Investigation of Biogenic Passivating Layers on Corroded Iron.
This study evaluates mechanisms of biogenic mineral formation induced by bacterial iron reduction for the stabilization of corroded iron. As an example, the Desulfitobacterium hafniense strain TCE1 was employed to treat corroded coupons presenting urban natural atmospheric corrosion, and spectroscopic investigations were performed on the samples' cross-sections to evaluate the corrosion stratigraphy. The treated samples presented a protective continuous layer of iron phosphates (vivianite Fe2+3(PO4)2·8H2O and barbosalite Fe2+Fe3+2(PO4)2(OH)2), which covered 92% of the surface and was associated with a decrease in the thickness of the original corrosion layer. The results allow us to better understand the conversion of reactive corrosion products into stable biogenic minerals, as well as to identify important criteria for the design of a green alternative treatment for the stabilization of corroded iron.


Changes in muscle size and MHC composition in response to resistance exercise with heavy and light loading intensity.
Muscle mass accretion is accomplished by heavy-load resistance training. The effect of light-load resistance exercise has been far more sparsely investigated with regard to potential effect on muscle size and contractile strength. We applied a resistance exercise protocol in which the same individual trained one leg at 70% of one-repetition maximum (1RM) (heavy load, HL) while training the other leg at 15.5% 1RM (light load, LL). Eleven sedentary men (age 25 +/- 1 yr) trained for 12 wk at three times/week. Before and after the intervention muscle hypertrophy was determined by magnetic resonance imaging, muscle biopsies were obtained bilaterally from vastus lateralis for determination of myosin heavy chain (MHC) composition, and maximal muscle strength was assessed by 1RM testing and in an isokinetic dynamometer at 60 degrees /s. Quadriceps muscle cross-sectional area increased (P < 0.05) 8 +/- 1% and 3 +/- 1% in HL and LL legs, respectively, with a greater gain in HL than LL (P < 0.05). Likewise, 1RM strength increased (P < 0.001) in both legs (HL: 36 +/- 5%, LL: 19 +/- 2%), albeit more so with HL (P < 0.01). Isokinetic 60 degrees /s muscle strength improved by 13 +/- 5% (P < 0.05) in HL but remained unchanged in LL (4 +/- 5%, not significant). Finally, MHC IIX protein expression was decreased with HL but not LL, despite identical total workload in HL and LL. Our main finding was that LL resistance training was sufficient to induce a small but significant muscle hypertrophy in healthy young men. However, LL resistance training was inferior to HL training in evoking adaptive changes in muscle size and contractile strength and was insufficient to induce changes in MHC composition.


Acid-sensing ion channel 3 decreases phosphorylation of extracellular signal-regulated kinases and induces synoviocyte cell death by increasing intracellular calcium.
Acid-sensing ion channel 3 (ASIC3) is expressed in synoviocytes, activated by decreases in pH, and reduces inflammation in animal models of inflammatory arthritis. The purpose of the current study was to characterize potential mechanisms underlying the control of inflammation by ASIC3 in fibroblast-like synoviocytes (FLS). Experiments were performed in cultured FLS from wild-type (WT) and ASIC3-/- mice, ASIC1-/- mice, and people with rheumatoid arthritis. We assessed the effects of acidic pH with and without interleukin-1β on FLS and the role of ASICs in modulating intracellular calcium [Ca(2+)](i), mitogen activated kinase (MAP kinase) expression, and cell death. [Ca(2+)](i) was assessed by fluorescent calcium imaging, MAP kinases were measured by Western Blots; ASIC, cytokine and protease mRNA expression were measured by quantitative PCR and cell death was measured with a LIVE/DEAD assay. Acidic pH increased [Ca(2+)](i) and decreased p-ERK expression in WT FLS; these effects were significantly smaller in ASIC3-/- FLS and were prevented by blockade of [Ca(2+)]i. Blockade of protein phosphatase 2A (PP2A) prevented the pH-induced decreases in p-ERK. In WT FLS, IL-1β increases ASIC3 mRNA, and when combined with acidic pH enhances [Ca(2+)](i), p-ERK, IL-6 and metalloprotienase mRNA, and cell death. Inhibitors of [Ca(2+)](i) and ERK prevented cell death induced by pH 6.0 in combination with IL-1β in WT FLS. Decreased pH activates ASIC3 resulting in increased [Ca(2+)](i), and decreased p-ERK. Under inflammatory conditions, acidic pH results in enhanced [Ca(2+)](i) and phosphorylation of extracellular signal-regulated kinase that leads to cell death. Thus, activation of ASIC3 on FLS by acidic pH from an inflamed joint could limit synovial proliferation resulting in reduced accumulation of inflammatory mediators and subsequent joint damage.


[Is it enough to recommend to patients take a walk? Importance of the cadence].
There are strong scientific evidences on the benefits of leading an active lifestyle. The most characteristic and inherent physical activity of the human being is walking. This activity is currently promoted by a number of professionals to improve the health status of the population. However, just suggesting "go for a walk" is not enough since a number of steps performed at a certain pace are necessary to induce a series of beneficial effects on the organism. The aim of this study was to show the latest advances on this topic so that the population and the patients can received more detailed recommendations when walking is prescribed. We carried out a literature search in PubMed and Scielo, as well as a manual search among the references of the studies selected. After analyzing the literature, it seems evident that it is important to reach a certain amount of steps during the day in order to improve the people's health, and it also seems essential to suggest the pace at which to walk. "Go for a walk" is a proofed and beneficial recommendation for achieving health benefits in the population. However, the health professionals should also suggest reaching a certain pace or minimum intensity in order to assure that their patients achieve the favourable effects on the organism.


Structural and Electronic Effects at the Interface between Transition Metal Dichalcogenide Monolayers (MoS2, WSe2, and Their Lateral Heterojunctions) and Liquid Water.
Transition metal dichalcogenides (TMDCs) can be used as optical energy conversion materials to catalyze the water splitting reaction. A good catalytical performance requires: (i) well-matched semiconductor bandgaps and water redox potential for fluent energy transfer; and (ii) optimal orientation of the water molecules at the interface for kinetically fast chemical reactions. Interactions at the solid-liquid interface can have an important impact on these two factors; most theoretical studies have employed semiconductor-in-vacuum models. In this work, we explored the interface formed by liquid water and different types of TMDCs monolayers (MoS2, WSe2, and their lateral heterojunctions), using a combined molecular dynamics (MD) and density functional theory (DFT) approach. The strong interactions between water and these semiconductors confined the adsorbed water layer presenting structural patterns, with the water molecules well connected to the bulk water through the hydrogen bonding network. Structural fluctuations in the metal chalcogenide bonds during the MD simulations resulted in a 0.2 eV reduction of the band gap of the TMDCs. The results suggest that when designing new TMDC semiconductors, both the surface hydrophobicity and the variation of the bandgaps originating from the water-semiconductor interface, need to be considered.


Resampling versus repair in evolution strategies applied to a constrained linear problem.
We study the behaviour of multi-recombination evolution strategies for the problem of maximising a linear function with a single linear constraint. Two variants of the algorithm are considered: a strategy that resamples infeasible candidate solutions and one that applies a simple repair mechanism. Integral expressions that describe the strategies' one-generation behaviour are derived and used in a simple zeroth order model for the steady state attained when operating with constant step size. Applied to the analysis of cumulative step size adaptation, the approach provides an intuitive explanation for the qualitative difference in the algorithm variants' behaviour. The findings have implications for the design of constraint handling techniques to be used in connection with cumulative step size adaptation.


Leukocyte protease binding to nucleic acids promotes nuclear localization and cleavage of nucleic acid binding proteins.
Killer lymphocyte granzyme (Gzm) serine proteases induce apoptosis of pathogen-infected cells and tumor cells. Many known Gzm substrates are nucleic acid binding proteins, and the Gzms accumulate in the target cell nucleus by an unknown mechanism. In this study, we show that human Gzms bind to DNA and RNA with nanomolar affinity. Gzms cleave their substrates most efficiently when both are bound to nucleic acids. RNase treatment of cell lysates reduces Gzm cleavage of RNA binding protein targets, whereas adding RNA to recombinant RNA binding protein substrates increases in vitro cleavage. Binding to nucleic acids also influences Gzm trafficking within target cells. Preincubation with competitor DNA and DNase treatment both reduce Gzm nuclear localization. The Gzms are closely related to neutrophil proteases, including neutrophil elastase (NE) and cathepsin G. During neutrophil activation, NE translocates to the nucleus to initiate DNA extrusion into neutrophil extracellular traps, which bind NE and cathepsin G. These myeloid cell proteases, but not digestive serine proteases, also bind DNA strongly and localize to nuclei and neutrophil extracellular traps in a DNA-dependent manner. Thus, high-affinity nucleic acid binding is a conserved and functionally important property specific to leukocyte serine proteases. Furthermore, nucleic acid binding provides an elegant and simple mechanism to confer specificity of these proteases for cleavage of nucleic acid binding protein substrates that play essential roles in cellular gene expression and cell proliferation.


The copper centers of tyramine β-monooxygenase and its catalytic-site methionine variants: an X-ray absorption study.
Tyramine β-monooxygenase (TBM) is a member of a family of copper monooxygenases containing two noncoupled copper centers, and includes peptidylglycine monooxygenase and dopamine β-monooxygenase. In its Cu(II) form, TBM is coordinated by two to three His residues and one to two non-His O/N ligands consistent with a [Cu(M)(His)(2)(OH(2))(2)-Cu(H)(His)(3)(OH(2))] formulation. Reduction to the Cu(I) state causes a change in the X-ray absorption spectroscopy (XAS) spectrum, consistent with a change to a [Cu(M)(His)(2)S(Met)-Cu(H)(His)(3)] environment. Lowering the pH to 4.0 results in a large increase in the intensity of the Cu(I)-S extended X-ray absorption fine structure (EXAFS) component, suggesting a tighter Cu-S bond or the coordination of an additional sulfur donor. The XAS spectra of three variants, where the Cu(M) Met471 residue had been mutated to His, Cys, and Asp, were examined. Significant differences from the wild-type enzyme are evident in the spectra of the reduced mutants. Although the side chains of His, Cys, and Asp are expected to substitute for Met at the Cu(M) site, the data showed identical spectra for all three reduced variants, with no evidence for coordination of residue 471. Rather, the K-edge data suggested a modest decrease in coordination number, whereas the EXAFS indicated an average of two His residues at each Cu(I) center. These data highlight the unique role of the Met residue at the Cu(M) center, and pose interesting questions as to why replacement by the cuprophilic thiolate ligand leads to detectable activity whereas replacement by imidazole generates inactive TBM.


Dopamine-responsive pattern in tremor patients.
Diagnosis and treatment of tremor are largely based on clinical assessment. Whereas in some patients tremor may respond to dopaminergic treatment, in general l-Dopa response to tremor varies considerably. The aim of this study was to predict l-Dopa response by accelerometry. We included 60 tremor patients and measured harmonic oscillations by accelerometry. In addition to neurological assessment, we performed l-Dopa challenge tests and the individual tremor response was compared to the amount of harmonic oscillations. We found a strong correlation between harmonic oscillations and clinical l-Dopa response. Similarly, harmonic oscillations were significantly greater in patients with subjective tremor reduction upon l-Dopa administration. We conclude that harmonic oscillations are a measure for l-Dopa response to tremor irrespective of the underlying disease. Because of the observational character of the study, any causal relation remains speculative. Nevertheless, we propose a novel, non-invasive approach to predict l-Dopa response in tremor patients.


Insulin Signaling in the Peripheral and Central Nervous System Regulates Female Sexual Receptivity during Starvation in Drosophila.
Many animals adjust their reproductive behavior according to nutritional state and food availability. Drosophila females for instance decrease their sexual receptivity following starvation. Insulin signaling, which regulates many aspects of insect physiology and behavior, also affects reproduction in females. We show that insulin signaling is involved in the starvation-induced reduction in female receptivity. More specifically, females mutant for the insulin-like peptide 5 (dilp5) were less affected by starvation compared to the other dilp mutants and wild-type flies. Knocking-down the insulin receptor, either in all fruitless-positive neurons or a subset of these neurons dedicated to the perception of a male aphrodisiac pheromone, decreased the effect of starvation on female receptivity. Disrupting insulin signaling in some parts of the brain, including the mushroom bodies even abolished the effect of starvation. In addition, we identified fruitless-positive neurons in the dorso-lateral protocerebrum and in the mushroom bodies co-expressing the insulin receptor. Together, our results suggest that the interaction of insulin peptides determines the tuning of female sexual behavior, either by acting on pheromone perception or directly in the central nervous system.


RNase P activity in the mitochondria of Saccharomyces cerevisiae depends on both mitochondrion and nucleus-encoded components.
A requisite step in the biosynthesis of tRNA is the removal of 5' leader sequences from tRNA precursors. We have detected an RNase P activity in yeast mitochondrial extracts that can carry out this reaction on a homologous precursor tRNA. This mitochondrial RNase P was sensitive to both micrococcal nuclease and protease, demonstrating that it requires both a nucleic acid and protein for activity. The presence of RNase P activity in vitro directly correlated with the presence of a locus on yeast mitochondrial DNA previously shown by genetic and biochemical studies to be required for tRNA maturation. The product of the locus, the 9S RNA, and this newly described mitochondrial RNase P activity cofractionated, providing further evidence that the 9S RNA is the RNA component of yeast mitochondrial RNase P.


Modified Augmented Renal Clearance score predicts rapid piperacillin and tazobactam clearance in critically ill surgery and trauma patients.
Recent evidence suggests that current antimicrobial dosing may be inadequate for some critically ill patients. A major contributor in patients with unimpaired renal function may be Augmented Renal Clearance (ARC), wherein urinary creatinine clearance exceeds that predicted by serum creatinine concentration. We used pharmacokinetic data to evaluate the diagnostic accuracy of a recently proposed ARC score. Pharmacokinetic data from trauma/surgical intensive care unit patients receiving piperacillin/tazobactam were evaluated. We combined intermediate scores (4-6 points) into a single low score (≤6) group and compared pharmacokinetic parameters against the high (≥7) ARC score group. Diagnostic performance was evaluated using median clearance and volume of distribution, area under the antibiotic time-concentration curve (AUC), and achievement of free concentrations greater than a minimum inhibitory concentration (MIC) of 16 μg/mL for at least 50% of the dose interval (fT > MIC ≥ 50%). Alternative dosing strategies were explored in silico. The ARC score was 100% sensitive and 71.4% specific for detecting increased clearance, increased volume of distribution, decreased AUC, and fT > MIC < 50% at an MIC of 16 μg/mL. The area under the receiver operating characteristic curve was 0.86 for each, reflecting a high degree of diagnostic accuracy for the ARC score. Serum creatinine less than 0.6 mg/dL had comparable specificity (71.4%) but was less sensitive (66.7%) and accurate (area under the receiver operating characteristic curve, 0.69) for detecting higher clearance rates. Monte Carlo pharmacokinetic simulations demonstrated increased time at therapeutic drug levels with extended infusion dosing at a drug cost savings of up to 66.7% over multiple intermittent dosing regimens. Given its ability to predict antimicrobial clearance above population medians, which could compromise therapy, the ARC score should be considered as a means to identify patients at risk for subtherapeutic antibiotic levels. Adequately powered studies should prospectively confirm the utility of the ARC score and the role of antimicrobial therapeutic drug monitoring in such patients. Diagnostic tests, level III.


Immunologic Memory in Pregnancy: Focusing on Memory Regulatory T Cells.
A successful pregnancy requires the maternal immune system to tolerate an allogeneic fetus. The incidence of preeclampsia and other complications related to impaired fetal tolerance is lower during the second pregnancy than during the first pregnancy. At the same time, compared with normal pregnant women in the previous pregnancy, patients with pregnancy complications in the previous pregnancy also have an increased risk of the disease when they become pregnant again. This difference may be related to the immunological memory of pregnancy. Regulatory T cells (Tregs) are immunosuppressive CD4+ T cells that play a predominant role in maintaining immune tolerance. In addition, Tregs possess immunological memory properties, including fetal or paternal-specific memory Tregs and Tregs expressing memory cell makers, forming an immunoregulatory memory against fetal antigens. In this review, we provide an overview of the characteristics of memory Tregs in pregnancy, evidence regarding the existence of memory Tregs in human pregnancy, as well as in mouse models. We also discuss the mechanism of memory Tregs induction, maintenance, and action. In addition, we described their changes during the first pregnancy, second pregnancy, postpartum, and pathological pregnancy in order to provide new targets for the diagnosis and treatment of pregnancy related diseases.


Plant responses to cold: Transcriptome analysis of wheat.
Temperature and light are important environmental stimuli that have a profound influence on the growth and development of plants. Wheat varieties can be divided on the basis of whether they require an extended period of cold to flower (vernalization). Varieties that have a requirement for vernalization also tend to be winter hardy and are able to withstand quite extreme subzero temperatures. This capacity, however, is not constitutive and plants require a period of exposure to low, non-freezing temperatures to acquire freezing tolerance: this process is referred to as cold acclimation. Cold acclimation and the acquisition of freezing tolerance require the orchestration of many different, seemingly disparate physiological and biochemical changes. These changes are, at least in part, mediated through the differential expression of many genes. Some of these genes code for effector molecules that participate directly to alleviate stress. Others code for proteins involved in signal transduction or transcription factors that control the expression of further banks of genes. In this review, we provide an overview of some of the main features of cold acclimation with particular focus on transcriptome reprogramming. In doing so, we highlight some of the important differences between cold-hardy and cold-sensitive varieties. An understanding of these processes is of great potential importance because cold and freezing stress are major limiting factors for growing crop plants and periodically account for significant losses in plant productivity.


A neural network-based 2D/3D image registration quality evaluator for pediatric patient setup in external beam radiotherapy.
Our purpose was to develop a neural network-based registration quality evaluator (RQE) that can improve the 2D/3D image registration robustness for pediatric patient setup in external beam radiotherapy. Orthogonal daily setup X-ray images of six pediatric patients with brain tumors receiving proton therapy treatments were retrospectively registered with their treatment planning computed tomography (CT) images. A neural network-based pattern classifier was used to determine whether a registration solution was successful based on geometric features of the similarity measure values near the point-of-solution. Supervised training and test datasets were generated by rigidly registering a pair of orthogonal daily setup X-ray images to the treatment planning CT. The best solution for each registration task was selected from 50 optimizing attempts that differed only by the randomly generated initial transformation parameters. The distance from each individual solution to the best solution in the normalized parametrical space was compared to a user-defined error tolerance to determine whether that solution was acceptable. A supervised training was then used to train the RQE. Performance of the RQE was evaluated using test dataset consisting of registration results that were not used in training. The RQE was integrated with our in-house 2D/3D registration system and its performance was evaluated using the same patient dataset. With an optimized sampling step size (i.e., 5 mm) in the feature space, the RQE has the sensitivity and the specificity in the ranges of 0.865-0.964 and 0.797-0.990, respectively, when used to detect registration error with mean voxel displacement (MVD) greater than 1 mm. The trial-to-acceptance ratio of the integrated 2D/3D registration system, for all patients, is equal to 1.48. The final acceptance ratio is 92.4%. The proposed RQE can potentially be used in a 2D/3D rigid image registration system to improve the overall robustness by rejecting unsuccessful registration solutions. The RQE is not patient-specific, so a single RQE can be constructed and used for a particular application (e.g., the registration for images acquired on the same anatomical site). Implementation of the RQE in a 2D/3D registration system is clinically feasible.


The oak wilt enigma: perspectives from the Texas epidemic.
Ceratocystis fagacearum (Bretz) Hunt, the oak wilt pathogen, is currently causing massivel osses of semievergreen live oaks (Quercus fusiformis Small and Q. virginiana Mill.) in central Texas. Given the relatively limited oak mortality caused by C. fagacearum in the deciduous forests of the North Central, Midwestern, and Mid-Atlantic United States, this Texas epidemic was not anticipated. The intensity of oak wilt in Texas is attributed to a number of factors related to host characteristics and the ability of the pathogen to adapt to limiting environmental conditions. Oak wilt management in semievergreen oaks requires considerable revision of the control techniques previously designed for deciduous oaks. The Texas oak wilt epidemic provides a new perspective from which to evaluate questions concerning oak wilt, including the origins of the pathogen as well as the potential for future losses in unaffected oak forests.


Common lines modeling for reference free Ab-initio reconstruction in cryo-EM.
We consider the problem of estimating an unbiased and reference-free ab initio model for non-symmetric molecules from images generated by single-particle cryo-electron microscopy. The proposed algorithm finds the globally optimal assignment of orientations that simultaneously respects all common lines between all images. The contribution of each common line to the estimated orientations is weighted according to a statistical model for common lines' detection errors. The key property of the proposed algorithm is that it finds the global optimum for the orientations given the common lines. In particular, any local optima in the common lines energy landscape do not affect the proposed algorithm. As a result, it is applicable to thousands of images at once, very robust to noise, completely reference free, and not biased towards any initial model. A byproduct of the algorithm is a set of measures that allow to asses the reliability of the obtained ab initio model. We demonstrate the algorithm using class averages from two experimental data sets, resulting in ab initio models with resolutions of 20Å or better, even from class averages consisting of as few as three raw images per class.


[Experience using spinal anesthesia in a central regional hospital].
Spinal anesthesia was used in 2402 patients. The method is thought by the author to retain its significance in modern anesthesiology since it gives pronounced anesthesia and myorelaxation.


Prophylactic Negative Pressure Wound Therapy in Reducing Surgical Site Infections in Closed Abdominal Incision: A Randomized Controlled Trial.
Objective: This study aimed to evaluate the efficacy of prophylactic negative pressure wound therapy (PNPWT) in reducing the incidence of surgical site infection (SSI) and other wound complications in closed abdominal incisions. Approach: This was a prospective, single-center, open-label parallel arm superiority randomized controlled trial conducted over 2 years. Participants were randomly assigned to PNPWT and standard surgical dressing (SSD) group. The occurrence of postoperative SSI within 30 days, other wound-related complications, length of hospital (LOH) stay, and readmission within 1 month among both the study group were studied. Results: A total of 140 participants were included, with 70 each randomized to the PNPWT and SSD groups. In this study, 28.5% and 5.8% developed SSI in the SSD and PNPWT groups, respectively (relative risk = 0.26; 95% confidence interval = 0.08-0.80; p = 0.001). Similarly, the incidence of seroma (7.2% vs. 18.5%, p = 0.016), wound dehiscence (0% vs. 4.2%, p = 0.244), superficial and deep SSI (5.7% vs. 24.3%, p = 0.001) and (0% vs. 4.2%, p = 0.244), and LOH stay (days) (9 vs. 10.5, p = 0.07) were less in PNPWT compared to SSD group. Innovation: Despite the advances in surgical care, SSI rates continue to be high. The present findings might facilitate the use of PNPWT as a novel preventive strategy to reduce SSI in closed abdominal incision. Conclusion: The PNPWT in closed incisions following elective laparotomy can reduce the incidence of SSI when compared to SSD. The use of PNPWT was associated with a lower incidence of superficial SSI and seroma but without significant reduction in hospital stay.


Revealing Co-N4 @Co-NP Bridge-Enabled Fast Charge Transfer and Active Intracellular Methanogenesis in Bio-Electrochemical CO2 -Conversion with Methanosarcina Barkeri.
To significantly advance the bio-electrochemical CO2 -conversion rate and unfold the correlation between the abiotic electrode and the attached microorganisms, an atomic-nanoparticle bridge of Co-N4 @Co-NP crafted in metal-organic frameworks-derived nanosheets is integrated with a model methanogen of Methanosarcina barkeri (M. barkeri). The direct bonding of N in Co-N4 and Fe in member protein of Cytochrome b (Cytb) activates a fast direct electron transfer path while the Co nanoparticles further strengthen this bonding via decreasing the energy gap between the p-band center of N and the d-band center of Fe. This multiorbital tuning operation of Co nanoparticles also enhances the coenzyme F420-mediated electron transfer by enabling the electron flow direct to the hydrogenation sites. Particularly, the increased surface electric field of the Co-N4 @Co-NP bridge-based nanosheet electrode facilitates the interfacial Na+ accumulation to expedite ATPase transport for powering intracellular CO2 conversion. Remarkably, the self-assembled M.barkeri-Co-N4 @Co-NP biohybrid achieves a high methane production rate of 3860 mmol m-2 day-1 , which greatly outperforms other reported biohybrid systems. This work demonstrates a comprehensive scrutinization of biotic-abiotic energy transfer, which may serve as a guiding principle for efficient bio-electrochemical system design.


Effects of informal caregivers on function of older adults in home health care.
This study aimed to examine the effects of informal caregivers on the functioning of older adults in home health care (HHC). The authors performed a secondary data analysis using the Outcome and Assessment Information Set of older adults (N = 8,750) who were admitted to a HHC agency from acute care hospitals. We conducted hierarchical multiple linear regression with functional dependence after a 60-day episode of formal HHC as an outcome variable. The older adults with informal caregivers showed less functional dependence at discharge (β = -0.821, p = .027) than those without informal caregivers. Older adults who have a spouse (β = -3.886, p < .001), offspring (β = -3.614, p < .001), relative (β = -4.360, p < .001), or nonrelative (β = -4.977, p < .001) caregiver showed less functional dependence at discharge compared with those who had a paid caregiver when controlling for risk factors.


Ovarian Metastases of Breast Cancers With Signet Ring Cells: A Report of 17 Cases Including 14 Krukenberg Tumors.
Krukenberg tumor, defined as metastatic adenocarcinoma to the ovary containing at least 10% signet ring cells, usually arises from the stomach but can also originate from other sites. We reviewed 17 metastatic breast carcinomas to the ovary with signet ring cells to potentially identify features indicative of mammary origin as opposed to other possible primary sites. The patients ranged from 41 to 76 (mean, 53.6) yr. Fourteen had a prior history of invasive breast carcinoma (invasive ductal carcinoma, 4; invasive lobular carcinoma, 3; adenocarcinoma not otherwise specified, 3; carcinoma with ductal and lobular features, 2; and unspecified carcinoma, 2) and metastases were identified 2 to 284 (mean, 79) mo after the original diagnosis. Three patients had no known history of invasive breast carcinoma: 1 was subsequently diagnosed with invasive lobular carcinoma, 1 had suspicious bilateral breast masses identified on imaging, and 1 was lost to follow-up. Bilateral ovarian metastases were present in 87%, and the tumors ranged from 3.8 to 19 (mean, 8) cm. Microscopically the ovarian architecture was effaced in 71% by discrete tumor lobules separated by striking edema. The tumors exhibited a variety of histologic patterns: nests were most common (88%), followed by cords (82%), diffuse sheets (82%), single cells (71%), small clusters (41%), glands (29%), and follicle-like cysts (12%). Signet ring cells comprised 2% to 70% (mean, 33%) of the tumors, with 14 cases meeting the criteria for Krukenberg tumor. Signet ring cells were most frequently observed within diffuse sheets (71%) and cords (65%). Tumor cells arranged in nests, cords, and diffuse sheets are typical of Krukenberg tumor of breast origin, and the patterns recapitulate those seen in primary breast carcinomas. Features characteristic of gastrointestinal origin, such as extracellular mucin, intestinal-type glands, dirty necrosis, microcysts, and goblet cell carcinoid-like foci, were absent. The overall morphologic picture in cases of ovarian spread of breast cancer with signet ring cells is usually strongly suggestive of mammary origin. The diagnosis can be further supported by the clinical history and immunohistochemical evaluation.


Cretaceous sauropods from the sahara and the uneven rate of skeletal evolution among dinosaurs
Lower Cretaceous fossils from central Niger document the succession of sauropod dinosaurs on Africa as it drifted into geographic isolation. A new broad-toothed genus of Neocomian age ( approximately 135 million years ago) shows few of the specializations of other Cretaceous sauropods. A new small-bodied sauropod of Aptian-Albian age ( approximately 110 million years ago), in contrast, reveals the highly modified cranial form of rebbachisaurid diplodocoids. Rates of skeletal change in sauropods and other major groups of dinosaurs are estimated quantitatively and shown to be highly variable.


A chimaeric plant virus vaccine protects mice against a bacterial infection.
The plant virus cowpea mosaic virus (CPMV) is an efficient carrier of foreign peptides for the generation of strong humoral immune responses. Peptides derived from both viruses and bacteria are strongly immunogenic when displayed on the surface of CPMV and elicit high titres of peptide-specific antibody. However, the protective effects of antibodies generated using bacterial epitopes in this system have yet to be demonstrated. In this study the ability of chimaeric virus particles (CVPs) to afford protection against bacterial infection was assessed. Immunization of outbred mice with CPMV expressing a peptide derived from outer-membrane protein F of Pseudomonas aeruginosa (CPMV-PAE5) generated high titres of P. aeruginosa-specific IgG that opsonized the bacteria for phagocytosis by human neutrophils and afforded protection upon challenge with two different immunotypes of P. aeruginosa in a model of chronic pulmonary infection. When examined 8 d after challenge, CVP-immunized mice had fewer severe lung lesions and fewer bacteria in their lungs compared to mice immunized with wild-type virus. Different levels of protection were seen with CPMV-PAE5 when Freund's or alum adjuvants were used. These studies highlight the ability of CVPs to generate protective immunity against infectious disease agents.


The Hospital Readmissions Reduction Program: Nationwide Perspectives and Recommendations: A JACC: Heart Failure Position Paper.
The mandatory federal pay-for-performance Hospital Readmissions Reduction Program (HRRP) was created to decrease 30-day hospital readmissions by instituting accountability and stimulating quality care and coordination, particularly during care transitions. The HRRP has changed the landscape of hospital readmissions and reimbursement within the United States by imposing substantial Medicare payment penalties on hospitals with higher-than-expected readmission rates. However, the HRRP has been controversial since its inception, particularly in the field of heart failure. Proponents argue that it has reduced national readmission rates, in part by raising awareness and investment in mechanisms to better assist patients during discharge and transitions; opponents contend that it unfairly penalizes hospitals for issues beyond their control, has unintended negative consequences due to incentivizing readmission over survival, that it encourages "gaming" the system, was not tested before implementation, and that it does not specify how hospitals can improve their performance. This paper incorporates the diverse, nuanced, and sometimes divergent interpretations presented during a multifaceted expert clinician discussion regarding the HRRP and heart failure; in cases in which consensus opinions were achieved, they are presented, including regarding potential new iterations of the HRRP for the future. Potential improvements include more comprehensive incorporation of outcomes into the HRRP measure and better risk adjustment to improve equality and fairness.


Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium.
Corticosteroids influence the development and function of the heart and its response to injury and pressure overload via actions on glucocorticoid (GR) and mineralocorticoid (MR) receptors. Systemic corticosteroid concentration depends largely on the activity of the hypothalamic-pituitary-adrenal (HPA) axis, but glucocorticoid can also be regenerated from intrinsically inert metabolites by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), selectively increasing glucocorticoid levels within cells and tissues. Extensive studies have revealed the roles for glucocorticoid regeneration by 11β-HSD1 in liver, adipose, brain and other tissues, but until recently, there has been little focus on the heart. This article reviews the evidence for glucocorticoid metabolism by 11β-HSD1 in the heart and for a role of 11β-HSD1 activity in determining the myocardial growth and physiological function. We also consider the potential of 11β-HSD1 as a therapeutic target to enhance repair after myocardial infarction and to prevent the development of cardiac remodelling and heart failure.


MR-guidance of HIFU therapy.
MR guidance of high intensity focused ultrasound is evolving with each new application. In this paper we describe ongoing research in the MR-guidance aspect of MR-guided focused ultrasound. The structure is divided into the pretreatment/setup phase of the procedure, MR thermometry for monitoring the actual treatment, and methods for assessment and follow-up.


Arachidonic acid activates an open rectifier potassium channel in cultured rat cortical astrocytes.
A pathophysiological increase in free arachidonic acid (AA) is thought to regulate the channel-mediated astrocytic swelling occurring in several brain injuries. We report that in cultured rat type-1 cortical astrocytes, exposure to 10 microM AA activates an open rectifier K(+) channel, which exhibits many similarities with TREK/TRAAK members of the two-pore-domain K(+) channel family KCNK. Patch-clamp experiments showed that the current developed with a long latency and was preceded by a depression of the previously described outward rectifier K(+) conductance. Pharmacologic studies indicate that the K(+) open rectifier was differentially sensitive to classic K(+)-channel blockers (quinine, quinidine, tetraethylammonium, and barium) and was inhibited potently by gadolinium ions. The activation of this K(+) current occurred independently of the AA metabolism as pharmacologic inhibition of the lipoxygenase, cyclooxygenase, and cytochrome P450 epoxygenase signaling cascades did not alter the AA effect. Moreover, neither the neutralization of the NADPH-oxidase pathway nor scavenging intracellular free radicals modified the AA response. Finally, the AA-induced K(+) current was unaffected by protein kinase C inhibitors. The activation mechanism of the K(+) open rectifier was through an extracellular interaction of AA with the plasma membrane. RT-PCR analysis revealed that the AA-induced K(+) conductance was mediated likely by TREK-2 channels. Collectively, the results demonstrate that in cultured cortical astrocytes, pathological levels of AA directly activate an open rectifier K(+) channel, which may play a role in the control of K(+) homeostasis under pathophysiological conditions.


Plumbagin, isolated from Plumbago zeylanica, induces cell death through apoptosis in human pancreatic cancer cells.
Pancreatic cancer is one of the most resistant malignancies. Several studies have indicated that plumbagin isolated from Plumbago zeylanica possesses anticancer activity. However, its antitumor effects against pancreatic cancer have not been explored. We investigated the effect of plumbagin on the growth of human pancreatic carcinoma cells and its possible underlying mechanisms. Plumbagin inhibited the growth of Panc-1 and Bxpc-3 cells in a dose-dependent and time-dependent manner. Liu's staining and transmission electron microscopy demonstrated morphological changes resembling apoptosis in Panc-1 cells treated with plumbagin. The degree of apoptosis was assessed by measuring the proportions of sub-G(1), annexin V+/propidium iodide-, and terminal- deoxynucleotidyl-transferase-mediated-nick-end labeling (TUNEL)+ cells, and a significant increment in apoptotic cells was observed. Exposure to plumbagin caused the upregulation of Bax, a rapid decline in mitochondrial transmembrane potential, apoptosis-inducing factor overexpression in cytosol, and the cleavage of procaspase-9 and poly ADP-ribose polymerase. Activation of caspase-3, but not caspase-8, was evidenced by fluorometric substrate assay. Pretreatment with caspase inhibitors did not block plumbagin-induced apoptosis. Alternatively, it is possible that plumbagin downregulated phosphoinositide 3-kinase activity through a negative feedback mechanism. In an orthotopic pancreatic tumor model, plumbagin markedly inhibited the growth of Panc-1 xenografts without any significant effect on leukocyte counts or body weight. Plumbagin may induce apoptosis in human pancreatic cancer cells primarily through the mitochondria-related pathway followed by both caspase-dependent and caspase-independent cascades. It indicates that plumbagin can be potentially developed as a novel therapeutic agent against pancreatic cancer.


Occlusion Guided Double-Barreled Fibular Osteoseptocutaneous Free Flap for Refined Mandibular Reconstruction Aided by Virtual Surgical Planning.
There were many articles about double-barreled fibular flap for mandibular reconstruction. The upper layer bone was suit for implant placement as a new alveolar. The lower layer was necessary for contour. But the accurate relationship between the 2 layers bone was rarely reported. The purpose of this study was twofold: to evaluate the feasibility of the novel design of the double-barreled fibular flap from virtual surgery to actual result; to evaluate the accuracy and results of occlusion-guided double-barreled fibular free flap in mandible reconstruction. From 2010 to 2016, 52 patients underwent segmental mandibular reconstruction with double-barreled fibular osteoseptocutaneous flaps with computer aided design/computer aided manufacturing technique. Preoperative computer tomographic (CT) scans were imported into Mimics 10.01 software (Materialise, Leuven, Belgium) for surgical planning. The peroneal vessel pedicel was designed at the lower barrel segmental bone of the double-barreled fibular flap. The double-barreled bone was strung with 16 mm fixation screws instead of mini-plate. Sixty-three dental implants placement was simultaneous in 30 patients and 32 dental implants placement was in second stage in 18 patients. Postoperative CT and digital imaging were evaluated to assess surgical accuracy using software. The pre- and postoperative morphometric measurements were compared using the Fisher exact t test. Two flaps occurred vascular crisis postoperatively. There was no flap necrosis. Four implants failed during 1 to 5 weeks postoperative. Sixty-six CT scans from 33 patients who underwent partial mandibular resection were analyzed. The dimensions of the double-barreled fibula segments after osteotomy showed no difference from the preoperative virtual surgical planning (VSP). But the condylar locations showed a disposition out of the fossa (P < 0.05), between VSP and postoperative CT scans. There was no difference in implants between VSP and postoperative CT scans. The VSP of relationship of double-barreled fibular is important for segmental mandible reconstruction. The benefit of VSP was to enhance surgical accuracy and safety.


Mapping trends in insecticide resistance phenotypes in African malaria vectors.
Mitigating the threat of insecticide resistance in African malaria vector populations requires comprehensive information about where resistance occurs, to what degree, and how this has changed over time. Estimating these trends is complicated by the sparse, heterogeneous distribution of observations of resistance phenotypes in field populations. We use 6,423 observations of the prevalence of resistance to the most important vector control insecticides to inform a Bayesian geostatistical ensemble modelling approach, generating fine-scale predictive maps of resistance phenotypes in mosquitoes from the Anopheles gambiae complex across Africa. Our models are informed by a suite of 111 predictor variables describing potential drivers of selection for resistance. Our maps show alarming increases in the prevalence of resistance to pyrethroids and DDT across sub-Saharan Africa from 2005 to 2017, with mean mortality following insecticide exposure declining from almost 100% to less than 30% in some areas, as well as substantial spatial variation in resistance trends.


Bacterial colonization of host cells in the absence of cholesterol.
Reports implicating important roles for cholesterol and cholesterol-rich lipid rafts in host-pathogen interactions have largely employed sterol sequestering agents and biosynthesis inhibitors. Because the pleiotropic effects of these compounds can complicate experimental interpretation, we developed a new model system to investigate cholesterol requirements in pathogen infection utilizing DHCR24(-/-) mouse embryonic fibroblasts (MEFs). DHCR24(-/-) MEFs lack the Δ24 sterol reductase required for the final enzymatic step in cholesterol biosynthesis, and consequently accumulate desmosterol into cellular membranes. Defective lipid raft function by DHCR24(-/-) MEFs adapted to growth in cholesterol-free medium was confirmed by showing deficient uptake of cholera-toxin B and impaired signaling by epidermal growth factor. Infection in the absence of cholesterol was then investigated for three intracellular bacterial pathogens: Coxiella burnetii, Salmonella enterica serovar Typhimurium, and Chlamydia trachomatis. Invasion by S. Typhimurium and C. trachomatis was unaltered in DHCR24(-/-) MEFs. In contrast, C. burnetii entry was significantly decreased in -cholesterol MEFs, and also in +cholesterol MEFs when lipid raft-associated α(V)β(3) integrin was blocked, suggesting a role for lipid rafts in C. burnetii uptake. Once internalized, all three pathogens established their respective vacuolar niches and replicated normally. However, the C. burnetii-occupied vacuole within DHCR24(-/-) MEFs lacked the CD63-positive material and multilamellar membranes typical of vacuoles formed in wild type cells, indicating cholesterol functions in trafficking of multivesicular bodies to the pathogen vacuole. These data demonstrate that cholesterol is not essential for invasion and intracellular replication by S. Typhimurium and C. trachomatis, but plays a role in C. burnetii-host cell interactions.


Life history traits and the activity of antioxidative enzymes in Lymantria dispar L. (lepidoptera, lymantriidae) larvae exposed to benzo[a]pyrene.
Increased presence of benzo[a]pyrene in the environment underlines the need for development of sensitive biomarkers for monitoring. Antioxidative enzymes could be used as early-warning signals because of their sensitivity and applicability. The activity of 2 antioxidative enzymes, superoxide dismutase (SOD) and catalase (CAT), were measured in midgut tissues of fifth instar Lymantria dispar larvae exposed to different concentrations of benzo[a]pyrene: 2 ng, 10 ng, 20 ng, 100 ng, 200 ng, and 2000 ng benzo[a]pyrene/g dry food weight. Larval development, larval mass, and relative growth rate were also monitored. The authors detected prolonged larval development, as well as reduced larval mass and relative growth rate in larvae exposed to all benzo[a]pyrene concentrations. The L. dispar midgut SOD activity was significantly increased, and 2 SOD isoforms were detected on native polyacrylamide gel electrophoresis in larvae fed on artificial diet supplemented with benzo[a]pyrene. In contrast, the control group had only 1 isoform. Catalase activity was significantly increased in all benzo[a]pyrene-treated larvae. Native gel electrophoresis showed that a switch in active CAT isoforms occurred after benzo[a]pyrene treatment. Thus, SOD and CAT in polyphagous herbivorous L. dispar larvae are very sensitive to low concentrations of benzo[a]pyrene. Therefore, they could be used as biomarkers for exposure and effects of this toxic polycyclic aromatic hydrocarbon.


Multi-dimensional liquid phase based separations in proteomics.
This review covers recent developments towards the implementation of multi-dimensional (MuD) liquid phase based systems for proteome investigations. Although two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) has been used as a standard approach in proteomics, its drawbacks including the limited dynamic range and molecular mass range, together with lack of on-line integration with biological mass spectrometery (Bio-MS) have limited its widespread use and applications in proteomics. In the meantime, various liquid-phase based multi-dimensional separation techniques have been explored. Especially, with the emergence of the combination of nanoflow capillary high-performance liquid chromatography (cHPLC) and Bio-MS, attention is again refocused on utilizing multi-dimensional liquid-phase based separation of proteins. Some remarkable applications of on-line analysis of intact proteins and on-column digested proteins, and the emergence of approaches such as multiple HPLC-electrospray ionization tandem MS and capillary array electrophoresis-matrix assisted laser desorption ionization MS, have stimulated thinking towards developing a automated multi-dimensional system (MuDSy) that integrates liquid phase based separation, digestion and identification of proteins in complex biological mixtures.


SmpB: a protein that binds to double-stranded segments in tmRNA and tRNA.
Binding of the SmpB protein to tmRNA is essential for trans-translation, a process that facilitates peptide tagging of incompletely synthesized proteins. We have used three experimental approaches to study these interactions in vitro. Gel mobility shift assays demonstrated that tmRNA(Delta90-299), a truncated tmRNA derivative lacking pseudoknots 2-4, has the same affinity for the Escherichia coli and Aquifex aeolicus SmpB proteins as the intact E. coli tmRNA. These interactions can be challenged by double-stranded RNAs such as tRNAs and 5S rRNA and are abolished by removal of 24 amino acids from the C-terminus of the A. aeolicus protein. A combination of enzymatic probing and UV-induced cross-linking showed that three SmpB molecules can bind to a single tmRNA(Delta90-299) and tRNA molecule. Irradiation of E. coli tmRNA and yeast tRNA(Phe) bound to a single SmpB molecule with UV light induced cross-links to residues C343 and m(1)A48, respectively, in their T-loops and to their 3' terminal adenosines. These findings indicate that the acceptor-T arm constitutes the primary SmpB binding site in both tmRNA and tRNA. The remaining two SmpB molecules associate with the anticodon stem-like region of tmRNA and the anticodon arm of tRNAs. As the T and anticodon loops are dispensable for SmpB binding, it seems that SmpB recognizes double helical segments in both tmRNA and tRNA molecules. Although these interactions involve analogous elements in both molecules, their different effects on aminoacylation appear to reflect subtle structural differences between the tRNA-like domain of tmRNA and tRNA.


Surgical Treatment of Atrial Fibrillation.
Atrial fibrillation (AF) is the most common chronic arrhythmia in the adult population. Ablation lines have largely replaced the historical and challenging cut and sew techniques. Surgical ablation of AF is commonly performed in cases with other indications for cardiac surgery and less commonly as a stand-alone therapy. Pulmonary vein isolation is the cornerstone of this procedure. Extended left atrial ablation lines may increase efficacy in cases with longstanding persistent or permanent AF. Additional efficacy by adding right atrial ablation is controversial but is often performed in cases undergoing right atrial or atrial septal surgery. Left atrial volume reduction is recommended in cases with large left atria and AF undergoing another cardiac surgery. Arrhythmia recurrence is not uncommon after surgical ablation of AF and varies among studies due to heterogeneity in patient population, lesion set and endpoints. Freedom from AF recurrence was 65-87% at 12 months and 58-70% at 2 years follow-up. Long-term monitoring is recommended due to an increased prevalence of asymptomatic recurrences. The strongest predictors of AF recurrence are longstanding or persistent AF and a large left atrium. The most common mechanisms of recurrence are pulmonary vein reconnection, nonpulmonary vein triggers, and gaps in the ablation lines. About 20% of atrial tachyarrhythmia recurrences are atrial flutter or atrial tachycardia. There are not enough data in the surgical literature to support withdrawal of anticoagulation after surgical AF ablation. Patients selected for stand-alone surgical ablation usually have low risk profiles and low postoperative mortality rates (0.2%).


Personality dimensions of schizophrenia patients compared to control subjects by gender and the relationship with illness severity.
Personality traits and schizophrenia present gender differences; however, gender has not been considered in most studies on personality and schizophrenia. This study aims to identify the different personality dimensions of schizophrenia patients and healthy control subjects by gender and to explore the relationship between personality dimensions and illness severity variables by analyzing data for males and females separately. Temperament and Character Inventory-Revised dimensions were compared by gender between 161 schizophrenia patients and 214 healthy controls from a population-based sample using independent t-tests. We then investigated whether personality dimensions are related to illness severity variables using correlation analyses and bivariate logistic regression, also by gender. The patients had significantly higher scores for harm avoidance (HA) and self-transcendence (ST) and lower scores for reward dependence (RD), cooperativeness (C), and self-directedness (SD) than the controls. Similar results were obtained when the sample was stratified by gender, however the differences were higher and more significant for HA among males and for RD among females. The number of admissions to a psychiatric hospital positively correlated with novelty seeking (NS) in males and negatively with SD in females. In males, SD and ST negatively correlated with the number of suicide attempts. Male and female patients present difficulties for regulating and adapting behavior to achieve goals (SD) and for identifying and accepting others (C), as well as a great sense of spirituality and universe identification (ST). However, male patients are more characterized by being fearful, doubtful and easily fatigued (HA), while female patients are characterized by presenting difficulties maintaining and pursuing associated reward behaviors (RD). Furthermore, male and female patients who are frequently admitted to psychiatric hospitals and male patients who attempt suicide should be evaluated regarding their personality dimensions. Future studies assessing the relationship between personality dimensions and the clinical features of schizophrenia should consider gender differences.


Fruit tree model for uptake of organic compounds from soil.
Apples and other fruits are frequently cultivated in gardens and are part of our daily diet. Uptake of pollutants into apples may therefore contribute to the human daily intake of toxic substances. In current risk assessment of polluted soils, regressions or models are in use, which were not intended to be used for tree fruits. A simple model for uptake of neutral organic contaminants into fruits is developed. It considers xylem and phloem transport to fruits through the stem. The mass balance is solved for the steady-state, and an example calculation is given. The Fruit Tree Model is compared to the empirical equation of Travis and Arms (T&A), and to results from fruits, collected in contaminated areas. For polar compounds, both T&A and the Fruit Tree Model predict bioconcentration factors fruit to soil (BCF, wet weight based) of > 1. No empirical data are available to support this prediction. For very lipophilic compounds (1ogK(ow) > 5), T&A overestimates the uptake. The conclusion from the Fruit Tree Model is that the transfer of lipophilic compounds into fruits is not relevant. This was also found by an empirical study with PCDD/F. According to the Fruit Tree Model, polar chemicals are transferred efficiently into fruits, but empirical data to verify these predictions are lacking.


Hepatoprotective potential of aqueous extract of Butea monosperma against CCl(4) induced damage in rats.
Aqueous extract of flowers of Butea monosperma (Fabaceae) was evaluated at different dose levels (200, 400, 800 mg/kg, p.o.) for its protective efficacy against CCl(4) (1.5 ml/kg i.p.) induced acute liver injury to validate its use in traditional medicines. The CCl(4) administration altered various biochemical parameters, including serum transaminases, protein, albumin, hepatic lipid peroxidation, reduced glutathione and total protein levels, which were restored towards control by therapy of B. monosperma Adenosine triphosphatase and glucose-6-phosphatase activity in the liver were decreased significantly in CCl(4) treated animals. Therapy of B. monosperma showed its protective effect on biochemical and histopathological alterations at all the three doses in dose dependent manner. B. monosperma extract possess modulatory effect on drug metabolizing enzymes as it significantly decreased the hexobarbitone induced sleep time and increased excretory capacity of liver which was measured by BSP retention. Histological studies also supported the biochemical finding and maximum improvement in the histoarchitecture was seen at higher dose of BM extract.


Spontaneous improvement of optic pathway lesions in children with neurofibromatosis type 1.
Two cases of spontaneous improvement of optic pathway lesions in neurofibromatosis type 1 are reported. At time of diagnosis the children were aged 21 and 32 months respectively; they have been followed by both MRI and clinical evaluation for 5 and 4 years. MRI findings of the first 19 months of follow-up for Case 1 have been described by us before. On MRI serial evaluation, Case 1 showed an almost complete normalization of the size of lesions and a resolution of enhancement, whereas Case 2 showed a slight decrease in the size of lesions and a resolution of enhancement. From the clinical point of view Case 1 showed a normalization of his clinical signs, whereas in Case 2, a visual improvement was only slight, if at all present. In Case 1, the clinical improvement seemed to follow the spontaneous regression of the lesions detected by MRI.


Randomized, Double-Blind, Placebo-Controlled, Withdrawal Study of Colestilan after Dose Titration in Chronic Kidney Disease Dialysis Patients with Hyperphosphatemia.
Colestilan is a new non-calcium-based phosphate binder licensed in Europe for the treatment of hyperphosphatemia in chronic kidney disease patients on dialysis (CKD 5D). This study was conducted to evaluate efficacy in a North American patient population and also to examine secondary actions of colestilan on lipid profile and glycated hemoglobin (HbA1c). This was a multicenter, randomized, double-blind, placebo-controlled withdrawal study, after an initial open-label titration period. Patients (n = 245) with stable phosphate control received 6-15 g/day colestilan during a 12-week, flexible titration period after which 169 were randomized to continue the same dose (n = 85) or switch to placebo (n = 84) for 4 weeks. The primary endpoint was the change in serum phosphorus level during the placebo-controlled withdrawal period. A significant difference of -1.01 mg/dl (-0.33 mmol/l) in mean change in serum phosphorus, favoring colestilan, was seen during the placebo-controlled withdrawal period (p < 0.001). Colestilan reduced serum phosphorus significantly from baseline to week 12 (-1.54 mg/dl (-0.50 mmol/l); p < 0.001). Serum calcium levels were not affected. Colestilan significantly reduced and maintained reductions in calcium × phosphorus ion product (Ca × P), parathyroid hormone, total cholesterol, low-density lipoprotein cholesterol, uric acid and also HbA1c in patients with elevated baseline HbA1c. Colestilan was generally well tolerated; most adverse events were gastrointestinal. In this first clinical trial with colestilan in a North American patient population, colestilan demonstrated significant efficacy in controlling serum phosphorus levels in CKD 5D patients with hyperphosphatemia, without increasing calcium levels.


Regional location of T cell receptor gene Ti alpha on human chromosome 14.
The chromosomal location of Ti alpha was determined by hybridization of a radiolabeled cDNA for the alpha chain of human T cell receptor with 12 human X mouse cell hybrid DNAs cleaved with BamHI. Seven hybrids contained human Ti alpha, while the remaining five lacked it. Only human chromosome 14 matched the distribution of human Ti alpha signal across the mapping panel. Hybrids segregating a chromosome 14 translocation were used to demonstrate that Ti alpha is in the region 14pter greater than 14q21. Thus, the alpha and beta chain genes that contribute structural components to the Ti moiety of the human T cell receptor lie on different chromosomes. In humans, the immunoglobulin heavy chain locus and Ti alpha are in different regions of chromosome 14, with Ti alpha more proximal and the immunoglobulin heavy chain locus more distal.


Probing the multi-step crystallization dynamics of micelle templated nanoparticles: structural evolution of single crystalline γ-Fe2O3.
Iron oxide nanoparticles synthesized with narrow size distribution were characterized using Raman spectroscopy, transmission electron microscopy and a superconducting quantum interference device magnetometer to investigate their composition, crystal structure and magnetic properties. Raman allowed us to explore the polymorphous transition of the iron oxide from the beginning of the synthesis process, as Raman can be used to monitor the precursors, the diblock-copolymer micelles and the resultant particles simultaneously under various processing steps. As different polymorphs possess distinct Raman active phonon modes, it also allows the identification of the exact phases of the resultant nanoparticles. Consequently, we show that the reverse micelle process results in pure phase nanoparticles only under certain conditions. Using insights obtained from examining the entire synthesis process, we can adjust the structure of small nanoparticles (∼6 nm) to achieve coercivity and saturation magnetization values that are usually only obtainable from larger particles (25 nm or larger). In this way, we show a route to tunable magnetic response based on the purity of the crystal phase rather than the particle size. By understanding the evolution of the entire synthesis process, it is possible to adjust the processing conditions to yield monodisperse single crystal phase nanoparticles for widespread use in a variety of applications.


Density functional theory and hydrogen bonds: are we there yet?
Density functional theory (DFT) has become more successful at introducing dispersion interactions, and can be thus applied to a wide range of systems. Amongst these are systems that contain hydrogen bonds, which are extremely important for the biological regime. Here, the description of hydrogen-bonded interactions by DFT with and without dispersion corrections is investigated. For small complexes, for which electrostatics are the determining factor in the intermolecular interactions, the inclusion of dispersion with most functionals yields large errors. Only for larger systems, in which van der Waals interactions are more important, do dispersion corrections improve the performance of DFT for hydrogen-bonded systems. None of the studied functionals, including double hybrid functionals (with the exception of DSD-PBEP86 without dispersion corrections), are more accurate than MP2 for the investigated species.


Predicting self-assembly: from empirism to determinism.
Self-assembly is one of the most important concepts of the 21st century. Strikingly, despite the rational design of molecules for biological and pharmaceutical applications is rather well established, only few are the attempts to formally refine predictions of self-assembly in material science. In the present tutorial review, we encompass some of the most significant efforts towards the systematic study of (thermodynamically stable) self-assembly. We discuss experimental and computer-simulated self-assembly events in hard-matter, soft-matter and higher symmetry architectures under the common framework of partition functions. In this framework, we endeavor to correlate state-of-the-art chemical design, programming and/or engineering of reversible (thermal and chemical equilibrium) self-assembly with knowledge of the underlying partition function landscape in a step towards quantitative predictions and ab initio molecular design.


The art and science of incorporating cost effectiveness into evidence-based recommendations for clinical preventive services.
As medical technology continues to expand and the cost of using all effective clinical services exceeds available resources, decisions about health care delivery may increasingly rely on assessing the cost-effectiveness of medical services. Cost-effectiveness is particularly relevant for decisions about how to implement preventive services, because these decisions typically represent major investments in the future health of large populations. As such, decisions regarding the implementation of preventive services frequently involve, implicitly if not explicitly, consideration of costs. Cost-effectiveness analysis summarizes the expected benefits, harms, and costs of alternative strategies to improve health and has become an important tool for explicitly incorporating economic considerations into clinical decision making. Acknowledging the usefulness of this tool, the third U.S. Preventive Services Task Force (USPSTF) has initiated a process for systematically reviewing cost-effectiveness analyses as an aid in making recommendations about clinical preventive services. In this paper, we provide an overview and examples of roles for using cost-effectiveness analyses to inform preventive services recommendations, discuss limitations of cost-effectiveness data in shaping evidence-based preventive health care policies, outline the USPSTF approach to using cost-effectiveness analyses, and discuss the methods the USPSTF is developing to assess the quality and results of cost-effectiveness studies. While this paper focuses on clinical preventive services (i.e., screening, counseling, immunizations, and chemoprevention), the framework we have developed should be broadly portable to other health care services.


Conceptualization and measurement of coping during adolescence: a review of the literature.
The purpose of this review was to examine the conceptualization and measurement of coping in adolescent research. A review of the literature published and abstracted in four scientific databases was undertaken between July 2008 and June 2009 with the following key words: adolescent(s), cope/coping, stress(ors), and adaptation/psychological. A total of 367 articles were initially identified, and review of published abstracts yielded 104 empirical articles to retrieve and examine more closely for inclusion. Criteria for inclusion in the review were that the study (a) measured coping, (b) presented original data, (c) primarily targeted adolescent participants, (d) was reported in English, and (e) was published between 1998 and June 2009. Fifty-nine subsequent articles were organized using a matrix approach that facilitated cross-study comparisons of purpose, sample, and dependent variables. Fewer than half of the studies reviewed included a specific statement defining coping. Instead, many authors described coping in the context of stress response by identifying particular types or ways of coping or naming specific coping strategies used. The theoretical frameworks guiding examination of coping varied across studies. A range of measures, congruent with adolescent developmental processes, were used to assess adolescent coping. A wide range of stress-related risks or conditions were examined, including psychological stressors such as eating disorders, suicidal ideation, and depression; physical stressors such as chronic illness, HIV infection, sports participation, violence, or sexual abuse; familial stressors such as domestic violence or interparental conflict; social stressors such as romantic relationships or difficulties in settings such as school, prison, or a homeless shelter; and societal stressors such as discrimination. Coping is an important construct in understanding how adolescents react to the extensive stressors and adjustments they experience. Coping is a complex construct yet worthy of examination because it can be a critical point of intervention in the health trajectory of adolescents and young people. Research is needed to advance the conceptualization and measurement of adolescent coping such that interpretation of findings across studies is enhanced. In this way, future research, including interventions targeting coping, will work synergistically to advance the science and adolescent well-being. Nursing and other healthcare providers working with adolescents understand the need for interventions that promote use of healthy coping strategies and minimize unhealthy coping. Findings from this study demonstrate the state of coping conceptualization and measurement in adolescent research and indicate a need for research that will advance the science and improve the usefulness of adolescent coping data.


Visual scanning behavior and mental workload in aircraft pilots.
This paper describes an experimental paradigm and a set of preliminary results which demonstrate a relationship between the level of performance on a skilled man-machine control task, the skill of the operator, the level of mental difficulty induced by an additional task imposed on the basic control task, and visual scanning performance. During a constant, simulated piloting task, visual scanning of instruments was found to vary as a function of the level of difficulty of a verbal loading task. The average dwell time of each fixation on the pilot's primary instrument increased as a function of the loading. The scanning behavior was also a function of the estimated skill level of the pilots, with novices being affected by the loading task much more than experts. The results suggest that visual scanning of instruments in a controlled task may be an indicator of both workload and skill.


Exposure to forced swim stress alters local circuit activity and plasticity in the dentate gyrus of the hippocampus.
Studies have shown that, depending on its severity and context, stress can affect neural plasticity. Most related studies focused on synaptic plasticity and long-term potentiation (LTP) of principle cells. However, evidence suggests that following high-frequency stimulation, which induces LTP in principal cells, modifications also take place at the level of complex interactions with interneurons within the dentate gyrus, that is, at the local circuit level. So far, the possible effects of stress on local circuit activity and plasticity were not studied. Therefore, we set out to examine the possible alterations in local circuit activity and plasticity following exposure to stress. Local circuit activity and plasticity were measured by using frequency dependant inhibition (FDI) and commissural modulation protocols following exposure to a 15 minute-forced swim trial. Exposure to stress did not alter FDI. The application of theta-burst stimulation (TBS) reduced FDI in both control and stressed rats, but this type of plasticity was greater in stressed rats. Commissural-induced inhibition was significantly higher in stressed rats both before and after applying theta-burst stimulation. These findings indicate that the exposure to acute stress affects aspects of local circuit activity and plasticity in the dentate gyrus. It is possible that these alterations underlie some of the behavioral consequences of the stress experience.


[Ambulatory long-term management of a left ventricular assist device. Current modality in terminal heart failure].
We report about the first use and successful outpatient therapy with an implantable pulsatile left ventricular assist device (LVAD, Novacor) in a patient with a combined dilative and ischemic cardiomyopathy in Switzerland. The patient, a 51 year old man (112 kg, 191 cm, blood type A) developed end-stage heart failure (New York Heart Association class (NYHA) IV) while he was awaiting orthotopic heart transplantation. Due to his profession as an independent graphic-designer the patient was afraid of a long-term temporary disablement with consecutive bankruptcy. Therefore we decided and performed the implantation of a Novacor-LVAD as a bridge to transplantation with the possibility to outpatient therapy in a favourable course. The patient was supported by the device for more than five months. His cardiac functional status returned to NYHA class I, and the patient was discharged 5 weeks after implantation. He returned into his normal life and started working at 100% again. Furthermore the LVAD enabled the patient to participate in almost all activities. Five months (151 days) after implantation a donor organ became available and the patient underwent orthotopic heart transplantation. The use and successful outpatient therapy with an implantable pulsatile left ventricular assist device in our patient has proved to be save, reliable, life-saving, quality of life improving and could be an important alternative for the economic burden in heart failure therapy.


Prognostic significance of creatine kinase-MB elevation after percutaneous coronary intervention in patients with chronic renal dysfunction.
Multiple studies have demonstrated a relationship between creatine kinase-MB (CK-MB) elevation after percutaneous coronary intervention (PCI) and increased late mortality within the general population. Because CK-MB is frequently elevated in renal disease even in the absence of myocardial injury, the clinical significance of CK-MB elevation after PCI in patients with renal insufficiency has been questioned. We sought to examine the association between elevated CK-MB after PCI and late mortality in 190 consecutive patients with chronic renal insufficiency (serum creatinine > or =2.0 mg/dL) undergoing PCI at the Cleveland Clinic between January 1997 and March 2000. Of the total group, 20 patients undergoing PCI for acute myocardial infarction, cardiogenic shock, or both were excluded. Follow-up was 99.4% complete at a mean duration of 24.8 +/- 11.2 months (range 5-43 months). CK-MB elevation above the upper limit of normal after intervention was detected in 33 patients (19.4%). Baseline characteristics were not significantly different between the CK-MB elevation group and the normal CK-MB group. Late mortality, however, was significantly higher among patients with postprocedural CK-MB elevation (36.4% vs 17.5%, P =.017). Cox proportional hazard model revealed CK-MB elevation as an independent predictor of late mortality (hazard ratio 2.44, 95% CI 1.14-5.24, P =.02), in addition to New York Heart Association class (hazard ratio 1.35, 95% CI 1.05-1.73, P =.02). This analysis of patients with chronic renal insufficiency undergoing PCI suggests that postprocedural CK-MB elevation is an independent predictor of late mortality even in the presence of renal dysfunction.


Radiotherapy versus radiotherapy plus chemotherapy in stages I and II Hodgkin's disease. A prospective, randomized study by the Danish National Hodgkin Study Group, LYGRA.
In a multi-centre study in which data from all Danish Hodgkin patients have been registered since 1971, all patients in supradiaphragmatic stages I or II, as confirmed by staging laparotomy, were randomized to either radiotherapy (RT) to supra- and infradiaphragmatic lymph node regions (total nodal irradiation, TNI), or RT to a mantle field followed by 6 cycles of MOPP combination chemotherapy (RT+CT). Interim results up to July 1979, when 237 patients had entered the study, showed a treatment failure rate of 19/117 in the TNI group and 4/120 in the RT+CT group (P less than 0.05). 19 of the 23 relapsing patients were under the age of 40, and 14 in the TNI group and 3 in the RT+CT group belonged to stage II. 13 patients had nodular sclerosis, 9 had mixed cellularity and 1 had lymphocytic predominance histology. 12 of 19 relapsing patients in the TNI group had hilar or mediastinal involvement as against 51 of the 117 patients in the entire group. Most of the TNI failures could be retreated, and as yet there is no difference in the overall survival.


Cultured Cordyceps sinensis polysaccharides modulate intestinal mucosal immunity and gut microbiota in cyclophosphamide-treated mice.
The present study aimed to investigate the protective effect of cultured Cordyceps sinensis polysaccharides (CSP) on cyclophosphamide (Cy)-induced intestinal mucosal immunosuppression and microbial dysbiosis in mice. Results showed that CSP stimulated cytokines secretion (IL-12, IFN-γ, IL-4, IL-13, IL-6, IL-17, IL-10, TGF-β3, TNF-α, IL-2, IL-21) and transcription factors production (T-bet, GATA-3, RORγt, Foxp3). TLRs (TLR-2, TLR-4, TLR-6) and NF-κB pathway key proteins (p-IκB-α, NF-κB p65) were also upregulated after CSP administration. Moreover, CSP recovered SCFAs levels which decreased by Cy treatment. Furthermore, 16S rRNA sequencing of fecal samples was performed. α-diversity and β-diversity analysis revealed CSP improved microbial community diversity and modulated the overall structure of gut microbiota. Taxonomic composition analysis found that CSP increased the abundance of probiotics (Lactobacillus, Bifidobacterium, Bacteroides) and decreased pathogenic bacteria (Clostridium, Flexispira). These findings suggested the potential of CSP as a prebiotics to reduce side effects of Cy on intestinal mucosal immunity and gut microbiota.


Myopic excimer laser keratectomy: a preliminary report.
Six patients underwent excimer laser refractive keratectomy for the correction of myopia. All eyes, with the exception of patient 6, who underwent a previous failed epikeratophakia procedure and subsequent removal of the lenticule, had normal baseline ophthalmologic evaluations and best corrected visual acuities of 20/25 or better. Spherical equivalents ranged between -5.50 and -12.00 diopters. Under topical and peribulbar anesthesia, the central corneal epithelium was removed. The delivery system of the laser was programmed to ablate corrections onto the central 5.0 mm of the cornea that would result in approximate emetropia. Moderate fluctuation of refractive and topographic parameters was noted during the period of epithelial healing and remodeling. At the 12th postoperative week, five of the corneas were clear on biomicroscopic evaluation with best corrected acuities of 20/20. The final patient, who was noncompliant in the use of topical corticosteroid therapy, developed a central, 2-mm opacity and resulting best corrected acuity of 20/40. Overall, the group demonstrated that myopic excimer laser photorefractive keratectomy is consistent with good wound healing, insignificant corneal scarring, a stable refractive correction, and excellent visual acuity.


Effects of preincubation of primary monolayer cultures of rat hepatocytes with low- and high-density lipoproteins on the subsequent binding and metabolism of human low-density lipoprotein.
1. There are two distinct binding sites (Site 1 and Site 2) for human low-density lipoprotein (LDL) on rat hepatocytes in monolayer culture [Salter, Saxton & Brindley (1986) Biochem. J. 240, 549-557]. 2. Binding of 125I-LDL to Site 1, but not to Site 2, is up-regulated between 20 and 44 h in culture by preincubation of the cells with human high-density lipoprotein 3 (HDL3). 3. A similar preincubation with HDL2 had no significant effect on binding to either site. 4. Preincubation with human LDL led to a partial down-regulation of subsequent binding of 125I-LDL to Site 1. Since binding after incubation with LDL was measured at 37 degrees C, binding to Site 2 could not be distinguished from LDL that had been internalized by the cells. 5. Hepatocytes were shown to degrade 125I-LDL, resulting in the accumulation of [125I]iodotyrosine in the medium. Evidence was found that iodotyrosine may be further degraded by deiodinase produced by the cells. 6. Regulation of binding to Site 1 by preincubation with LDL or HDL3 was found to lead to a parallel regulation of LDL degradation. 7. It is concluded that rat hepatocytes not only bind but also metabolize human LDL and that these processes are under metabolic regulation.


Computational model of the effect of light scattering from cataracts in the human eye.
A model of the human eye has been developed, including scattering from cataracts inside the nucleus of the lens. The cataracts are modeled as spherical particles with refractive index different from that of the surrounding lens medium. Scattering from the retina is also included in the simulations. Variations of scattering particle diameter, number of particles, and wavelength of the illuminating light are investigated. It is shown that particle size is the most important parameter affecting the scattered light, and that the scattering from the retina can mask the effect of the scattering particles, for some range of the parameters.


Improvements in quadriceps sensorimotor function and disability of patients with knee osteoarthritis following a clinically practicable exercise regime.
Quadriceps sensorimotor dysfunction may be important in the pathogenesis of knee osteoarthritis (OA) and a determinant of disability. Exercise regimes can increase quadriceps strength, but whether this improves proprioception and reduces disability is uncertain. Moreover, research regimes involve protracted treatment which is clinically impracticable. We compared quadriceps sensorimotor function and disability in 60 patients with knee OA, before and after an exercise regime, with a control group (n = 37) who did not exercise. Exercise improved quadriceps strength (mean change, 95% CI; 73 N, 26-19 N), voluntary activation (14%, 5-20%), knee joint position sense (0.6 degrees, 0.1-1.8 degrees), and reduced the Lequesne Index (3.5, 0.5-4) and aggregate time of four activities of daily living (8.4 s, 0.2-16.7 s). At 6 month follow-up, these improvements were maintained. The parameters of the control group were unchanged. These results substantiate the association between quadriceps sensorimotor dysfunction and disability, emphasizing the importance of quadriceps exercise in the management of knee OA. The regimen is relatively brief and clinically practicable, but could be adapted to make it more cost effective.


Defect interactions with stepped CeO₂/SrTiO₃ interfaces: implications for radiation damage evolution and fast ion conduction.
Due to reduced dimensions and increased interfacial content, nanocomposite oxides offer improved functionalities in a wide variety of advanced technological applications, including their potential use as radiation tolerant materials. To better understand the role of interface structures in influencing the radiation damage tolerance of oxides, we have conducted atomistic calculations to elucidate the behavior of radiation-induced point defects (vacancies and interstitials) at interface steps in a model CeO2/SrTiO3 system. We find that atomic-scale steps at the interface have substantial influence on the defect behavior, which ultimately dictate the material performance in hostile irradiation environments. Distinctive steps react dissimilarly to cation and anion defects, effectively becoming biased sinks for different types of defects. Steps also attract cation interstitials, leaving behind an excess of immobile vacancies. Further, defects introduce significant structural and chemical distortions primarily at the steps. These two factors are plausible origins for the enhanced amorphization at steps seen in our recent experiments. The present work indicates that comprehensive examination of the interaction of radiation-induced point defects with the atomic-scale topology and defect structure of heterointerfaces is essential to evaluate the radiation tolerance of nanocomposites. Finally, our results have implications for other applications, such as fast ion conduction.


Survival benefit of taxane plus platinum in recurrent ovarian cancer with non-clear cell, non-mucinous histology.
This study was conducted to examine the effects of front-line chemotherapy on overall survival (OS) and postrecurrence survival (PRS) of patients with recurrent ovarian cancer, when stratifying the histologic type. Five hundred and seventy-four patients with recurrent ovarian cancer with sufficient clinical information, including front-line chemotherapy, were analyzed. The pathologic slides were evaluated by central pathologic review. The patients were divided into two groups: group A (n=261), who underwent taxane plus platinum, and group B (n=313), who underwent conventional platinum-based chemotherapy without taxanes. The median age was 54 years (range, 14 to 89 years). Group A had significantly better median OS (45.0 months vs. 30.3 months, p<0.001) and PRS (23.0 months vs. 13.0 months, p<0.001) compared to group B. The OS and PRS were similar between the groups in patients with clear cell or mucinous histology. In contrast, among patients with non-clear cell, non-mucinous histologies, the OS and PRS of group A were significantly better than those of group B (OS, p<0.001; PRS, p<0.001). Multivariable analyses revealed that, among patients with non-clear cell, non-mucinous histologies, chemotherapy including taxane and platinum was an independent predictor of favorable survival outcomes. Conversely, in patients with clear cell or mucinous histology, taxane-including platinum-based combination chemotherapy did not improve the OS and PRS compared to a conventional platinum-based regimen which did not include taxanes. Since the emergence of taxane plus platinum, the prognosis of patients with recurrent ovarian cancer has improved. However, we here demonstrate that this improvement is limited to patients with non-clear cell, non-mucinous histologies.


[Abnormal glucose tolerance and long-term prognosis in patients with acute myocardial infarction].
to assess clinical outcomes and cardiovascular events during long-term follow-up after acute myocardial infarction (AMI) in patients (pts) with newly detected abnormal glucose tolerance (AGT). Consecutive AMI pts (n=391, 24.3% with diabetes mellitus [DM]) were enrolled in the study. Pts with no DM underwent an oral glucose tolerance test (OGTT) at discharge (around 12-th day). All pts were divided into 3 groups: group I - pts with normal glucose tolerance (NGT), group II - pts with AGT, including impaired glucose tolerance (IGT) and newly diagnosed DM (NDM), group III - pts with previously known DM. General and cardiovascular mortality, adverse cardiovascular events during long-term follow-up (26.8+/-6 months) were studied. According to the OGTT 67.9% pts had NGT and 32.1% had AGT (28.7% IGT and 3.4% NDM). Pts with disturbances of glucose metabolism were older, had abdominal obesity, more frequently had Killip class >2 on admission, as well as reduced ejection fraction, left ventricular aneurism and progression of chronic heart failure at discharge. Cardiovascular and general mortality during follow-up were significantly higher in pts with AGT and DM compared to NGT (27.4 vs. 22.1 vs 11.1%, p=0.002, and 23.2 vs. 20.2 vs 10.1%, p<0.05, respectively). The incidence of recurrent nonfatal MI and stroke were similar in the three groups, however the proportion of subjects with heart failure NYHA class >2, revascularization procedures, hospitalization due to cardiovascular events was higher in pts with abnormalities of carbohydrate metabolism. Abnormal glucose tolerance (IGT and NDM) has high prevalence in AMI patients without known DM, is a major risk factor for future cardiovascular events and is associated with unfavorable long term prognosis after MI.


The Clinical Significance of RAS, PIK3CA, and PTEN Mutations in Non-Small Cell Lung Cancer Using Cell-Free DNA.
Mutations in the EGFR gene downstream signaling pathways may cause receptor-independent pathway activation, making tumors unresponsive to EGFR inhibitors. However, the clinical significance of RAS, PIK3CA or PTEN mutations in NSCLC is unclear. In this study, patients who were initially diagnosed with NSCLC or experienced recurrence after surgical resection were enrolled, and blood samples was collected. Ultra-deep sequencing analysis of cfDNA using Ion AmpliSeq Cancer Hotspot Panel v2 with Proton platforms was conducted. RAS/PIK3CA/PTEN mutations were frequently detected in cfDNA in stage IV NSCLC (58.1%), and a high proportion of the patients (47.8%) with mutations had bone metastases at diagnosis. The frequency of RAS/PIK3CA/PTEN mutations in patients with activating EGFR mutation was 61.7%. The median PFS for EGFR-TKIs was 15.1 months in patients without RAS/PIK3CA/PTEN mutations, and 19.9 months in patients with mutations (p = 0.549). For patients with activating EGFR mutations, the overall survival was longer in patients without RAS/PIK3CA/PTEN mutations (53.8 months vs. 27.4 months). For the multivariate analysis, RAS/PIK3CA/PTEN mutations were independent predictors of poor prognosis in patients with activating EGFR mutations. In conclusion, RAS, PIK3CA and PTEN mutations do not hamper EGFR-TKI treatment outcome; however, they predict a poor OS when activating EGFR mutations coexist.


Soil-mediated eco-evolutionary feedbacks in the invasive plant Alliaria petiolata.
Ecological and evolutionary processes historically have been assumed to operate on significantly different time-scales. We know now from theory and work in experimental and model systems that these processes can feed back on each other on mutually relevant time-scales.Here, we present evidence of a soil-mediated eco-evolutionary feedback on the population dynamics of an invasive biennial plant, Alliaria petiolata.As populations age, natural selection drives down production of A. petiolata's important antimycorrhizal allelochemical, sinigrin. This occurs due to density-dependent selection on sinigrin, which is favoured under interspecific, but disfavoured under intraspecific, competition.We show that population stochastic growth rates (λS) and plant densities are positively related to sinigrin concentration measured in seedling roots. This interaction is mediated by sinigrin's positive effect on seedling and summer survival, which are important drivers of λS.Together, these illustrate how the evolution of a trait shaped by natural selection can influence the ecology of a species over a period of just years to decades, altering its trajectory of population growth and interactions with the species in the soil and plant communities it invades.Our findings confirm the predictions that eco-evolutionary feedbacks occur in natural populations. Furthermore, they improve our conceptual framework for projecting future population growth by linking the variation in plant demography to a critical competitive trait (sinigrin) whose selective advantages decrease as populations age.


Cellular and humoral factors involved in the mechanism of the micro-leukocyte adherence inhibition reaction.
To study the cellular basis for specific antigen-induced leukocyte adherence inhibition, enriched populations of B-cells, T-cells, and monocytes were prepared by a two-stage adherence separation procedure from spleen cells of normal C57BL/6J mice and mice bearing progressively growing MCA-38 tumors. The reactor cell undergoing specific antigen-induced adherence inhibition was identified as a monocyte (esterase positive, did not respond to mitogens, and did not bear Thy 1.2 antigen or surface immunoglobulin). Furthermore, an enriched population of MCA-38-sensitized B-cells could program normal monocytes to undergo specific antigen-induced adherence inhibition. In contrast, enriched populations of MCA-38-sensitized T-cells could not program normal nylon wool-adherent cells to undergo antigen-specific adherence inhibition. Programming of normal monocytes by MCA-38-sensitized B-cells occurs through a soluble mediator and not by direct cell contact. The soluble mediator appears to be immunoglobulin in nature and induced both adherence inhibition and the inhibition of adherence. Thus, in this murine tumor model, leukocyte adherence inhibition appears to be due to programming of monocytes by a secretory product of specifically sensitized B-cells.


Osteoblastic molecular scaffold Gab1 is required for maintaining bone homeostasis.
The Grb2-associated binder 1 (Gab1), which serves as a scaffolding adaptor protein, plays a crucial role in transmitting key signals that control cell growth, differentiation and function from multiple receptors. However, its biological role in osteoblast activity and postnatal bone metabolism remains unclear. To elucidate the in vivo function of Gab1 in postnatal bone remodeling, we generated osteoblast-specific Gab1 knockout mice. Disruption of Gab1 expression in osteoblasts led to decreased trabecular bone mass with a reduced bone formation rate and a decreased bone resorption. Bones from Gab1 mutants also exhibited inferior mechanical properties. Moreover, primary osteoblasts from Gab1 mutant mice demonstrated markedly suppressed osteoblast mineralization, increased susceptibility to apoptosis and decreased expression of receptor activator of NF-kappaB ligand (RANKL). Activation of serine-threonine Akt kinase and extracellular signal-regulated kinase in response to insulin and insulin-like growth factor 1 was attenuated in Gab1 mutant osteoblasts. Our results show that Gab1-mediated signals in osteoblasts are crucial for normal postnatal bone homeostasis.


Measuring the financial productivity of physician assistants.
The first formal physician assistant (PA) program began at Duke University 25 years ago, write David M.S., and Kenneth Harbert, M.H.A., PA-C. Since then, PAs have become widely utilized in the medical field, yet little has been done to measure their financial contribution. The authors provide a methodology and framework for groups to measure the financial productivity of their PAs.


Atypical Neuroleptic Malignant Syndrome: Diagnosis and Proposal for an Expanded Treatment Algorithm: A Case Report.
Neuroleptic malignant syndrome (NMS) in the absence of an elevated creatine kinase is atypical and more difficult to diagnose. We present a patient with NMS significant risk factors who developed atypical NMS 6 days after a liver transplant. Symptoms of hyperthermia, altered mental status, dyskinesia, and autonomic instability (hypertension and tachycardia) coincided with promethazine administration, with rapid progression to fulminant NMS with lead pipe rigidity after a single injection of intramuscular ziprasidone. Rapid diagnosis and management resulted in full patient recovery. Differential diagnoses for NMS are discussed and a treatment algorithm is proposed.


Animal model of Mycobacterium abscessus lung infection.
Chronic lung disease as a result of Mycobacterium abscessus is an emerging infection in the United States. We characterized the lung immune responses in mice and guinea pigs infected with M. abscessus. C57BL/6 and leptin-deficient ob/ob mice challenged with a low-dose aerosol (LDA) of M. abscessus did not develop an infection. However, when challenged with a high-dose aerosol (HDA), C57BL/6 and ob/ob mice developed an established infection and a pulmonary immune response consisting of an early influx of IFN-gamma+ CD4+ T cells; this immune response preceded the successful clearance of M. abscessus in both strains of mice, although mycobacterial elimination was delayed in the ob/ob mice. Infected guinea pigs showed an increased influx of lymphocytes into the lungs with bacterial clearance by Day 60. In contrast to the C57BL/6 and ob/ob mice and guinea pigs, IFN-gamma knockout (GKO) mice challenged with a LDA or HDA of M. abscessus showed a progressive lung infection despite a robust influx of T cells, macrophages, and dendritic cells, culminating in extensive lung consolidation. Furthermore, with HDA challenge of the GKO mice, emergence of IL-4- and IL-10-producing CD4+ and CD8+ T cells was seen in the lungs. In conclusion, IFN-gamma is critically important in the host defense against M. abscessus. As the number of effective drugs against M. abscessus is limited, the GKO mice provide a model for in vivo testing of novel drugs.


Antibody targeting of the insulin-like growth factor I receptor enhances the anti-tumor response of multiple myeloma to chemotherapy through inhibition of tumor proliferation and angiogenesis.
Although many multiple myeloma (MM) patients initially respond to cytotoxic therapy, most eventually relapse. Novel therapeutic strategies employing a combination of chemotherapy with targeted biologics may significantly enhance the response of tumor cells to treatment. We tested a fully human anti-IGF-IR antibody (A12) against MM, and showed specific inhibition of IGF-I or serum-induced IGF-IR signaling in MM cells in vitro. The A12 as a single agent was demonstrated to exert modest to significant inhibition of tumor growth in vivo in various subcutaneous xenograft MM models. The A12 was also evaluated in a disseminated xenograft MM.1S NOD/SCID model as monotherapy or in combination with other drugs (bortezomib, melphalan) currently in clinical use. The tumor burden, as determined by luciferase bioimaging, was sharply decreased, and overall survival significantly prolonged when the therapies were combined. Immunohistochemical analysis demonstrated that the A12 treated tumors had significantly decreased vascularization compared to control tumors. Furthermore, most MM lines constitutively secreted significant quantities of VEGF, and this was enhanced following IGF-I treatment. Inhibition of IGF-IR by the A12 in vitro suppressed both constitutive and IGF-I-induced secretion of VEGF, indicating that a putative anti-angiogenic mechanism associated with the A12 treatment may contribute to its anti-tumor effect.