Sensitivity of Haemophilus influenzae to antibiotics.
The use of many different antibiotics to treat chest infection has led us to test the sensitivity of 68 strains of Haemophilus influenzae to 15 different compounds. These included established compounds such as ampicillin and tetracycline and newer agents such as cephalosporins and clindamycin. The minimum inhibitory concentrations of the compounds for H. influenzae were then compared with blood levels attained after the usual dose regimens. There has been a significant increase in tetracycline resistance in the last few years, but all strains were sensitive to ampicillin, chloramphenicol, sulphamethoxazole, and trimethoprim, Several antibiotics were found to be microbiologically unsuitable for treating H. influenzae infections.


Universal PCR for bacteria, mycobacteria, and fungi: a 10-year retrospective review of clinical indications and patient outcomes.
Our work provides a retrospective analysis of universal PCR orders for bacteria, mycobacteria, and fungi across our institution across a 10-year period. We assessed the positivity rates for this diagnostic tool by test type and specimen type and, critically, studied whether and how the results influenced the outcomes from treatment change, to readmission, to death.


Alternating-day cyclosporine and prednisone for treatment of high-risk chronic graft-v-host disease.
Therapy of chronic graft-v-host disease (GVHD) has been unsatisfactory in patients with platelet counts less than 100,000/microL. Survival at 5 years after marrow transplant is only 26% in such patients treated with trimethoprim-sulfamethoxazole (TMP-SMX) and every other day with prednisone. Since October 1982, 61 patients with high-risk extensive chronic GVHD were treated with a new alternating-day regimen of prednisone (1 mg/kg every other day) and oral cyclosporine (6 mg/kg every 12 hours every other day) with one double-strength TMP-SMX tablet twice daily. Forty patients (group I) received primary treatment of thrombocytopenic chronic GVHD (median platelet count 35 [range 7 to 87] x 10(3)/microL). Twenty-one patients (group II) received salvage treatment after failing initial prednisone +/- azathioprine. Twenty-one patients in group I and 15 in group II survive with a minimum of 2 years and a median of 3.7 years follow-up. At 4 years after transplant, actuarial survival is 51% (group I) and 67% (group II). Causes of death included interstitial pneumonia (six), relapse (five), GVHD without infection (five), infection (four), organ failure (three), and hemorrhage (two). Mortality increased with the progressive type onset of chronic GVHD and treatment failure. Toxicity included hypertension (13), nephrotoxicity (nine), nausea (seven), aseptic necrosis (five), neurologic abnormalities (four), and diabetes (three). Median cyclosporine levels at four and 36 hours were 296 and 64 ng/mL, respectively. Four patients required permanent discontinuation of cyclosporine, but none required renal dialysis. Karnofsky performance scores for 25 survivors are 90% to 100%, scores for six survivors are 70% to 89%, and scores for five survivors are less than 70%. Alternating-day cyclosporine and prednisone has acceptable toxicity and appears to improve survival in patients with high-risk chronic GVHD.


The dark side of daylight: photoaging and the tumor microenvironment in melanoma progression.
Continued thinning of the atmospheric ozone, which protects the earth from damaging ultraviolet radiation (UVR), will result in elevated levels of UVR reaching the earth's surface, leading to a drastic increase in the incidence of skin cancer. In addition to promoting carcinogenesis in skin cells, UVR is a potent extrinsic driver of age-related changes in the skin known as "photoaging." We are in the preliminary stages of understanding of the role of intrinsic aging in melanoma, and the tumor-permissive effects of photoaging on the skin microenvironment remain largely unexplored. In this Review, we provide an overview of the impact of UVR on the skin microenvironment, addressing changes that converge or diverge with those observed in intrinsic aging. Intrinsic and extrinsic aging promote phenotypic changes to skin cell populations that alter fundamental processes such as melanogenesis, extracellular matrix deposition, inflammation, and immune response. Given the relevance of these processes in cancer, we discuss how photoaging might render the skin microenvironment permissive to melanoma progression.


Genomic organization of rat rDNA.
A detailed restriction map was determined for a 10.9 KB region that contains the initiation site for 45S pre-rRNA and the first 1.7 KB of the 18S rRNA coding region. When the restriction pattern of the cloned rDNA was compared with that of total rat DNA, the rDNA regions of both Sprague-Dawley and BD-9 rats were identical to each other and to that of the cloned rDNA. However, both strains exhibit a major polymorphism consisting of an insertion of 0.9 KB of DNA in the nontranscribed spacer between 0.29 KB and 1.8 KB upstream from the 45S RNA initiation site. This region consists of tandem repeats approximately 130 base pairs in length. These repeats contain large poly T tracts and are similar in sequence to analogous elements 5' to the origin of mouse rRNA transcription. Regions containing highly repetitious DNA sequences were located at sites 2.8 KB and 4.3 KB upstream from the initiation site. The repetitive sequence at 2.8 KB from the initiation site anneal to a known Alu-equivalent type 2 sequence derived from the second intron of the rat growth hormone gene.


Need for objective task-based evaluation of AI-based segmentation methods for quantitative PET.
Artificial intelligence (AI)-based methods are showing substantial promise in segmenting oncologic positron emission tomography (PET) images. For clinical translation of these methods, assessing their performance on clinically relevant tasks is important. However, these methods are typically evaluated using metrics that may not correlate with the task performance. One such widely used metric is the Dice score, a figure of merit that measures the spatial overlap between the estimated segmentation and a reference standard (e.g., manual segmentation). In this work, we investigated whether evaluating AI-based segmentation methods using Dice scores yields a similar interpretation as evaluation on the clinical tasks of quantifying metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of primary tumor from PET images of patients with non-small cell lung cancer. The investigation was conducted via a retrospective analysis with the ECOG-ACRIN 6668/RTOG 0235 multi-center clinical trial data. Specifically, we evaluated different structures of a commonly used AI-based segmentation method using both Dice scores and the accuracy in quantifying MTV/TLG. Our results show that evaluation using Dice scores can lead to findings that are inconsistent with evaluation using the task-based figure of merit. Thus, our study motivates the need for objective task-based evaluation of AI-based segmentation methods for quantitative PET.


Condylomatous lesions of the lower female genital tract.
Current views on the aetiology of condylomatous lesions of the lower female genital tract are presented. In addition to the morphology of overt condylomata, the colposcopic, histological and cytological appearances are described, and association with epithelial neoplasia is considered in detail. Problems of nomenclature are discussed.


Invasive endocervical adenocarcinoma: a new pattern-based classification system with important clinical significance.
A new 3-tier pattern-based system to classify endocervical adenocarcinoma was recently presented. In short, pattern A tumors were characterized by well-demarcated glands frequently forming clusters or groups with relative lobular architecture. Pattern B tumors demonstrated localized destructive invasion defined as desmoplastic stroma surrounding glands with irregular and/or ill-defined borders or incomplete glands and associated tumor cells (individual or small clusters) within the stroma. Tumors with pattern C showed diffusely infiltrative glands with associated extensive desmoplastic response. In total, 352 cases (all FIGO stages) from 12 institutions were identified. Mean patient age was 45 years (range, 20 to 83 y). Forty-nine (13.9%) cases demonstrated lymph nodes (LNs) with metastatic endocervical carcinoma. Using this new system, 73 patients (20.7%) were identified with pattern A tumors (all stage I); none had LN metastases and/or recurrences. Ninety patients (25.6%) were identified with pattern B tumors (all stage I); only 4 (4.4%) had LN metastases; 1 had vaginal recurrence. The 189 (53.7%) remaining patients had pattern C tumors; 45 (23.8%) of them had LN metastases. This new classification system demonstrated 20.7% of patients (pattern A) with negative LNs, and patients with pattern A tumors can be spared of lymphadenectomy. Patients with pattern B tumors rarely presented with metastatic LNs, and sentinel LN examination could potentially identify these patients. Aggressive treatment is justified in patients with pattern C tumors.


γ-Interferon-inducible lysosomal thiol reductase (GILT) maintains phagosomal proteolysis in alternatively activated macrophages.
Although it is known that lysosomal cysteine cathepsins require a reducing environment for optimal activity, it is not firmly established how these enzymes are maintained in their reduced-active state in the acidic and occasionally oxidative environment within phagosomes and lysosomes. γ-Interferon-inducible lysosomal thiol reductase (GILT) has been the only enzyme described in the endosomes, lysosomes, and phagosomes with the potential to catalyze the reduction of cysteine cathepsins. Our goal in the current study was to assess the effect of GILT on major phagosomal functions with an emphasis on proteolytic efficiency in murine bone marrow-derived macrophages. Assessment of phagosomal disulfide reduction upon internalization of IgG-opsonized experimental particles confirmed a major role for GILT in phagosomal disulfide reduction in both resting and interferon-γ-activated macrophages. Furthermore we observed a decrease in early phagosomal proteolytic efficiency in GILT-deficient macrophages, specifically in the absence of an NADPH oxidase-mediated respiratory burst. This deficiency was more prominent in IL-4-activated macrophages that inherently possess lower levels of NADPH oxidase activity. Finally, we provide evidence that GILT is required for optimal activity of the lysosomal cysteine protease, cathepsin S. In summary, our results suggest a role for GILT in maintaining cysteine cathepsin proteolytic efficiency in phagosomes, particularly in the absence of high NADPH oxidase activity, which is characteristic of alternatively activated macrophages.


Degradation of heparin in mouse mastocytoma tissue.
1. Heparin was prepared from mouse mastocytoma tissue by mild procedures, including extraction of mast-cell granules with 2m-potassium chloride, precipitation of the extracted polysaccharide with cetylpyridinium chloride from 0.8m-potassium chloride and finally digestion of the isolated material with testicular hyaluronidase. The resulting product (fraction GE(H)) represented approx. 40% of the total heparin content of the tissue. 2. Fraction GE(H) was fractionated by gel chromatography on Sepharose 4B into three subfractions, with average molecular weights ( M(w)) of approx. 60000-70000 (highly polydisperse material), 26000 and 9000 respectively. Treatment of each of the subfractions with alkali or with papain did not affect their behaviour on gel chromatography. Amino acid and neutral sugar analyses indicated that the two low-molecular-weight fractions consisted largely of single polysaccharide chains lacking the carbohydrate-protein linkage region. It was suggested that these heparin molecules had been degraded by an endopolysaccharidase. 3. Pulse labelling in vivo of mastocytoma heparin with [(35)S]sulphate showed initial labelling of large molecules followed by a progressive shift of radioactivity toward fractions of lower molecular weight. Further, heparin-depolymerizing activity was demonstrated by incubating (35)S-labelled heparin in vitro with a mastocytoma 10000g-supernatant fraction. Appreciable degradation of the polysaccharide occurred, as demonstrated by gel chromatography. In contrast, no depolymerization was observed on subjecting (14)C-labelled chondroitin sulphate to the same procedure.


The surface-charge asymmetry and dimerisation of cytochrome c550 from Paracoccus denitrificans--implications for the interaction with cytochrome c peroxidase.
The implications of the dimeric state of cytochrome c550 for its binding to Paracoccus cytochrome c peroxidase and its delivery of the two electrons required to restore the active enzyme during catalysis have been investigated. The amino acid sequence of cytochrome c550 of Paracoccus denitrificans strain LMD 52.44 was determined and showed 21 differences from that of strain LMD 22.21. Based on the X-ray structure of the latter, a structure for the cytochrome c550 monomer from strain 52.44 is proposed and a dipole moment of 945 debye was calculated with an orientation close to the exposed haem edge. The behaviour of the cytochrome on molecular-exclusion chromatography is indicative of an ionic strength-dependent monomer (15 kDa)/dimer (30 kDa) equilibrium that can also be detected by 1H-NMR spectroscopy. The apparent mass of 50 kDa observed at very low ionic strength was consistent with the presence of a strongly asymmetric dimer. This was confirmed by cross-linking studies, which showed that a cross-linked species of mass 30 kDa on SDS behaved with an apparent mass of 50 kDa on molecular-exclusion chromatography. A programme which carried out and evaluated molecular docking of two monomers to give a dimer generated a most probable dimer in which the monomer dipoles lay almost antiparallel to each other. The resultant dipole moment of the dimer is therefore small. Although this finding calls into question the possibility of preorientation of a strongly asymmetrically charged cytochrome as it collides with a redox partner, the stoichiometry of complex formation with cytochrome c peroxidase as studied by 1H-NMR spectroscopy shows that it is the monomer that binds.


Recent developments in azole compounds as antibacterial and antifungal agents.
Azole compounds are an important class of nitrogen heterocycles with electron-rich property. This special structure endows azole-based derivatives easily bind with the enzymes and receptors in organisms through noncovalent interactions such as hydrogen bonds, coordination bonds, ion-dipole, cation-π,π-π stacking and hydrophobic effect as well as van der Waals force etc., thereby possessing various applications in medicinal chemistry, especially their protrudent effects such as imidazoles and triazoles against fungal strains. The design, synthesis and antimicrobial activity of azole derivatives have been extensively investigated and have become one of the highly active highlights in recent years, and the progress is quite rapid. In particular, a large number of azole-based antibacterial and antifungal agents have been penetratingly studied as candidates and even some of them have been used in clinic, which have shown the great potential and development value of azole compounds. Based on our researches on azole compounds and referring to other literature, this work scientifically reviewed the researches and developments of azole-based compounds as antibacterial and antifungal agents, including oxazole, imidazole, benzimidazole, triazole, benzotriazole, pyrazole, thiazole, carbazole as well as tetrazole in recent three years. It is hopeful that azole compounds may continue to serve as an important direction for the exploitation of azole-based antibacterial and antifungal drugs with better curative effect, lower toxicity, less side effects, especially fewer resistances and so on.


Antibody and immune memory persistence post infant hepatitis B vaccination.
This study aimed to evaluate the level of hepatitis B immunity among undergraduate students 23 years after commencement of the nationwide hepatitis B childhood immunization program in Malaysia. A total of 402 serum samples obtained from volunteer undergraduate students were screened for the presence of hepatitis B surface antibodies using qualitative ELISA. Results showed that 62.7% of volunteers had protective anti-hepatitis B surface antigens (≥10 IU/L), of whom 67.9% received three doses of the vaccine. The estimated post-vaccination immunity was found to be at least 20 years, indicating persistent immunity against hepatitis B and a significant association (P < 0.05) with duration of vaccination. Anamnestic response 1 month post-hepatitis B booster was 94.0% and highly significant (P < 0.01). Isolated antihepatitis B core antigen (anti-HBc) prevalence was found to be 5.0%, all having had a positive anamnestic response. Immunity after primary vaccination with hepatitis B recombinant vaccine persists for at least 20 years post-vaccination, with significant association with the number of vaccinations. Furthermore, the presence of anamnestic response to booster vaccine indicates long-lasting immunity despite decreasing antibody levels; therefore, the need for hepatitis B vaccine boosters may not be of significant benefit after complete infant vaccination.


Psychiatric disorders in women with fertility problems: results from a large Danish register-based cohort study.
Do women who don't succeed in giving birth after an infertility evaluation have a higher risk of psychiatric disorders compared with women who do? The results indicated that being unsuccessful in giving birth after an infertility evaluation could be an important risk factor for psychiatric disorders. Several studies have investigated the association between fertility treatment and psychological distress, but the results from these studies show substantial variation and lack of homogeneity that may be due to methodological limitations. A retrospective cohort study was designed using data from a cohort of 98 320 Danish women evaluated for fertility problems during 1973-2008 and linked to several Danish population-based registries. All women were followed from the date of first infertility evaluation until date of hospitalization for the psychiatric disorder in question, date of emigration, date of death or 31 December 2008, whichever occurred first. Owing to the precise linkage between the infertility cohort and the Danish population-based registries, using the unique Danish personal identification number, virtually no women were lost to follow-up. Information on reproductive status for all women in the infertility cohort was obtained by linkage to the Danish Medical Birth Registry. A total of 53 547 (54.5%) women gave birth after the initial infertility evaluation, whereas 44 773 (45.5%) women did not gave birth after the evaluation. To determine psychiatric disorders diagnosed in the women after enrolment in the infertility cohort, the cohort was linked to the Danish Psychiatric Central Registry. A total of 4633 women were hospitalized for a psychiatric disorder. The Cox proportional hazard regression model was applied to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the association between parity status after the initial infertility evaluation and risk of hospitalization for various groups of psychiatric disorders, including 'all mental disorders' and six main discharge subgroups labelled: 'alcohol and intoxicant abuse', 'schizophrenia and psychoses', 'affective disorders', 'anxiety, adjustment and obsessive compulsive disorders', 'eating disorder' and 'other mental disorders'. The incidence rate for all mental disorders was 393 cases per 100 000 person-years among women who did not succeed in giving birth after the infertility evaluation but only 353 cases per 100 000 person-years among women who succeeded in giving birth after the infertility evaluation. Women not giving birth after the infertility evaluation had an increased risk of hospitalization for all mental disorders (HR 1.17, 95% CI 1.11; 1.25), alcohol and intoxicant abuse (HR 2.02, 95% CI 1.69; 2.41), schizophrenia and psychoses (HR 1.46, 95% CI 1.17; 1.82) and other mental disorders (HR 1.42, 95% CI 1.27; 1.58) compared with women who gave birth after the infertility evaluation. In contrast, the risk of affective disorders (HR 0.90, 95% CI 0.81; 0.99) was decreased among women not giving birth after the infertility evaluation. Finally, the risk of anxiety, adjustment and obsessive compulsive disorders (HR 1.07, 95% CI 0.97; 1.17) as well as of eating disorders (HR 1.40, 95% CI 0.88; 2.22) was not significantly affected by parity status after the infertility evaluation. As only psychiatric conditions warranting hospitalization could be included in the present study, the true incidence of all psychiatric disorders among women with fertility problems is likely to be somewhat underestimated. Furthermore, since detailed information on fertility treatment was not available for all cohort members the association between different modalities of assisted reproductive techniques and risk of psychiatric disorders was not assessed. Clinicians and other healthcare personnel involved in diagnosis and treatment of women with fertility problems should be aware of the potential risk modification of psychiatric disorders associated with unsuccessful fertility treatment. Hence, our results may point to new aspects of follow-up of women with fertility problems who are unsuccessful in giving birth in order to prevent or identify and treat these possible psychological side effects. The study was supported by the Danish Cancer Society (award number: 96 222 54). All authors report no conflicts of interest.


Evaluation of the digestibility of solid lipid nanoparticles of glyceryl dibehenate produced by two techniques: Ultrasonication and spray-flash evaporation.
To evaluate the digestibility of Solid Lipid Nanoparticles (SLN) of glyceryl dibehenate prepared either with surfactants by ultrasonication or without surfactant by spray-flash evaporation. SLN of glyceryl dibehenate (Compritol® 888 ATO) were produced by two processes: (i) high-shear homogenization with a solution of water-soluble surfactants followed by ultrasonication (ii) and Spray-Flash Evaporation (SFE) of the pure lipid. The digestibility of these nanoparticles was then tested by in vitro lipolysis using a pH-stat apparatus and the assay of glycerides by gel phase chromatography. SLN of glyceryl dibehenate prepared by ultrasonication exhibited a mean particle size of 180nm and showed a limited digestion of the lipid excipient. SLN comprising only glyceryl dibehenate produced by SFE have a mean particle size between 235 and 411nm depending on process parameters. These nanoparticles were not digested by lipases. The presence of surfactant at the lipid/water interface of the SLN seems to be mandatory to allow the adsorption of the lipase and degradation of glyceryl behenate. Glyceryl dibehenate as a solid particle - even as a SLN - is not digested by pancreatin during in vitro lipolysis test.


An Inverse-Designed Nanophotonic Interface for Excitons in Atomically Thin Materials.
Efficient nanophotonic devices are essential for applications in quantum networking, optical information processing, sensing, and nonlinear optics. Extensive research efforts have focused on integrating two-dimensional (2D) materials into photonic structures, but this integration is often limited by size and material quality. Here, we use hexagonal boron nitride (hBN), a benchmark choice for encapsulating atomically thin materials, as a waveguiding layer while simultaneously improving the optical quality of the embedded films. When combined with a photonic inverse design, it becomes a complete nanophotonic platform to interface with optically active 2D materials. Grating couplers and low-loss waveguides provide optical interfacing and routing, tunable cavities provide a large exciton-photon coupling to transition metal dichalcogenide (TMD) monolayers through Purcell enhancement, and metasurfaces enable the efficient detection of TMD dark excitons. This work paves the way for advanced 2D-material nanophotonic structures for classical and quantum nonlinear optics.


Time-domain fluorescence lifetime imaging techniques suitable for solid-state imaging sensor arrays.
We have successfully demonstrated video-rate CMOS single-photon avalanche diode (SPAD)-based cameras for fluorescence lifetime imaging microscopy (FLIM) by applying innovative FLIM algorithms. We also review and compare several time-domain techniques and solid-state FLIM systems, and adapt the proposed algorithms for massive CMOS SPAD-based arrays and hardware implementations. The theoretical error equations are derived and their performances are demonstrated on the data obtained from 0.13 μm CMOS SPAD arrays and the multiple-decay data obtained from scanning PMT systems. In vivo two photon fluorescence lifetime imaging data of FITC-albumin labeled vasculature of a P22 rat carcinosarcoma (BD9 rat window chamber) are used to test how different algorithms perform on bi-decay data. The proposed techniques are capable of producing lifetime images with enough contrast.


Clinical and laboratory evaluation of specific chemiluminescence assays for intact and total proinsulin.
Measurement of proinsulin is an important tool in the assessment of pancreatic beta cell function in patients with type 2 diabetes. The goal of this study was to perform a technical and clinical evaluation of two specific chemiluminescence assays (CLIA) for the determination of intact and total proinsulin in comparison to a radioimmunoassay (RIA) method for the measurement of total proinsulin. A total of 191 serum samples from patients with type 2 diabetes were used to perform a regression analysis. The total proinsulin CLIA showed higher proinsulin levels than the two other proinsulin assays (mean +/- SD: 55.9 +/- 58.1 pmol/l, p < 0.001 in both cases). The intact proinsulin CLIA (22.5 +/- 20.9 pmol/l) gave lower values than the RIA for total proinsulin (31.9 +/- 25.4 pmol/l, p < 0.001 vs. CLIA, r = 0.948). The RIA has a 95% cross-reactivity to des31,32-proinsulin, which is secreted during the process of beta cell deterioration. The intact proinsulin CLIA has virtually no cross-reactivity with des31,32-proinsulin (1.4%) and is therefore more specific for intact proinsulin than the RIA. This test does not measure further degradation products, in contrast to the total proinsulin CLIA. The CLIA is, therefore, more specific for total proinsulin measurement than the RIA. Both CLIAs could be performed much faster (4 hours) than the RIA method (75 hours/ 4 days). In conclusion, the CLIA methods show improved qualitative outcomes, higher specificity and several technical advantages over the RIA method.


New species and records of Apseudomorpha (Crustacea: Tanaidacea) from Taiwan.
The present study reports the first record of Apseudomorpha from Taiwan and includes descriptions of three new species and one new species record. Paradoxapseudes pangcahi sp. nov. differs from the most similar congener, Paradoxapseudes littoralis, by having one segment less in the antennal flagellum and fewer segments in the uropod endopod. Pseudoapseudomorpha tagopilosus sp. nov. is distinguished from its most similar congener, Pseudoapseudomorpha ornata, by having one long lateral seta on pleonite 4, a four-segmented antennular outer flagellum, and a male with smaller and thinner 'small' cheliped than that of the female and with vestigial pleopods on pleonite 3. Indoapseudes multituberculata sp. nov. stands out from its congeners by having pleopods only on the last two pleonites in females, many small tubercles terminally on the pleotelson, and mandibular palp article 1 with noticeable distal teeth. The Synapseudes species recorded in the present study morphologically agrees with Synapseudes hansmuelleri that was originally described from the Tioman Archipelago, Malaysia, South China Sea. Morphological comparisons between each of the three newly described species and its congeners are tabulated.


Genome-wide bisulfite sensitivity profiling of yeast suggests bisulfite inhibits transcription.
Bisulfite, in the form of sodium bisulfite or metabisulfite, is used commercially as a food preservative. Bisulfite is used in the laboratory as a single-stranded DNA mutagen in epigenomic analyses of DNA methylation. Recently it has also been used on whole yeast cells to induce mutations in exposed single-stranded regions in vivo. To understand the effects of bisulfite on live cells we conducted a genome-wide screen for bisulfite sensitive mutants in yeast. Screening the deletion mutant array, and collections of essential gene mutants we define a genetic network of bisulfite sensitive mutants. Validation of screen hits revealed hyper-sensitivity of transcription and RNA processing mutants, rather than DNA repair pathways and follow-up analyses support a role in perturbation of RNA transactions. We propose a model in which bisulfite-modified nucleotides may interfere with transcription or RNA metabolism when used in vivo.


Mental health provider attitudes toward adoption of evidence-based practice: the Evidence-Based Practice Attitude Scale (EBPAS).
Mental health provider attitudes toward organizational change have not been well studied. Dissemination and implementation of evidence-based practices (EBPs) into real-world settings represent organizational change that may be limited or facilitated by provider attitudes toward adoption of new treatments, interventions, and practices. A brief measure of mental health provider attitudes toward adoption of EBPs was developed and attitudes were examined in relation to a set of provider individual difference and organizational characteristics. Participants were 322 public sector clinical service workers from 51 programs providing mental health services to children and adolescents and their families. Four dimensions of attitudes toward adoption of EBPs were identified: (1) intuitive Appeal of EBP, (2) likelihood of adopting EBP given Requirements to do so, (3) Openness to new practices, and (4) perceived Divergence of usual practice with research-based/academically developed interventions. Provider attitudes varied by education level, level of experience, and organizational context. Attitudes toward adoption of EBPs can be reliably measured and vary in relation to individual differences and service context. EBP implementation plans should include consideration of mental health service provider attitudes as a potential aid to improve the process and effectiveness of dissemination efforts.


IL-1 beta convertase (ICE) does not play a requisite role in apoptosis induced in T lymphoblasts by Fas-dependent or Fas-independent CTL effector mechanisms.
Both IL-1beta convertase (ICE) and other members of the ICE-like family of proteases have been reported to play a role in Fas-mediated apoptosis. Con A-stimulated T lymphoblasts generated from splenocytes isolated from ICE-deficient H-2b mice were found to be more susceptible than wild-type lymphoblasts to DNA fragmentation induced by H-2b-specific CTL derived from normal or Fas ligand-deficient gld/gld mice. Trinitrophenyl (TNP)-modified, H-2b target cell-specific CTL were generated from perforin-deficient mice and were found to induce DNA fragmentation only in target cells expressing functional Fas receptors. Similar rates of DNA fragmentation were induced in TNP-modified ICE -/- and ICE +/+ T lymphoblast targets by perforin -/- TNP-modified, H-2b target cell-specific CTL. In addition, anti-Fas Abs induced apoptosis in thymocytes, Con A-stimulated spleen T cells, LPS-stimulated spleen B cells, and thymocytes from ICE -/- mice. However, DNA fragmentation induced by either allospecific FasL-defective CTL, or by perforin-deficient, TNP-modified, H-2b target cell-specific CTL was prevented in ICE -/- target cells loaded by electroporation with Ac-DEVD-CHO, an inhibitor of CPP32 and related ICE family proteases. These findings indicate that ICE does not play a requisite role in Fas-dependent or Fas-independent mechanisms of apoptosis induced in peripheral T lymphoblasts by CTL. However, both major pathways of CTL-induced apoptosis appear to be dependent on the enzymatic activity of other ICE family proteases.


Musashi1 modulates cell proliferation genes in the medulloblastoma cell line Daoy.
Musashi1 (Msi1) is an RNA binding protein with a central role during nervous system development and stem cell maintenance. High levels of Msi1 have been reported in several malignancies including brain tumors thereby associating Msi1 and cancer. We used the human medulloblastoma cell line Daoy as model system in this study to knock down the expression of Msi1 and determine the effects upon soft agar growth and neurophere formation. Quantitative RT-PCR was conducted to evaluate the expression of cell proliferation, differentiation and survival genes in Msi1 depleted Daoy cells. We observed that MSI1 expression was elevated in Daoy cells cultured as neurospheres compared to those grown as monolayer. These data indicated that Msi1 might be involved in regulating proliferation in cancer cells. Here we show that shRNA mediated Msi1 depletion in Daoy cells notably impaired their ability to form colonies in soft agar and to grow as neurospheres in culture. Moreover, differential expression of a group of Notch, Hedgehog and Wnt pathway related genes including MYCN, FOS, NOTCH2, SMO, CDKN1A, CCND2, CCND1, and DKK1, was also found in the Msi1 knockdown, demonstrating that Msi1 modulated the expression of a subset of cell proliferation, differentiation and survival genes in Daoy. Our data suggested that Msi1 may promote cancer cell proliferation and survival as its loss seems to have a detrimental effect in the maintenance of medulloblastoma cancer cells. In this regard, Msi1 might be a positive regulator of tumor progression and a potential target for therapy.


The role of cobalt phosphate in enhancing the photocatalytic activity of α-Fe2O3 toward water oxidation.
Transient absorption spectroscopy was used to probe the dynamics of photogenerated charge carriers in α-Fe(2)O(3)/CoO(x) nanocomposite photoelectrodes for water splitting. The addition of cobalt-based electrocatalysts was observed to increase the lifetime of photogenerated holes in the photoelectrode by more than 3 orders of magnitude without the application of electrical bias. We therefore propose that the enhanced photoelectrochemical activity of the composite electrode for water photooxidation results, at least in part, from reduced recombination losses because of the formation of a Schottky-type heterojunction.


Research Pearls: The Significance of Statistics and Perils of Pooling. Part 3: Pearls and Pitfalls of Meta-analyses and Systematic Reviews.
Within the health care environment, there has been a recent and appropriate trend towards emphasizing the value of care provision. Reduced cost and higher quality improve the value of care. Quality is a challenging, heterogeneous, variably defined concept. At the core of quality is the patient's outcome, quantified by a vast assortment of subjective and objective outcome measures. There has been a recent evolution towards evidence-based medicine in health care, clearly elucidating the role of high-quality evidence across groups of patients and studies. Synthetic studies, such as systematic reviews and meta-analyses, are at the top of the evidence-based medicine hierarchy. Thus, these investigations may be the best potential source of guiding diagnostic, therapeutic, prognostic, and economic medical decision making. Systematic reviews critically appraise and synthesize the best available evidence to provide a conclusion statement (a "take-home point") in response to a specific answerable clinical question. A meta-analysis uses statistical methods to quantitatively combine data from single studies. Meta-analyses should be performed with high methodological quality homogenous studies (Level I or II) or evidence randomized studies, to minimize confounding variable bias. When it is known that the literature is inadequate or a recent systematic review has already been performed with a demonstration of insufficient data, then a new systematic review does not add anything meaningful to the literature. PROSPERO registration and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines assist authors in the design and conduct of systematic reviews and should always be used. Complete transparency of the conduct of the review permits reproducibility and improves fidelity of the conclusions. Pooling of data from overly dissimilar investigations should be avoided. This particularly applies to Level IV evidence, that is, noncomparative investigations. With proper technique, systematic reviews and meta-analyses have the potential to be powerful investigations that efficiently assist clinicians in decision making.


Adaptive gain control of vestibuloocular reflex by the cerebellum.
1. The gain of the vestibuloocular reflex (slow-phase eye velocity/head velocity) was measured in 17 adult cats. 2. The gain of the reflex, in the dark, was 0.90 (+/-0.15 SD) over the frequency range 0.03-1.2 Hz. 3. In the range 0.01-0.15 Hz, the phase behaved as though the overall reflex time constant were 12 s or greater. The cupula time constant is 4 s. Therefore, the central part of the reflex must manipulate the canal signal to improve its low-frequency response by a factor of at least three. 4. When the cats wore left-right reversing prisms chronically and were also rotated for 2 h every day, the reflex underwent large, plastic changes. The gain, tested in the dark, decreased by 93% at 0.05 Hz and 55% at 1.2 Hz. In effect, the low-frequency response was abolished. The process took about 8 days. 5. In the light, with reversed vision, the gain decreased further and, at low frequencies, the eye movements did reverse in direction. 6. When the vestibulocerebellum was removed, the gain, in the dark, rose to about 1.17 and the plastic changes caused by reversing prisms were completely abolished. 7. Reversing prisms create vestibuloocular dysmetria. The change in gain they produce is considered to be an adaptive response designed to reduce image motion on the retina during head movements. The vestibulocerebellum is necessary for this adaptive process. It is proposed that detecting and repairing dysmetria (of natural origin) is an important cerebellar function.


[Hemodynamic chronosensitivity to metopress-retard in patients with stage ii hypertension].
Time-dependent effects of metopress-retard (TEVA, Israel) were studied in 38 patients with stage II hypertension who were randomized to two groups, 19 patients each. Group 1 received 100 mg of metopress-retard at 8 a.m., group 2--at 8 p.m. Before the drug was taken and each 2 hours for 12 running hours after its 100 mg intake hemodynamic parameters were measured non-invasively. It was found that metopress-retard had no negative chronotropic and more strong hypotensive effects when taken in the evening (at 20.00).


Impact of trauma centre capacity and volume on the mortality risk of incoming new admissions.
Trauma centre capacity and surge volume may affect decisions on where to transport a critically injured patient and whether to bypass the closest facility. Our hypothesis was that overcrowding and high patient acuity would contribute to increase the mortality risk for incoming admissions. For a 6-year period, we merged and cross-correlated our institutional trauma registry with a database on Trauma Resuscitation Unit (TRU) patient admissions, movement and discharges, with average capacity of 12 trauma bays. The outcomes of overall hospital and 24 hours mortality for new trauma admissions (NEW) were assessed by multivariate logistic regression. There were 42 003 (mean=7000/year) admissions having complete data sets, with 36 354 (87%) patients who were primary trauma admissions, age ≥18 and survival ≥15 min. In the logistic regression model for the entire cohort, NEW admission hospital mortality was only associated with NEW admission age and prehospital Glasgow Coma Scale (GCS) and Shock Index (SI) (all p<0.05). When TRU occupancy reached ≥16 patients, the factors associated with increased NEW admission hospital mortality were existing patients (TRU >1 hour) with SI ≥0.9, recent admissions (TRU ≤1 hour) with age ≥65, NEW admission age and prehospital GCS and SI (all p<0.05). The mortality of incoming patients is not impacted by routine trauma centre overcapacity. In conditions of severe overcrowding, the number of admitted patients with shock physiology and a recent surge of elderly/debilitated patients may influence the mortality risk of a new trauma admission.


Response of Campylobacter pyloridis to antibiotics, bismuth and an acid-reducing agent in vitro--an ultrastructural study.
Campylobacter pyloridis was cultured for maximal growth in liquid medium, and effects of exposure to various beta-lactam and macrolide antibiotics, metronidazole, tripotassium dicitrato bismuthane (TDB) and cimetidine were monitored by transmission electronmicroscopy after periods of exposure up to 24 h. With amoxycillin and benzylpenicillin (0.12-1 mg/L) and cephalexin (2 mg/L) the normal bacilliform morphology was replaced by bulging and dumb-bell-like profiles showing cell-wall blebbing and vesiculation, and eventually by swollen forms with incomplete cell walls undergoing lysis. These changes developed progressively between 2 h and 24 h and were accelerated at the higher antibiotic concentrations. Erythromycin and clindamycin caused central clearing, ribosomal coagulation and impaired cross-wall formation. There were no gross structural changes in the presence of metronidazole (4 mg/L), TDB (1000 and 2400 mg/L) or cimetidine (1000 and 2000 mg/L); but with TDB focal accumulation of particulate bismuth complex was detected under the cell wall, affecting nearly all organisms by 24 h. In parallel viability tests, metronidazole and TDB both showed bactericidal activity, but cimetidine did not. These findings support the clinical experience that favours combination therapy with bismuth plus an appropriate systemic antibiotic as the regimen of choice for effective clearance of the organisms in C. pyloridis-associated gastritis.


The highs that bind: school context, social status and marijuana use.
Substance use has been closely linked with the structural characteristics of adolescent social networks. Those who drink, smoke, and use drugs typically enjoy an elevated status among their peers. Rates of substance use vary substantially across schools, and indicators of school structure and climate account for at least part of this variation. Emerging research suggests peer-group processes are contingent on school context, but questions remain regarding the school-level mechanisms which condition the influence of network characteristics on substance use. The present study uses multilevel logistic regression models to examine the moderating influence of school connectedness, school drug culture, and global network density on the association between peer network status and marijuana use. The analyses draw on self, peer, and parental data from a sample of 7,548 high-school aged youth nested within 106 schools participating in the National Longitudinal Study of Adolescent to Adult Health (mean age = 15.2; % white = 59 %; male = 45 %). The results indicate that school connectedness significantly reduces the effect of social status on marijuana use. This provides evidence that school-level mechanisms can reduce the instrumentality of marijuana consumption in the status attainment process in adolescence.


In vitro Glycation of Human IgG and Its Effect on Interaction with Anti-IgG.
Non-enzymatic glycosylation of proteins is one of the key mechanisms in the pathogenesis of diabetic complications. Glycation of IgG is of special interest due to its possible influence on the functionality of immunoglobulins and overall immuno-competence. The aim of this study was to clarify more details of in vitro glycation of IgG and to study the effect of this modification on its interation with anti-IgG. Purified human IgG was glycated in the presence of 50 and 100 mM glucose. Glycation was measured using spectrophotometric thiobarbituric acid method. To study the effect of glycation on interaction with anti IgG the Single Radial Immunodiffusion (SRID) was used and the diameters of precipitation rings of glycated IgG and non-glycated IgG were measured and compared. The results showed that IgG was glycated in presence of 50 and 100 mM glucose at 27 degrees and 37 degrees C and the extent of glycation was dependent on glucose concentration and time of incubation. In higher concentration of glucose and longer period of incubation glycation was higher at 27 degrees C (p<0.01). Similar results were obtained at 37 degrees C.The results of SRID indicated that glycated IgG showed reduced interaction with anti-IgG. The diameters of precipitated rings for glycated IgG were significantly lower than those of non-glycated IgG (p < 0.01). It can be concluded that modification that occurred in IgG structure due to glycation can be the reason of the reduction of its interaction with anti-IgG.


[Inversion polymorphism in the malaria mosquito Anopheles messeae. VI. Local selection and 3-dimensional differentiation of the inversion gene complexes for fertility].
A field experiment was carried on with the view of compulsory change of the frequency of chromosomal inversion (2R1) in the population of Anopheles messeae from the centre of the area. Quick return of the population to the original structure was observed. This confirmed that the local differentiation of chromosomal polymorphism is supported by natural selection. The fertility of the females was shown to be connected with the inversion polymorphism. The females with inversion complexes of genes of the "northern" type (with homozygotes 2R1) had higher fertility and lower dispersion of the fertility, in comparison with those having gene complexes which prevailed in the south part of the area.


Costorage and coexistence of neuropeptides in the mammalian CNS.
The term neuropeptides commonly refers to a relatively large number of biologically active molecules that have been localized to discrete cell populations of central and peripheral neurons. I review here the most important histological and functional findings on neuropeptide distribution in the central nervous system (CNS), in relation to their role in the exchange of information between the nerve cells. Under this perspective, peptide costorage (presence of two or more peptides within the same subcellular compartment) and coexistence (concurrent presence of peptides and other messenger molecules within single nerve cells) are discussed in detail. In particular, the subcellular site(s) of storage and sorting mechanisms within neurons are thoroughly examined in the view of the mode of release and action of neuropeptides as neuronal messengers. Moreover, the relationship of neuropeptides and other molecules implicated in neural transmission is discussed in functional terms, also referring to the interactions with novel unconventional transmitters and trophic factors. Finally, a brief account is given on the presence of neuropeptides in glial cells.


A novel symptom cluster analysis among ambulatory HIV/AIDS patients in Uganda.
Symptom clusters are gaining importance given HIV/AIDS patients experience multiple, concurrent symptoms. This study aimed to: determine clusters of patients with similar symptom combinations; describe symptom combinations distinguishing the clusters; and evaluate the clusters regarding patient socio-demographic, disease and treatment characteristics, quality of life (QOL) and functional performance. This was a cross-sectional study of 302 adult HIV/AIDS outpatients consecutively recruited at two teaching and referral hospitals in Uganda. Socio-demographic and seven-day period symptom prevalence and distress data were self-reported using the Memorial Symptom Assessment Schedule. QOL was assessed using the Medical Outcome Scale and functional performance using the Karnofsky Performance Scale. Symptom clusters were established using hierarchical cluster analysis with squared Euclidean distances using Ward's clustering methods based on symptom occurrence. Analysis of variance compared clusters on mean QOL and functional performance scores. Patient subgroups were categorised based on symptom occurrence rates. Five symptom occurrence clusters were identified: Cluster 1 (n=107), high-low for sensory discomfort and eating difficulties symptoms; Cluster 2 (n=47), high-low for psycho-gastrointestinal symptoms; Cluster 3 (n=71), high for pain and sensory disturbance symptoms; Cluster 4 (n=35), all high for general HIV/AIDS symptoms; and Cluster 5 (n=48), all low for mood-cognitive symptoms. The all high occurrence cluster was associated with worst functional status, poorest QOL scores and highest symptom-associated distress. Use of antiretroviral therapy was associated with all high symptom occurrence rate (Fisher's exact=4, P<0.001). CD4 count group below 200 was associated with the all high occurrence rate symptom cluster (Fisher's exact=41, P<0.001). Symptom clusters have a differential, affect HIV/AIDS patients' self-reported outcomes, with the subgroup experiencing high-symptom occurrence rates having a higher risk of poorer outcomes. Identification of symptom clusters could provide insights into commonly co-occurring symptoms that should be jointly targeted for management in patients with multiple complaints.


Eliminating age differences in children's and adults' suggestibility and memory conformity effects.
We examined whether typical developmental trends in suggestion-induced false memories (i.e., age-related decrease) could be changed. Using theoretical principles from the spontaneous false memory field, we adapted 2 often-used false memory procedures: misinformation (Experiment 1) and memory conformity (Experiment 2). In Experiment 1, 7- to 9-year-old children (n = 33) and adults (n = 39) received stories containing associatively related details. They then listened to misinformation in the form of short narratives preserving the meaning of the story. Children and adults were equally susceptible to the misinformation effect. In Experiment 2, younger (7- to 8-year-olds, n = 30) and older (11- to 12-year-olds, n = 30) children and adults (n = 30) viewed pictures containing associatively related details. They viewed these pictures in pairs. Although the pictures differed, participants believed they had viewed the same pictures. Participants had to report what they could recollect during collaborative and individual recall tests. Children and adults were equally susceptible to memory conformity effects. When correcting for response bias, adults' false memory scores were even higher than children's. Our results show that age trends in suggestion-induced false memories are not developmentally invariant. (PsycINFO Database Record


All-printed semiquantitative paper-based analytical devices relying on QR code array readout.
The wide spread of smartphones and QR codes for various end-user applications has had an impact beyond traditional fields of use, recently also reaching point-of-care testing (POCT). This work presents the integration of QR code recognition into paper-based analytical devices (PADs) with "distance-based" colorimetric signalling, resulting in semiquantitative readout fully relying on straightforward barcode reader solutions. PADs consist of an array of QR codes arranged in series inside a paperfluidic channel. A mask dye concept has been developed, which enables utilisation of colour changing indicators by initially hiding QR codes. The colour change of the indicator induced by the presence of an analyte of interest results in gradual unmasking of QR codes, which become recognisable by the smartphone barcode reader app. To reproducibly fabricate devices, all fabrication steps were performed by commercial desktop solid ink and inkjet printing. The QR code masking function was optimised by controlling the amount of printed mask dye through adjusting the opacity of printing patterns during the inkjet deposition process. For proof-of-concept, a model assay in the form of colorimetric copper ion (Cu2+) detection in the concentration range of 0.4 mM to 3.2 mM was evaluated. Consistent results independent of the smartphone model and environmental light condition were achieved with a free barcode reader app. To the best of our knowledge, this work is the first demonstration of a semiquantitative assay approach fully relying on QR code readout without digital colour analysis, customised app or hardware modification.


Identification and characterization of a novel, psoriasis susceptibility-related noncoding RNA gene, PRINS.
To identify genetic factors contributing to psoriasis susceptibility, gene expression profiles of uninvolved epidermis from psoriatic patients and epidermis from healthy individuals were compared. Besides already characterized genes, we identified a cDNA with yet unknown functions, which we further characterized and named PRINS (Psoriasis susceptibility-related RNA Gene Induced by Stress). In silico structural and homology studies suggested that PRINS may function as a noncoding RNA. PRINS harbors two Alu elements, it is transcribed by RNA polymerase II, and it is expressed at different levels in various human tissues. Real time reverse transcription-PCR analysis showed that PRINS was expressed higher in the uninvolved epidermis of psoriatic patients compared with both psoriatic lesional and healthy epidermis, suggesting a role for PRINS in psoriasis susceptibility. PRINS is regulated by the proliferation and differentiation state of keratinocytes. Treatment with T-lymphokines, known to precipitate psoriatic symptoms, decreased PRINS expression in the uninvolved psoriatic but not in healthy epidermis. Real time reverse transcription-PCR analysis showed that stress signals such as ultraviolet-B irradiation, viral infection (herpes simplex virus), and translational inhibition increased the RNA level of PRINS. Gene-specific silencing of PRINS by RNA interference revealed that down-regulation of PRINS impairs cell viability after serum starvation but not under normal serum conditions. Our findings suggest that PRINS functions as a noncoding regulatory RNA, playing a protective role in cells exposed to stress. Furthermore, elevated PRINS expression in the epidermis may contribute to psoriasis susceptibility.


Importance of surgical margin in the outcomes of hepatocholangiocarcinoma.
To evaluate the significance of resection margin width in the management of hepatocholangiocarcinoma (HCC-CC). Data of consecutive patients who underwent hepatectomy for hepatic malignancies in the period from 1995 to 2014 were reviewed. Patients with pathologically confirmed HCC-CC were included for analysis. Demographic, biochemical, operative and pathological data were analyzed against survival outcomes. Forty-two patients were included for analysis. The median age was 53.5 years. There were 29 males. Hepatitis B virus was identified in 73.8% of the patients. Most patients had preserved liver function. The median preoperative indocyanine green retention rate at 15 min was 10.2%. The median tumor size was 6.5 cm. Major hepatectomy was required in over 70% of the patients. Hepaticojejunostomy was performed in 6 patients. No hospital death occurred. The median hospital stay was 13 d. The median follow-up period was 32 mo. The 5-year disease-free survival and overall survival were 23.6% and 35.4% respectively. Multifocality was the only independent factor associated with disease-free survival [P < 0.001, odds ratio 4, 95% confidence interval (CI): 1.9-8.0]. In patients with multifocal tumor (n = 20), resection margin of ≥ 1 cm was associated with improved 1-year disease-free survival (40% vs 0%; log-rank, P = 0.012). HCC-CC is a rare disease with poor prognosis. Resection margin of 1 cm or above was associated with improved survival outcome in patients with multifocal HCC-CC.


The reinforced sternal closure system is reliable to use in elderly patients.
Sternal dehiscence is a rare, but serious complication after cardiac surgery procedures when performed through mid-line sternotomy. Osteoporosis, especially at advanced age, may be a significant factor in the unfavorable results of sternum fixation. The present prospective, randomized study was carried out to evaluate whether the reinforced sternal-closure system is an effective and safe fixation and approximation of the sternum in cardiac procedures, and to compare with the conventional sternal-closure method in elderly patients. Forty elderly patients underwent various cardiac procedures via mid-line sternotomy under cardiopulmonary bypass. Patients were randomized into two groups: group I (n = 20) closed with the reinforced sternal-closure system, and group II (n = 20) with standard stainless steel wires. The mean age of patients in group I was 70.5 years, and group II with 70.4 years. Superficial wound infection appeared in only one case of stapler group and in two cases of control group. Deep wound infections or dehiscence was not detected in the patients of both groups. There were no significant differences in the patient's age, drainage, pain index, time of removal of the drains, and postoperative hospital stay between the groups (p > 0.05). The reinforced sternal-closure system provided no additional risk with similar postoperative pain index and postoperative hospital stay compared with conventional method. It is reliable to use in elderly patients undergoing open heart surgery, in the cases presenting a risk factor such as osteoporosis for increased incidence of sternal dehiscence.


Total abdominal hysterectomy in a patient with immune thrombocytopenic Purpura: A case report.
Immune Thrombocytopenic Purpura poses unique challenges in surgical settings due to an increased risk of bleeding. This report details the perioperative management of a patient with Immune Thrombocytopenic Purpura undergoing Total Abdominal Hysterectomy, emphasizing the importance of tailored approaches for such cases. A 41-year-old female with Immune Thrombocytopenic Purpura and symptomatic uterine fibroids, despite medical management, opted for Total Abdominal Hysterectomy. Prednisolone therapy and platelet transfusion were used preoperatively to optimize platelet counts. Effective management was achieved through meticulous surgery, continued prednisolone therapy, and vigilant postoperative monitoring. This case highlights the value of a multidisciplinary approach in ensuring positive surgical outcomes for Immune Thrombocytopenic Purpura patients. This case underscores the significance of individualized perioperative care for Immune Thrombocytopenic Purpura patients undergoing major surgery. By optimizing medical therapy and maintaining close monitoring, favorable results can be achieved, enhancing the quality of life for such patients. It is recommended that such comprehensive approaches are considered in similar cases.


[Systems analysis of behavior in conditions of environmental uncertainty].
The paper deals with the organizational features of the functional behavior system under environmental uncertainty conditions (probability training processes, formation of a conditioned reflex at a low intensity of a signal stimulus), as well as with the probability pattern of reinforcement. It shows that the experimental findings are not always in full conformity with the classical behavior act model developed by P. K. Anokhin. The main difficulty is associated with the fact that the above model in its systems content considers a behavioral act merely alone whereas while teaching under great uncertainty conditions, correction of the programme of actions is possible only when many search reactions are simultaneously analyzed. While making a systems analysis of behavioral performance, it is proposed to use a concept of probability decision to alter the programme of action, as well as an idea of memory buffer (results of search reactions). The proposed approach allows one to describe various training conditions, and it operates as the Anokhin model in a specific case. The organizational features of the functional system of behavior under great uncertainty conditions should be taken into account while specifying the informational mechanism responsible for systems quantization of behavior. The above mechanism of the comprehensive evaluation of the positive and negative results of the performed pattern of behavioral acts can be used to explain the discreteness of an action in the programme alteration process when the same quantum of behavior is implemented.


[Cavum carcinoma. A review of retrospective study about 18 patients in 12 year period].
The cavum or rhinopharynx carcinomas are rare tumors who are divided basically in two histologic types: epidermoid carcinoma and indiferenciated carcinoma. We present a personal revision of 18 patients (15 males and 3 females) diagnosed of cavum carcinoma, the majority (72.2% of indiferenciated type. We have done a descriptive-retrospective study of 12 years (1990-2001) with the following parameters: clinic presentation, associated symptoms, TNM stage, anatomopathology, treatment and clinic evolution. The 38.9% of the patients (7) are actually in complete remission after at last 2 years treatment completion. 3 patients have died and another 2 have not followed the periodic controls in our hospital. The others present a residual tumor in rhinopharynx or in ganglionar level. In one case there are distant metastasis (liver and lungs).


[Catheterization of the Eustachian tube in the combined treatment of exudative otitis].
The objective of the present study was to determine the amount of a medicinal agent entering the tympanic cavity during catheterization of the Eustachian tube in 26 patients presenting with exudative otitis and admitted for its treatment to N.I. Pirogov Clinical Hospital No 1, Moscow. The patients were managed by combined therapy in conjunction with catheterization of the Eustachian tube using radiocontrast matter (the iodine containing (76%) preparation trazograf having viscosity identical with that of dexamethasone). The administration of trazograf was followed by multispiral CT of the temporal bones. It was shown that trazograf penetrated into the tympanic cavity during catheterization of the Eustachian tube and accumulated inside it in 19.2% and 77% of the cases respectively. This finding suggests that the therapeutic effect in the patients presenting with exudative otitis is due not only to the direct action of the pharmaceutical product being used on the site of inflammation but also to the restoration of the draining and aerating functions of the course of Eustachian tube catheterization.


Voltage-controlled cellular viability of preosteoblasts on polarized cpTi with varying surface oxide thickness.
Cathodic voltage shifts of metallic biomaterials were recently shown to induce cell apoptosis in-vitro. The details of the reduction-based physico-chemical phenomena have not yet been fully elucidated. This study shows how surface oxide thickness of commercially pure titanium affects the voltage viability range, and whether anodic oxidation can extend this range. Cell viability, cytoskeletal organization, and cellular adhesion on bare and anodized Ti, at -500, -400 mV(Ag/AgCl) and open circuit potential were assessed. Surfaces were characterized using contact angle measurement and atomic force microscopy, and the observed cellular response was related to the changes in electrochemical currents, and impedance of the samples. Results show that anodization at 9 V in phosphate buffer saline generates a compact surface oxide with comparable surface roughness and energy to the starting bare surface. The anodized surface extends the viability range at 24h from -400 mV(Ag/AgCl) by about -100 mV, which corresponds to an increase in impedance of the surface from 58 kΩ cm(2) to 29 MΩ cm(2) at -400 mV(Ag/AgCl) and results in low average current densities below 0.1 μA cm(-2). The results demonstrate that the voltage range for cell viability under cathodic polarization is expanded due to anodization of the surface oxide and lowering of cathodic currents.


Complications following posterior cervical decompression and fusion: a review of incidence, risk factors, and prevention strategies.
Posterior cervical decompression and fusion (PCF) is a common surgical technique used to treat various cervical spine pathologies. However, there are various complications associated with PCF that can negatively impact patient outcome. We performed a comprehensive literature review to identify the most common complications following PCF using PubMed, Cochrane Database of Systematic Reviews, and Google Scholar. The overall complication rates of PCF are estimated to range from about 15% to 25% in the current literature. The most common immediate complications include acute blood loss anemia, surgical site infection (SSI), C5 palsy, and incidental durotomy; the most common long-term complications include adjacent segment degeneration, junctional kyphosis, and pseudoarthrosis. Three principal mechanisms are thought to contribute to complications. First, higher number of fusion levels, obesity, and more complex pathologies can increase the invasiveness of the planned procedure, thus increase complications. Second, wound healing and arthrodesis may be impaired due to poor blood flow due to various patient factors such as smoking, diabetes, increased frailty, steroid use, and other medical comorbidities. Finally, increased biomechanical stress on the upper instrumented vertebra (UIV) and lowest instrumented vertebra (LIV) may predispose patient to chronic degeneration and result in adjacent level degeneration and/or junctional problems. Reducing the modifiable risk factors pre-operatively can decrease the overall complication rate. Neurologic deficits may be reduced with adequate intraoperative decompression of neural elements. SSI may be reduced with meticulous wound closure that minimizes dead space, drain placement, and the use of intra-wound antibiotics. Careful design of the fusion construct with consideration in spinal alignment and biomechanics can help to reduce the rate of junctional problems. Spine surgeons should be aware of these complications associated with PCF and the corresponding prevention strategies optimize patient outcomes.


Impact of home-based family planning counselling and referral on modern contraceptive use in Karachi, Pakistan: a retrospective, cross-sectional matched control study.
To assess: (1) the impact of a reproductive health program on modern contraceptive use from baseline to program close; (2) the sustained impact from baseline to follow-up 36 months later; and (3) the exposure-adjusted impact at program close and follow-up. Retrospective, cross-sectional matched control study. Karachi, Pakistan. 2561 married women aged 16-49 years. The Willows Program, a community-based family planning counselling and referral program implemented from 2013 to 2015. The primary outcome was community-level modern contraceptive prevalence rate (mCPR), measured for January 2013 (baseline), June 2015 (program close) and at follow-up 36 months later. A secondary outcome was exposure-adjusted mCPR (among women reporting a family planning home visit) at program close and at follow-up. There was no significant effect on community-level mCPR at program close (2.4 percentage point increase in intervention over comparison; 95% CI -2.2 to 7.0) or at follow-up (1.9 percentage point decrease; 95% CI -6.7 to 2.8). Only 18% of women in the intervention area reported receiving a family planning visit in the preceding 5 years. Among those reporting a visit, we observed a significant 10.3 percentage point increase (95% CI 4.6 to 15.9) from baseline to close, and a non-significant 2.0 percentage point increase (95% CI -3.8 to 7.8) from baseline to follow-up, relative to matched women in the comparison area. The cost per new modern method user was US$1089, while the cost per user-year during the intervention period was US$455. The program had a positive short-term effect on women who received a family planning visit; however, this effect was not sustained. Program coverage was low and did not significantly increase community-level family planning use. Findings highlight the need to increase community coverage of high-quality counselling and contextually relevant interventions for family planning demand generation.


Endothelial-specific ablation of serum response factor causes hemorrhaging, yolk sac vascular failure, and embryonic lethality.
Serum response factor (SRF), a member of the MADS box family of nuclear transcription factors, plays an important role in cardiovascular development and function. Numerous studies demonstrate a central role for SRF in regulating smooth and cardiac muscle cell gene expression. Consistent with this, loss of SRF function blocks differentiation of coronary vascular smooth muscle cells from proepicardial precursors, indicating SRF is necessary for coronary vasculogenesis. The role of SRF in endothelial cell contribution during early vascular development, however, has not been addressed. To investigate this, we generated transgenic mice lacking expression of SRF in endothelial cells. Mice expressing Cre recombinase (Tie2Cre+) under Tie2 promoter control were bred to mice homozygous for Srf alleles containing loxP recombination sites within the Srf gene (Srff/f). Tie2 is a tyrosine kinase receptor expressed predominantly on endothelial cells that mediates signalling during different stages of blood vessel remodelling. Resulting embryos were harvested at specific ages for observation of physical condition and analysis of genotype. Tie2Cre+/-Srff/f embryos appeared to develop normally compared to wild-type littermates until embryonic day 10.5 (E10.5). Beginning at E11.5, Tie2Cre+/-Srff/f embryos exhibited cerebrovascular hemorrhaging and severely disrupted vascular networks within the yolk sac. Hemorrhaging in mutant embryos became more generalized with age, and by E14.5, most Tie2Cre+/-Srff/f embryos observed were nonviable and grossly necrotic. Hearts of mutant embryos were smaller relative to overall body weight compared to wild-type littermates. Immunohistochemical analysis revealed the presence of vascular endothelial cells; however, vessels failed to undergo appropriate remodelling. Initial analysis by electron microscopy suggested a lack of appropriate cell-cell contacts between endothelial cells. Consistent with this, disrupted E-cadherin staining patterns were observed in mutant embryos. These results provide the first in vivo evidence in support of a role for SRF in endothelial cell function and strongly suggest SRF is required for appropriate vascular remodelling.


Cisplatin versus carboplatin: comparative review of therapeutic management in solid malignancies.
The platinum analogues, cisplatin and carboplatin, are among the most widely used chemotherapeutic agents in oncology. Both agents have a broad spectrum of clinical activity in numerous malignancies including gynaecological cancers, germ cell tumours, head and neck cancer, thoracic cancers and bladder cancer. Although the final mechanism of inducing tumour cell apoptosis is similar for both compounds, cisplatin has been shown to be more effective in treating specific tumour types. Whilst more favourable toxicity profiles are often associated with carboplatin, this can frequently translate to inferior response in certain malignancies. This review succinctly collates the evidence for the preferential use of these platinum analogues in particular settings in addition to the long-standing dilemma surrounding the paucity of biomarkers predicting response to these agents.


Lateral asymmetries in finger-tapping by adolescents and young adults with Down syndrome.
Lateral asymmetries in finger-tapping were compared in right-handed adolescents and young adults with and without Down syndrome in order to examine cerebral specialization in the Down syndrome group. Finger-tapping data revealed that subjects with Down syndrome performed more slowly than did control subjects and failed to show a right-hand tapping advantage. Although the latter finding suggests that individuals with Down syndrome are less lateralized for sequential processing, they exhibited the same pattern of tapping variability as did control subjects; i.e., they were more variable when finger-tapping with their left hands.


Introduction of solid-phase microextraction as a high-throughput sample preparation tool in laboratory analysis of prohibited substances.
A fully automated, high-throughput method based on thin-film solid-phase microextraction (SPME) and liquid chromatography-mass spectrometry was developed for simultaneous quantitative analysis of 110 doping compounds, selected from ten classes and varying in physical and chemical properties. Among four tested extraction phases, C18 blades were chosen, as they provided optimum recoveries and the lowest carryover effect. The SPME method was optimized in terms of extraction pH, ionic strength of the sample, washing solution, extraction and desorption times for analysis of urine samples. Chromatographic separation was obtained in reversed-phase model; for detection, two mass spectrometers were used: triple quadrupole and full scan orbitrap. These combinations allowed for selective analysis of targeted compounds, as well as a retrospective study for known and unknown compounds. The developed method was validated according to the Food and Drug Administration (FDA) criteria, taking into account Minimum Required Performance Level (MRPL) values required by the World Anti-Doping Agency (WADA). In addition to analysis of free substances, it was also shown that the proposed method is able to extract the glucuronated forms of the compounds. The developed assay offers fast and reliable analysis of various prohibited substances, an attractive alternative to the standard methods that are currently used in anti-doping laboratories.


Investigation of associations between obesity and LEP G2548A and LEPR 668A/G polymorphisms in a Turkish population.
Obesity is a complex heterogeneous disease that is caused by genes, environmental factors, and the interaction between the two. The leptin (LEP) and leptin receptor (LEPR) genes have been evaluated for polymorphisms that could potentially be related to the pathophysiology of obesity and its complications. The aim of this study was to investigate the role of LEP G2548A and LEPR 668A/G polymorphisms in the pathogenesis of obesity. The study included 127 patients with obesity and 105 healthy controls. Polymerase chain reaction and restriction fragment length analysis for LEP G2548A and LEPR 668A/G polymorphisms were applied. There was no statistically significant difference in the genotype frequencies of the LEP gene polymorphism between patients and control groups (P > 0.05). We found a difference in the LEPR genotypes between patients and controls, but this was not statistically significant (P = 0.05). Additionally, we found an increased risk of obesity in the LEP/LEPR GG/GG combined genotype (P < 0.05). Our findings indicate that the LEP G2548A polymorphism is not a relevant obesity marker and that the LEPR 668A/G polymorphism may be related to obesity in a Turkish population. Further researches with larger patient population are necessary to ascertain the implications of LEP and LEPR polymorphisms in obesity.


Organochlorine residues in starlings, 1972.
During the fall of 1972 starlings were collected from 130 sites in conjunction with the National Pesticide Monitoring Program. They were analyzed for DDT and its metabolites, dieldrin, heptachlor epoxide, benzene hexachloride, polychlorinated biphenyls and, for the first time in the series, oxychlordane and HCB. Mean DDT and dieldrin residue levels have declined significantly since 1967 and a regression analysis suggests that levels of DDT and its metabolites should fall below a mean of 0.1 ppm for the 1974 starling collection.


Unsuspected intravestibular schwannoma.
The intravestibular schwannoma is physically minute and will often elude preoperative diagnosis. From time to time, such a tumor will be unexpectedly encountered during transcanal labyrinthectomy. A review of pathologic and surgical literature suggests that the lesion can be well managed by the transcanal route. A standard labyrinthectomy may be sufficient, but the translabyrinthine approach may be necessary for more extensive tumors.


Determining transport efficiency for the purpose of counting and sizing nanoparticles via single particle inductively coupled plasma mass spectrometry.
Currently there are few ideal methods for the characterization of nanoparticles in complex, environmental samples, leading to significant gaps in toxicity and exposure assessments of nanomaterials. Single particle-inductively coupled plasma-mass spectrometry (spICPMS) is an emerging technique that can both size and count metal-containing nanoparticles. A major benefit of the spICPMS method is its ability to characterize nanoparticles at concentrations relevant to the environment. This paper presents a practical guide on how to count and size nanoparticles using spICPMS. Different methods are investigated for measuring transport efficiency (i.e., nebulization efficiency), an important term in the spICPMS calculations. In addition, an alternative protocol is provided for determining particle size that broadens the applicability of the technique to all types of inorganic nanoparticles. Initial comparison, using well-characterized, monodisperse silver nanoparticles, showed the importance of having an accurate transport efficiency value when determining particle number concentration and, if using the newly presented protocol, particle size. Ultimately, the goal of this paper is to provide improvements to nanometrology by further developing this technique for the characterization of metal-containing nanoparticles.


[At what scale should proportionate universalism be applied to ensure health equity? Towards a contextualised approach to prevention and health promotion actions].
Reduction of social inequalities in health has been one of the main political pillars of Regional Health Agencies in France since their creation in 2009. This paper presents a contextual analysis of the effects on social inequalities in health of a hospital-based health promotion and disease prevention programme in terms of overall health policy and scope. Qualitative analysis was used to describe the impact on social inequalities in health according to the classification proposed by Diderichsen et al. Carey's framework was used to apply proportionate universalism in order to analyse its action on these inequalities, adopting a contextualised and holistic approach with regard to regional and national public policy. The results showed that the intervention focused on targeted actions, but may have broader applications. The intervention strategy shifts between closing the inequality gap and levelling up the social gradient. However, analysis of this type of intervention using the proportionate universalism framework may lead to a revised view of the effects of the intervention on social inequalities in health. Implementing health-equity focused interventions remains a challenge for each institution, including Regional Health Agencies. However, research on hospital-based preventive interventions highlights contrasting results in terms of social gradient, depending on whether the intervention is considered in isolation or in its broader context. This article advocates a contextualised approach to analysing local interventions and their effects on social inequalities in health.


Use of volumetric modulated arc radiotherapy in patients with early stage glottic cancer.
We compared conformal, intensity-modulated radiotherapy (IMRT) and intensity-modulated arc therapy (IMAT) in early stage glottic cancer in terms of dosimetric features as target coverage, dose to the organs at risk and total treatment time. Five consecutive T1 glottic squamous cell carcinoma patients were selected for the study. Three-dimensional conformal radiotherapy (3D-CRT), 3-field or 5-field intensity-modulated radiotherapy (3F-IMRT and 5F-IMRT), or IMAT, which was in 2 different forms--a regular IMAT (R-IMAT) and an alternative IMAT (A-IMAT) with an unirradiated section, was planned for each patient. The prescribed dose was 63 Gy in 28 fractions. The minimum dose for 95% of the clinical target volume (D95), maximum dose point at clinical target volume (Dmax), total monitor units, left and right carotid artery doses (V35 and V50 - percentage of volume receiving 35 Gy and 50 Gy), and total treatment time were calculated for each plan. Median D95 values in the 5 plans studied with each technique ranged between 63 and 63.3 Gy (P = NS). Median Dmax values for each technique ranged between 65.4 and 70.8 Gy. The number of hot spots with IMRT and IMAT was significantly higher than with 3D-CRT plans. Conformal radiotherapy plans median V35 (93.6%) and V50 (76.6-83.3%) values for carotid arteries were significantly higher than with IMRT and IMAT (2.9%-11.4% and 0.0%). Average treatment times for 3D-CRT, 3F-IMRT, 5F-IMRT, R-IMAT and A-IMAT techniques were calculated as 64, 119, 147, 39 and 32 seconds, respectively. IMAT has significantly decreased the treatment time compared to IMRT and 3D-CRT with acceptable homogeneous clinical target volume coverage and low carotid dose.


Evidence of hypervirulence in Listeria monocytogenes clonal complex 14.
Purpose. Listeria monocytogenes is a foodborne pathogen that causes central nervous system (CNS) and maternal-neonatal (MN) infections, bacteremia (BAC), and gastroenteritis in humans and ruminants. Specific clonal complexes (CC) have been associated with severe listeriosis cases, however, less is known about differences among subgroup virulence patterns. This study aimed to assess variation in virulence across different CC and clinical outcomes.Methodology. Galleria mellonella larvae were used to compare virulence phenotypes of 34 L. monocytogenes strains representing isolates from CC1, CC6 (from lineage I), and CC7, CC9, CC14, CC37 and CC204 (from lineage II) classified by clinical outcome: BAC, CNS and MN infection. Larvae survival, LD50, cytotoxicity, health index scores and bacterial concentrations post-infection were evaluated as quantifiable indicators of virulence.Results. Isolates belonging to CC14 and MN-associated infections are hypervirulent in G. mellonella as they led to lower G. mellonella survival rates and health index scores, as well as reduced cytotoxic effects when compared to other CC and clinical outcomes included here. CC14 isolates also showed increased bacterial concentrations at 8 and 24 h post-infection, indicating ability to survive the initial immune response and proliferate within G. mellonella larvae.Conclusion. Subgroups of L. monocytogenes possess different virulence phenotypes that may be associated with niche-specificity. While hypervirulent clones have been identified so far in lineage I, our data demonstrate that hypervirulent clones are not restricted to lineage I, as CC14 belongs to lineage II. Identification of subgroups with a higher ability to cause disease may facilitate surveillance and management of listeriosis.


Identification of peptides that target the endothelial cell-specific LOX-1 receptor.
Current gene delivery vectors demonstrate inefficient and nonselective gene transfer to vascular endothelial cells, limiting their use in cardiovascular gene transfer and therapy. The lectinlike oxidized LDL receptor (LOX-1) is expressed selectively at low levels on endothelial cells but is strongly upregulated in dysfunctional endothelial cells associated with hypertension and atherogenesis. Using LOX-1 as a target receptor, we have sought to isolate peptide ligands that mediate binding to the extracellular domain of LOX-1 as a definitive step in the development of targeted gene transfer aimed at dysfunctional endothelium. To achieve this, we ectopically overexpressed LOX-1 in cells lacking endogenous LOX-1 by using an episomally maintained expression system and designed a novel subtractive phage display strategy to identify peptides selective for LOX-1. After extensive biopanning, we sequenced individual phage and identified 60 novel peptides. This population of peptides contained a number of potential consensus motifs. To define the selectivity of individual peptides for LOX-1 with the use of an independent gene transfer system, we developed a novel adenoviral vector to overexpress LOX-1 transiently in primary cells and cell lines. We then quantified recovery of each peptide from LOX-1-positive and LOX-1-negative cells after adenovirus-mediated gene transfer. This strategy confirmed selectivity to LOX-1 for many peptides and highlighted the peptides LSIPPKA, FQTPPQL, and LTPATAI as principal candidates. These peptides will be useful for the selective targeting of viral and nonviral gene transfer vectors to endothelial cells expressing the LOX-1 receptor in vitro and in vivo and in particular dysfunctional endothelial cells associated with hypertension and atherosclerosis.


Field Application of Digital Technologies for Health Assessment in the 10,000 Families Study.
We field tested new-to-market portable, digital applications to assess hearing, pulmonary, and cognitive function to determine the feasibility of implementing these applications across a range of age groups in the pilot phase of the 10,000 Families Study (10KFS), a new Minnesota family-based prospective cohort study. We followed manufacturer recommended protocols for audiometry (SHOEBOX Inc), spirometry (NuvoAir), and the digital clock drawing test (dCDT; Digital Cognition Technologies Inc). These digital devices were low cost and readily implemented in a 2.5-hour health fair visit with minimal training (2-3 hours) of study staff. To date, we have performed these measurements on 197 eligible 10KFS participants during an in-person clinic visit. A total of 37 children (age 4-17 years), 107 adults (18-64 years), and 53 seniors (≥65 years) were eligible to undergo hearing and pulmonary assessments. Children were less likely to successfully complete the hearing test (76%) compared with adults (86%) and seniors (89%). However, successful completion of the pulmonary assessment was high across all groups: 100% of children and seniors and 98% of adults. The dCDT was performed among those over the age of 40, and completion rates were 92% for those aged 41-64 and 94% for those ≥65 years. Our field testing indicates these digital applications are easy and cost-effective to implement in epidemiologic studies. Digital applications provide exciting opportunities to collect data in population studies. Issues related to data privacy, data access, and reproducibility of measurements need to be addressed before deploying digital applications in epidemiologic studies.See all articles in this CEBP Focus section, "Modernizing Population Science."


Exercise training, NADPH oxidase p22phox gene polymorphisms, and hypertension.
Oxidative stress that is mediated through NADPH oxidase activity plays a role in the pathology of hypertension, and aerobic exercise training reduces NADPH oxidase activity. The involvement of genetic variation in the p22phox (CYBA) subunit genes in individual oxidative stress responses to aerobic exercise training has yet to be examined in Pre and Stage 1 hypertensives. Ninety-four sedentary Pre and Stage 1 hypertensive adults underwent 6 months of aerobic exercise training at a level of 70% VO2max to determine whether the CYBA polymorphisms, C242T and A640G, were associated with changes in urinary 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), urinary nitric oxide metabolites (NOx), and plasma total antioxidant capacity (TAC). Demographic and subject characteristics were similar among genotype groups for both polymorphisms. At baseline, a significant (P = 0.03) difference among the C2424T genotype groups in 8-iso-PGF2alpha levels was detected, with the TT homozygotes having the lowest levels and the CC homozygotes having the highest levels. However, no differences were found at baseline between the A640G genotype groups. After 6 months of aerobic exercise training, there was a significant increase in VO2max (P < 0.0001) in the entire study population. In addition, there were significant increases in both urinary 8-iso-PGF2alpha (P = 0.002) and plasma TAC (P=0.03) levels and a significant decrease in endogenous urinary NOx (P < 0.0001). Overall, aerobic exercise training elicited no significant differences among genotype groups in either CYBA variant for any of the oxidative stress variables. We found that compared with CYBA polymorphisms C242T and A640G, it was aerobic exercise training that had the greatest influence on the selected biomarkers; furthermore, our results suggest that the C242T CYBA variant influences baseline levels of urinary 8-iso-PGF2alpha but not the aerobic exercise-induced responses.


Renal effects of aprotinin after 24 hours of unilateral ureteral obstruction.
We have previously demonstrated that, after the release of 24-h unilateral ureteral obstruction (UUO), glomerular filtration rate (GFR), and renal blood flow (RBF) are reduced because of increased production of the potent vasoconstrictors thromboxane A2 (TxA2) and angiotensin II (ANG II). Captopril, which blocks ANG II production, increases GFR and RBF. Sequential administration of aprotinin, a kallikrein inhibitor, has an additive effect to further decrease renal vasoconstriction, even though kinins are generally thought to be vasodilators. Therefore, we assessed mechanisms by which aprotinin might improve renal function of previously obstructed anesthetized rats. When given alone to UUO rats, aprotinin improved renal hemodynamics. Since kinins stimulate TxA2 production by UUO kidneys perfused in vitro, our data suggest that aprotinin improved postobstructive function by decreasing kinin-stimulated TxA2 production, although this may not be its only effect. Aprotinin also improved postobstructive function, even if TxA2 formation was blocked with indomethacin. But when both ANG II and TxA2 formation were blocked by the simultaneous administration of captopril and indomethacin, aprotinin had no effect. This suggests that aprotinin may also affect ANG II formation. These pharmacological effects of aprotinin suggest that the kallikrein-kinin system may also contribute to postobstructive renal vasoconstriction by stimulating the production of both vasoconstrictor eicosanoids and ANG II.


Comparison of Trends in Nonprofit Hospitals' Charity Care Eligibility Policies Between Medicaid Expansion States and Medicaid Nonexpansion States.
Nonprofit hospitals provide charity care to financially disadvantaged patients according to their self-designed eligibility policies. The Affordable Care Act may have prompted nonprofit hospitals to adopt more generous eligibility policies, but no prior research has examined the longitudinal trend. The expansion of Medicaid coverage in many states has been found to reduce charity care provision, but it is unclear whether the change in charity care eligibility policies differed between Medicaid expansion and nonexpansion states. Using mandatory tax filings, we found that both hospitals in Medicaid expansion states and hospital in nonexpansion states adopted more generous eligibility policies in 2018 than in 2010, but the change was greater in the former for discounted charity care; while the former provided less charity care regardless of their policy changes, the latter provided more when their policies became more generous. This study has implications for policy discussions on the justification of nonprofit hospitals' tax-exempt status.


Indistinguishability and identifiability of kinetic models for the MurC reaction in peptidoglycan biosynthesis.
An important question in Systems Biology is the design of experiments that enable discrimination between two (or more) competing chemical pathway models or biological mechanisms. In this paper analysis is performed between two different models describing the kinetic mechanism of a three-substrate three-product reaction, namely the MurC reaction in the cytoplasmic phase of peptidoglycan biosynthesis. One model involves ordered substrate binding and ordered release of the three products; the competing model also assumes ordered substrate binding, but with fast release of the three products. The two versions are shown to be distinguishable; however, if standard quasi-steady-state assumptions are made distinguishability cannot be determined. Once model structure uniqueness is ensured the experimenter must determine if it is possible to successfully recover rate constant values given the experiment observations, a process known as structural identifiability. Structural identifiability analysis is carried out for both models to determine which of the unknown reaction parameters can be determined uniquely, or otherwise, from the ideal system outputs. This structural analysis forms an integrated step towards the modelling of the full pathway of the cytoplasmic phase of peptidoglycan biosynthesis.


Adenovirus E4 gene promotes selective endothelial cell survival and angiogenesis via activation of the vascular endothelial-cadherin/Akt signaling pathway.
The early 4 region (E4) of the adenoviral vectors (AdE4(+)) prolongs human endothelial cell (EC) survival and alters the angiogenic response, although the mechanisms for the EC-specific, AdE4(+)-mediated effects remain unknown. We hypothesized that AdE4(+) modulates EC survival through activation of the vascular endothelial (VE)-cadherin/Akt pathway. Here, we showed that AdE4(+), but not AdE4(-) vectors, selectively stimulated phosphorylation of both Akt at Ser(473) and Src kinase in ECs. The phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin abrogated AdE4(+) induction of both phospho-Akt expression and prolonged EC survival. Regulation of phospho-Akt was found to be under the control of various factors, namely VE-cadherin activation, Src kinase, tyrosine kinase, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). Downstream targets of Akt signaling resulted in glycogen synthase kinase-3alpha/beta phosphorylation, beta-catenin up-regulation, and caspase-3 suppression, all of which led to AdE4(+)-mediated EC survival. Furthermore, infection with AdE4(+) vectors increased the angiogenic potential of ECs by promoting EC migration and capillary tube formation in Matrigel plugs. This selective AdE4(+)-mediated enhanced motility of ECs was also blocked by PI3K inhibitors. Taken together, these results suggest that activation of the VE-cadherin/Akt pathway is critical for AdE4(+)-mediated survival of ECs and angiogenic potential.


Simulating force-induced conformational transitions in polysaccharides with the SMD replica exchange method.
Conventional steered molecular dynamics (SMD) simulations do not readily reproduce equilibrium conditions of atomic force microscopy (AFM) stretch and release measurements of polysaccharides undergoing force-induced conformational transitions because of the gap between the timescales of computer simulations ( approximately 1 mus) and AFM measurements ( approximately 1 s). To circumvent this limitation, we propose using the replica exchange method (REM) to enhance sampling during SMD simulations. By applying REM SMD to a small polysaccharide system and comparing the results with those from AFM stretching experiments, we demonstrate that REM SMD reproduces the experimental results not only qualitatively but quantitatively, approaching near equilibrium conditions of AFM measurements. As tested in this work, hysteresis and computational time of REM SMD simulations of short polysaccharide chains are significantly reduced as compared to regular SMD simulations, making REM SMD an attractive tool for studying forced-induced conformational transitions of small biopolymer systems.


Early, local motion signals generate directional preferences in depth ordering of transparent motion.
Superposition of two dot clouds moving in different directions results in the perception of two transparent layers. Despite the ambiguous depth order of the layers, there are consistent preferences to perceive the layer, which is moving either rightward or downward in front of the other layer. Here we investigated the origin of these depth order biases. For this purpose, we measured the interaction with stereoscopic disparity and the influence of global and local motion properties. Motion direction and stereoscopic disparity were equally effective in determining depth order at a disparity of one arcmin. Global motion properties, such as the aperture location in the visual field or the aperture's motion direction did not affect directional biases. Local motion properties however were effective. When the moving elements were oriented lines rather than dots, the directional biases were shifted towards the direction orthogonal to the lines rather than the actual motion direction of the lines. Therefore, depth order was determined before the aperture problem was fully resolved. Varying the duration of the stimuli, we found that the time constant of the aperture problem was much lower for depth order than for perceived motion direction. Altogether, our results indicate that depth order is determined in one shot on the basis of an early motion signal, while perceived motion direction is continuously updated. Thus, depth ordering in transparent motion appears to be a surprisingly fast process, that relies on early, local motion signals and that precedes high-level motion analysis.