opposed to the radial component measured by most SQUID-based MEG systems. Herein, we compare the results of the OPM- and SQUID-based MEG systems on the auditory and somatosensory data recorded in the same individuals on both systems.


Cardiac transplantation: immune mechanisms and alloantigens involved in graft rejection.
Recent advances in surgical and chemotherapeutic approaches to cardiac transplantation have resulted in substantial improvements in patient survival. Rejection of the cardiac allograft by the recipient's immune system and complications associated with immunosuppressive therapy remain, however, important clinical problems. The rejection of the transplanted heart is a complex set of immunological reactions. Previous experimental work has indicated that a variety of mechanisms may be involved in the pathogenesis of heart rejection; these include alloantibodies, specifically sensitized cytotoxic T-lymphocytes, lymphokine-dependent T-lymphocyte delayed-type hypersensitivity reactions, and natural killer cells. The current knowledge of the role that genetic incompatibilities play in stimulating the cardiac allograft reaction and the effector mechanisms implicated in the pathogenesis of the rejection process will be discussed.


An agent-based model of leukocyte transendothelial migration during atherogenesis.
A vast amount of work has been dedicated to the effects of hemodynamics and cytokines on leukocyte adhesion and trans-endothelial migration (TEM) and subsequent accumulation of leukocyte-derived foam cells in the artery wall. However, a comprehensive mechanobiological model to capture these spatiotemporal events and predict the growth and remodeling of an atherosclerotic artery is still lacking. Here, we present a multiscale model of leukocyte TEM and plaque evolution in the left anterior descending (LAD) coronary artery. The approach integrates cellular behaviors via agent-based modeling (ABM) and hemodynamic effects via computational fluid dynamics (CFD). In this computational framework, the ABM implements the diffusion kinetics of key biological proteins, namely Low Density Lipoprotein (LDL), Tissue Necrosis Factor alpha (TNF-α), Interlukin-10 (IL-10) and Interlukin-1 beta (IL-1β), to predict chemotactic driven leukocyte migration into and within the artery wall. The ABM also considers wall shear stress (WSS) dependent leukocyte TEM and compensatory arterial remodeling obeying Glagov's phenomenon. Interestingly, using fully developed steady blood flow does not result in a representative number of leukocyte TEM as compared to pulsatile flow, whereas passing WSS at peak systole of the pulsatile flow waveform does. Moreover, using the model, we have found leukocyte TEM increases monotonically with decreases in luminal volume. At critical plaque shapes the WSS changes rapidly resulting in sudden increases in leukocyte TEM suggesting lumen volumes that will give rise to rapid plaque growth rates if left untreated. Overall this multi-scale and multi-physics approach appropriately captures and integrates the spatiotemporal events occurring at the cellular level in order to predict leukocyte transmigration and plaque evolution.


ret transforming gene encodes a fusion protein homologous to tyrosine kinases.
The ret transforming gene was activated by recombination between two unlinked segments of human DNA, most likely during transfection of NIH 3T3 cells. To further define this transforming gene, we isolated and sequenced ret cDNA clones. The nucleotide sequence indicates that the active ret transforming gene encodes a fusion protein with a carboxy-terminal domain which is 40 to 50% homologous to members of the tyrosine kinase gene family. This tyrosine kinase domain is preceded by a hydrophobic sequence characteristic of a transmembrane domain. Transcription of the ret tyrosine kinase sequence was detected in the SK-N-SH neuroblastoma, HL-60 promyelocytic leukemia, and THP-1 monocytic leukemia cell lines, but not in 25 other human tumor cell lines surveyed. The ret tyrosine kinase may thus represent a cell surface receptor which is expressed in a restricted range of human cells.


Overlap between Medicare's Voluntary Bundled Payment and Accountable Care Organization Programs.
Accountable care organizations (ACOs) and bundled payments represent prominent value-based payment models, but the magnitude of overlap between the two models has not yet been described. Using Medicare data, we defined overlap based on attribution to Medicare Shared Savings Program (MSSP) ACOs and hospitalization for Bundled Payments for Care Improvement (BPCI) episodes at BPCI participant hospitals. Between 2013 and 2016, overlap as a share of ACO patients increased from 2.7% to 10% across BPCI episodes, while overlap as a share of all bundled payment patients increased from 19% to 27%. Overlap from the perspectives of both ACO and bundled payments varied by specific episode. In the first description of overlap between ACOs and bundled payments, one in every ten MSSP patients received care under BPCI by the end of our study period, whereas more than one in every four patients receiving care under BPCI were also attributed to MSSP. Policymakers should consider strategies to address the clinical and policy implications of increasing payment model overlap.


Psychiatric disorders and changes in immune response in labor and postpartum.
Women may present with psychiatric disorders during pregnancy, normal labor, following delivery by caesarean section, or in the postpartum period. The accumulating evidence suggests that these disorders may be due to changes in immune responses. During pregnancy complications such as the prolongation of cervical ripening or descent, placental abruption, premature labor, and preeclampsia increase the risk of postpartum psychiatric disorders. Women may exhibit depression and postpartum psychosis following either normal birth or caesarean section. Since psychiatric disorders like schizophrenia, major depression, and bipolar disorder are associated with both alterations in the immune response and changes in immune cell subpopulations, in this study we have chosen to examine whether the psychiatric disorders in women during labor or postpartum also lead to aberrant immune responses.


Interactions of dynorphin A-(1-13) and nociceptin with cardiac D2 binding sites: inhibition of ischemia-evoked release of noradrenaline from synaptosomal-mitochondrial fractions.
The effect of dynorphin A (Dyn A)-related peptides and nociceptin on the binding of the D2 receptor antagonist, [(3)H]raclopride, was examined in membrane preparations of rat heart. Non-linear regression saturation binding analysis of [(3)H]raclopride binding revealed the presence of a single high-affinity binding site with a K(d)of 4.1 n M and a B(max)of 220 fmol/mg protein. The D2 stereospecificity of [(3)H]raclopride binding was demonstrated by competition experiments using two enantiomer pairs of antagonists. (+)-Butaclamol (IC(50): 8.0 n M) and (-)-sulpiride (IC(50): 112.3 n M) were 27 000 and 24 times more potent than (-)-butaclamol (IC(50): >100 microm) and (+)-sulpiride (IC(50): 2666 n M), respectively. Nociceptin and Dyn A-(1-13) were also potent inhibitors of the binding of [3H]raclopride with shallow inhibition curves that fitted best with two sites model. Their order of potency on the low affinity site [alpha -Neo-endorphin>nociceptin>Dyn A-(2-13)>Dyn A-(1-13)>Dyn B>Dyn A-(6-10)] correlated well with their ability to inhibit the binding of [3H]nociceptin (r=0.82). The indirect nature of the inhibitory effects of the peptides on the D2 receptor was demonstrated by their inability to inhibit [(3)H]raclopride binding to a membrane preparation (Sf9 cells transfected with the human D2(long)receptor) that does not contain the ORL(1)receptor and the lack of effect of raclopride (0.1 n M-10 microm) on both [(3)H]nociceptin and [(3)H]Dyn A-(1-13) binding. Isolated cardiac mitochondrial-synaptosomal fractions submitted to ischemic conditions (1 m M iodoacetate +2 m M NaCN, 5 min at 37 degrees C) released 10.9% of their content in preloaded [(3)H]noradrenaline ([(3)H]NA). Dyn A-(1-13) (10 microm), nociceptin (10 microm) and the selective D2 receptor agonist, quinpirole (10 microm) were potent blockers of the release of [(3)H]NA evoked by the ischemic conditions. The inhibitory effect of Dyn A-(1-13), nociceptin and quinpirole were antagonized by the selective D2 receptor antagonist, raclopride (10 microm); whereas naloxone, at a concentration (1 microm) known to affect the ORL(1)receptor, blocked the effects of the peptides but not those of quinpirole. The results demonstrate the presence of D2 receptors in rat heart and suggest that Dyn A-(1-13) and nociceptin modulate ischemia-induced NA release by a mechanism that involves the participation of both ORL(1)and D2 receptors.


Self-polymerization of dopamine and polyethyleneimine: novel fluorescent organic nanoprobes for biological imaging applications.
The development of novel fluorescent nanoprobes has attracted great current research interest over the past few decades due to their superior optical properties and multifunctional capability as compared with small organic dyes. Although great advance has been made in the utilization of fluorescent nanoprobes for biomedical applications, development of novel fluorescent nanoprobes that possess good fluorescent properties, biocompatibility, biodegradability and water dispersibility through a convenient and effective route is still highly desirable. In this work, we reported for the first time that novel fluorescent organic nanoparticles (FONs) can be conveniently fabricated via self-polymerization of dopamine and polyethyleneimine at room temperature and in an air atmosphere within 2 h. These FONs exhibited strong green fluorescence, high water stability and excellent biocompatibility, making them highly potential for biological imaging applications. More importantly, due to the high reactivity of polydopamine, these FONs might also be further functionalized with other functional components through Michael addition or Schiff base reaction. Therefore the method described in this work would open new avenues for the fabrication of fluorescent nanoprobes for various biomedical applications.


Fixation strength of three different graft types used in posterior cruciate ligament reconstruction.
Surgical reconstruction is generally recommended for PCL and associated ligament injuries. A variety of graft choices exist for PCL reconstruction surgery. This study evaluated the initial fixation strength of three grafts using in PCL reconstruction in a porcine model. Twenty fresh porcine knees were harvested and randomly assigned to four groups: bone-patellar tendon-bone graft, quadruple tendons graft, Achilles tendon graft, and normal PCL. After reconstruction the knee was tested on an MTS testing machine by translating the tibia posteriorly until failure at 30 degrees of flexion, neutral rotation, and anatomical vertical alignment. Biomechanical parameters including maximal failure load, stiffness, and failure modes, were analyzed and compared. In the maximal failure load, the four-strand tendon group was significantly greater than the other two grafts. However, it had greatest translation. There were no significant differences between the three grafts in stiffness. All three of these commonly used grafts had weaker initial fixation strength and stiffness than normal PCL. Graft failure occurred mainly at the tendon-bone junction and tendon-suture sites. The Patellar tendon group had significantly least translation during continuing loading.


Absence of Notch1 in murine myeloid cells attenuates the development of experimental autoimmune encephalomyelitis by affecting Th1 and Th17 priming.
Inhibition of Notch signalling in T cells attenuates the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Growing evidence indicates that myeloid cells are also key players in autoimmune processes. Thus, the present study evaluates the role of the Notch1 receptor in myeloid cells on the progression of myelin oligodendrocyte glycoprotein (MOG)35-55 -induced EAE, using mice with a myeloid-specific deletion of the Notch1 gene (MyeNotch1KO). We found that EAE progression was less severe in the absence of Notch1 in myeloid cells. Thus, histopathological analysis revealed reduced pathology in the spinal cord of MyeNotch1KO mice, with decreased microglia/astrocyte activation, demyelination and infiltration of CD4+ T cells. Moreover, these mice showed lower Th1 and Th17 cell infiltration and expression of IFN-γ and IL-17 mRNA in the spinal cord. Accordingly, splenocytes from MyeNotch1KO mice reactivated in vitro presented reduced Th1 and Th17 activation, and lower expression of IL-12, IL-23, TNF-α, IL-6, and CD86. Moreover, reactivated wild-type splenocytes showed increased Notch1 expression, arguing for a specific involvement of this receptor in autoimmune T cell activation in secondary lymphoid tissues. In summary, our results reveal a key role of the Notch1 receptor in myeloid cells for the initiation and progression of EAE.


Material Parameter Identification for Acoustic Simulation of Additively Manufactured Structures.
One possibility in order to manufacture products with very few restrictions in design freedom is additive manufacturing. For advanced acoustic design measures like Acoustic Black Holes (ABH), the layer-wise material deposition allows the continuous alignment of the mechanical impedance by different filling patterns and degrees of filling. In order to explore the full design potential, mechanical models are indispensable. In dependency on process parameters, the resulting homogenized material parameters vary. In previous investigations, especially for ABH structures, a dependency of the material parameters on the structure's thickness can be observed. In this contribution, beams of different thicknesses are investigated experimentally and numerically in order to identify the material parameters in dependency on the frequency and the thickness. The focused material is polyactic acid (PLA). A parameter fitting is conducted by use of a 3D finite element model and it's reduced version in a Krylov subspace. The results yield homogenized material parameters for the PLA stack as a function of frequency and thickness. An increasing Young's modulus with increasing frequency and increasing thickness is observed. This observed effect has considerable influence and has not been considered so far. With the received parameters, more reliable results can be obtained.


Interview with a quality leader: Paul Uhlig on transforming healthcare. Interviewer by Jason Trevor Fogg.
Paul N. Uhlig, MD, MPA, FACS, a cardiothoracic surgeon who lives in Wichita, KS, is associate professor of preventive medicine and public health at the University of Kansas School of Medicine-Wichita. In 2002 Dr. Uhlig and the cardiac surgery team he led at Concord Hospital, Concord, NH, received the John M. Eisenberg Patient Safety Award from the National Quality Forum and the Joint Commission. Dr. Uhlig has received international recognition for research concerning patient safety, teamwork, and healthcare culture, including a 2007-2008 King James IV Professorship of the Royal College of Surgeons of Edinburgh, Scotland.


Molecular basis of the interaction between complement receptor type 2 (CR2/CD21) and Epstein-Barr virus glycoprotein gp350.
The binding of the Epstein-Barr virus glycoprotein gp350 by complement receptor type 2 (CR2) is critical for viral attachment to B lymphocytes. We set out to test hypotheses regarding the molecular nature of this interaction by developing an enzyme-linked immunosorbent assay (ELISA) for the efficient analysis of the gp350-CR2 interaction by utilizing wild-type and mutant forms of recombinant gp350 and also of the CR2 N-terminal domains SCR1 and SCR2 (designated CR2 SCR1-2). To delineate the CR2-binding site on gp350, we generated 17 gp350 single-site substitutions targeting an area of gp350 that has been broadly implicated in the binding of both CR2 and the major inhibitory anti-gp350 monoclonal antibody (MAb) 72A1. These site-directed mutations identified a novel negatively charged CR2-binding surface described by residues Glu-21, Asp-22, Glu-155, Asp-208, Glu-210, and Asp-296. We also identified gp350 amino acid residues involved in non-charge-dependent interactions with CR2, including Tyr-151, Ile-160, and Trp-162. These data were supported by experiments in which phycoerythrin-conjugated wild-type and mutant forms of gp350 were incubated with CR2-expressing K562 cells and binding was assessed by flow cytometry. The ELISA was further utilized to identify several positively charged residues (Arg-13, Arg-28, Arg-36, Lys-41, Lys-57, Lys-67, Arg-83, and Arg-89) within SCR1-2 of CR2 that are involved in the binding interaction with gp350. These experiments allowed a comparison of those CR2 residues that are important for binding gp350 to those that define the epitope for an effective inhibitory anti-CR2 MAb, 171 (Asn-11, Arg-13, Ser-32, Thr-34, Arg-36, and Tyr-64). The mutagenesis data were used to calculate a model of the CR2-gp350 complex using the soft-docking program HADDOCK.


[The functional state of the neutrophilic granulocytes in burns].
In 57 patients with severe burns the dynamic state of peripheral blood neutrophil granulocytes was studied. It was established that the effect of combined detoxication therapy expresses the rise of the cells dynamic activity, attended by the rise of the organism natural resistance, what correlates with infection complications frequency diminution from 14 to 2%.


Diagnosis and detection of pneumonia using weak-label based on X-ray images: a multi-center study.
Development and assessment the deep learning weakly supervised algorithm for the classification and detection pneumonia via X-ray. This retrospective study analyzed two publicly available dataset that contain X-ray images of pneumonia cases and normal cases. The first dataset from Guangzhou Women and Children's Medical Center. It contains a total of 5,856 X-ray images, which are divided into training, validation, and test sets with 8:1:1 ratio for algorithm training and testing. The deep learning algorithm ResNet34 was employed to build diagnostic model. And the second public dataset were collated by researchers from Qatar University and the University of Dhaka along with collaborators from Pakistan and Malaysia and some medical doctors. A total of 1,300 images of COVID-19 positive cases, 1,300 normal images and 1,300 images of viral pneumonia for external validation. Class activation map (CAM) were used to location the pneumonia lesions. The ResNet34 model for pneumonia detection achieved an AUC of 0.9949 [0.9910-0.9981] (with an accuracy of 98.29% a sensitivity of 99.29% and a specificity of 95.57%) in the test dataset. And for external validation dataset, the model obtained an AUC of 0.9835[0.9806-0.9864] (with an accuracy of 94.62%, a sensitivity of 92.35% and a specificity of 99.15%). Moreover, the CAM can accurately locate the pneumonia area. The deep learning algorithm can accurately detect pneumonia and locate the pneumonia area based on weak supervision information, which can provide potential value for helping radiologists to improve their accuracy of detection pneumonia patients through X-ray images.


The nudix hydrolase 7 is an Acyl-CoA diphosphatase involved in regulating peroxisomal coenzyme A homeostasis.
Coenzyme A (CoASH) is an obligate cofactor for lipids undergoing beta-oxidation in peroxisomes. Although the peroxisomal membrane appears to be impermeable to CoASH, peroxisomes contain their own pool of CoASH. It is believed that CoASH enters peroxisomes as acyl-CoAs, but it is not known how this pool is regulated. The mouse nudix hydrolase 7 (NUDT7alpha) was previously identified in peroxisomes as a CoA-diphosphatase, and therefore suggested to be involved in regulation of peroxisomal CoASH levels. Here we show that mouse NUDT7alpha mainly acts as an acyl-CoA diphosphatase, with highest activity towards medium-chain acyl-CoAs, and much lower activity with CoASH. Nudt7alpha mRNA is highly expressed in liver, brown adipose tissue and heart, similar to enzymes involved in peroxisomal lipid degradation. Nudt7alpha mRNA is down-regulated by Wy-14,643, a peroxisome proliferator-activated receptor alpha (PPARalpha) ligand, in a PPARalpha-dependent manner in mouse liver. In highly purified peroxisomes, nudix hydrolase activity is highest with C(6)-CoA and is decreased by fibrate treatment. Under certain conditions, such as treatment with peroxisome proliferators or fasting, an increase in peroxisomal CoASH levels has been reported, which is in line with a decreased expression/activity of NUDT7alpha. Taken together these data suggest that NUDT7alpha function is tightly linked to peroxisomal CoASH/acyl-CoA homeostasis.


Renal cell carcinoma of end-stage renal disease: a histopathologic and molecular genetic study.
Renal cell carcinomas (RCC) are responsible for the deaths of 3% to 4% of patients with ESRD. The clear cell carcinoma of the kidney, which comprises 80% of sporadic RCC within the general population, shows a deletion of gene sequences in the short arm of chromosome 3 (3p) in as many as 100% of cases. The von Hippel-Lindau tumor suppressor gene at 3p25-26 is found to be mutated in the nondeleted allele in 57% of these sporadic clear cell carcinomas. This study was undertaken to determine the histopathologic types of RCC occurring in ESRD patients in the United States and to investigate the frequency with which 3p genetic changes can be found in these ESRD tumors. Seventeen end-stage kidneys containing RCC were collected from 15 ESRD patients at ten US medical centers. The tumors were classified by Thoenes' histopathologic typing. DNA extracted from paraffin blocks of tumor and nontumorous tissue was analyzed by single-stranded conformational polymorphism analysis for von Hippel-Lindau mutations and by microsatellite amplification for deletion of 3p gene sequences. Twenty-one RCC were identified in the 18 kidneys. The 21 RCC were classified histopathologically as follows: clear cell, compact, three cases; chromophilic, tubulopapillary, 15 cases; chromophilic, compact, three cases. Among the three clear cell carcinomas, one showed 3p genetic loss. None of the chromophilic RCC showed a 3p deletion and none of 19 tumors studied by single-stranded conformational polymorphism analysis disclosed von Hippel-Lindau mutations. In contrast to the general population, clear cell RCC with 3p abnormalities represent only a small proportion of the renal carcinomas in this collection of ESRD tumors. The findings indicate that the genetic changes underlying the development of most ESRD tumors are different from those occurring in sporadic clear cell RCC and do not characteristically involve the inactivation of a 3p tumor suppressor gene.


Characteristics and prognosis of lone atrial fibrillation. 30-year follow-up in the Framingham Study.
In 30 years of follow-up of 5,209 participants in the Framingham Study, 193 men and 183 women developed atrial fibrillation (AF). Among this group, "lone" AF occurred in 32 men and 11 women free of coronary heart disease, congestive heart failure, rheumatic heart disease, and hypertensive cardiovascular disease. To determine the characteristics and prognosis of lone AF, each case was matched to controls in the remaining Framingham sample. Comparisons indicated that levels of several risk factors associated with coronary heart disease were similar between the two groups. Atrial fibrillation cases, however, had significantly higher rates of preexisting nonspecific T- or ST-wave abnormalities and intraventricular block as determined by electrocardiograms. Follow-up for new cardiovascular events indicated similar rates of coronary heart disease and congestive heart failure, but the rate of strokes was significantly greater in the lone AF group. Findings suggest that subjects with lone AF, despite similar cardiovascular risk profiles to normal controls, have a distinct preponderance of preexisting electrocardiographic abnormalities. Furthermore, contrary to general belief, lone AF is not a benign condition; it has a serious prognosis, indicating a greater need for detection and treatment.


Observation of Traveling Breathers and Their Scattering in a Two-Fluid System.
The observation of traveling breathers (TBs) with large-amplitude oscillatory tails realizes an almost 50-year-old theoretical prediction [E. A. Kuznetsov and A. V. Mikhailov, Stability of stationary waves in nonlinear weakly dispersive media, Zh. Eksp. Teor. Fiz. 67, 1717 (1974) ZETFA70044-4510[E. A. Kuznetsov and A. V. MikhailovSov. Phys. JETP 40, 855 (1975)] SPHJAR0038-5646] and generalizes the notion of a breather. Two strongly nonlinear TB families are created in a core-annular flow by interacting a soliton and a nonlinear periodic (cnoidal) carrier. Bright and dark TBs are observed to move faster or slower, respectively, than the carrier while imparting a phase shift. Agreement with model equations is achieved. Scattering of the TBs is observed to be physically elastic. The observed TBs generalize to many continuum and discrete systems.


Object-constrained meshless deformable algorithm for high speed 3D nonrigid registration between CT and CBCT.
High-speed nonrigid registration between the planning CT and the treatment CBCT data is critical for real time image guided radiotherapy (IGRT) to improve the dose distribution and to reduce the toxicity to adjacent organs. The authors propose a new fully automatic 3D registration framework that integrates object-based global and seed constraints with the grayscale-based "demons" algorithm. Clinical objects were segmented on the planning CT images and were utilized as meshless deformable models during the nonrigid registration process. The meshless models reinforced a global constraint in addition to the grayscale difference between CT and CBCT in order to maintain the shape and the volume of geometrically complex 3D objects during the registration. To expedite the registration process, the framework was stratified into hierarchies, and the authors used a frequency domain formulation to diffuse the displacement between the reference and the target in each hierarchy. Also during the registration of pelvis images, they replaced the air region inside the rectum with estimated pixel values from the surrounding rectal wall and introduced an additional seed constraint to robustly track and match the seeds implanted into the prostate. The proposed registration framework and algorithm were evaluated on 15 real prostate cancer patients. For each patient, prostate gland, seminal vesicle, bladder, and rectum were first segmented by a radiation oncologist on planning CT images for radiotherapy planning purpose. The same radiation oncologist also manually delineated the tumor volumes and critical anatomical structures in the corresponding CBCT images acquired at treatment. These delineated structures on the CBCT were only used as the ground truth for the quantitative validation, while structures on the planning CT were used both as the input to the registration method and the ground truth in validation. By registering the planning CT to the CBCT, a displacement map was generated. Segmented volumes in the CT images deformed using the displacement field were compared against the manual segmentations in the CBCT images to quantitatively measure the convergence of the shape and the volume. Other image features were also used to evaluate the overall performance of the registration. The algorithm was able to complete the segmentation and registration process within 1 min, and the superimposed clinical objects achieved a volumetric similarity measure of over 90% between the reference and the registered data. Validation results also showed that the proposed registration could accurately trace the deformation inside the target volume with average errors of less than 1 mm. The method had a solid performance in registering the simulated images with up to 20 Hounsfield unit white noise added. Also, the side by side comparison with the original demons algorithm demonstrated its improved registration performance over the local pixel-based registration approaches. Given the strength and efficiency of the algorithm, the proposed method has significant clinical potential to accelerate and to improve the CBCT delineation and targets tracking in online IGRT applications.


Down-regulation of the tumor suppressor gene C-terminal Src kinase: an early event during premalignant colonic epithelial hyperproliferation.
Hyperproliferation of the premalignant epithelium is critical for colonic carcinogenesis; however the mechanisms remain largely unexplored. We report herein that prior to occurrence of neoplastic lesions in the azoxymethane-rat model of colon carcinogenesis; the tumor suppressor gene C-terminal Src kinase (Csk) was down-regulated with a concomitant increase in Src activity. Furthermore, pharmacological or genetic (RNA interference) inhibition of Csk resulted in increased proliferation in colon cancer cell lines through the mitogen-activated protein kinase dependent pathway. Thus, we demonstrate, for the first time, that Csk suppression is an important early event in colorectal cancer pathogenesis.


The correlation between emotional intelligence and gray matter volume in university students.
A number of recent studies have investigated the neurological substrates of emotional intelligence (EI), but none of them have considered the neural correlates of EI that are measured using the Schutte Self-Report Emotional Intelligence Scale (SSREIS). This scale was developed based on the EI model of Salovey and Mayer (1990). In the present study, SSREIS was adopted to estimate EI. Meanwhile, magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) were used to evaluate the gray matter volume (GMV) of 328 university students. Results found positive correlations between Monitor of Emotions and VBM measurements in the insula and orbitofrontal cortex. In addition, Utilization of Emotions was positively correlated with the GMV in the parahippocampal gyrus, but was negatively correlated with the VBM measurements in the fusiform gyrus and middle temporal gyrus. Furthermore, Social Ability had volume correlates in the vermis. These findings indicate that the neural correlates of the EI model, which primarily focuses on the abilities of individuals to appraise and express emotions, can also regulate and utilize emotions to solve problems.


Effect of estrogen on leptin and expression of leptin receptor transcripts in prepubertal dairy heifers.
Plasma leptin concentrations increase as growing dairy heifers approach puberty and have greater plasma estrogen. In intact and ovariectomized rodents, estrogen has been shown to modulate expression of leptin and its receptor (Ob-R). To determine if estrogen regulates the bovine leptin system, prepubertal dairy heifers were ovariectomized at 140 d of age or left intact. A month later, both groups received a subcutaneous injection of excipient or 17beta-estradiol for 3 consecutive days. Neither ovarian status nor 17beta-estradiol injection altered plasma leptin or leptin mRNA abundance in adipose tissue depots. To assess whether these factors affected Ob-R expression, we tested 20 bovine tissues for leptin receptor (Ob-R) by using quantitative real-time PCR assays for the short receptor isoform (Ob-Ra), the long receptor isoform (Ob-Rb), and all receptor isoforms (Ob-R(TOTAL)). Ob-R(TOTAL) was detected in all tissues, with copy numbers covering 3 orders of magnitude between the lowest and highest expressing tissues (kidney cortex vs. liver). The Ob-Rb isoform accounted for 40% of Ob-R(TOTAL) in the hypothalamus, but averaged less than 3% of Ob-R(TOTAL) in peripheral tissues. Reciprocally, Ob-Ra accounted for only 19% of Ob-R(TOTAL) in the hypothalamus and for nearly all of Ob-R(TOTAL) in most peripheral tissues. Finally, we evaluated the effects of ovarian status and 17beta-estradiol on Ob-R expression in selected tissues. Treatment with 17beta-estradiol reduced Ob-R(TOTAL), Ob-Rb, and Ob-Ra expression by 70% in the uterine endometrium and tended to do the same in mammary adipose tissue. There was no effect of 17beta-estradiol on Ob-R in the hypothalamus, liver, soleus muscle, or subcutaneous adipose tissue. We conclude that greater estrogen secretion does not cause increased plasma leptin in prepubertal dairy heifers but estradiol can modulate Ob-R expression in some estrogen-responsive tissues.


Effect of TB/HIV Integration on TB and HIV Indicators in Rural Ugandan Health Facilities.
The World Health Organization recommends integrating services for patients coinfected with tuberculosis (TB) and HIV. We assessed the effect of TB/HIV integration on antiretroviral therapy (ART) initiation and TB treatment outcomes among TB/HIV-coinfected patients using data collected from 14 rural health facilities during 2 previous TB and HIV quality of care studies. A facility was considered to have integrated TB/HIV services if patients with TB/HIV had combined treatment for both illnesses by 1 provider or care team at 1 treatment location. We analyzed the effect of integration by conducting a cross-sectional analysis of integrated and nonintegrated facility periods comparing performance on ART initiation and TB treatment outcomes. We conducted logistic regression, with the patient as the unit of analysis, controlling for other intervention effects, adjusting for age and sex, and clustering by health facility. From January 2012 to June 2014, 996 patients with TB were registered, 97% were tested for HIV, and 404 (42%) were HIV-positive. Excluding transfers, 296 patients were eligible for analysis with 117 and 179 from nonintegrated and integrated periods, respectively. Being treated in a facility with TB/HIV integration was associated with lower mortality [adjusted odds ratio (aOR) = 0.38, 95% confidence interval (CI): 0.18 to 0.77], but there was no difference in the proportion initiating ART (aOR = 1.34, 95% CI: 0.40 to 4.47), with TB treatment success (aOR = 1.43, 95% CI: 0.73 to 2.82), lost to follow-up (aOR = 1.64, 95% CI: 0.53 to 5.04), or failure (aOR = 1.21, 95% CI: 0.34 to 4.32). TB/HIV service integration was associated with lower mortality during TB treatment even in settings with suboptimal proportions of patients completing TB treatment and starting on ART.


Impact of the Affordable Care Act on Prescription Contraceptive Use and Costs Among Privately Insured Women, 2006-2020.
In the years immediately following the Affordable Care Act (ACA)'s contraceptive coverage requirement, out-of-pocket costs fell for all Food and Drug Administration-approved contraceptive methods and use of long-acting reversible contraception (LARC) increased. This analysis examines whether these trends have continued through 2020 for privately insured women. Using 2006-2020 MarketScan data, we examined trends in prescription contraceptive use and out-of-pocket costs among women 13 to 49 years old. Multivariable analyses model the likelihood of contraceptive use and paying $0 post-ACA requirement (vs. pre-ACA requirement) for contraception, controlling for age group, U.S. region, urban versus rural, and cohort year. The likelihood of LARC insertion increased post-ACA requirement (adjusted odds ratio [aOR] 1.127, 95% confidence interval [CI] 1.121-1.133), with insertion rates peaking at 3.73% for intrauterine devices (IUDs) and 1.08% for implants in 2019, before declining with the onset of the COVID-19 pandemic in 2020. Although the likelihood of paying $0 for LARC increased after the ACA requirement (IUD: aOR 5.495, 95% CI 5.278-5.716; implant: aOR 7.199, 95% CI 6.992-7.412), the proportion of individuals paying $0 declined to 69% for IUDs and 73% for implants in 2020, after having peaked at 88% in 2014 and 90% in 2016, respectively. For oral contraceptives, both use (aOR 1.028, 95% CI 1.026-1.030) and paying $0 (aOR 20.399, 95% CI 20.301-20.499) increased significantly after the ACA requirement. With the exception of oral contraceptives, the proportion of individuals paying $0 for all contraceptive methods declined after peaking in 2014 for IUDs, 2016 for the implant, and 2019 for non-LARC methods. Future monitoring is needed to understand the continuing impact of the ACA requirement on prescription contraceptive use and costs.


The Efficacy of Hospice-In-Place Care Versus Traditional Inpatient Care.
Introduction: The hospice-in-place program at Vanderbilt University Medical Center (VUMC) is available to patients and families who elect for hospice benefits and are too unstable to be transported for hospice care. The goal of this study was to assess the satisfaction of family members of patients who died while hospitalized at VUMC and received hospice-in-place compared to the families of patients who did not receive hospice care. Methods: Next-of-kin satisfaction was measured through the administration of qualitative interviews and quantitative questionnaires. Semi-structured interviews were audio-recorded, and transcripts were analyzed using an iterative inductive-deductive approach to develop a conceptual framework. Participants were also asked to respond to a 10-question satisfaction questionnaire. Results: Forty participants were enrolled: 20 next-of-kin of patients who received hospice-in-place and 20 next-of-kin of patients who passed without hospice. Factors influencing satisfaction were organized into a conceptual framework with three categories: individual-level factors, systems-level factors, and modifying factors. For the questionnaires, the hospice-in-place group had a mean satisfaction score of 4.54 (0.76) out of five, while the non-hospice group had a mean score of 4.14 (1.00). A comparison of the two groups' responses did not show a statistically significant difference (P = 0.06). Discussion: Quantitative findings of this study showed improved satisfaction but were unable to show a significant difference in satisfaction with hospice-in-place compared to traditional care. Questionnaire results suggest that both types of care yield high satisfaction scores and are successfully supporting patients and families. The conceptual framework also adds to the understanding of end-of-life experiences at VUMC.


Prevalence of Takotsubo cardiomyopathy in the United States.
The aim of this study was to describe the prevalence of Takotsubo cardiomyopathy (TTC), age-gender interaction, and various comorbidities associated with it based on nationwide hospitalization records. Takotsubo cardiomyopathy is an increasingly reported clinical syndrome; however, there are no data on its prevalence in the general US population. The Nationwide Inpatient Sample discharge records were queried for the year 2008 using the International Classification of Diseases, Ninth Revision, code 429.83. There were 6,837 patients diagnosed with TTC among 33,506,402 hospitalizations in the Nationwide Inpatient Sample database. Women were found to have higher odds of developing TTC (odds ratio 8.8). Women >55 years old had 4.8 times higher odds for developing TTC when compared with women <55 years old. Smoking, alcohol abuse, anxiety states, and hyperlipidemia were commonly associated with TTC. The peak incidence of hospitalization for TTC was in summer. Takotsubo cardiomyopathy was diagnosed in about 0.02% of all hospitalizations in the United States, mostly in elderly women with history of smoking, alcohol abuse, anxiety states, and hyperlipidemia.


In vivo and in vitro measurement of tendon strain in the horse.
Strains gauges were applied to the superficial flexor tendon, deep flexor tendon, and suspensory ligament of sound adult horses. Maximum tendon strain occurred during full weight bearing while walking, when the forelimb was perpendicular to the group surface. There was decrease in tendon strain with increase in hoof angle for the deep digital flexor, but no change in tendon strain for the superficial digital flexor and suspensory ligament with changing hoof angle. At physiologic rates of strain, tendons were able to withstand large loads without yielding. Load strain curves developed in vitro indicated that during walking, the deep digital flexor was calculated to load to 416.8 kg; the superficial flexor tendon to 362.9 kg; and the suspensory ligament to 172.4 kg. This study shows that in the horse, strain in flexor tendons during walking was in excess of 5%, indicating strains within the visco-elastic range.


Housing Mobility and Downsizing at Older Ages in Britain and the United States.
This paper examines geographic mobility and housing downsizing at older ages in Britain and America. Americans downsize housing much more than the British largely because Americans are much more mobile. The principal reasons for greater mobility among older Americans are two fold: (1) greater spatial distribution of geographic distribution of amenities (such as warm weather) and housing costs and (2) greater institutional rigidities in subsidized British rental housing providing stronger incentives for British renters not to move. This relatively flat British housing consumption with age may have significant implications for the form and amount of consumption smoothing at older ages.


CC16 Regulates Inflammation, ROS Generation and Apoptosis in Bronchial Epithelial Cells during Klebsiella pneumoniae Infection.
Gram-negative (G-) bacteria are the leading cause of hospital-acquired pneumonia in the United States. The devastating damage caused by G- bacteria results from the imbalance of bactericidal effects and overwhelming inflammation. Despite decades of research, the underlying mechanisms by which runaway inflammation is developed remain incompletely understood. Clara Cell Protein 16 (CC16), also known as uteroglobin, is the major protein secreted by Clara cells and the most abundant protein in bronchoalveolar lavage fluid (BALF). However, the regulation and functions of CC16 during G- bacterial infection are unknown. In this study, we aimed to assess the regulation of CC16 in response to Klebsiella pneumoniae (K. pneu) and to investigate the role of CC16 in bronchial epithelial cells. After K. pneu infection, we found that CC16 mRNA expression was significantly decreased in bronchial epithelial cells. Our data also showed that K. pneu infection upregulated cytokine and chemokine genes, including IL-1β, IL-6, and IL-8 in BEAS-2B cells. Endogenously overexpressed CC16 in BEAS-2B cells provided an anti-inflammatory effect by reducing these markers. We also observed that endogenous CC16 can repress NF-κB reporter activity. In contrast, the recombinant CC16 (rCC16) did not show an anti-inflammatory effect in K. pneu-infected cells or suppression of NF-κB promoter activity. Moreover, the overexpression of CC16 reduced reactive oxygen species (ROS) levels and protected BEAS-2B cells from K. pneu-induced apoptosis.


Refixation of Osteochondral Fractures by an Ultrasound-Activated Pin System - An Ovine In Vivo Examination Using CT and Scanning Electron Microscope.
Osteochondral injuries, if not treated appropriately, often lead to severe osteoarthritis of the affected joint. Without refixation of the osteochondral fragment, human cartilage only repairs these defects imperfectly. All existing refixation systems for chondral defects have disadvantages, for instance bad MRI quality in the postoperative follow-up or low anchoring forces. To address the problem of reduced stability in resorbable implants, ultrasound-activated pins were developed. By ultrasound-activated melting of the tip of these implants a higher anchoring is assumed. Aim of the study was to investigate, if ultrasound-activated pins can provide a secure refixation of osteochondral fractures comparing to conventional screw and conventional, resorbable pin osteosynthesis. CT scans and scanning electron microscopy should proovegood refixation results with no further tissue damage by the melting of the ultrasound-activated pins in comparison to conventional osteosynthesis. Femoral osteochondral fragments in sheep were refixated with ultrasound-activated pins (SonicPin™), Ethipins(®) and screws (Asnis™). The quality of the refixated fragments was examined after three month of full weight bearing by CT scans and scanning electron microscopy of the cartilage surface. The CT examination found almost no statistically significant difference in the quality of refixation between the three different implants used. Concerning the CT morphology, ultrasound-activated pins demonstrated at least the same quality in refixation of osteochondral fragments as conventional resorbable pins or screws. The scanning electron microscopy showed no major surface damage by the three implants, especially any postulated cartilage damage induced by the heat of the ultrasound-activated pin. The screws protruded above the cartilage surface, which may affect the opposingtibial surface. Using CT scans and scanning electron microscopy, the SonicPin™, the Ethipin(®) and screws were at least equivalent in refixation quality of osteochondral fragments.


Calretinin staining pattern aids in the differentiation of mesothelioma from adenocarcinoma in serous effusions.
The differentiation between malignant mesothelioma and adenocarcinoma based on morphology alone can be a diagnostic challenge. The majority of the available antibodies recognize molecules expressed by adenocarcinoma whereas to the authors' knowledge specific markers for mesothelial cells are lacking. Calretinin, a calcium-binding protein, has been reported to be a selective marker for mesothelioma and largely is absent from adenocarcinoma on histologic material. The results with cytologic preparations have been inconsistent. To evaluate the specificity of calretinin in differentiating mesothelioma from adenocarcinoma in cytologic preparations, 21 paraffin embedded cells blocks of serous effusions from 15 patients with metastatic adenocarcinoma and 16 cell blocks from 9 patients with malignant mesothelioma were stained with a monoclonal antibody against calretinin. The immunoreactivity was evaluated blindly by two observers. Positive staining was defined as nuclear and cytoplasmic staining with or without intense membranous decoration. The former resulted in a characteristic "fried egg" appearance. Calretinin staining was positive in all but 2 cases of mesothelioma (14 of 16 cases; 87.5%). The latter contained predominantly spindle-shaped neoplastic mesothelial cells in the cell block preparations. All adenocarcinoma specimens were classified as negative for calretinin staining; 9 (42.9%) lacked any immunoreactivity and 12 (57.1%) showed weak, sparse, coarse, granular cytoplasmic staining without nuclear or membranous staining. Benign reactive mesothelial cells, when observed in association with adenocarcinoma, also showed the characteristic "fried egg" appearance. The difference in the staining pattern of calretinin between cells of mesothelial origin and adenocarcinoma cells was statistically significant. Calretinin is a useful marker in differentiating mesothelioma of the epithelial type from adenocarcinoma in serous effusions. The "fried-egg" appearance or cytoplasmic and nuclear staining pattern is characteristic of cells of mesothelial origin.


Double balloon enteroscopy to retrieve an accidentally swallowed dental reamer deep in the jejunum.
Accidentally swallowed foreign objects are not uncommon but difficult to manage without complications. We describe the case of a 68 year old man who accidentally a swallowed sharp-pointed dental reamer that had reached deep in his jejunum. Double balloon enteroscopic retrieval was performed with polypectomy snare but the reamer was entangled in the wire loop of the snare and penetrated the jejunal wall. After releasing the reamer by pushing and pulling the snare for approximately 30 min, the reamer was retrieved with biopsy forceps. This is the first report of double balloon enteroscopic removal of a dental reamer. Furthermore, this is a novel case with regard to decision making in situations when sharp objects are swallowed.


Polynuclear lanthanide complexes of a series of bridging ligands containing two tridentate N,N',O-donor units: structures and luminescence properties.
A set of three potentially bridging ligands containing two tridentate chelating N,N',O-donor (pyrazole-pyridine-amide) donors separated by an o, m, or p-phenylene spacer has been prepared and their coordination chemistry with lanthanide(III) ions investigated. Ligand L(1) (p-phenylene spacer) forms complexes with a 2:3 M:L ratio according to the proportions used in the reaction mixture; the Ln(2)(L(1))(3) complexes contain two 9-coordinate Ln(III) centres with all three bridging ligands spanning both metal ions, and have a cylindrical (non-helical) 'mesocate' architecture. The 1:1 complexes display a range of structural types depending on the conditions used, including a cyclic Ln(4)(L(1))(4) tetranuclear helicate, a Ln(2)(L(1))(2) dinuclear mesocate, and an infinite one-dimensional coordination polymer in which metal ions and bridging ligands alternate along the sequence. ESMS studies indicate that the 1:1 complexes form a mixture of oligonuclear species {Ln(L(1))}(n) in solution (n up to 5) which are likely to be cyclic helicates. In contrast, ligands L(2) and L(3) (with o- and m-phenylene spacers, respectively) generally form dinuclear Ln(2)L(2) Ln(III) complexes in which the two ligands may be arranged in a helical or non-helical architecture about the two metal ions. These complexes also contain an additional exogenous bidentate bridging ligand, either acetate or formate, which has arisen from hydrolysis of solvent molecules promoted by the Lewis-acidity of the Ln(III) ions. Luminescence studies on some of the Nd(III) complexes showed that excitation into ligand-centred pi-pi* transitions result in the characteristic near-infrared luminescence from Nd(III) at 1060 nm.


Site-directed mutation affecting polyomavirus capsid self-assembly in vitro.
Nonequivalent bonding of identical protein subunits occurs in the polyomavirus capsid were identical pentameric capsomeres occupy both hexavalent and pentavalent positions in the icosahedral surface lattice. The polyomavirus major capsid protein VP1, purified after expression of the recombinant gene in Escherichia coli, has been isolated as capsomeres that self-assemble into capsid-like structures in vitro. The ability to switch bonding specificity in different symmetry environments therefore must be intrinsic to the VP1 molecule. In vitro self-assembly provides an assay for VP1 mutations affecting capsomere and capsid formation. We report here that a directed mutation in the VP1 expression vector, leading to a protein truncated at the carboxy terminus, results in a mutant VP1 that forms capsomeres, but not capsids, in the in vitro assembly assay. The carboxy terminus of VP1 therefore appears to be involved in the specific bonding responsible for the non-equivalent association of capsomeres.


Evaluation of prototype equipment for digital subtraction angiography in diagnosing intracranial lesions.
Two prototype units for digital subtraction angiography have been developed by Japanese manufacturers. Their performance in demonstrating various intracranial lesions in 121 patients was evaluated. Comparison with conventional selective catheter angiography was possible in 77 patients. Digital subtraction angiography proved useful in preoperative evaluation of pituitary tumors when transsphenoidal surgery was being considered; demonstration of faint tumor stains which might be missed on conventional angiography; demonstration of larger aneurysms, arteriovenous malformations, and tumors as a screening technique; demonstration of abnormalities involving the dural sinuses; and follow-up of patients after surgery or embolization.


The methanogenic archaeon Methanosarcina thermophila TM-1 possesses a high-affinity glycine betaine transporter involved in osmotic adaptation.
Methanogenic Archaea are found in a wide range of environments and use several strategies to adjust to changes in extracellular solute concentrations. One methanogenic archaeon, Methanosarcina thermophila TM-1, can adapt to various osmotic conditions by synthesis of alpha-glutamate and a newly discovered compatible solute, Ne-acetyl-beta-lysine, or by accumulation of glycine betaine (betaine) and potassium ions from the environment. Since betaine transport has not been characterized for any of the methanogenic Archaea, we examined the uptake of this solute by M. thermophila TM-1. When cells were grown in mineral salts media containing from 0.1 to 0.8 M NaC1, M. thermophila accumulated betaine in concentrations up to 140 times those of a concentration gradient within 10 min of exposure to the solute. The betaine uptake system consisted of a single, high-affinity transporter with an apparent K3 of 10 microM and an apparent maximum transport velocity of 1.15 nmol/min/mg of protein. The transporter appeared to be specific for betaine, since potential substrates, including glycine, sarcosine, dimethyl glycine, choline, and proline, did not significantly inhibit betaine uptake. M. thermophila TM-1 cells can also regulate the capacity for betaine accumulation, since the rate of betaine transport was reduced in cells pregrown in a high-osmolarity medium when 500 microM betaine was present. Betaine transport appears to be H+ and/or Na+ driven, since betaine transport was inhibited by several types of protonophores and sodium ionophores.


Predictors of literacy in adulthood: Evidence from 33 countries.
What makes a literate person? What leads to literacy gains and losses within and between individuals and countries? This paper provides new evidence that helps answer these questions. The present comparative analysis of literacy is based on large representative samples from the Survey of Adult Skills conducted in 33 countries, with 25-65 year old participants. We provide, for the first time, estimates of relative importance for a comprehensive set of experiential factors, motivations, incentives, parental influence, demands of workplace, and other predictors of influence. We sketch a configuration of factors that predicts an "ideal" reader, i.e., the optimal literacy performance. Moreover, we discover a pivotal role of the age effect in predicting variability between countries. Countries with the highest literacy scores are the ones where literacy decreases with age the most strongly. We discuss this finding against current accounts of aging effects, cohort effects and others. Finally, we provide methodological recommendations for experimental studies of aging in cognitive tasks like reading.


A walk on the wild side: Wild ungulates as potential reservoirs of multi-drug resistant bacteria and genes, including Escherichia coli harbouring CTX-M beta-lactamases.
Extended-spectrum β-lactamases (ESBL)-producing Enterobacterales have been classified as critical priority pathogens by the World Health Organization (WHO). ESBL are universally distributed and, in 2006, were firstly reported on a wild animal. Understanding the relative contributions of wild animals to ESBL circulation in the environment is urgently needed. In this work, we have conducted a nationwide study in Portugal to investigate the occurrence of bacteria carrying clinically significant antimicrobial resistance genes (ARG), using widely distributed wild ungulates as model species. A total of 151 antimicrobial resistant-Enterobacterales isolates were detected from 181 wild ungulates: 50% (44/88) of isolates from wild boar (Sus scrofa), 40.3% (25/62) from red deer (Cervus elaphus), 41.4% (12/29) from fallow deer (Dama dama) and 100% (2/2) from mouflon (Ovis aries subsp. musimon). Selected isolates showed a diversified resistance profile, with particularly high values corresponding to ampicillin (71.5%) and tetracycline (63.6%). Enterobacterales strains carried blaTEM, tetA, tetB, sul2, sul1 or dfrA1 ARG genes. They also carried blaCTX-M-type genes, which are prevalent in human infections, namely CTX-M-14, CTX-M-15 and CTX-M-98. Strikingly, this is the first report of CTX-M-98 in wildlife. Almost 40% (n = 59) of Enterobacterales were multi-drug resistant. The diversity of plasmids carried by ESBL isolates was remarkable, including IncF, K and P. This study highlights the potential role of wild ungulates as environmental reservoirs of CTX-M ESBL-producing E. coli and in the spill-over of AMR bacteria and their determinants. Our findings suggest that wild ungulates are useful as strategic sentinel species of AMR in terrestrial environments, especially in response to potential sources of anthropogenic pollution, providing early warning of potential risks to human, animal and environmental health.


A metabonomic analysis of the effect of quercetin on toxicity induced by chronic exposure to low-level dichlorvos in rat plasma.
A previous study of ours has reported that chronic exposure to low-level dichlorvos (DDVP, 7.2 mg per kg bw) damages the liver, interferes with fatty acid metabolism, and disturbs the antioxidant defense system in rats. This study aims to investigate whether or not quercetin can protect against DDVP-induced toxicity through metabonomics and to elucidate the mechanism underlying this protective effect. Rats were randomly assigned into the control group, DDVP-treated group, quercetin-treated group, and quercetin plus DDVP-treated group. DDVP and quercetin were administered to the rats daily via drinking water and gavage, respectively, continuously for 90 d. The metabonomic profiles of rat plasma were analyzed using ultra-performance liquid chromatography-mass spectrometry. Finally, 11 metabolites were identified, including those of quercetin, isorhamnetin, and quercetin-3-glucuronide. The 11 metabolites showed significant changes in some treatment groups compared with the control group. Arachidonic acid, phytosphingosine, and C16 sphinganine significantly decreased while p-cresol, lysoPE (16:0/0:0), lysoPC (15:0/0:0), lysoPC (16:0/0:0), lysoPC (0:0/18:0), and tryptophan significantly increased in the DDVP-treated group compared with the control group. The tendency of the aforementioned metabolites to change was significantly ameliorated in the high-dose quercetin (50 mg per kg bw per day) plus DDVP-treated group compared with the DDVP-treated group. However, the levels of these metabolites in the high-dose quercetin plus DDVP-treated group were still significantly different from those in the control group. The results indicate that high-dose quercetin (50 mg per kg bw per day) elicits a partial protective effect on DDVP-induced toxicity. The histopathology of the liver tissues was consistent with the above results. Quercetin demonstrated regulatory effects on the metabolism of lipids and amino acids, the antioxidant defense system, etc. Therefore, increasing the daily intake of quercetin can ameliorate the toxicity induced by chronic exposure to low-level DDVP residue in food and/or water.


Multicenter study of the feasibility and safety of using the memotherm carotid arterial stent for extracranial carotid artery stenosis.
Carotid artery (CA) angioplasty with stent placement has been proposed as an alternative technique for revascularization in cases of CA stenosis. In this report the authors review the results of a multicenter Phase I study in which they evaluated the safety and feasibility of using a new self-expanding nitinol stent, the Bard Memotherm, to treat CA stenosis. Enrollment was limited to patients in whom there was either 50% or greater symptomatic or 70% or greater asymptomatic stenosis of the internal CA. The primary endpoint was a technically successful implantation procedure (delivery of the stent to the target site and retrieval of the delivery device), resulting in less than 30% residual stenosis demonstrated on immediate postprocedure (control) angiograms, and no incidence of mortality, ipsilateral stroke, Q-wave myocardial infarction, or other major cardiovascular events immediately after or within 30 days following the procedure. Stent placement was attempted for 73 lesions in 71 patients (mean age 71.3 +/- 8.5 years), 43 (61%) of whom were men. The mean degree of stenosis was 82.6 +/- 9%. The stenosis was symptomatic in 27 (37%) and asymptomatic in 46 (63%) of 73 lesions. In four procedures the stent could not be delivered or released. The mean residual stenosis observed on angiograms was 3.8 +/- 6.9% in the 69 lesions treated with the Bard Memotherm stent; residual stenosis was greater than 30% in one of the 69 procedures. The primary endpoint was achieved in 65 (89%) of the 73 procedures. One patient experienced a major ischemic stroke and another patient died of intracerebral hemorrhage. The overall 1-month stroke rate was 2.7% for 73 attempted procedures. One patient died of pneumonia and acute respiratory distress syndrome, which occurred 3 weeks after the stent procedure and was unrelated to the procedure. The Memotherm stent can be used to treat patients with CA stenosis and is associated with a low peri-procedure complication rate. Long-term follow-up studies are underway to determine the impact of stent placement on the risk of ipsilateral ischemic events.


A rationale for monitoring the periodontal microbiota after periodontal treatment.
Strict control of dental plaque accumulation remains the cornerstone of successful maintenance of the treated patient. However, some recurrences of periodontitis appear to take place despite good oral hygiene habits. A proportion of these are likely due to qualitative features of the periodontal microbiota rather than merely increased mass. Microscopic as well as cultural monitoring of qualitative features of the periodontal microbiota may be helpful in detecting critical changes. This review presents some of the research findings that provide a rationale for microbiological monitoring. Some of the advantages as well as difficulties encountered with these procedures are discussed.


Correlation between the effects of local and intracerebroventricular infusions of galanin on 5-HT release studied by microdialysis, and distribution of galanin and galanin receptors in prefrontal cortex, ventral hippocampus, amygdala, hypothalamus, and striatum of awake rats.
The neuropeptide galanin is implicated in regulation of affective behavior, including modulation of 5-HT signaling. Here, we investigated, by use of microdialysis in freely moving rats, the effects of intracerebral (i.c.) and intracerebroventricular (i.c.v.) infusions of galanin on basal extracellular 5-HT levels in medial prefrontal cortex (mPFC), CA1 area of ventral hippocampus (vHPC), central amygdaloid nucleus (CeA), ventromedial hypothalamic nucleus ventrolateral part (VMHvl), and ventromedial caudate putamen (CPu). These results were compared with a parallel immunohistochemical analysis of the distribution of galanin, 5-HT, and noradrenaline (NA) nerve terminals, and with data on galanin receptors. Galanin i.c.v. significantly decreased the 5-HT levels in mPFC to 79% and in vHPC to 72%. Local infusions of galanin caused a long-lasting decrease in 5-HT levels in vHPC to 88%, and a moderate decrease in CeA, whereas the 5-HT levels in mPFC significantly increased to 121%. These effects of i.c. galanin correlated well with the density of 5-HT and galanin nerve terminals and galanin receptors autoradiography in mPFC, vHPC, and CeA. No effects of i.c. or i.c.v. galanin on 5-HT levels were observed in CPu or VMHvl, in agreement with the low numbers of galanin-positive terminals and low/moderate galanin receptor density. Galanin was often found to coexist in NA, but could never be detected in 5-HT terminals. Together the results show a neuroanatomical correlation between the effects of galanin infusions on 5-HT release and distribution of galanin and its receptors, and that i.c.v. and i.c. administration can give opposite effects on 5-HT release.


Less small-bowel injury with lumiracoxib compared with naproxen plus omeprazole.
The selective cyclooxygenase-2 inhibitor lumiracoxib has been shown to reduce endoscopically detected ulcers and ulcer complications in the upper gastrointestinal tract compared with nonselective nonsteroidal anti-inflammatory drugs. We investigated whether lumiracoxib would reduce small-bowel injury compared with naproxen plus omeprazole. Healthy volunteers were randomized to receive lumiracoxib 100 mg once daily, naproxen 500 mg twice daily plus omeprazole 20 mg once daily, or placebo in a 16-day double-blind, parallel-group study. Small-bowel mucosal injury and inflammation were assessed by video capsule endoscopy, the lactulose:L-rhamnose permeability assessment, and the fecal calprotectin test. Of 152 randomized subjects, 139 completed the study with valid video capsule endoscopies (lumiracoxib, n = 47; naproxen plus omeprazole, n = 45; placebo, n = 47). Compared with placebo, an increased number of subjects on naproxen plus omeprazole had small-bowel mucosal breaks (77.8% vs 40.4%, P < .001), with increased permeability (P = .023) and increased fecal calprotectin (increase, 96.8 vs 14.5 mg/kg for placebo; P < .001). With lumiracoxib, 27.7% of subjects had small-bowel mucosal breaks (P = .196 vs placebo; P < .001 vs naproxen), there was no increase in permeability (P = .157 vs placebo; P = .364 vs naproxen), and no increase in fecal calprotectin (-5.7 mg/kg; P = .377 vs placebo; P < .001 vs naproxen). As assessed by 3 different measures, acute small-bowel injury on lumiracoxib treatment is less frequent than with naproxen plus omeprazole and similar to placebo.


Incidence of microbial infection after amniotic membrane transplantation.
To report the incidence and characteristics of microbial infection following amniotic membrane transplantation (AMT). We retrieved the clinical and microbiological records of a total of 326 patients undergoing AMT from January 1994 to February 2001 at Bascom Palmer Eye Institute to determine the incidence and characteristics of post-AMT infections with respect to the interval between AMT and the time of microbial culturing, types of organisms, and clinical outcomes and to correlate these infections with the microbiologic results of AM storage media submitted immediately after AMT and the underlying ocular diagnosis. We subdivided these 326 patients into two groups: 76 patients (from January 1994 to June 1998) used AM prepared from a research laboratory and did not submit AM storage media for culture under an Institutional Review Board-approved protocol, and 250 patients thereafter used AM obtained from a commercial source and routinely submitted AM storage media for culture. A total of 11 culture-positive infections (3.4%) were identified, and among them 7 infections (9.2%) were from the first group, and 4 (1.6%) were from the second group (P = 0.004). All 4 infections (5.2%) occurring within 1 month after AMT were exclusively from the first group (P = 0.003). All AM storage media from the second group were culture negative. Gram-positive organisms were the most frequent isolate (64%). Infections were not correlated with the underlying ocular diagnosis. AMT is a safe method for ocular surface reconstruction with a very low rate of microbial infections, especially if AM is prepared according to Good Tissue Banking Practice set forth by FDA. Gram-positive isolates seem to be the most frequent isolates in infections after AMT.


Light at Night and Measures of Alertness and Performance: Implications for Shift Workers.
Rotating-shift workers, particularly those working at night, are likely to experience sleepiness, decreased productivity, and impaired safety while on the job. Light at night has been shown to have acute alerting effects, reduce sleepiness, and improve performance. However, light at night can also suppress melatonin and induce circadian disruption, both of which have been linked to increased health risks. Previous studies have shown that long-wavelength (red) light exposure increases objective and subjective measures of alertness at night, without suppressing nocturnal melatonin. This study investigated whether exposure to red light at night would not only increase measures of alertness but also improve performance. It was hypothesized that exposure to both red (630 nm) and white (2,568 K) lights would improve performance but that only white light would significantly affect melatonin levels. Seventeen individuals participated in a 3-week, within-subjects, nighttime laboratory study. Compared to remaining in dim light, participants had significantly faster reaction times in the GO/NOGO test after exposure to both red light and white light. Compared to dim light exposure, power in the alpha and alpha-theta regions was significantly decreased after exposure to red light. Melatonin levels were significantly suppressed by white light only. Results show that not only can red light improve measures of alertness, but it can also improve certain types of performance at night without affecting melatonin levels. These findings could have significant practical applications for nurses; red light could help nurses working rotating shifts maintain nighttime alertness, without suppressing melatonin or changing their circadian phase.


From holy war to opium war? A case study of the opium economy in north-eastern Afghanistan.
This paper examines the recent growth of the opium economy in north-eastern Afghanistan. A detailed analysis of one village in Badakshan Province reveals profound changes in the local economy and social institutions. The paper describes two major shifts in the local economy: first, the switch from wheat to poppy cultivation; and second, the shift from the livestock trade to the opium trade. It then examines the underlying causes and impacts of the opium economy on social relations in the village. Although a case study of a community living on the margins of the global economy, it is argued that these changes have important implications for international policymakers. The emergence of the opium economy in north-eastern Afghanistan is symptomatic of new and expanding forms of trans-border trade associated with the restructuring of the global political economy.