Modulation of cationicity of chitosan for tuning mesenchymal stem cell adhesion, proliferation, and differentiation.
The aim of this study was to modulate the cationicity of chitosan to influence the mesenchymal stem cell (MSC) responses in terms of cell adhesion, proliferation, and differentiation. The authors prepared water-soluble carboxymethyl chitosan hydrogels using genipin as the crosslinking agent. The chitosan cationicity was modulated by varying the genipin content from 0.5 to 10 wt. %. The results indicated that the cationicity exerted a striking modulation effect on various MSC responses. The increase of the genipin content, i.e., decrease of the free amino group content (cationicity), overall promoted the MSC adhesion, cytoskeleton organization, proliferation, and differentiation into the osteogenic lineage. A surprising cell alignment effect was also observed on chitosan samples with high genipin concentrations (>2.5%). The chitosan sample with the highest genipin concentrations (10%) exhibited the best MSC proliferation and highest protein expression levels toward osteogenic lineages. The genipin content also showed a strong modulation effect on MSC condensation, and cell-cell and cell-matrix interactions, as suggested by the expressions of the sry related HMG box9 (Sox9), intercellular adhesion molecule 1, and N-Cadherin. Overall, the authors have demonstrated that modulation of cationicity (amino content) of chitosan is an effective and simple approach to tuning various MSC responses, including adhesion, proliferation, differentiation, as well as cell-cell interactions. Such findings might have important implications in biomaterial design for various biomedical applications.


Safeguard the world's worst pathogens.
More people in more places are researching the world's most dangerous pathogens. This work helps prepare against future pandemics, but it's not without danger. Pathogens could escape from research facilities, so it is vital for countries to assess potential hazards and have procedures in place to manage the risks. This doesn't happen enough.


Adverse health effects of children's exposure to pesticides: what do we really know and what can be done about it.
Children may be exposed to pesticides in several ways, such as by transplacental transfer during foetal life, by intake of contaminated breast milk and other nutrients, or by contact with contaminated subjects and areas in the environment such as pets treated with insecticides, house dust, carpets and chemically treated lawns and gardens. Exposure early in life, and particularly during periods of rapid development, such as during foetal life and infancy, may have severe effects on child health and development by elevating the risk of congenital malformations, cancer, malabsorption, immunological dysfunction, endocrine disease, and neurobehavioural deficiencies. As pesticides can also interfere with parental reproductive health, exposure of parents may have consequences for the offspring leading to reduced chance of male birth and increased risk of childhood cancer. Current knowledge about tolerable levels and consequences of toxic exposure to pesticides during human development is rather scarce. Owing to the high risk of exposure to pesticides, particularly in less developed countries, further elucidation by well-controlled epidemiological studies in this field it is urgently needed. The Policy Interpretation Network on Children's Health and Environment (PINCHE), which is financed by the EU DG research has suggested actions against pesticide exposure. They have been presented and discussed in this paper. Several suggestions of PINCHE concerning action needed regarding pesticides were presented in the paper.


Prognostic factors of palatal mucoepidermoid carcinoma: a retrospective analysis based on a double-center study.
Mucoepidermoid carcinoma (MEC) of the palate is a common malignancy of minor salivary glands. This study was designed to identify the prognostic factors for MEC of the palate. The medical records of patients diagnosed with MEC of the palate who visited the Department of Oral and Maxillofacial Surgery at Nanjing Stomatological Hospital and the Department of Stomatology at Central Hospital of Xuzhou were retrospectively studied. The prognostic factors were determined using a Cox proportional hazards model. Furthermore, the expression of cancer stem cell (CSC) markers CD44, CD133, Nanog and Sox2 were detected in neoplastic samples of these patients by immunohistochemistry. As a result, both univariate analysis and multivariate analysis proved a high histological grade and an advanced tumor stage as negative prognostic factors for overall survival. By immunohistochemistry staining and survival analysis, a combination of CD44/CD133/SOX2 was found to have the strongest prognostic value for palatal MEC patients. In conclusion, the proposed nomogram which include histological grade and tumor stage along with cancer stem cell markers provides a more accurate long-term prediction for palatal MEC patients.


Antibody-dependent cellular cytotoxicity and natural killer cytotoxicity of peritoneal cells from nude mice to herpes simplex virus-infected cells.
Nude BALB/c mice (athymic) were more susceptible to fatal herpes simplex virus (HSV) than normal BALB/c mice (P = 0.002). The peritoneal cells of nude mice mediated levels of antibody-dependent cellular cytotoxicity (ADCC) of equal or greater magnitude than cells from normal BALB/c, heterozygote nu/+, or C57BL/6 mice. Unstimulated natural killer cytotoxicity of peritoneal cells from nude mice was higher (P less than 0.05) than that mediated by cells from C57BL/6 mice. Nude mice failed to make anti-HSV ADCC antibody 6 to 14 days post HSV inoculation, at times when nu/+, BALB/c, and C57BL/6 mice produced antibody. Passive reconstitution of nude mice with high titer intraperitoneal anti-HSV immune globulin provided circulating anti-HSV ADCC antibody and significant protection against lethal HSV infection.


Mitochondrial Proteome Studies in Seeds during Germination.
Seed germination is considered to be one of the most critical phases in the plant life cycle, establishing the next generation of a plant species. It is an energy-demanding process that requires functioning mitochondria. One of the earliest events of seed germination is progressive development of structurally simple and metabolically quiescent promitochondria into fully active and cristae-containing mitochondria, known as mitochondrial biogenesis. This is a complex and tightly regulated process, which is accompanied by sequential and dynamic gene expression, protein synthesis, and post-translational modifications. The aim of this review is to give a comprehensive summary of seed mitochondrial proteome studies during germination of various plant model organisms. We describe different gel-based and gel-free proteomic approaches used to characterize mitochondrial proteomes of germinating seeds as well as challenges and limitations of these proteomic studies. Furthermore, the dynamic changes in the abundance of the mitochondrial proteomes of germinating seeds are illustrated, highlighting numerous mitochondrial proteins involved in respiration, tricarboxycylic acid (TCA) cycle, metabolism, import, and stress response as potentially important for seed germination. We then review seed mitochondrial protein carbonylation, phosphorylation, and S-nitrosylation as well as discuss the possible link between these post-translational modifications (PTMs) and the regulation of seed germination.


Identification of MupP as a New Peptidoglycan Recycling Factor and Antibiotic Resistance Determinant in Pseudomonas aeruginosa.
Peptidoglycan (PG) is an essential cross-linked polymer that surrounds most bacterial cells to prevent osmotic rupture of the cytoplasmic membrane. Its synthesis relies on penicillin-binding proteins, the targets of beta-lactam antibiotics. Many Gram-negative bacteria, including the opportunistic pathogen Pseudomonas aeruginosa, are resistant to beta-lactams because of a chromosomally encoded beta-lactamase called AmpC. In P. aeruginosa, expression of the ampC gene is tightly regulated and its induction is linked to cell wall stress. We reasoned that a reporter gene fusion to the ampC promoter would allow us to identify mutants defective in maintaining cell wall homeostasis and thereby uncover new factors involved in the process. A library of transposon-mutagenized P. aeruginosa was therefore screened for mutants with elevated ampC promoter activity. As an indication that the screen was working as expected, mutants with transposons disrupting the dacB gene were isolated. Defects in DacB have previously been implicated in ampC induction and clinical resistance to beta-lactam antibiotics. The screen also uncovered murU and PA3172 mutants that, upon further characterization, displayed nearly identical drug resistance and sensitivity profiles. We present genetic evidence that PA3172, renamed mupP, encodes the missing phosphatase predicted to function in the MurU PG recycling pathway that is widely distributed among Gram-negative bacteria.IMPORTANCE The cell wall biogenesis pathway is the target of many of our best antibiotics, including penicillin and related beta-lactam drugs. Resistance to these therapies is on the rise, particularly among Gram-negative species like Pseudomonas aeruginosa, a problematic opportunistic pathogen. To better understand how these organisms resist cell wall-targeting antibiotics, we screened for P. aeruginosa mutants defective in maintaining cell wall homeostasis. The screen identified a new factor, called MupP, involved in the recycling of cell wall turnover products. Characterization of MupP and other components of the pathway revealed that cell wall recycling plays important roles in both the resistance and the sensitivity of P. aeruginosa to cell wall-targeting antibiotics.


[Progressive sensorineural hearing loss from infectious agents].
The progressive sensorineural hearing loss due to infectious causes can involve different etiological agents like bacteria, viruses, protozoons or mycetes. These infectious agents can act in various ways: directly through a labyrinthitis that may destroy the neuroepithelium; through an ischaemic process secondary to a septic embolus; or through a thrombus. In some cases the damage can occur in a meningitis context, because of the passage of the germ in the inner through the nerves, the vases or the labyrinthine liquids. Bacterial meningitis is one of the causes of progressive sensorinueral hearing loss. Among bacteria, the Mycobacterium Tuberculosis has nowadays acquired a remarkable importance which is also due to its considerable diffusion, despite modern therapy, and to its association with HIV infection. Bacteria can also cause a labyrinthitis acting directly on the inner ear: among these, Treponemas Pallidum, a spirochaete which causes syphilis and Borrelia Burgdorferi, a spirochaete that causes Lyme Disease, must be mentioned. The viruses that are certainly involved in the etiology of progressive sensorineural hearing loss are Cytomegalovirus and Rubella virus. The virus usually causes a labyrinthitis after the viraemia, wich may be due to the passage of the virus from the blood to the endolymph, through the stria vascularis with the consequent infection of the sensorial cells of the organ of Corti. Less frequently the viral damage to the inner ear can occur after a vasculitis, a meningitis or an alteration of the cell-mediated immunity. Progressive sensorineural hearing loss can also occur because of some congenital viral infections such as those caused by Cytomegalovirus and Rubella virus. More recently even the Human Parvovirus B19 seems to have been involved. This virus seems to act through autoimmune and/or immunologic processes, like that causing sudden hearing loss in Lassa fever. Another viral infection which can nowadays more frequently be considered among the cause of progressive hearing loss is HIV. In the HIV infection the neurological toxic lesions due to the administered ototoxic drugs are added up to the damages caused by the opportunistic infectious agents (virus, bacterium, protozoon mycete). However, in these patients HIV itself could be the cause of the auditory and vestibular lesions. More rarely, a progressive hearing loss may be due to the action of a protozoon or mycete only.


Acetyl-L-carnitine supplementation to old rats partially reverts the age-related mitochondrial decay of soleus muscle by activating peroxisome proliferator-activated receptor gamma coactivator-1alpha-dependent mitochondrial biogenesis.
The age-related decay of mitochondrial function is a major contributor to the aging process. We tested the effects of 2-month-daily acetyl-L-carnitine (ALCAR) supplementation on mitochondrial biogenesis in the soleus muscle of aged rats. This muscle is heavily dependent on oxidative metabolism. Mitochondrial (mt) DNA content, citrate synthase activity, transcript levels of some nuclear- and mitochondrial-coded genes (cytochrome c oxidase subunit IV [COX-IV], 16S rRNA, COX-I) and of some factors involved in the mitochondrial biogenesis signaling pathway (peroxisome proliferator-activated receptor gamma [PPARgamma] coactivator-1alpha [PGC-1alpha], mitochondrial transcription factor A mitochondrial [TFAM], mitochondrial transcription factor 2B [TFB2]), as well as the protein content of PGC-1alpha were determined. The results suggest that the ALCAR treatment in old rats activates PGC-1alpha-dependent mitochondrial biogenesis, thus partially reverting the age-related mitochondrial decay.


Influence of chemotherapeutic agents on chorionic gonadotropin-alpha subunit secretion in a human lung cancer cell line (ChaGo): discordance of cytotoxic and secretory effects.
Cells from cultures of ChaGo, a cell line of a human lung cancer that ectopically produces chorionic gonadotropin (hCG) and its alpha subunit (hCG-alpha) were exposed to five different cancer chemotherapeutic agents in vitro in separate experiments (one drug/expt). The control doubling time averaged 4 days, with molar biphasic secretory rates of hCG-alpha ranging from a high of 58.1 to a low of 10.5 pmoles/10(6) cells/24 hours. Drug concentrations were chosen to induce a 30-60% inhibition of cell replication over a period of 8-10 days. Neither methotrexate nor vincristine demonstrated major effects on extracellular hCG-alpha production, but each agent moderately depressed cell number and each produced major inhibition of intracellular protein synthesis. Procarbazine inhibited marker production only in slight excess of inhibition of cell growth and cell protein. Actinomycin D and mechlorethamine, however, had profound effects on inhibition of hCG-alpha production in excess of cell growth. Our results indicated that cancer chemotherapeutic agents have specific and differing effects on cell growth and cell protein on the one hand and marker production on the other. These data suggested a mechanism for certain cases of discordance between hormone production and clinical status.


Ionizing radiation and tobacco use increases the risk of a subsequent lung carcinoma in women with breast cancer: case-only design.
To analyze the risk of lung cancer in women treated with radiotherapy for breast cancer. We accessed the lung dose in relation to different radiotherapy techniques, provided the excess relative risk (ERR) estimate for radiation-associated lung cancer, and evaluated the influence of tobacco use. The Swedish Cancer Registry was used to identify 182 women diagnosed with breast and subsequent lung cancers in Stockholm County during 1958 to 2000. Radiotherapy was administered to 116 patients. Radiation dose was estimated from the original treatment charts, and information on smoking history was searched for in case records and among relatives. The risk of lung cancer was assessed in a case-only approach, where each woman contributed a pair of lungs. The average mean lung dose to the ipsilateral lung was 17.2 Gy (range, 7.1 to 32.0 Gy). A significantly increased relative risk (RR) of a subsequent ipsilateral lung cancer was observed at > or = 10 years of follow-up (RR = 2.04; 95% CI, 1.24 to 3.36). Squamous cell carcinoma (RR = 4.00; 95% CI, 1.50 to 10.66) was the histopathologic subgroup most closely related to ionizing radiation. The effect of radiotherapy was restricted to smokers only (RR = 3.08; 95% CI, 1.61 to 5.91). The ERR/Gy for women with latency > or = 10 years after exposure was 0.11 (95% CI, 0.02 to 0.44). Radiotherapy for breast cancer significantly increases the risk of lung carcinoma more than 10 years after exposure in women who smoked at time of breast cancer.


Topography preserved microwave plasma etching for top-down layer engineering in MoS2 and other van der Waals materials.
A generic and universal layer engineering strategy for van der Waals (vW) materials, scalable and compatible with the current semiconductor technology, is of paramount importance in realizing all-two-dimensional logic circuits and to move beyond the silicon scaling limit. In this letter, we demonstrate a scalable and highly controllable microwave plasma based layer engineering strategy for MoS2 and other vW materials. Using this technique we etch MoS2 flakes layer-by-layer starting from an arbitrary thickness and area down to the mono- or the few-layer limit. From Raman spectroscopy, atomic force microscopy, photoluminescence spectroscopy, scanning electron microscopy and transmission electron microscopy, we confirm that the structural and morphological properties of the material have not been compromised. The process preserves the pre-etch layer topography and yields a smooth and pristine-like surface. We explore the electrical properties utilising a field effect transistor geometry and find that the mobility values of our samples are comparable to those of the pristine ones. The layer removal does not involve any reactive gasses or chemical reactions and relies on breaking the weak inter-layer vW interaction making it a generic technique for a wide spectrum of layered materials and heterostructures. We demonstrate the wide applicability of the technique by extending it to other systems such as graphene, h-BN and WSe2. In addition, using microwave plasma in combination with standard lithography, we illustrate a lateral patterning scheme making this process a potential candidate for large scale device fabrication in addition to layer engineering.


Route of hysterectomy and surgical outcomes from a statewide gynecologic oncology population: is there a role for vaginal hysterectomy?
Recent policy changes by insurance companies have been instituted to encourage vaginal hysterectomy (VH) as the preferred route for removal of the uterus. It is not known if advantages of VH for benign indications apply to women with gynecologic cancer. The goal of this study was to assess trends in surgical approach to hysterectomy among gynecologic cancer patients and to evaluate outcomes by approach. We hypothesized that, among gynecologic oncology patients, postoperative complications and hospital stay would differ by surgical approach, and that advantages of VH for benign indications may not apply to gynecologic cancer patients. We performed a population-based retrospective cohort study of cervical, endometrial, or ovarian/fallopian tube cancer patients treated surgically in Washington State from 2004 through 2013 using the Comprehensive Hospital Abstract Reporting System. Surgery was categorized as abdominal hysterectomy (AH), laparoscopic hysterectomy (LH), or VH. We determined rate of surgical approach by year and the association with length of stay, 30-day readmission rate, and perioperative complications. We identified 10,117 patients who underwent surgery for gynecologic cancer, with 346 (3.4%) VH, 2698 (26.7%) LH, and 7073 (69.9%) AH. Patients undergoing AH had more comorbidities than patients with VH or LH (Charlson Comorbidity Index ≥2: 11.3%, 7.9%, and 8.1%, respectively; P < .001). From 2004 through 2013 AH and VH declined (94.4-47.9% and 4.4-0.8%, respectively; P < .001) while LH increased from 1.2-51.4% in 2013 (P < .001). Mean length of stay was 4.6 days for women undergoing AH and was 1.9 days shorter for VH (95% confidence interval, 1.6-2.3 days) and 2.6 days shorter for LH (95% confidence interval, 2.4-2.7 days) (P < .001). Risk of 30-day readmission for patients undergoing LH was 40% less likely compared to AH but not different for VH vs AH. AH and LH remain the preferred routes for hysterectomy in gynecologic oncology. Over the past decade, there has been a significant shift to LH with lower 30-day readmission and complication rates. There may be a limited role for VH in select patients. Current efforts to standardize the surgical approach to hysterectomy should not apply to patients with known or suspected gynecologic cancer.


Contagious depression: existence, specificity to depressed symptoms, and the role of reassurance seeking.
This study prospectively examined the phenomenon of contagious depression in 96 pairs of college roommates during 2 assessment sessions separated by 3 weeks. Depression, anxiety, negative and positive affect, negative life stress, and reassurance seeking were assessed. Consistent with prediction, roommates of depressed target students became more depressed themselves over the course of the 3-week study. The effect persisted when baseline levels of roommate depression and roommate negative life events were controlled. Furthermore, these findings were specific to depressed symptoms. Finally, as predicted, reassurance seeking served as a vulnerability factor for the contagion effect: High-but not low-reassurance-seeking roommates of depressed target students became more depressed themselves. However, the moderating effects of reassurance seeking were not specific to depressed symptoms.


Reimbursement issues with hormonal therapies for prostate cancer.
Reimbursement issues surrounding the treatment of prostate cancer with hormonal therapies have changed dramatically in the past 2 years. The ultimate goal for urologists when making treatment decisions regarding LHRH agonist use is to continue to provide hassle-free, complete care for patients, including whatever medications they need. This is still fully possible under the new rules without sacrificing the opportunity to profit from office-based administration of injectable medications.


Historical development of ornithophily in the western North American flora.
The 129 ornithophilous plant species in western North America have floristic affinities with one or the other of four geofloras: the Arcto-Tertiary flora (101 species), Madro-Tertiary flora (19 species), Madrean-Tethyan flora (8 species), and Neotropical flora (1 species). The last three floras have been in continuous contact with hummingbirds since some time early in the Tertiary, and ornithophily is old in this subset of western ornithophilous plants. The Arcto-Tertiary flora had no contact with hummingbirds in Eurasia or in its early history in North America. Ornithophily is a new condition in Arcto-Tertiary plant groups, dating from the first significant contact of these plants with hummingbirds in the Eocene. Buildup of the hummingbird pollination system in the Arcto-Tertiary flora is expected to be gradual and stepwise for several reasons. Ornithophilous plant groups with Arcto-Tertiary affinities in the modern western flora form a graded series with respect to taxonomic rank, taxonomic size, and ecological diversity. The series consists of one large genus (Castilleja), three small genera (Zauschneria, etc.), species groups in several genera (Penstemon, Aquilegia, etc.), single ornithophilous species in otherwise nonornithophilous genera (seven genera--e.g., Pedicularis, Monardella), and ornithophilous races in otherwise nonornithophilous species (known in two species). It is suggested that the gradations in size of the groups approximately reflect stages in their development, with the largest ornithophilous genus being oldest, with single ornithophilous species being relatively recent, and with ornithophilous races being most recent. The observed distribution of numbers of ornithophilous species among genera is in agreement with the expectation of a gradual and stepwise development of ornithophily.


[Antigenic similarity between polysaccharide and ribosomal vaccine extracts from Klebsiella pneumonia].
We describe in this report the vaccinating power of a polysaccharidic preparation from Klebsiella pneumoniae type I. The essential part played by this extract in the vaccinating capacities of the ribosomal preparations from the same bacterium is demonstrated.


Three-dimensional topological insulators on the pyrochlore lattice.
Electrons hopping on the sites of a three-dimensional pyrochlore lattice are shown to form topologically nontrivial insulating phases when the spin-orbit (SO) coupling and lattice distortions are present. Of 16 possible topological classes 9 are realized for various parameters in this model. Specifically, at half-filling an undistorted pyrochlore lattice with a SO term yields a "pristine" strong topological insulator with a Z(2) index (1;000). At quarter filling various strong and weak topological phases are obtained provided that both SO coupling and uniaxial lattice distortion are present. Our analysis suggests that many of the nonmagnetic insulating pyrochlores could be topological insulators.


UBC-Nepal expedition: markedly lower cerebral blood flow in high-altitude Sherpa children compared with children residing at sea level.
Developmental cerebral hemodynamic adaptations to chronic high-altitude exposure, such as in the Sherpa population, are largely unknown. To examine hemodynamic adaptations in the developing human brain, we assessed common carotid (CCA), internal carotid (ICA), and vertebral artery (VA) flow and middle cerebral artery (MCA) velocity in 25 (9.6 ± 1.0 yr old, 129 ± 9 cm, 27 ± 8 kg, 14 girls) Sherpa children (3,800 m, Nepal) and 25 (9.9 ± 0.7 yr old, 143 ± 7 cm, 34 ± 6 kg, 14 girls) age-matched sea level children (344 m, Canada) during supine rest. Resting gas exchange, blood pressure, oxygen saturation and heart rate were assessed. Despite comparable age, height and weight were lower (both P < 0.01) in Sherpa compared with sea level children. Mean arterial pressure, heart rate, and ventilation were similar, whereas oxygen saturation (95 ± 2 vs. 99 ± 1%, P < 0.01) and end-tidal Pco2 (24 ± 3 vs. 36 ± 3 Torr, P < 0.01) were lower in Sherpa children. Global cerebral blood flow was ∼30% lower in Sherpa compared with sea level children. This was reflected in a lower ICA flow (283 ± 108 vs. 333 ± 56 ml/min, P = 0.05), VA flow (78 ± 26 vs. 118 ± 35 ml/min, P < 0.05), and MCA velocity (72 ± 14 vs. 88 ± 14 cm/s, P < 0.01). CCA flow was similar between Sherpa and sea level children (425 ± 92 vs. 441 ± 81 ml/min, P = 0.52). Scaling flow and oxygen uptake for differences in vessel diameter and body size, respectively, led to the same findings. A lower cerebral blood flow in Sherpa children may reflect specific cerebral hemodynamic adaptations to chronic hypoxia.NEW & NOTEWORTHY Cerebral blood flow is lower in Sherpa children compared with children residing at sea level; this may reflect a cerebral hemodynamic pattern, potentially due to adaptation to a hypoxic environment.


Improved stability of methanolic wright's stain with additive reagents.
Additive reagents have been investigated to improve the stability of methanolic Wright's stain. The addition of ammonium halides, monoalkylamine hydrochlorides, dialkylamine hydrochlorides or trialkylamine hydrochlorides to methanolic Wright's stain was found to enhance the stability of stain components in methanol. No change in performance is observed with these additives present. Random precipitation in the stain solution was still observed with the addition of ammonium halides and monoalkylamine hydrochlorides. No precipitation was found in stain solutions containing hydrochlorides of most dialkylamines and trialkylamines. Of the compounds evaluated, 0.6% diethylamine hydrochloride added to methanolic stain solutions produced the most desirable overall results. Mechanisms of stabilization and precipitation in these stain solutions are proposed. Essentially, separation of the thiazine-eosinate ion pair through interaction with an appropriate additive increases stain stability. The solubilities of thiazine-eosinate or additive cation-eosinate ion pairs in methanol determine the formation of precipitate in such stain solutions.


Binding and internalization of NGR-peptide-targeted liposomal doxorubicin (TVT-DOX) in CD13-expressing cells and its antitumor effects.
In an effort to develop new agents and molecular targets for the treatment of cancer, aspargine-glycine-arginine (NGR)-targeted liposomal doxorubicin (TVT-DOX) is being studied. The NGR peptide on the surface of liposomal doxorubicin (DOX) targets an aminopeptidase N (CD13) isoform, specific to the tumor neovasculature, making it a promising strategy. To further understand the molecular mechanisms of action, we investigated cell binding, kinetics of internalization as well as cytotoxicity of TVT-DOX in vitro. We demonstrate the specific binding of TVT-DOX to CD13-expressing endothelial [human umbilical vein endothelial cells (HUVEC) and Kaposi sarcoma-derived endothelial cells (SLK)] and tumor (fibrosarcoma, HT-1080) cells in vitro. Following binding, the drug was shown to internalize through the endosomal pathway, eventually leading to the localization of doxorubicin in cell nuclei. TVT-DOX showed selective toxicity toward CD13-expressing HUVEC, sparing the CD13-negative colon-cancer cells, HT-29. Additionally, the nontargeted counterpart of TVT-DOX, Caelyx, was less cytotoxic to the CD13-positive HUVECs demonstrating the advantages of NGR targeting in vitro. The antitumor activity of TVT-DOX was tested in nude mice bearing human prostate-cancer xenografts (PC3). A significant growth inhibition (up to 60%) of PC3 tumors in vivo was observed. Reduction of tumor vasculature following treatment with TVT-DOX was also apparent. We further compared the efficacies of TVT-DOX and free doxorubicin in the DOX-resistant colon-cancer model, HCT-116, and observed the more pronounced antitumor effects of the TVT-DOX formulation over free DOX. The potential utility of TVT-DOX in a variety of vascularized solid tumors is promising.


An Exposure-Based Cognitive-Behavioral Therapy for Youth with Severe Irritability: Feasibility and Preliminary Efficacy.
Clinically impairing irritability and temper outbursts are among the most common psychiatric problems in youth and present transdiagnostically; however, few mechanistically informed treatments have been developed. Here, we test the acceptability, feasibility, and preliminary efficacy of a novel exposure-based treatment with integrated parent management skills for youth with severe irritability using a randomized between-subjects multiple baseline design. N = 41 patients (Age, Mean (SD) = 11.23 years (1.85), 62.5% male, 77.5% white) characterized by severe and impairing temper outbursts and irritability were randomized to different baseline observation durations (2, 4, or 6 weeks) prior to active treatment; 40 participants completed the 12 session treatment of exposure-based cognitive-behavioral therapy for irritability with integrated parent management skills. Masked clinician ratings were acquired throughout baseline and treatment phases, as well as 3- and 6-months post-treatment. To examine acceptability and feasibility, drop-out rates and adverse events were examined. Primary clinical outcome measures included clinician-administered measures of irritability severity and improvement. Secondary clinical outcome measures included multi-informant measures of irritability, depression, anxiety, and attention-deficit/hyperactivity disorder symptoms. No patients dropped out once treatment began, and no adverse events were reported. Irritability symptoms improved during the active phase of treatment across all measurements (all βs > -0.04, ps < .011, Cohen's d range: -0.33 to -0.98). Treatment gains were maintained at follow-up (all βs(39) < -0.001, ps > .400). Sixty-five percent of patients were considered significantly improved or recovered post-treatment based on the primary clinician-rated outcome measure. Results support acceptability, feasibility, and preliminary efficacy of this novel treatment for youth with severe irritability. Limitations and future directions are also discussed.


Skeletal muscle oxygen pressure fields during controlled hypotension with adenosine and sodium nitroprusside. A comparative study in the rabbit.
The MDO (Mehrdraht Dortmund Oberfläche) multiwire oxygen electrode was used for studies of oxygen pressure fields in eight rabbit skeletal muscle preparations during controlled hypotension with adenosine and sodium nitroprusside (SNP). Tissue oxygen histograms were constructed from 120 simple tissue oxygen pressures (PtO2) samples that were collected during 5 min. Statistical analysis between histograms was performed with the two-sample Kolmogorov-Smirnov test. Mean arterial blood pressure was reduced to 60 mmHg with both drugs, corresponding to a 42-43% reduction during the 25-min hypotension period. SNP-induced hypotension caused significant reduction of muscle oxygenization (compared to normotensive controls) in six of the animals, while this occurred on three occasions during adenosine administration. When comparing the histograms during hypotension, the tissue oxygenation during adenosine infusion was higher than during SNP in five and equal to SNP in three animals. Low tissue oxygen pressure values (0-0.6 kPa) were four times more frequent during SNP than during adenosine hypotension, although systemic arterial oxygen pressures were unaffected. We conclude that controlled hypotension with adenosine preserves tissue oxygen pressures better than hypotension induced by SNP.


Ontogeny of the pulmonary surfactant and antioxidant enzyme systems in the viviparous lizard, Tiliqua rugosa.
The antioxidant enzyme (AOE) system protects the lung from oxidative damage. The pulmonary surfactant (PS) system lowers the interfacial pressure within the lung, improving lung compliance and aiding lung clearance. In mammals, the AOE and PS systems develop in tandem during the final 10%-20% of gestation. Here, we investigated the development of these systems in the viviparous skink, Tiliqua rugosa. The content of total phospholipid (PL), disaturated phospholipid (DSP), and cholesterol (Chol) increased in lung washings from foetal lizards with advancing gestational age. Similarly, the relative saturation of the PLs increased throughout gestation, with mid-stage 40 foetuses having a DSP/PL equivalent to newborns and adults. Maternal lizards had significantly less total PL, DSP, and Chol than nongravid and newborn lizards; however, the relative composition did not differ from nongravid animals. This presumably results from compression of the lungs under the bulk of the developing foetus. The Chol/PL and Chol/DSP ratios declined early in development such that mid-stage 40 embryos had comparable ratios to both newborns and adults. Thus, it appears that the PS system matures in a similar manner in skinks and in mammals. However, the composition of surfactant is complete some weeks before parturition, probably to enable improved survivorship of the precocial young in the event of premature birth. Unlike the surfactant lipids, the AOEs, catalase, superoxide dismutase, and glutathione peroxidase did not differ appreciably throughout gestation. It appears therefore that like the surfactant lipids the AOE system is in readiness for air breathing throughout the latter stages of gestation, possibly in preparation for premature birth. Unlike mammals, the PS and AOE systems develop independently from one another.


Synergistic Effects of Fluconazole Combined with Doxycycline Against Dual-Species Cultures of Candida albicans and Staphylococcus epidermidis and the Mechanisms of Action.
Bacterial and fungal coinfections have posed great clinical challenges in recent years, and combination therapy may be a useful way to treat these mixed infections. The objective of this study was to find an effective drug combination to treat dual-species cultures of fungi and bacteria. In this study, we focused on poorly investigated mixed cultures of Candida albicans and Staphylococcus epidermidis. In this research, we investigated the effects of fluconazole (FLC) and doxycycline (DOX) against dual-species cultures of C. albicans and S. epidermidis. Both the fractional inhibitory concentration index model and ΔE model revealed a synergistic antimicrobial effect between FLC and DOX against the four groups of dual-species cultures. Mechanistic studies revealed that the synergism of FLC and DOX against dual-species cultures may be associated with the inhibition of biofilms and calcium dysregulation. Fluconazole+doxycycline appears to be a potential drug combination for the treatment of bacterial and fungal coinfections. These findings are of great significance for overcoming clinical bacterial and fungal coinfections and might provide novel insights into drug discovery for combination therapy.


Hemodynamic changes do not mediate the cardioprotection induced by the A1, adenosine receptor agonist CCPA in the rabbit.
Stimulation of adenosine A1 receptors is known to reduce infarct size in the rabbit heart. The aim of the present study was to verify whether a protective activity similar to that of the selective A1 receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA), could also be obtained by inducing comparable hemodynamic effects with drugs having different mechanisms of action. The effects of the beta-adrenoceptor blocker atenolol, the calcium channel blocker felodipine, the A2A-selective adenosine receptor agonist 2-hexynyl-5'-N-ethyl-carboxamidoadenosine (2HE-NECA), and the non-selective adenosine receptor agonist 5'-N-ethyl-carboxamidoadenosine (NECA) were tested. Groups of 12-15 anesthetized open-chest rabbits received a 5-min infusion of CCPA (50 micrograms kg-1 min-1), atenolol (1 mg kg-1 min-1), felodipine (50 micrograms kg-1 min-1), 2HE-NECA (1 microgram kg-1 min-1), and NECA ( 1 microgram kg-1 min-1). Myocardial infarction was induced by a 30-min occlusion of a branch of the left coronary artery, followed by 3-h reperfusion. Infarct size was measured by tetrazolium staining. In controls, infarct size was about 40% of the zone at risk. Pretreatment with CCPA induced a marked decrease in heart rate (-40%) and blood pressure (-48%), and showed antiischemic activity (28% of the zone at risk). The other drugs tested produced similar effects on either heart rate (atenolol, -25%), or blood pressure (felodipine, 2HE-NECA and NECA, about -45%), but did not affect infarct size. IN this model, the reduction in infarct size by CCPA is most likely mediated by A1 receptors, since comparable hemodynamic effects, induced by other means, are not effective. A2A receptor stimulation does not appear to exert a protective effect.


Novel inhibitor of p38 MAP kinase as an anti-TNF-alpha drug: discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent.
The p38 mitogen-activated protein (MAP) kinase has been implicated in the proinflammatory cytokine signal pathway, and its inhibitors are potentially useful for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease. To develop a new drug for RA, we synthesized a novel series of 4-phenyl-5-pyridyl-1,3-thiazoles and evaluated their inhibition of p38 MAP kinase, lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor-alpha (TNF-alpha) from human monocytic THP-1 cells in vitro, and LPS-induced TNF-alpha production in vivo in mice. During the course of the study, we found that these compounds risk the inhibition of cytochrome P450 (CYP) isoforms by coordination of the 4-pyridyl nitrogen with heme iron. We therefore investigated the effects of substitution at the 2-position of the pyridyl ring on the inhibitory activity of p38 MAP kinase and CYPs in more detail. As a result, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (8h, TAK-715) exhibited potent inhibitory activity in these assays (inhibition of p38alpha, IC50 = 7.1 nM; LPS-stimulated release of TNF-alpha from THP-1, IC50 = 48 nM; LPS-induced TNF-alpha production in mice, 87.6% inhibition at 10 mg/kg, po) and no inhibitory activity for major CYPs, including CYP3A4. This compound also showed good bioavailability in mice and rats and significant efficacy in a rat adjuvant-induced arthritis model. Compound 8h was selected as a clinical candidate and is now under clinical investigation for the treatment of RA.


Reva Rubin revisited.
A review and analysis of Reva Rubin's major publications is presented. Rubin's contributions to maternity nursing are acknowledged and questions concerning the applicability of Rubin's theories to current practice are raised. Nursing implications are drawn for contemporary nursing practice, and areas for future research are identified.


Central venous catheter-related infections in hematology and oncology: 2012 updated guidelines on diagnosis, management and prevention by the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology.
Cancer patients are at increased risk for central venous catheter-related infections (CRIs). Thus, a comprehensive, practical and evidence-based guideline on CRI in patients with malignancies is warranted. A panel of experts by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) has developed a guideline on CRI in cancer patients. Literature searches of the PubMed, Medline and Cochrane databases were carried out and consensus discussions were held. Recommendations on diagnosis, management and prevention of CRI in cancer patients are made, and the strength of the recommendation and the level of evidence are presented. This guideline is an evidence-based approach to the diagnosis, management and prevention of CRI in cancer patients.


Process performance of dry, batch anaerobic digestion of sewage sludge: methanogenic seed mixtures.
A dry, batch anaerobic digestion (DBAD) process was tested on two sewage sludge types with different methanogenic seed fractions under laboratory conditions. The aim was to indicate optimal sludge:seed mixing ratios and analyse process performance based on degradation rate and reactor-specific methane production. The attained results were compared with the performance of a liquid-state, laboratory-scale stirred reactor (SR). A mixing ratio of at least 1:1.25 (sludge:seed) yielded processes free from significant inhibitions. Further seeding increments resulted in slightly better performances, but much lower sludge fractions treated in the reactors. Compared with the SR process, the DBAD reactors produced comparable degradation rates albeit in a significantly longer process and with somewhat lower reactor-specific methane production rates. These findings indicate that the DBAD method may provide a viable alternative to liquid-state processes if sludge drying is already applied and reactor volume requirements are of importance.


[Indication rules of Baliao points based on the clinical literature research].
To summarize the indication rules of Baliao points (bilateral BL 31, 32, 33 and 34) based on the clinical literature research. The relevant articles of clinical research on the treatment with Baliao points were retrieved electronically from CNKI (1979 to 2017), VIP (1989 to 2017), CBM (1979 to 2017) and PubMed (1966 to 2017). The paper were collected and analyzed. The indications, common therapeutic methods, common acupoint combination, treatment frequency, treatment duration and therapeutic effects of Baliao points were summarized. A total 160 articles were collected, of them, 43.75% (70/160) of the articles were related to the treatment of urinary diseases, followed by the gynecological diseases (34/160, 21.25%), proctologic diseases (23/160, 14.38%) and motor system diseases (16/160, 10.00%). Regarding the individual disease, the articles for post-stroke urination disorder were of the highest proportion (26/160, 16.25%), followed by neurogenic bladder induced by spinal injury (15/160, 9.38%), dysmenorrheal (14/160, 8.75%) and constipation (14/160, 8.75%). Regarding the therapeutic method, the electroacupuncture intervention accounts for 30.36% (34/112), followed by the common acupuncture (30/112, 26.79%), warm acupuncture (11/112, 9.82%) and tuina therapy (9/112, 8.04%). The treatment was given commonly once a day. The point combinations and the treatment duration were different in terms of individual case. The effective rates of common disorders were up to over 75%. In clinic, Baliao points are mainly used for the disorders in the urinary system, gynecological department, proctology department, motor system, andrology department, etc., or for particular diseases. The main indications are post-stroke urination disorder, neurogenic bladder induced by spinal injury, dysmenorrheal and constipation. Regarding the therapeutic method, electroacupuncture and common needling techniques are adopted generally. The treatment is given generally once a day. The point combination and treatment duration are different in individual case. The treatment with Baliao points is high in the effective rates for the common disorders, good in safety and less in adverse reactions.


Visualization and Quantification of Digitally Dissected Muscle Fascicles in the Masticatory Muscles of Callithrix jacchus Using Nondestructive DiceCT.
The organization and length of a muscle's fascicles imparts its contractile properties. Longer fascicles permit increased muscle excursion, whereas changes in fascicle orientation relate to the overall vector of contractile force. Collecting data on fascicle architecture has traditionally involved destructive and irreversible gross dissection. In recent years, however, new imaging modalities have permitted muscles and their fascicles to be visualized nondestructively. Here, we present data from a primate (Callithrix jacchus), in which, for the first time, individual muscle fascicles are digitally "dissected" (segmented and reconstructed) using nondestructive, high-resolution diffusible iodine-based contrast-enhanced computed tomography (DiceCT) techniques. We also present quantitative data on the length and orientation of these fascicles within 10 muscle divisions of the jaw adductor and abductor musculature (superficial, deep, and zygomatic portions of temporalis and masseter; medial and lateral pterygoid; anterior and posterior digastric) and compare these digitally measured lengths to fascicular lengths measured using traditional gross and chemical dissection. Digitally derived fascicle lengths correspond well to their dissection-derived counterparts. Moreover, our analyses of changes in fascicle orientation across the adductor complex enable us to visualize previously uncharacterized levels of detail and highlight significant variation between adjacent muscle layers within muscle groups (e.g., between superficial, deep, and zygomatic portions of masseter and temporalis). We conclude that this technique offers great potential to future research, particularly for questions centered around the visualization and quantification of obscured and often-overlooked muscles such as the pterygoid and digastric muscles, and for deriving more accurate models of the masticatory system as a whole. Anat Rec, 302:1891-1900, 2019. © 2019 American Association for Anatomy.


[Effects of Amlodipine/Lisinopril Fixed-Dose Combination on Severity of Left Ventricular Hypertrophy and Parameters of Myocardial Stiffness in Patients With Hypertension].
To assess effects of 12 weeks treatment with the amlodipine/lisinopril fixed-dose combination (ALFDC) on the left ventricular (LV) mass index (LVMI), parameters of LV and left atrial stiffness. At phase 1 of the study we examined 44 healthy subjects (21 men, 23 women, mean age 51.5+/-1.0 years) and 60 untreated patients (31 men, 29 women, mean age 53.6+/-0.8 years) with stage II grade 1-2hypertension. Myocardial stiffness parameters, LVMI were calculated using data of transthoracic echocardiography. 2-D speckle tracking echocardiography was used for determination of LV myocardial global longitudinal peak strain (GLPS). All participants underwent ambulatory blood pressure (BP) monitoring, and office BP measurement. At phase 2 a subgroup of 30 untreated patients (16 men, 14 women; mean age 52.7+/-1.11years) received ALFDC in a start dose of 5 mg/10 mg titrated every 14 days to achieve BP<140/90 mm Hg. Therapy in selected doses was continued for 12 weeks thereafter. In hypertensive patients LV GLPS was significantly lower while LA stiffness index higher compared with controls (17.08+/-0.38 vs. 19.91+/-0.41%, p<0.001, and 0.20+/-0.01 vs. 0.16+/-0.01, p<0.01, respectively). There were no significant differences in the LA tissue Doppler derived strain, LV end-systolic elastance, LA expansion index between hypertensive and control groups. After ALFDC therapy BP was significantly (p<0.001) reduced: systolic (S)BP from 154.4+/-2.7 to 130.6+/-1.2, diastolic (D)BP from 96.5+/-1.3 to 83.0+/-0.5 mm Hg. After therapy LV GLPS, LA expansion index, LV diastolic elastance significantly increased (from 17.10+/-0.57 to 18.29+/-0.35%, p<0.01; from 1.47+/-0.08 to 1.68+/-0.08, p<0.001; from 9.25+/-0.99 [10-2] to 10.88+/-1.0 8 [10-2], p<0.05, respectively) while LVMI, LV end-diastolic stiffness, and LA stiffness index significantly (p<0.001) decreased (from 129.4+/-4.5 to 111.8+/-3.3 g/m2, from 0.16+/-0.01 to 0.12+/-0.01 mm Hg/ml, from 0.21+/-0.02 to 0.15+/-0.01, respectively). Change in the LA tissue Doppler derived strain correlated with the change in dynamics of nighttime SBP (r=-0.410, p<0.05). There was direct relationship between change in LV diastolic elastance and nighttime DBP (r=0.424; p<0.05); and an inverse correlation between changes in LV end-diastolic stiffness and dynamics of the daytime SBP and DBP (r=-0.404; p<0.05 and r=-0.364; p<0.05, respectively). Change of LVMI after ALFDC treatment correlated with dynamics of 24-hour, daytime SBP, and daytime pulse pressure (r=0.382, p<0.05, r=0.478, p<0.01, and r=0.364, p<0.05, respectively). In untreated patients with stage II, 1-2 degree hypertension 12-week therapy with ALFDC allowed to achieve target BP levels, reduced severity of LV hypertrophy and improved stiffness parameters of the myocardium.


3D Nitrogen, Sulfur-Codoped Carbon Nanomaterial-Supported Cobalt Oxides with Polyhedron-Like Particles Grafted onto Graphene Layers as Highly Active Bicatalysts for Oxygen-Evolving Reactions.
The extensive research and developments of highly efficient oxygen electrode electrocatalysts to get rid of the kinetic barriers for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) are very important in energy conversion and storage devices. Especially, exploring nonprecious metal alternatives to replace traditional noble metal catalysts with high cost and poor durability is the paramount mission. In this paper, we utilize property-flexible ZIF-67 and sulfur-functionalized graphene oxide to obtain a cobalt, nitrogen, and sulfur codoped nanomaterial with 3D hierarchical porous structures, owing to their rich dopant species and good conductivity. The crosslinked structures of polyhedron particles throughout the whole carbon framework speeds up the mass transportation and charge-delivery processes during oxygen-evolving reactions. Also, by exploring the location and coordination type of sulfur dopants, we emphasize the effects of sulfone and sulfide functional groups anchored into the graphitic structure on enhancing the catalytic abilities for ORR and OER. To note, compared to the noble metal electrocatalysts, the best-performing CoO@Co3O4/NSG-650 (0.79 V) is 40 mV less active than the commercial Pt/C catalyst (0.83 V) for ORR and merely 10 mV behind IrO2 (1.68 V) for OER. Besides, the metric between ORR and OER difference for CoO@Co3O4/NSG-650 to evaluate its overall electrocatalytic activity is 0.90 V, surpassing 290 and 430 mV over Pt/C (1.19 V) and IrO2 (1.33 V). Comprehensively, the as-prepared CoO@Co3O4/NSG-650 indicates excellent bifunctional catalytic activities for ORR and OER, which shows great potential for replacing noble metal catalysts in the application of fuel cells and metal-air batteries.


The T-cell leukemia related rpl10-R98S mutant traps the 60S export adapter Nmd3 in the ribosomal P site in yeast.
Mutations in the ribosomal protein Rpl10 (uL16) can be drivers of T-cell acute lymphoblastic leukemia (T-ALL). We previously showed that these T-ALL mutations disrupt late cytoplasmic maturation of the 60S ribosomal subunit, blocking the release of the trans-acting factors Nmd3 and Tif6 in S. cerevisiae. Consequently, these mutant ribosomes do not efficiently pass the cytoplasmic quality control checkpoint and are blocked from engaging in translation. Here, we characterize suppressing mutations of the T-ALL-related rpl10-R98S mutant that bypass this block and show that the molecular defect of rpl10-R98S is a failure to release Nmd3 from the P site. Suppressing mutations were identified in Nmd3 and Tif6 that disrupted interactions between Nmd3 and the ribosome, or between Nmd3 and Tif6. Using an in vitro system with purified components, we found that Nmd3 inhibited Sdo1-stimulated Efl1 activity on mutant rpl10-R98S but not wild-type 60S subunits. Importantly, this inhibition was overcome in vitro by mutations in Nmd3 that suppressed rpl10-R98S in vivo. These results strongly support a model that Nmd3 must be dislodged from the P site to allow Sdo1 activation of Efl1, and define a failure in the removal of Nmd3 as the molecular defect of the T-ALL-associated rpl10-R98S mutation.


[Radiation-induced constrictive pericarditis. Associated cardiac lesions, therapy and follow-up].
To evaluate the diagnostic and therapeutic problems that occur in managing patients with radiation-induced constrictive pericarditis. Radiation therapy of the chest and mediastinum can damage all cardiac structures, the pericardium being the most frequently involved one. It is little appreciated, however, that radiation-induced constrictive pericarditis can be associated with significant involvement of coronary arteries, myocardium and valves. Retrospective evaluation of clinical, hemodynamic, surgical and postoperative data in 8 patients, (7 women, 1 man, aged 26-67 years, mean 44), who had received 30-50 Gy to the chest because of Hodgkin's disease, lymphoma, or breast cancer 7-23 years before the diagnosis of constrictive pericarditis. Six patients had symptoms related to the pericardial disease, one had angina and syncope, one was in congestive heart failure. Hemodynamic signs of constriction were obvious in 6, and were revealed by volume load in 2. All patients had mitral regurgitation, 5 had also tricuspid insufficiency and 5 had aortic regurgitation. The degree of the valvular regurgitation was > or = 3+ in four instances. Critical coronary arterial stenoses were discovered in 3 cases. The coronary ostia were involved in 5 cases (2 critical, 3 non critical). A diagnosis of restrictive cardiomyopathy was arrived at in 4 instances, always after pericardiectomy. Seven patients were operated on: there were 6 pericardiectomies, associated with either valvular surgery or myocardial revascularization or both in 3. One patient underwent myocardial revascularization only. The remaining patient is being treated medically. One patient died at surgery, two died 16 and 72 months thereafter. The remaining 5 have mild symptoms 11-60 months (mean 29) after the discharge from the hospital. Radiation-induced pericardial constriction is frequently associated with coronary artery disease, mostly silent, with valvular insufficiency, and with myocardial disease. Thorough cardiac evaluation in such patients is mandatory. Surgical treatment frequently uncovers an underlying restrictive myopathy that presents a serious diagnostic and therapeutic challenge.


Cap Analysis of Gene Expression Clarifies Transcriptomic Divergence Within Monozygotic Twin Pairs.
Phenotypic variation is the result of gene expression based on complex interaction between genetic and environmental factors. It is well known that genetic and environmental factors influence gene expression, but our understanding of their relative importance remains limited. To obtain a hint for the understanding of their contributions, we took advantage of monozygotic twins, as they share genetic and shared environmental factors but differ in nonshared factors, such as environmental differences and stochastic factors. In this study, we performed cap analysis of gene expression on three pairs of twins and clustered each individual based on their expression profiles of annotated genes. The dendrogram of annotated gene transcripts showed a monophyletic clade for each twin pair. We also analyzed the expression of retrotransposons, such as human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs), given their abundance in the genome. Clustering analyses demonstrated that HERV and LINE expression diverged even within monozygotic twin pairs. Thus, HERVs and LINEs are more susceptible to nonshared factors than annotated genes. Motif analysis of differentially expressed annotated genes suggests that specificity protein/Krüppel-like factor family transcription factors are involved in the expression divergence of annotated gene influenced by nonshared factors. Collectively, our findings suggest that expressions of annotated genes and retrotransposons are differently regulated, and that the expression of retrotransposons is more susceptible to nonshared factors than annotated genes.


DENV-2 subunit proteins fused to CR2 receptor-binding domain (P28)-induces specific and neutralizing antibodies to the Dengue virus in mice.
Domain III (DIII) of the dengue virus (DENV) envelope (E) protein induces strong neutralizing type-specific antibodies. In addition, a region near the fusion loop in domain II (DII) induces the production of cross-reactive antibodies with neutralizing potential. Thus, this study aimed to generate DENV-2 recombinant fusion proteins (i.e., rEII*EIII and rEII*EIII/NS1*) either alone or fused to 3 copies of P28, the minimum CR2-binding domain of the complement protein C3d. The 4 recombinant proteins were generated in a Drosophila melanogaster Schneider 2 (S2) cell system. The expression and secretion of the recombinant proteins were confirmed in vitro using immunofluorescence (IF) and western blot (WB) analyses. Human dengue immune serum samples recognized recombinant proteins. The immunogenicity of the 4 proteins in BALB/c mice was analyzed using ELISA, and the results revealed that the induced specific antibody response was higher in the groups of mice immunized with the P28 fusion proteins. Interestingly, although the 4 recombinant proteins were able to elicit high levels of neutralizing antibodies in BALB/c mice; no adjuvant effect was observed in terms of neutralizing antibodies in the groups immunized with proteins containing P28. Thus, ELISA and PRNT50 assays may evaluate different epitopes and responses, where ELISA showed a wider response that did not always correlate with neutralization. Furthermore, the elicited antibodies were able to recognize the immobilized E glycoprotein of DENV. All mice vaccinated with the DENV-2 recombinant proteins showed induction of higher levels of IgG1 antibodies than of IgG2a antibodies.


Methacrylate dressing on refractory venous leg ulcers.
Chronic leg ulcers can have a major impact on the quality of life of patients. These wounds can be complex and hard to heal, as several factors may affect the outcome. Underlying conditions, bacterial growth and excess moisture may prevent wounds from healing. We describe the case of a patient with known chronic venous disease, who was admitted to our hospital for several complex, irregular and infected chronic venous ulcers in his lower legs. The management was frustrating for several months, until we began to use methacrylate powder dressing for his hard-to-heal wounds.


[Preparation and characteristics of small intestinal submucosa].
To review the research advance of the preparation and characteristics of small intestinal submucosa(SIS). Recent original articles related to such aspects of small intestinal submucosa were reviewed extensively. Small intestinal submucosa was an easily obtained biomaterial. SIS was a bio-absorbable and degradable material. SIS had tissue specific regeneration properties. SIS is a suitable bio-derived material for tissue engineering of blood vessel, muscle tendon, urinary bladder and abdomen.


Construction of a cDNA fragment library from SH-SY5Y cells using restriction display PCR.
A complementary DNA (cDNA) fragment library from SH-SY5Y cells is constructed using a restriction display polymerase chain reaction (RD-PCR) technique. Messenger RNA (mRNA) is extracted from SH-SY5Y cells and single-strand cDNA synthesised using an anchored oligo primer (dT18). The second strand is produced by nick translation. The double strands are cleaved with the restriction enzyme Sau3AI and the fragments ligated with universal linker. The products are amplified with universal primers and selected primers, ligated into the pMDI8-T vector, and then sequenced. The library constructed contained 136 subgroups, each comprising seven to 12 cDNA fragments. RD-PCR proved a simple, effective way to construct a cDNA library, and this will contribute to the investigation of gene expression in the neuron in future microarray studies.


Chiral squaramide-catalysed enantioselective Michael/cyclization cascade reaction of 3-hydroxyoxindoles with α,β-unsaturated N-acylated succinimides.
A bifunctional squaramide-catalysed asymmetric Michael/cyclization cascade reaction of 3-hydroxyoxindoles with α,β-unsaturated N-acylated succinimides is disclosed. With quinine-derived squaramide as the catalyst, a broad range of the desired spirooxindole lactone derivatives bearing two contiguous stereocenters were obtained in good yields (up to 89%) with high diastereoselectivities (up to >95 : 5 dr) and excellent enantioselectivities (up to 99% ee).


Identification and functional analysis of CG3526 in spermatogenesis of Drosophila melanogaster.
Spermatogenesis is a critical part of reproduction in insects; however, its molecular mechanism is still largely unknown. In this study, we identified a testis-specific gene CG3526 in Drosophila melanogaster. Bioinformatics analysis showed that CG3526 contains a zinc binding domain and 2 C2 H2 type zinc fingers, and it is clustered to the vertebrate really interesting new gene (RING) family E3 ubiquitin-protein ligases. When CG3526 was knocked down by RNA interference (RNAi), the testis became much smaller in size, and the apical tip exhibited a sharp and thin end instead of the blunt and round shape in the control testis. More importantly, compared to the control flies, only a few mature sperm were present in the seminal vesicle of C587-Gal4 > CG3526 RNAi flies. Immunofluorescence staining of the testis from CG3526 RNAi flies showed that the homeostasis of testis stem cell niche was disrupted, cell distribution in the apical tip was scattered, and the process of spermatogenesis was not completed. Furthermore, we found that the phenotype of CG3526 RNAi flies' testis was similar to that of testis of Stat92E RNAi flies, the expression level of CG3526 was significantly downregulated in the Stat92EF06346 mutant flies, and the promoter activity of CG3526 was upregulated by STAT92E. Taken together, our results indicated that CG3526 is a downstream effector gene in the JAK-STAT signaling pathway that plays a key role in the spermatogenesis of Drosophila.


Competition among the axonal projections of an identified neuron contributes to the retraction of some of those projections.
AP neurons in the embryonic leech CNS extend lateral projections to peripheral targets through the ganglionic nerve roots and longitudinal projections toward neighboring ganglia through the connective nerves. The lateral projections grow extensively in the periphery; in contrast, the longitudinal projections achieve relatively little growth and eventually retract, the majority having essentially disappeared by the end of embryogenesis. Cutting both nerve roots, which eliminates both lateral projections, however, induces the longitudinal projections of the AP neuron to begin to grow rapidly toward adjacent ganglia within 14 hr after the axotomy. By using a laser microbeam to cut just the lateral projections of the AP cells, we further show that it is indeed the loss of its lateral projections, and not a secondary response to the cutting of other components of the root nerves, that induces the longitudinal projections of the AP cell to grow extensively. In addition, we report that reducing the outgrowth of the lateral projections by: (1) cutting only one lateral projection, or (2) ablating pioneer neurons required by the AP neuron to establish its peripheral arbor, also results in a significant increase in the growth of the longitudinal projections. Finally, we demonstrate that increasing the outgrowth of the longitudinal projections by ablating the AP cells in adjacent ganglia results in a significant reduction in the outgrowth of the lateral projections. Taken together, these results indicate, first, that the longitudinal and lateral projections usually grow at the expense of each other, and second, that normally the extensive outgrowth of its lateral projections is a necessary condition for a developing AP neuron to retract its longitudinal projections.


Preliminary data concerning association of porphyria cutanea tarda and adrenocortical insufficiency. Report of two cases.
The paper presents two cases in which clinical and laboratory investigations have revealed the simultaneous presence of porphyria cutanea tarda (PCT) and adrenocortical insufficiency (ACI). Whether this association is a coincidence, whether there is a common cause, or a "cause to effect" type relationship between the two entities is a question of debate. Without ignoring other possible causes (tuberculosis, hemochromatosis, autoimmunity, drugs) it is suggested that heme deficit consequent to inefficient protoporphyrin synthesis results in impaired steroidogenesis, due to decreased levels of adrenocortical hemoprotein enzymes, especially cytochrome P-450 dependent hydroxylases. Cytochrome P-450 has a well known sine-qua-non activity in steroid hydroxylations within steroid tissues, and a decrease in the levels of this heme-enzyme might be expected to result in impaired steroidogenesis. However, the association between PCT and ACI (whether pathogenic or not) is pathophysiologically characterized by the coexistence of a disease (PCT) in which the anatomo-clinical manifestations are determined by oxygen derived free radicals ( ODFR ), and a disease (ACI) which, among other consequences, presents a marked reduction in ODFR -scavenge capacity. The authors consider this supposition an attractive working hypothesis, suitable to further clinical laboratory direct testing.


Analyte flux through chronically implanted subcutaneous polyamide membranes differs in humans and rats.
The rat is commonly used to evaluate physiological responses of subcutaneous tissue to implanted devices. In vivo longevity of various devices and the biocompatibility of biomaterials depend on how adjacent tissue interacts. How closely the rat model predicts the human response has not been well characterized. The objective of this study was to compare rat and human subcutaneous foreign body responses by monitoring the biochemical environment at a polymer-tissue interface over 8 days using microdialysis. Polyamide microdialysis probes were implanted subcutaneously in humans and rats (n = 12). Daily microdialysis samples were analyzed for glucose, lactate, pyruvate, glycerol, and urea. Blood glucose was also monitored. Analyte concentrations differed significantly between rats and humans at the implant-tissue interface. There were also qualitative differences in the 8-day trends. For example, over 8 days, microdialysate glucose increased two- to fourfold in humans but decreased in rats (P < 0.001). This study reveals profound physiological differences at material-tissue interfaces in rats and humans and highlights the need for caution when extrapolating subcutaneous rat biocompatibility data to humans.


Heterogeneous Network Switching Strategy Based on Communication Blind Area Dwell Time.
The limitation of indoor visible light coverage and the attenuation of its signal when propagating in line-of-sight has seriously affected the stable communication of receiving devices when users move randomly and also aggravated the power consumption of visible light networking systems. According to the above situation, on the basis of the heterogeneous networking of visible light communication (VLC) and RF communication integration, this article proposes a horizontal-vertical collaborative handover strategy based on the communication blind area dwell time (CBD-HVHO). Combining asymmetrically clipped optical orthogonal frequency division multiplexing (ACO-OFDM) technology with networking handover technology, ACO-OFDM is used to determine the indoor communication blind area by calculating the bit error rate (BER) value at the signal receiver while reducing the multipath interference generated by visible light signals during channel transmission. To achieve this, set the communication blind channel interruption time as the threshold time, compare the communication blind area dwell time with the threshold time, and finally combine the horizontal and vertical collaborative handover strategies based on the communication blind area dwell time. The simulation results show that the handover probability is 0.009, the average number of handovers is 1.006, and the average network throughput is 195.2826 Mbps. Compared with the previously proposed immediate vertical handover (I-VHO) scheme and the dwell vertical handover (D-VHO) scheme, the communication stability is significantly improved, and the power consumption of the network system is reduced to a certain extent.


Na(+)-K(+)-ATPase gene expression during in vitro development of rat fetal forebrain.
The existence of at least three isoforms of Na(+)-K(+)-ATPase in adult brain tissues [alpha 1, kidney type; alpha 2 [or alpha(+)]; alpha 3] suggests that these genes might be regulated in a cell-specific and time-dependent manner during development. We have studied this question in serum-free aggregating cell cultures of mechanically dissociated rat fetal telencephalon. At the protein level, the relative rate of synthesis of the pool of alpha 1-, alpha 2-, and alpha 3-subunits increased approximately twofold over 15 days of culture, leading to a marked increase in the immunochemical pool of alpha-subunits as measured by a panspecific polyclonal antibody. Concomitantly, Na(+)-K(+)-ATPase enzyme-specific activity increased three- (lower forebrain) to sixfold (upper forebrain). The transcripts of all three alpha-isoforms and beta-subunit were detected in vitro in similar proportion to the level observed in vivo. alpha 3-mRNA (3.7 kb) was more abundant than alpha 1 (3.7 kb) or alpha 2 (5.3 and 3.4 kb). Cytosine arabinoside (0.4 microM) and cholera toxin (0.1 microM) were used to selectively eliminate glial cells or neurons, respectively. It was found that alpha 2-mRNA is predominantly transcribed in glial cell cultures, whereas alpha 3- and beta 1-mRNA (2.7, 2.3, and 1.8 kb) are predominant in neuronal cultures.


The biology of the Gaucher cell: the cradle of human chitinases.
Gaucher disease (GD) is the most common lysosomal storage disorder and is caused by inherited deficiencies of glucocerebrosidase, the enzyme responsible for the lysosomal breakdown of the lipid glucosylceramide. GD is characterized by the accumulation of pathological, lipid laden macrophages, so-called Gaucher cells. Following the development of enzyme replacement therapy for GD, the search for suitable surrogate disease markers resulted in the identification of a thousand-fold increased chitinase activity in plasma from symptomatic Gaucher patients and that decreases upon successful therapeutic intervention. Biochemical investigations identified a single enzyme, named chitotriosidase, to be responsible for this activity. Chitotriosidase was found to be an excellent marker for lipid laden macrophages in Gaucher patients and is now widely used to assist clinical management of patients. In the wake of the identification of chitotriosidase, the presence of other members of the chitinase family in mammals was discovered. Amongst these is AMCase, an enzyme recently implicated in the pathogenesis of asthma. Chitinases are omnipresent throughout nature and are also produced by vertebrates in which they play important roles in defence against chitin-containing pathogens and in food processing.


An analysis of interactions between fluorescently-tagged mutant and wild-type SOD1 in intracellular inclusions.
By mechanisms yet to be discerned, the co-expression of high levels of wild-type human superoxide dismutase 1 (hSOD1) with variants of hSOD1 encoding mutations linked familial amyotrophic lateral sclerosis (fALS) hastens the onset of motor neuron degeneration in transgenic mice. Although it is known that spinal cords of paralyzed mice accumulate detergent insoluble forms of WT hSOD1 along with mutant hSOD1, it has been difficult to determine whether there is co-deposition of the proteins in inclusion structures. In the present study, we use cell culture models of mutant SOD1 aggregation, focusing on the A4V, G37R, and G85R variants, to examine interactions between WT-hSOD1 and misfolded mutant SOD1. In these studies, we fuse WT and mutant proteins to either yellow or red fluorescent protein so that the two proteins can be distinguished within inclusions structures. Although the interpretation of the data is not entirely straightforward because we have strong evidence that the nature of the fused fluorophores affects the organization of the inclusions that form, our data are most consistent with the idea that normal dimeric WT-hSOD1 does not readily interact with misfolded forms of mutant hSOD1. We also demonstrate the monomerization of WT-hSOD1 by experimental mutation does induce the protein to aggregate, although such monomerization may enable interactions with misfolded mutant SOD1. Our data suggest that WT-hSOD1 is not prone to become intimately associated with misfolded mutant hSOD1 within intracellular inclusions that can be generated in cultured cells.


Having a Regular Primary Care Provider Is Associated With Improved Markers of Well-Being Among Children With Attention-Deficit Hyperactivity Disorder.
We examined the association between having a regular primary care physician (PCP) and measures of flourishing and academic success in children with attention-deficit hyperactivity disorder (ADHD). We performed a cross-sectional study using data from the 2011-2012 National Survey of Children's Health. Children aged 6 to 17 years with a diagnosis of ADHD were included in the study (n = 8173). The exposure was whether the guardian identified a regular PCP for their child. The outcomes were parental-reported measures of child well-being and academic performance. Among the study population, 8.9% reported no regular PCP. These children were found to be significantly less likely to finish assigned tasks (adjusted odds ratio [OR] = 0.52, 95% confidence interval [CI] = 0.35-0.79), care about school (adjusted OR = 0.62, 95% CI = 0.38-0.92), and finish homework (adjusted OR = 0.58, 95% CI = 0.36-0.88). There were no differences in other examined outcomes. Enhancing longitudinal care for this population may optimize their academic performance.


Referred pain from myofascial trigger points in head, neck, shoulder, and arm muscles reproduces pain symptoms in blue-collar (manual) and white-collar (office) workers.
To describe the prevalence and referred pain area of trigger points (TrPs) in blue-collar (manual) and white-collar (office) workers, and to analyze if the referred pain pattern elicited from TrPs completely reproduces the overall spontaneous pain pattern. Sixteen (62% women) blue-collar and 19 (75% women) white-collar workers were included in this study. TrPs in the temporalis, masseter, upper trapezius, sternocleidomastoid, splenius capitis, oblique capitis inferior, levator scapulae, scalene, pectoralis major, deltoid, infraspinatus, extensor carpi radialis brevis and longus, extensor digitorum communis, and supinator muscles were examined bilaterally (hyper-sensible tender spot within a palpable taut band, local twitch response with snapping palpation, and elicited referred pain pattern with palpation) by experienced assessors blinded to the participants' condition. TrPs were considered active when the local and referred pain reproduced any symptom and the patient recognized the pain as familiar. The referred pain areas were drawn on anatomic maps, digitized, and measured. Blue-collar workers had a mean of 6 (SD: 3) active and 10 (SD: 5) latent TrPs, whereas white-collar workers had a mean of 6 (SD: 4) active and 11 (SD: 6) latent TrPs (P>0.548). No significant differences in the distribution of active and latent TrPs in the analyzed muscles between groups were found. Active TrPs in the upper trapezius, infraspinatus, levator scapulae, and extensor carpi radialis brevis muscles were the most prevalent in both groups. Significant differences in referred pain areas between muscles (P<0.001) were found; pectoralis major, infraspinatus, upper trapezius, and scalene muscles showed the largest referred pain areas (P<0.01), whereas the temporalis, masseter, and splenius capitis muscles showed the smallest (P<0.05). The combination of the referred pain from TrPs reproduced the overall clinical pain area in all participants. Blue-collar and white-collar workers exhibited a similar number of TrPs in the upper quadrant musculature. The referred pain elicited by active TrPs reproduced the overall pain pattern. The distribution of TrPs was not significantly different between groups. Clinicians should examine for the presence of muscle TrPs in blue-collar and white-collar workers.


Sequence analysis and transcriptional organization of the Rhodopseudomonas viridis cytochrome c2 gene.
The cytochrome c2 gene (cycA) of the purple nonsulfur bacterium Rhodopseudomonas viridis was isolated from a genomic library by using two degenerate oligonucleotides containing all possible DNA sequences predicted from the published amino acid sequence of this protein (Ambler et al., Proc. Natl. Acad. Sci. USA 73:472-475, 1976). Cloning and sequence analysis of the cytochrome c2 gene indicated the presence of a typical procaryotic 20-residue signal peptide, suggesting that this periplasmic protein in synthesized in vivo as a precursor. In addition, four amino acids were found to be different by comparing the published sequence of the mature protein with that deduced from the isolated cycA gene (Lys-14----Leu, Ser-46----Ala, Ile-84----Val, Leu-97----Ile). Northern (RNA) blot analysis and fine mapping of the 5' and 3' ends of the cycA gene transcript from photoheterotrophically grown R. viridis cells revealed one abundant transcript of 523 to 530 nucleotides in length, with the transcription start site at position -39 relative to the coding region of cytochrome c2. A low-abundance transcript with an extended 3' end (about 600 bases in length) is thought to be processed by exonucleases, resulting in the slightly shorter main transcript.


[Endonasal endoscopic approach in the treatment of sino-nasal inverted papillomas].
Sino-nasal inverted papilloma is a rare benign tumor of the nasal fossa and the paranasal sinuses for which the successful surgical treatment by an endonasal approach has been corroborated in the literature. Nevertheless, the authors aim in this study to evaluate the advantages and the limits of this approach, to analyse its failures and its recurrences, and to define the indications for using it with the external or dissimulated approach. 42 patients presenting with a sino-nasal inverted papilloma and treated surgically over a ten year period were included in this retrospective study. The operative technique was chosen as a function of the endonasal and radiological examination results (CT scan and MRI). Follow-up was over one year for all patients. Twenty eight patients were operated exclusively through an endoscopic endonasal approach. Fourteen patients were operated using a combined approach, associating either a vestibular (9 cases), a paralateral nasal (3 cases) or a fronto-orbital (2 cases) approach with endonsal endoscopy. In two cases, an associated squamous cell carcinoma was found. We observed a recurrence in 9.5% of the all cases and in 14.2% of the patients treated using a combined approach. Endoscopic endonasal surgery is a validated surgical approach for the treatment of sino-nasal inverted papilloma in that total tumor removal is possible. This approach is particularly indicated in medially-situated papillomas without frontal or maxillary extension. In all other cases, associating an external or dissimulated approach is usually necessary.


17 beta-Estradiol increases intracellular free calcium concentrations of human vascular endothelial cells and modulates its responses to acetylcholine.
In this study, we have investigated the effect of 17 beta-estradiol (E2) on intracellular free calcium concentrations ([Ca2+]i) in human umbilical vein endothelial cells (HUVEC) using fura-2 fluorescence. E2 at concentrations of 1nM -1 microM was added subsequently to HUVEC cultures which were either deprived of estrogens or preincubated with E2 (100 nM) for 24 hours. In both groups of cultures, E2 stimulated significant increases in [Ca2+]i in a dose-dependent manner. The effects were more prominent in E2-deprived cells. Preincubation of cells with tamoxifen or the presence of it in the buffer during the experiments did not inhibit the response of the cells to E2. Experiments performed in Ca2+ free/EGTA buffer yielded transient increases in [Ca2+]i suggesting release of Ca2+ from intracellular stores was responsible for the initial peak, while sustained elevations were supported by Ca2+ influx from the extracellular space. Addition of La3+ abolished the sustained [Ca2+]i elevations. Carbachol (CCh) (1nM, 100 nM) did not induce changes in [Ca2+]i of estrogen-deprived cells but produced significant increases in [Ca2+]i of the same cells after incubation with E2 for 30 minutes. The cultures which were preincubated with E2 for 24 hours responded to carbachol directly. The results of our study indicate that E2 may modulate the functions of endothelial cells after only a brief exposure and also may be necessary for the response to acetylcholine especially at low concentrations.


[History of scurvy therapy and the injustice done to Dr. Maksim Nikolić-Miskovićev of Sremski Karlovci in the 19th century].
This paper reviews historical aspects regarding medical knowledge on scurvy, vitamin C deficiency, and its etiological factors. This disease used to affect naval-crews on long lasting sea voyages, soldiers during times of war and the poor. Although efficient therapy of scurvy (fresh vegetables, lemon juice) was known in the mid-18th century, its etiology was not known. It was believed to be caused by the cold, moist winds, unhealthy evaporations, malnutrition and it was called "alkaline disease". It was established that acid substances like lemon juice, had beneficial effects on the disease. However, it was soon generally accepted that it was caused by deficient diet. In 1830, Dr. John Elliotson, Professor of Medicine at London University supported this opinion. In 1928, Albert Szent Gyordyi, professor of Chemistry and Biochemistry at Szeged and Budapest Universities, isolated vitamin C from green pepper, vegetable proved to be rich with vitamin C. Due to this discovery, and some discoveries regarding biological processes, he was awarded the Nobel Prize for medicine and physiology in 1937. Back in 1864, a military doctor in Belgrade, Dr. Maksim Nikolić-Miskovićev from Sremski Karlovci, wrote to Ministry of Defence of the Serbian Principality. He informed the authorities about a successful, quick and cheap cure for scurvy-pepper juice. A medical board headed by Dr. Vladan Dordević was formed to evaluate his discovery. Dr. Nikolić-Miskovićev was underestimated and laughed at, and his discovery was completely forgotten. The aim of this paper was to correct injustice done to Dr. Maksim Nikolić-Miskovićev.


Thermoresponsive coatings strongly adhering to (semi)conducting surfaces.
Thermoresponsive brushes have been efficiently grafted onto (semi)conductive surfaces by a two-step process. In the first step, poly(N-succinimidyl acrylate) chains have been chemisorbed onto silicon or stainless steel by the electrografting method. Then, these modified electrodes were immersed in isopropylamine in order to transform the grafted chains to the thermoresponsive poly(N-isopropyl acrylamide). The thermal response of these brushes has been shown by AFM. This straightforward grafting process is quite attractive for surface modification in confined media and is thus promising for microfludics application.


Environment is not the most important variable in determining oral morphine consumption in Wistar rats.
The role of differential housing on sucrose-morphine consumption in outbred Wistar rats was investigated in two studies. The results of earlier research, indicating rats housed in a quasinatural colony drank significantly less sucrose-morphine than rats isolated in standard laboratory cages, could not be replicated, as the consumption of sucrose-morphine by the isolated animals in the present two studies was reduced. It is possible that during a colony conversion the supplier inadvertently introduced strain differences making the present rats more resistant to xenobiotic consumption. Discussion documents the role of genetics in morphine consumption.


Comparison of the roex and gammachirp filters as representations of the auditory filter.
Although the rounded-exponential (roex) filter has been successfully used to represent the magnitude response of the auditory filter, recent studies with the roex(p, w, t) filter reveal two serious problems: the fits to notched-noise masking data are somewhat unstable unless the filter is reduced to a physically unrealizable form, and there is no time-domain version of the roex(p, w, t) filter to support modeling of the perception of complex sounds. This paper describes a compressive gammachirp (cGC) filter with the same architecture as the roex(p, w, t) which can be implemented in the time domain. The gain and asymmetry of this parallel cGC filter are shown to be comparable to those of the roex(p, w, t) filter, but the fits to masking data are still somewhat unstable. The roex(p, w, t) and parallel cGC filters were also compared with the cascade cGC filter [Patterson et al., J. Acoust. Soc. Am. 114, 1529-1542 (2003)], which was found to provide an equivalent fit with 25% fewer coefficients. Moreover, the fits were stable. The advantage of the cascade cGC filter appears to derive from its parsimonious representation of the high-frequency side of the filter. It is concluded that cGC filters offer better prospects than roex filters for the representation of the auditory filter.


Acute effects of feeding fructose, glucose and sucrose on blood lipid levels and systemic inflammation.
Recent studies have demonstrated a relationship between fructose consumption and risk of developing metabolic syndrome. Mechanisms by which dietary fructose mediates metabolic changes are poorly understood. This study compared the effects of fructose, glucose and sucrose consumption on post-postprandial lipemia and low grade inflammation measured as hs-CRP. This was a randomized, single blinded, cross-over trial involving healthy subjects (n=14). After an overnight fast, participants were given one of 3 different isocaloric drinks, containing 50 g of either fructose or glucose or sucrose dissolved in water. Blood samples were collected at baseline, 30, 60 and 120 minutes post intervention for the analysis of blood lipids, glucose, insulin and high sensitivity C-reactive protein (hs-CRP). Glucose and sucrose supplementation initially resulted in a significant increase in glucose and insulin levels compared to fructose supplementation and returned to near baseline values within 2 hours. Change in plasma cholesterol, LDL and HDL-cholesterol (measured as area under curve, AUC) was significantly higher when participants consumed fructose compared with glucose or sucrose (P<0.05). AUC for plasma triglyceride levels however remained unchanged regardless of the dietary intervention. Change in AUC for hs-CRP was also significantly higher in subjects consuming fructose compared with those consuming glucose (P<0.05), but not sucrose (P=0.07). This study demonstrates that fructose as a sole source of energy modulates plasma lipids and hsCRP levels in healthy individuals. The significance of increase in HDL-cholesterol with a concurrent increase in LDL-cholesterol and elevated hs-CRP levels remains to be delineated when considering health effects of feeding fructose-rich diets. ACTRN12614000431628.


Mesoscopic Mechanical Properties of Aggregate Structure in Asphalt Mixtures and Gradation Optimization.
Particle media are widely used in engineering and greatly influence the performance of engineering materials. Asphalt mixtures are multi-phase composite materials, of which coarse aggregates account for more than 60%. These coarse aggregates form a stable structure to transfer and disperse traffic loads. Therefore, knowing how to adjust the structural composition of coarse aggregates to optimize their performance is the key to optimize the performance of asphalt mixtures. In this study, the effects of different roughness and different sizes on the interlocking force and contact force of coarse aggregates were investigated through means of simulation (DEM), and then the formation-evolution mechanism of the coarse aggregate structure and the role of different sizes of aggregates in the coarse aggregate structure were analyzed. Subsequently, the optimal ratio of coarse aggregates was explored through indoor tests, and finally, the gradation of asphalt mixture based on the optimization of fine structure was formed and verified through indoor tests. The results showed that the major model can effectively reveal the role of different types of aggregates in the fine structure and the relationship between the strength of contact forces between them and clarify that the strength of the fine structure increases with the increase in aggregate roughness. Hence, the coarse aggregate structure can be regarded as a contact force transmission system composed of some strong and sub-strong contact forces. Their formation-evolution mechanism can be regarded as a process of the formation of strong and sub-strong contact forces and the transformation from sub-strong contact force to strong contact force. Moreover, the dynamic stability of the optimized graded asphalt mixture was increased by 30%, and the fracture toughness was increased by 26%.


Overview of antibody therapy in B-cell non-Hodgkin's lymphoma.
The main treatment modalities for lymphoma in the past decade have been radiation therapy and chemotherapy. Recently, molecular engineering provided humanized antibodies with promising clinical activity, and rituximab is the first commercially available antibody. This anti-CD20 monoclonal antibody (MoAb) showed little toxicity and demonstrated excellent clinical activity. Given as a single agent, it induces a high-response rate even in pretreated low-grade non-Hodgkin's lymphoma, the effect being higher if administered for a prolonged period of time. Its action is synergistic with chemotherapy, and combination treatment could improve survival in patients with aggressive lymphomas. Rituximab also demonstrated the ability to clear tumor cells from the circulation, allowing for an in vivo purging effect in the setting of peripheral stem cell collection and transplantation. Still, a number of issues related to its use need to be addressed, such as optimal dose and schedule and the situations in which rituximab should be given as a single agent or in addition to chemotherapy or other drugs, such as other MoAbs or interferons. We also need to understand when rituximab should be used in first-line treatment, with which type of chemotherapy the combination is most cost-effective, and patient population that will benefit most from this antibody treatment.


Effects of Local Sequence, Reaction Conditions, and Various Additives on the Formation and Stability of Interstrand Cross-Links Derived from the Reaction of an Abasic Site with an Adenine Residue in Duplex DNA.
The experiments described here examined the effects of reaction conditions, various additives, and local sequence on the formation and stability interstrand cross-links (ICLs) derived from the reaction of an apurinic/apyrimidinic (AP) site with the exocyclic amino group of an adenine residue on the opposing strand in duplex DNA. Cross-link formation was observed in a range of different buffers, with faster formation rates observed at pH 5. Inclusion of the base excision repair enzyme alkyladenine DNA glycosylase (hAAG) which binds tightly to AP-containing duplexes decreased, but did not completely prevent, formation of the dA-AP ICL. Formation of the dA-AP ICL was not altered by the presence of the biological metal ion Mg2+ or the biological thiol, glutathione. Several organocatalysts of imine formation did not enhance the rate of dA-AP ICL formation. Duplex length did not have a large effect on dA-AP yield, so long as the melting temperature of the duplex was not significantly below the reaction temperature (the duplex must remain hybridized for efficient ICL formation). Formation of the dA-AP ICL was examined in over 40 different sequences that varied the neighboring and opposing bases at the cross-linking site. The results indicate that ICL formation can occur in a wide variety of sequence contexts under physiological conditions. Formation of the dA-AP ICL was strongly inhibited by the aldehyde-trapping agents methoxyamine and hydralazine, by NaBH3CN, by the intercalator ethidium bromide, and by the minor groove-binding agent netropsin. ICL formation was inhibited to some extent in bicarbonate and Tris buffers. The dA-AP ICL showed substantial inherent stability under a variety of conditions and was not a substrate for AP-processing enzymes APE1 or Endo IV. Finally, we characterized cross-link formation in a small (11 bp) stem-loop (hairpin) structure and in DNA-RNA hybrid duplexes.


Basal Cell Carcinoma with Myoepithelial Differentiation: Case Report and Literature Review.
Basal cell carcinoma is the most common skin cancer. Myoepithelial cells are specialized epithelial cells. Basal cell carcinoma with myoepithelial differentiation is a rare tumor. A 71-year-old man with a basal cell carcinoma with myoepithelial differentiation that presented as an asymptomatic red papule of two months duration on his forehead is described. Including the reported patient, this variant of basal cell carcinoma has been described in 16 patients: 11 men and five women. The patients ranged in age at diagnosis from 43 years to 83 years; the median age at diagnosis was 66 years. All of the tumors were located on the face-most were papules or nodules of less than 10 x 10 mm. Their pathology demonstrated two components: one was that of a typical basal cell carcinoma and the other was myoepithelioma-like in which the tumor cells were plasmacytoid or signet ring in appearance and contained abundant eosinophilic cytoplasm or hyaline inclusions or both. The myoepithelial tumor cells had variable immunohistochemical expression that included not only cytokeratin but also actin, glial fibrillary acid protein, S100, and vimentin. The most common clinical impression, prior to biopsy, was a basal cell carcinoma. The pathologic differential diagnosis included cutaneous mixed sweat gland tumor of the skin, myoepithelioma, myoepithelial carcinoma, and tumors that contain a prominent signet ring cell component (such as metastatic gastrointestinal and breast carcinoma, melanoma, plasmacytoid squamous cell carcinoma, and T-cell lymphoma). Mohs micrographic surgical excision, with complete removal of the tumor, was recommended for treatment of the carcinoma.


Comparison of ESHG2016 and AAP2017 hypertension guidelines in adolescents between the ages of 13 and 16: effect of body mass index on guidelines.
The diagnosis of hypertension in adolescents aged ≥13 and <16 years is based on the percentile according to age, gender, and height in the European Society of Hypertension guidelines guideline; whereas, the American Academy of Pediatrics guideline uses blood pressure above 130/80 mmHg as a single criterion. Therefore, this study aimed to evaluate the compatibility of these two guidelines in adolescents aged ≥13 and <16 years. This study was designed by retrospectively screening the records of 395 adolescents with both office and 24-hour ambulatory blood pressure measurements. Each blood pressure measurement was classified according to both the ESGH2016 and AAP2017 guidelines. Patients were divided into three subgroups according to body mass index. Cohen's kappa analysis was used to evaluate the agreement between the two guidelines. The majority of adolescents were normotensive according to both guidelines, 55.9% by ESHG2016 and 43.1% by AAP2017. For the whole group, the frequency of hypertension was 32.4% with ESHG2016 and 34.4% with AAP2017; while, in obese patients, hypertension frequencies were 38.8% and 43.3%, respectively. The diagnosis of hypertension was demonstrated with the two guidelines, and there was significant agreement at a substantial level, both for the obese subgroup and the whole study group (kappa value = 0.738 and 0.785, respectively). The frequency of white-coat hypertension was higher with the AAP2017 guideline (28.1% versus 16.2%, p < 0.001). With our experience in this single-centre study, it seems that both the AAP2017 and the ESHG2016 guidelines can be used in the diagnosis of hypertension in adolescents.