Changes in inositol lipid metabolism and protein kinase C translocation in nuclei of mitogen stimulated Swiss 3T3 cells.
The correlation between changes in nuclear polyphosphoinositide levels preceding PKC translocation to the nucleus and the onset of DNA synthesis has been discussed. Using two different clones of Swiss 3T3 fibroblasts belonging to the same original cell line, one of which is unresponsive to mitogenic stimulation with IGF-I on its own or in combination with bombesin, it has been observed that a rapid and transient breakdown of nuclear PIP and PIP2 occurs only in responsive cells and this precedes the translocation of PKC to the nucleus, as evidenced by immunochemical analysis as well as by enzymatic activity. Therefore, it seems that a direct link exists between nuclear polyphosphoinositide metabolism, PKC translocation to the nucleus and cell division. Since IGF-I acts at the plasma membrane through a tyrosine kinase receptor it seems that the mitogenic stimulation induced by this factor utilizes different signalling pathways at the plasma membrane and at the nucleus. Because of the evidence that type I IGF receptor is expressed in both responsive and unresponsive cells and that the receptor machinery at the plasma membrane is active the lack of the transient changes in nuclear inositol lipids and of PKC translocation in unresponsive cells further suggests that the cell nucleus is capable of an autonomous signalling system based on polyphosphoinositide metabolism.


Differentiation of human embryonic stem cells toward the chondrogenic lineage.
Human embryonic stem cells (hESCs) have the ability to self-replicate and differentiate into cells from all three embryonic germ layers, thereby holding great promise for tissue regeneration applications. However, controlling the differentiation of hESCs and obtaining homogenous differentiated cell populations still remain a challenge. We present a highly efficient and reproducible experimental system that mimics the three-dimensional (3-D) environment of in vivo chondrogenesis and that supports the directed differentiation of human embryoid body (EB)-derived cells toward the chondrogenic lineage under serum-free chondrogenic culture conditions in the presence of bone morphogenetic protein-2 (BMP-2).


Body-weight variability and risk of cardiovascular outcomes in patients with type 1 diabetes: a retrospective observational analysis of data from the DCCT/EDIC population.
Cardiovascular risk and body-weight management are both emerging challenges of type 1 diabetes care. We evaluated the association between intraindividual variability of body-weight and risk of cardiovascular events in people with type 1 diabetes. We analyzed 1,398 participants from the DCCT/EDIC studies. Five indices of intraindividual variability of body-weight were calculated for each participant taking into account body-weight measures obtained during the DCCT follow-up (average 6 ± 2 years). The Average Successive Variability (ASV) index, the main variable of interest, was defined as the average absolute difference between successive body-weight measures. The primary outcome was a composite of major adverse cardiovascular events (MACE: nonfatal myocardial infarction or stroke, or cardiovascular death) occurring during the subsequent EDIC follow-up (20 ± 3 years). All-cause death was a secondary outcome. Risk of outcomes were assessed by Cox proportional hazards regression analyses, adjusted for traditional cardiovascular risks factors, including BMI. The cumulative incidence of MACE and all-cause death during follow-up were 5.6% (n = 79) and 6.8% (n = 95), respectively. The adjusted Hazard Ratio (HR) for MACE by every increase of 1 standard deviation (SD) of ASV was 1.34 (95% CI, 1.06-1.66), p = 0.01. For all-cause death, the adjusted HR for 1 SD increase of ASV was 1.25 (1.03-1.50), p = 0.03. Similar results were observed when considering the other indices of intraindividual variability of body-weight. High body-weight variability (body-weight cycling) is associated with increased risk of MACE and all-cause death in people with type 1 diabetes, independently of the BMI and traditional cardiovascular risk factors.


Murine mesothelin: characterization, expression, and inhibition of tumor growth in a murine model of pancreatic cancer.
Mesothelin has attracted much interest as a tumor specific antigen; it has been reported to promote tumor development and to be a good target for cancer treatment. Most studies to date have used human mesothelin in immunocompromised mice. Since these models do not allow for study of the natural immune response to mesothelin expressing tumors, we have undertaken the characterization of mouse mesothelin so the effects of this protein can be assessed in immunocompetent mouse strains. We analyzed mouse mesothelin expression, tissue distribution, shedding and biochemistry. In addition we constructed stable mesothelin overexpressing lines of the pancreatic cancer line Panc02 by two methods and tested them for growth and tumorigencity in vitro and in vivo. We show here that mouse mesothelin is similar to human mesothelin in biochemical characteristics, tumor expression and tissue distribution, suggesting the mouse may be a suitable model for study of mesothelin. Stable overexpression of mesothelin in a pancreatic cancer cell line did not increase cell proliferation or anchorage-independent growth in vitro, suggesting that mesothelin is not necessarily a tumor progression factor. Surprisingly overexpression of mesothelin inhibited tumor formation in vivo in immunocompetent mice. The mouse may be a good model for studying mesothelin in the context of an intact immune response. Mesothelin is not necessarily a tumor progression factor, and indeed mesothelin overexpression inhibited tumor growth in immunocompetent mice.


TERT promoter mutations in primary and secondary glioblastomas.
Telomerase reverse transcriptase (TERT) is up-regulated in a variety of human neoplasms. Mutations in the core promoter region of the TERT gene, which increases promoter activity, have been reported in melanomas and a variety of human neoplasms, including gliomas. In the present study, we screened for TERT promoter mutations by direct DNA sequencing in a population-based collection of 358 glioblastomas. TERT promoter mutations (C228T, C250T) were detected in 55 % glioblastomas analysed. Of these, 73 % had a C228T mutation, and 27 % had a C250T mutation; only one glioblastoma had both C228T and C250T mutations. TERT promoter mutations were significantly more frequent in primary (IDH1 wild-type) glioblastomas (187/322; 58 %) than in secondary (IDH1 mutated) glioblastomas (10/36, 28 %; P = 0.0056). They showed significant inverse correlations with IDH1 mutations (P = 0.0056) and TP53 mutations (P = 0.043), and a significant positive correlation with EGFR amplification (P = 0.048). Glioblastoma patients with TERT mutations showed a shorter survival than those without TERT mutations in univariate analysis (median, 9.3 vs. 10.5 months; P = 0.015) and multivariate analysis after adjusting for age and gender (HR 1.38, 95 % CI 1.01-1.88, P = 0.041). However, TERT mutations had no significant impact on patients' survival in multivariate analysis after further adjusting for other genetic alterations, or when primary and secondary glioblastomas were separately analysed. These results suggest that the prognostic value of TERT mutations for poor survival is largely due to their inverse correlation with IDH1 mutations, which are a significant prognostic marker of better survival in patients with secondary glioblastomas.


Adhesion and rupture of liposomes mediated by electrostatic interaction monitored by thickness shear mode resonators.
Adhesion and spreading of negatively charged unilamellar vesicles composed of POPG/POPC and DPPG/DPPC on positively charged self-assembly monolayers of 11-amino-1-undecanethiol were monitored by means of thickness shear mode (TSM) resonators with a fundamental frequency of 5 MHz. Changes of frequency and motional resistance upon vesicle adsorption were recorded as a function of surface charge density and lyotropic phase state of the lipids. From the readout of the TSM resonator, changes of the shape of the vesicles as well as the formation of supported lipid bilayers can be inferred in a quantitative manner. Increasing surface charge densities on the vesicles, which are tunable by the POPG content, led to decreasing frequency and resistance changes. At very high PG content, a lower limit of 3-12 Hz was found, indicative of the formation of planar bilayers due to vesicle rupture induced by the strong electrostatic interaction forces. Vesicles composed of DPPG/DPPC were less susceptible to deformation and rupture, a fact that can be attributed to the higher bending rigidity of DPPG/DPPC liposomes. More than 70 mol% of DPPG were needed to induce adhesion-controlled rupture of surface-attached vesicles, while only 30-50% of POPG were sufficient to form planar lipid bilayers on the quartz.


The importance of post hoc approaches for overcoming non-response and attrition bias in population-sampled studies.
Population-based health studies are critical resources for monitoring population health and related factors such as substance use, but reliable inference can be compromised in various ways. Non-response and attrition are major methodological problems which reduce power and can hamper the generalizability of findings if individuals who participate and who remain in a study differ systematically from those who do not. In this issue of SPPE, McCabe et al. studied participants of the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions, comparing attrition in Wave 2 across participants with different patterns of substance use at Wave 1. The implications of differential follow-up and further possibilities for addressing selective participation are discussed.


Arsenite-induced ROS/RNS generation causes zinc loss and inhibits the activity of poly(ADP-ribose) polymerase-1.
Arsenic enhances the genotoxicity of other carcinogenic agents such as ultraviolet radiation and benzo[a]pyrene. Recent reports suggest that inhibition of DNA repair is an important aspect of arsenic cocarcinogenesis, and DNA repair proteins such as poly(ADP ribose) polymerase (PARP)-1 are direct molecular targets of arsenic. Although arsenic has been shown to generate reactive oxygen/nitrogen species (ROS/RNS), little is known about the role of arsenic-induced ROS/RNS in the mechanism underlying arsenic inhibition of DNA repair. We report herein that arsenite-generated ROS/RNS inhibits PARP-1 activity in cells. Cellular exposure to arsenite, as well as hydrogen peroxide and NONOate (nitric oxide donor), decreased PARP-1 zinc content, enzymatic activity, and PARP-1 DNA binding. Furthermore, the effects of arsenite on PARP-1 activity, DNA binding, and zinc content were partially reversed by the antioxidant ascorbic acid, catalase, and the NOS inhibitor, aminoguanidine. Most importantly, arsenite incubation with purified PARP-1 protein in vitro did not alter PARP-1 activity or DNA-binding ability, whereas hydrogen peroxide or NONOate retained PARP-1 inhibitory activity. These results strongly suggest that cellular generation of ROS/RNS plays an important role in arsenite inhibition of PARP-1 activity, leading to the loss of PARP-1 DNA-binding ability and enzymatic activity.


Transcriptome Analysis of Gossypium hirsutum L. Reveals Different Mechanisms among NaCl, NaOH and Na2CO3 Stress Tolerance.
As an important source of fiber and edible oil, cotton has great economic value. In comparison to their individual studies, association and differentiation between salt and alkaline tolerance has not been focused yet by scientists. We have used next-generation RNA-Seq technique to analyze transcriptional changes under salt and alkaline stresses in cotton. Overall, 25,929 and 6,564 differentially expressed genes (DEGs) were identified in roots and leaves, respectively. Gene functional annotation showed that genes involving ionic homeostasis were significantly up-regulated under NaCl stress and Na2CO3 stress, and genes enriched in starch and sucrose metabolism were up-regulated under NaOH stress and Na2CO3 stress. Furthermore, a synergistic enhancing effect between NaCl and NaOH stress was also observed in this study. Likewise, our studies indicate further that genes related with starch and sucrose metabolism were regulated to respond to the high pH under Na2CO3 stress, inducing plant hormone signal transduction and key enzyme reactive oxygen species (ROS) activity to respond to ionic toxicity and intracellular ionic homeostasis. By analyzing the expression profiles of diverse tissues under different salt and alkaline stresses, this study provides valuable ideas for genetic improvements of cotton tolerance to salt-alkaline stress.


Effects of rolipram and CI-930 on IL-2 mRNA transcription in human Jurkat cells.
Interleukin-2 (IL-2) is a major mediator of immunologic responses involved in many chronic inflammatory diseases. We have investigated the effects of rolipram, a PDE-IV inhibitor, and CI-930, a PDE-III inhibitor, on IL-2 gene expression in the Jurkat human T cell line. The immunosuppressant cyclosporin A (CsA) was included as a positive control. Jurkat cells were stimulated with 1 microgram/ml phytohemagglutinin (PHA) and 50 ng/ml phorbol 12-myristate, 13-acetate (PMA) for 6 h, and mRNA was analyzed using reverse transcription and polymerase chain reaction (RT/PCR). IL-2 transcription was greatly inhibited by 1 microM CsA, whereas neither 10 microM rolipram nor 10 microM CI-930 had any effect on steady-state levels of IL-2 mRNA. Therefore, PDE inhibitors do not affect synthesis of IL-2 mRNA in this model of activated T cells. This is of interest given that these agents inhibit the proliferation of primary T cells. For murine splenocytes stimulated by 2.5 micrograms/ml concanavalin A (Con A), rolipram had an IC50 of 0.09 microM and CI-930 an IC50 of 4.4 microM. These concentrations are below those at which IL-2 mRNA synthesis was shown to be unaffected. Therefore, the mechanism by which inhibitors of PDE-III and PDE-IV affect T cell proliferation is not likely to involve suppression of IL-2 mRNA transcription.


Seeding efficiency, plating efficiency, and population doublings of human skin fibroblastlike cells: results of replicate testing.
Using skin fibroblastlike cells from 10 healthy volunteers, 12 to 54 yr old, we measured, in replicates, seeding efficiency (SE), plating efficiency (PE), and population doublings (PD) during 2 wk of growth and the cumulative replicative life span (CRLS). We determined the effects of donor age and of in vitro cell age on the test results and test precision. We found that (a) On the average, SE was 82% +/- 24 SD, PE was 12% +/- 9 SD, PD was 7.3 doublings +/- 2.5 SD, and CRLS was 31.1 doublings +/- 9.6 SD. (b) Plating efficiency and PD correlated well with each other and with CRLS whereas SE did not correlate with PE, PD, or CRLS. (c) Plating efficiency and PD were affected negatively by increasing passage levels and by donor ages, but the influence of age was evident only for cells from early passages. Seeding efficiency was not affected by either of the two variables. (d) Variations in PD from early passages explained half of the donor-to-donor variation in CRLS whereas PD from later passages had little or no predictive power. (e) Of the two short term tests, PD had better precision than PE. For replicate runs with cells from early passages the coefficient of variation was 44% for PE and 15% for PD. The results show that PD for cells from early passages in mass culture give rapid results, which express the in vitro replicating potential of cells from different donors with greater precision than do measurements of CRLS.


Toxoplasmosis transmitted to a newborn from the mother infected 20 years earlier.
To present a case of congenital toxoplasmosis in a newborn whose mother had a 20-year history of a chorioretinal macular scar and positive serology for toxoplasmosis. Case report. SETTING/RESULTS: A 38-year-old woman who had been treated for ocular toxoplasmosis 20 years earlier delivered a newborn who presented with a focal necrotizing retinochoroiditis characteristic of toxoplasmosis, as well as positive immunoglobulin (Ig) G and M serology for toxoplasmosis. The workup was negative for other entities. This case suggests that women with old retinal scars due to toxoplasmosis and long-standing IgG antibodies to toxoplasmosis are also at risk of transmitting this disease to the fetus.


Ruptured heterotopic pregnancy presenting with relative bradycardia in a woman not receiving reproductive assistance.
We report a case of heterotopic pregnancy in a woman who had not undergone in vitro fertilization or any other reproductive assistance. The patient failed to mount a tachycardic response to hemorrhagic shock. Bradycardia is a well-established phenomenon in the setting of hemoperitoneum and particularly with ruptured ectopic pregnancy. This is a case of heterotopic pregnancy with relative bradycardia in a woman without predisposing factors for heterotopic pregnancy. We make suggestions on avoiding common pitfalls in the emergency department diagnosis of heterotopic pregnancy. We also address the similar clinical presentations of heterotopic pregnancy and intrauterine pregnancy with ruptured corpus luteum cyst.


Efficient delivery of dsRNA into zona-enclosed mouse oocytes and preimplantation embryos by electroporation.
Conditions for the electroporation of mouse oocytes and preimplantation embryos have been optimised by following the incorporation of rhodamine labeled dextran. This procedure includes a step to weaken but not remove the zona pellucida that helps achieve good survival. This approach has been applied to introduce double-stranded RNA for c-mos into oocytes and green fluorescent protein (GFP) into transgenic GFP-expressing embryos at the 1- and 4-cell stages. In both cases we were able to observe sequence-specific interference with the expression of the target gene--a failure of oocytes to arrest at metaphase II and a loss in the green fluorescence of embryos by the morula or blastocyst stages. These effects could be observed in multiple oocytes or embryos allowed to develop together following electroporation.


Topography of carotid bifurcation: considerations for neck examination.
Clinical examination and surgical procedures require the knowledge of anatomical structures of such a complex area as neck, especially the developmental anomalies in vascular drainage may occur. The aim of this study was to describe the common carotid artery bifurcation to its surrounding structures to locate it properly by using external and internal landmarks. Measurements were performed on 43 Thai cadavers by the direct inspection method. Carotid bifurcation level was compared to the level of cervical vertebra, isthmus of thyroid cartilage, angle of mandible and origins of superior thyroid artery, and lingual artery. Most of carotid bifurcations were found at the level of C3, between C3 and C4, and C4 vertebra, as well as the tendency to lower position in men was noted. Measurements to the angle of mandible on the left sides were significantly different in studied groups (P = 0.02), also with lower position of bifurcation in men. The mean level of carotid bifurcation was approximately 6 mm above ITC, which literally is at the level of the superior border of thyroid cartilage. Moreover, in four cases, common carotid artery did not bifurcate bilaterally, and in four cases, no bifurcations were found at the right side of neck. Further, many superior thyroid arteries originated from common carotid artery. To sum up, during the clinical procedures, the level of thyroid cartilage is mostly advised to follow to locate the carotid sinus. Further, the described variations in topography of carotid bifurcation and arteries origins may have important clinical implications.


A new type of antiserum to thyrotropin-releasing hormone; detection of new TRH-immunoreactive cell groups in rat hypothalamus.
We produced a new type of antiserum to thyrotropin-releasing hormone (TRH) in rabbits. The immunogen is TRH-BSA, the production of which is based on the formation of an amide bond using carbodiimide (EDC). The specificity of the antiserum was assessed by enzyme immunoassay (EIA) and immunohistochemistry. When using the anti-TRH serum for immunohistochemistry in rat hypothalamus, new magnocellular groups were detected in the ventrolateral parts of the posterior hypothalamus and the dorsal parts of the third ventricle. Colchicine treatment was found not to be necessary to visualize perikarya containing TRH.


FGF2 and FGF10 expression patterns in the epidermis and mesenchyme during homeotic transformation of tail into hindlimbs in frog tadpoles.
Limbs are trunk quintessential in tetrapods. Their development relies on the Retinoic acid (RA) gradient in association with the Fibroblast Growth Factors (FGFs). The role of various FGFs have been probed extensively and confirmed during the induction of ectopic limbs in vertebrates. On such factual backdrops, we studied the expression patterns of FGF2 and FGF10 in the epidermis and mesenchyme by immunohistochemical localization in the regenerating tails of tadpoles of the Indian tree frog, Polypedates maculatus. These tadpoles are known to exhibit a kind of homeotic transformation of tail to limbs during regeneration, whose exact mechanism is still to be established by scientific investigations. Here in this study, we provide the first evidence of the putative involvement of FGF2 and FGF10 during such ectopic appendage development.


Effect of adenotonsillectomy on attention deficit-hyperactivity disorder in children with adenotonsillar hypertrophy: A prospective cohort study.
This study was conducted to explore the effect of adenotonsillectomy on the improvement of attention deficit hyperactivity disorder (ADHD) symptoms in children with adenotonsillar hypertrophy. This prospective cohort study was conducted on 59 children aged 6-12 years with adenotonsillar hypertrophy and ADHD who were candidates for adenotonsillectomy at Besat Hospital, Hamadan University of Medical Sciences, in 2014. The status of ADHD was evaluated at baseline and one and three months after surgery using Conners' Rating Scales. Of 59 children with ADHD (35 boys and 24 girls), 41 improved one month after surgery and 51 after three months. Only 8 children had no improvement. The Conners' score decreased significantly from 71.37 at baseline to 61.31 (P = 0.001) and 49.14 (P = 0.001) one and three months after surgery, respectively. The score of attention deficit and hyperactivity decreased from 1.76 and 2.10 at baseline to 1.52 and 1.83 after one month (P = 0.001) and to 1.24 and 1.52 after three months (P = 0.001), respectively. The results were statistically significant for both boys and girls. This study indicated that adenotonsillectomy can significantly improve ADHD in children with adenotonsillar hypertrophy and help them return to normal life.


Blood hormone levels related to stages and grades of prostatic cancer.
Human follicle stimulating hormone (FSH), human luteinizing hormone (LH), human prolactin, testosterone, estradiol, and sex hormone binding globulin (SHBG) were measured in the blood of 100 consecutive new patients with prostatic carcinoma. According to the VACURG classification, 14% of the patients were in Stage I, 25% in Stage II, 25% in Stage III, and 36% in Stage IV. Within each stage the tumors were further subdivided into either highly, moderately, or poorly differentiated carcinomas. Thus the whole group consisted of 12 categories (stages and grades) of prostatic carcinoma. No specific hormonal pattern emerged which could distinguish any particular category or group of categories. We, therefore, conclude that single hormone measurements are of no practical value for diagnostic purposes related to staging and grading of prostatic carcinoma.


Evaluation of SERS labeling of CD20 on CLL cells using optical microscopy and fluorescence flow cytometry.
Immunophenotyping of lymphoproliferative disorders depends on the effective measurement of cell surface markers. The inherent light-scattering properties of plasmonic nanoparticles (NPs) combined with recent developments in NP design may confer significant advantages over traditional fluorescence probes. We report and evaluate the use of surface-enhanced Raman scattering (SERS) gold NPs (AuNPs) conjugated to therapeutic rituximab antibodies for selective targeting of CD20 molecules. SERS AuNPs were prepared by adsorbing a Raman-active dye onto the surface of 60 nm spherical AuNPs, coating the particles with 5 kDa polyethylene glycol, and conjugating rituximab to functional groups on polyethylene glycol. The effective targeting of CD20 on chronic lymphocytic leukemia cells by rituximab-conjugated SERS AuNPs was evaluated by dark-field imaging, Raman spectroscopy, and flow cytometry with both competitive binding and fluorescence detection procedures. Evidence of CD20 clustering within approximately 100 nm was observed. This study discusses the use of surface enhancement Raman scattering (SERS)-based plasmonic gold nanoparticles, which can be used for cell specific labeling. In this example rituximab, a commercially available CD20 humanized monoclonal antibody is used. Dark field imaging, Raman spectroscopy and flow cytometry was utilized to demonstrate the sensitive labeling capability of these gold nanoparticle based hybrid nanodevices.


Biologic principles of minced cartilage implantation: a narrative review.
Cartilage tissue has a very limited ability to regenerate. Symptomatic cartilage lesions are currently treated by various cartilage repair techniques. Multiple treatment techniques have been proposed in the last 30 years. Nevertheless, no single technique is accepted as a gold standard. Minced cartilage implantation is a newer technique that has garnered increasing attention. This procedure is attractive because it is autologous, can be performed in a single surgery, and is therefore given it is cost-effective. This narrative review provides an overview of the biological potential of current cartilage regenerative repair techniques with a focus on the translational evidence of minced cartilage implantation.


Role of non-receptor protein tyrosine kinases in spermatid transport during spermatogenesis.
Non-receptor protein tyrosine kinases are cytoplasmic kinases that activate proteins by phosphorylating tyrosine residues, which in turn affect multiple functions in eukaryotic cells. Herein, we focus on the role of non-receptor protein tyrosine kinases, most notably, FAK, c-Yes and c-Src, in the transport of spermatids across the seminiferous epithelium during spermatogenesis. Since spermatids, which are formed from spermatocytes via meiosis, are immotile haploid cells, they must be transported by Sertoli cells across the seminiferous epithelium during the epithelial cycle of spermatogenesis. Without the timely transport of spermatids across the epithelium, the release of sperms at spermiation fails to occur, leading to infertility. Thus, the molecular event pertinent to spermatid transport is crucial to spermatogenesis. We provide a critical discussion based on recent findings in this review. We also provide a hypothetical model on spermatid transport, and the role of non-receptor protein tyrosine kinases in this event. We also highlight areas of research that deserve attention by investigators in the field.


Rice-arsenate interactions in hydroponics: a three-gene model for tolerance.
In this study, the genetic mapping of the tolerance of root growth to 13.3 muM arsenate [As(V)] using the BalaxAzucena population is improved, and candidate genes for further study are identified. A remarkable three-gene model of tolerance is advanced, which appears to involve epistatic interaction between three major genes, two on chromosome 6 and one on chromosome 10. Any combination of two of these genes inherited from the tolerant parent leads to the plant having tolerance. Lists of potential positional candidate genes are presented. These are then refined using whole genome transcriptomics data and bioinformatics. Physiological evidence is also provided that genes related to phosphate transport are unlikely to be behind the genetic loci conferring tolerance. These results offer testable hypotheses for genes related to As(V) tolerance that might offer strategies for mitigating arsenic (As) accumulation in consumed rice.


Experience with a medical education research group at the Mayo Clinic.
Clinician-educators are encouraged to engage in scholarly activity despite numerous barriers to conducting educational research. We found no reports of formal educational research groups among general internists. To evaluate a Scholarship in Medical Education Group (SIMEG) for general internists. The setting is a Division of General Internal Medicine at a large academic medical center. In 2005 twenty-two faculty members formed SIMEG to collaborate on educational research and award protected days for scholarly education projects. Through monthly dialogue and literature review, standards for critiquing educational research were created. A total of 63 protected days were awarded to successful applicants. SIMEG members' curriculum vitae were monitored over two years. From 2005 to 2006, SIMEG members' presentations (15 to 29; p=0.125), peer-reviewed publications (8 to 27; p=0.016) and collaborative projects (19 to 42; p=0.047) increased. Our educational research group enjoyed improving scholarly productivity over two years. Keys to success were supportive leadership, a culture of collaboration, creating a useful framework for critiquing research, and involving medical learners as co-investigators. Since faculty members are pressured to teach and care for patients while maintaining scholarly productivity, groups like SIMEG should become increasingly valued.


A simple computational model of the evolution of a communicative trait and its phenotypic plasticity.
We consider a simple computational model of the evolution of a quantitative trait and its phenotypic plasticity based on directional and positive frequency-dependent selection in order to explore whether and how leaning might facilitate evolution under the dynamics that arise from communicative interactions among individuals. In the model, each individual expresses, at many different times in its lifetime, its real-valued trait depending on the probability distribution determined by its own genotypes. In communicative interactions between two individuals, the contribution of an interaction to the fitness is high when their trait values are close to each other as well as large, which represents the positive frequency-dependent and directional components of selection, respectively. The iterative interactions allow individuals to acquire a more adaptive trait pair through trial and error. Under the stochastic evolution process with the limited number of individuals, we show that learning allows the population to avoid getting stuck in the global but low optimum of the innate and individual-level fitness landscape via both aspects of the components of selection, and brings about the successful evolution by increasing the genetic variation of the population. We also analyze how such an effect of learning can be realized by measuring the degree of the two different contributions for increasing the adaptivity and similarity of communicative traits, respectively. We show that this effect of learning arises from these different types of contributions depending on the biological and environmental conditions such as the mutation rate and the duration of communicative interactions. We further show the condition for the complete genetic assimilation to occur.


A randomised controlled trial of the sirolimus-eluting biodegradable polymer ultra-thin Supraflex stent versus the everolimus-eluting biodegradable polymer SYNERGY stent for three-vessel coronary artery disease: rationale and design of the Multivessel TALENT trial.
The purpose of the Multivessel TALENT trial is to compare clinical outcomes of the novel Supraflex Cruz stent with those of the SYNERGY stent in patients with three-vessel disease (3VD) undergoing state-of-the-art percutaneous coronary intervention (PCI). In this prospective, randomised, 1:1 balanced, multicentre, open-label trial, 1,550 patients with de novo 3VD without left main disease will be assigned to the Supraflex Cruz or SYNERGY arm. The following treatment principles of "best practice" PCI will be applied: Heart Team consensus based on SYNTAX score II treatment recommendation, functional lesion evaluation by quantitative flow ratio (QFR), stent optimisation by intravascular imaging, optimal pharmacological treatment and prasugrel monotherapy. The primary endpoint is a non-inferiority comparison of the patient-oriented composite endpoint (POCE) of all-cause death, any stroke, any myocardial infarction, or any revascularisation, at 12 months post procedure. The powered secondary endpoint is a superiority comparison of the vessel-oriented composite endpoint (VOCE), defined as vessel-related cardiovascular death, vessel-related myocardial infarction, or clinically and physiologically indicated target vessel revascularisation, at 24 months. The Multivessel TALENT trial will be evaluating a novel treatment strategy for complex coronary artery disease with state-of-the-art PCI based on angiography-derived QFR with novel ultra-thin Supraflex Cruz stents, compared with SYNERGY stents. Clinical Trial Registration URL: https://www.clinicaltrials.gov/ct2/show/NCT04390672. Unique Identifier: NCT04390672


The role of oxidative damage in cataract etiopathogenesis.
Cataract usually occurs due to age and diabetes, but the mechanisms of cataract formation have not yet been fully elucidated. In this study, the relationship between cataract and oxidative stress was evaluated by examining the aqueous humor reflecting lens metabolism. In this study, the effect of oxidative stress on the etiopathogenesis of cataract was investigated through the total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), and arylesterase (ARE) levels in aqueous humor samples of patients with cataract. A prospective cohort study. This study was conducted on patients who were scheduled for cataract surgery between June 2020 and March 2021. The patients were divided into four groups according to their cataract density as grades 1, 2, 3, and 4. TOS, TAS, and ARE levels of aqueous humor samples were measured spectrophotometrically, and comparisons were made between groups. A total of 100 eyes of 100 patients were included in this study. TAS levels were found significantly higher in the grade 2 group compared with the grade 4 group (p = 0.006). In addition, a significant negative correlation was present between cataract grade and TAS level (r = -0.237; p = 0.018). There was no significant difference between diabetic and nondiabetic patients in terms of TAS, TOS, OSI, and ARE levels. The aqueous humor of patients with a high degree of cataract is characterized by low antioxidant capacity. Decreased antioxidant capacity has a role in cataract formation and progression.


Cardiovascular effects of methyleugenol, a natural constituent of many plant essential oils, in normotensive rats.
Cardiovascular effects of intravenous (i.v.) treatment with methyleugenol (ME), a natural constituent of many plant essential oils, were investigated in normotensive rats. Additionally this study examined (I) whether the autonomic nervous system is involved in the mediation of ME-induced changes in mean aortic pressure (MAP) and heart rate (HR), and (II) whether the hypotensive effects of ME could result from its vasodilatory effects directly upon vascular smooth muscle. In both pentobarbital-anesthetized and conscious rats, i.v. bolus injections of ME (1 to 10 mg/kg) elicited similar and dose-dependent decreases in MAP. In anesthetized rats, ME decreased HR only at the highest dose (10 mg/kg), while changes of this parameter were not uniform in conscious rats. Pretreatment of anesthetized rats with bilateral vagotomy significantly reduced the bradycardia response to ME (10 mg/kg) without affecting the hypotension. In conscious rats, i.v. pretreatment with methylatropine (1 mg/kg) or hexamethonium (30 mg/kg) had no significant effect on ME-induced hypotension. In rat isolated thoracic aorta preparations, ME (0.006-1.68 mM) induced a concentration-dependent reduction of potassium (60 mM)-induced contraction. This is the first physiological evidence that i.v. treatment with ME in either anesthetized or conscious rats elicits hypotension; an effect that seems related to an active vascular relaxation rather than withdrawal of sympathetic tone.


[Clinical Findings in Patients with Non-Arteritic Anterior Ischemic Optic Neuropathy (NA-AION) Under 50 Years of Age].
The aim of our study was to determine the prevalence of NA-AION patients younger than 50 years among all our NA-AION patients and to compare clinical findings between young and elderly NA-AION patients. This was a retrospective review of complete ophthalmic examinations, including fluorescein angiography and visual field testing, performed on all patients with the first attack of acute NA-AION admitted to our department during the period of ten years (2004 to 2013). Of 120 NA-AION patients, 10 (8.3 %) were under 50 years of age. The majority of these were men: 8 of 10 (80 %). The average best corrected visual acuity on admission was 0.34 (fingers counted up to 1.0) and on discharge 0.53 (fingers counted up to 1.0). Of 10 eyes, 6 were emmetropic and 4 hyperopic, from + 0.50 D to + 2.0 D. Aside from the clinical picture of AION, other ophthalmological findings were normal. In fluorescein angiography, typical changes for ischaemic optic neuropathy were observed in all patients. In a majority of patients, an inferior altitudinal visual field defect was found. As regards systemic risk factors, hyperlipidaemia was observed in 7, arterial hypertension in 3, diabetes mellitus without diabetic retinopathy in 3, and ischaemic heart disease in 1 of 10 patients. One patient was treated for rheumatoid arthritis without signs of vasculitis. In 3 patients, more than one systemic risk factor was observed. Two of our patients had no systemic risk factors except moderate hyperopia. Bilateral manifestation was observed only in one patient 8 months after the first attack. None of the patients experienced recurrent attacks. The prevalence of younger patients in our study was lower than in previous studies. The reason could be the better medical prevention in our region. Our study confirmed that even in young NA-AION patients, moderate hyperopia could be a predisposing factor. Our study did not confirm the differences between young and elderly NA-AION patients as observed in previous studies. During a period of 10 years, we did not observe recurrences, high risk of other eye involvement or severe vision loss in our young patients compared to the elderly.


Internet-based emotional awareness and expression therapy for somatic symptom disorder: A randomized controlled trial.
Somatic symptom disorder (SSD) is commonly encountered in health care settings. Cognitive-behavioural treatments have been most extensively studied, but they tend to have small effects of temporary duration. Emotional awareness and expression therapy (EAET) is a newly developed treatment for SSD, targeting emotional processing of trauma and conflict as a mechanism of symptom change. In an earlier uncontrolled study of self-guided, internet-administrated EAET (I-EAET), we found substantial reductions in somatic symptoms, prompting the need for a randomized controlled trial of I-EAET. We conducted a 2-arm RCT, comparing 10-week I-EAET (n = 37) to a waitlist control (WL; n = 37). Primary outcomes were reductions of somatic symptoms (PHQ-15) and pain intensity (BPI-4) at post-treatment, with a 4-month evaluation of effect duration. We also analysed emotional processing (EPS-25) and depression (PHQ-9) as possible mediators of I-EAET's effects. Compared to controls, I-EAET significantly reduced somatic symptoms at both post-treatment and follow-up. I-EAET also reduced pain, depression, insomnia, and anxiety at post-treatment, but these effects were not retained at follow-up. As hypothesized, a facet of emotional processing partially mediated the treatment effect on somatic symptoms, even when controlling for depression. Although treatment effects were smaller than in the previous uncontrolled trial, I-EAET is a promising treatment for SSD, with a minority of patients (around 20%) experiencing substantial clinical improvement. The benefits of I-EAET are partially mediated by improved emotional processing. Future research should identify and target patients who respond best to I-EAET and develop tailored treatment to enhance treatment effects. (Preregistered at clinicaltrials.gov: NCT04751825.).


Vaccine impedes the development of reflux-induced esophageal cancer in a surgical rat model: efficacy of the vaccine in a post-Barrett's esophagus setting.
We developed and evaluated a GM-CSF whole-cell tumor vaccine for esophageal cancer. Cell lines derived from surgically induced rat reflux esophageal tumors were passaged in vitro and transfected with GM-CSF. First, the GM-CSF whole cell vaccine was evaluated against subcutaneously transplanted esophageal tumor cells. In a subsequent study, the vaccine was tested to see if it could reduce the incidence of cancer in the surgical reflux model. While subcutaneously transplanted tumor cells produced lasting tumors in PBS non-vaccinated placebo rats, transplanted tumors regressed and were immunologically rejected in animals vaccinated prior to implantation. In the surgical reflux model, the vaccine reduced the incidence of cancer from 17/23 (74%) in the controls to 6/16 (38%) in the vaccinated animals (P = 0.046). The GM-CSF whole cell tumor vaccine effectively promoted a strong immune response against subcutaneously transplanted tumors and protected animals from developing esophageal cancer in the reflux model.


Personality disorders and accentuations in at-risk persons with and without conversion to first-episode psychosis.
The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Cluster A personality disorders (PDs), particularly schizotypal PD, are considered a part of the schizophrenia spectrum and a risk factor of psychosis. The role of PDs and personality accentuations (PAs) in predicting conversion to psychosis was studied in patients symptomatically considered at risk, assuming a major role of the schizotypal subtype. PDs and PAs, assessed at baseline with a self-report questionnaire, were compared between risk-, gender- and age-matched at-risk patients with (n = 50) and without conversion to psychosis (n = 50). Overall, Cluster A-PDs were the least frequent cluster (14%), and schizotypal PD was rare (7%). Yet, PDs in general were frequent (46%), especially Cluster B- (31%) and C-PDs (23%). Groups did not differ in frequencies of PDs, yet converters tended to have a higher expression of schizoid (P = 0.057) and Cluster A-PAs (P = 0.027). In regression analyses, schizoid PA was selected as sole but weak predictor of conversion (OR = 1.685; 95% CIs: 1.134/2.504). Unexpectedly, schizotypal PD was infrequent and did not predict conversion. Conversion was best predicted by schizoid PA, indicating more severe, persistent social deficits already at baseline in later converters. This corresponds to premorbid social deficits reported for genetic high-risk children and low social functioning in at-risk patients later converting to psychosis. Further, PDs occurred frequently in at-risk patients irrespective of conversion. As psychopathology and personality relate closely to one another, this result highlights that, beyond the current narrow focus on schizotypal PD, personality-related factors should be considered more widely in the prevention of psychosis.


Costs of Real-Life Endovascular Treatment of Critical Limb Ischemia: Report from Poland-A European Union Country with a Low-Budget Health Care System.
To analyze the costs of inhospital, percutaneous treatment of patients with critical limb ischemia (CLI) carried out in Poland, a European Union country with a low-budget national health system. A retrospective analysis of prospectively collected data on all patients admitted to a tertiary care hospital for endovascular treatment of CLI over 1 year. A single, large volume, tertiary angiology center located in Southern Poland. CLI patients due to aortoiliac, femoropopliteal, or infrapopliteal arterial stenoses or occlusions with indications for first-line endovascular therapy or similar patients who refused open surgical procedure despite having primary indications for vascular surgery. Direct stenting using bare-metal stents was the primary mode of treatment for lesions located within the aortoiliac and femoropopliteal arterial segments. Plain old balloon angioplasty (POBA) was the second most commonly used technique. For below-the-knee arteries, POBA was the mainstay of treatment, which was occasionally supported by drug-eluting stent angioplasty. Directional atherectomy, scoring balloon angioplasty, or local fibrinolysis was used infrequently. Drug-eluting balloon percutaneous transluminal angioplasty was not used. The main outcome measures were the mean reimbursement of costs provided by the Polish National Health Fund (NHF) for inhospital treatment of patients for whom endovascular procedures were performed as initial treatment for CLI and the inhospital costs of endovascular treatment calculated by the caregiver in the 2 years since the first procedure. The average total number of days spent in hospital, amputation-free survival (AFS), overall survival (OS), and limb salvage rate (LSR) according to a life-table method were also calculated for the 2 years. In the first year, there were 496 endovascular and 15 surgical hospitalizations for revascularization procedures to treat 340 limbs in 327 patients, with a further 53 revascularization procedures in the second year. There were an additional 90 hospitalizations over the first year and 38 over the second year for CLI-associated cardiovascular comorbidities. The mean reimbursement for hospitalizations of patients included into observation, provided by the NHF, was $4901.94 per patient for the first year and $833.57 per patient alive to the second year. The mean cost of hospitalization for percutaneous revascularization treatment was $3804.25 per patient for the first year and $3340.30 per patient requiring revascularization within the second year. All costs were calculated in constant 2011 USD. The average total number of days spent in hospital was 8.4 days for the first year and 1.97 days per patient alive to the second year. At 1 and 2 years, the AFS was 76.8% and 66.6%, the OS was 86.5% and 77.3%, and the LSR was 89.4% and 86%, respectively. Endovascular therapy using the currently available techniques can be performed in almost all patients suffering from CLI at relatively low costs, and satisfactory results can be obtained. Physicians play a pivotal role in ensuring quality of treatment and the reduction of treatment cost in these patients.


Modified Arrhenius equation for the frequency dependence of the transition temperatures of polymers.
A linear relationship was established for several polymers between the pre-exponential factor and the activation energy of a modified form of the standard Arrhenius equation. In addition, the energy term itself was modified such that the alpha and beta absorptions were related to the number of carbon atoms available for segmental motion. At large activation energies the modified Arrhenius relationship suggested upper limits of 495.5K and 321K for the alpha and beta transition temperatures, respectively.


Hippocampal, granule cell and CA3-4 lesions impair formation of a place learning-set in the rat and induce reflex epilepsy.
Rats were pretrained on a place learning-set task, in which a platform, submerged in a swimming pool filled with opaque water, was moved to a new location each day. Then they received either: suction removal of the dorsal hippocampus, intrahippocampal microinjections of colchicine to remove dentate gyrus granule cells, kainic acid to remove CA3-4 cells of the hippocampus proper, suction removal of parietal cortex overlying the hippocampus, or no surgery. Performance was then evaluated for 48 days. All lesion groups were chronically impaired with respect to the control group, but the rats with parietal cortex lesions retained the ability to solve the task, whereas rats with hippocampal damage did not. Training frequently induced task-related behavioural seizures in the rats with granule cell or CA3-4 lesions. The results show that the hippocampus, including granule cell and CA3-4 cell populations, is essential for the rapid acquisition of place responses in the swimming pool task. The finding that training on the task induced reflex epilepsy in granule cell and CA3-4-damaged rats, but not those with aspirative removals, suggests that residual portions of the hippocampus are activated by training and are involved in production of the epileptic attacks.


Mesenteric mast cell degranulation is not essential for conditioned taste aversion.
The possible role of mesenteric mast cell degranulation as the mediator of the initial UCS effects in the complex sequences leading to conditioned taste aversion (CTA) was studied. Both LiCl and Compound 48/80, a potent mast cell degranulator, produced CTA to 10% sucrose. Whereas the Compound 48/80 groups displayed massive mast cell degranulation, neither the LiCl treated nor saline control groups demonstrated any histologically determinable alterations. Administration of the antihistamine chlorpheniramine at dosages known to block radiation-induced CTA before the sucrose CS-UCS pairings did not block either LiCl- or Compound 48/80-induced CTA; the antihistamine actually facilitated the aversion. However, pretreatment with the antihistamine did not alter mesenteric mast cell morphology.


[Diagnostic and therapeutic difficultes in pityriasis rubra pilaris--case report].
Pityriasis rubra pilaris Devergie is a very rare papulosquamosus disease which has chronic course and still unclear etiology. Already, we know that this dermatosis occurs as often in male as in female, can be present in each age and has genethics background. Diagnostic and especially therapy of those skin diseases is very difficult and can make a lot of problems not only dermatologist. This paper presents the case of a 48-year-old man with diagnosed and histological confirmed Pityriasis rubra pilaris Devergie. Advantages of retinoids therapy were also discussed.


Importance of learned resourcefulness to weight loss and early success during maintenance: preliminary evidence.
The present study examined the importance of learned resourcefulness skills as measured by Rosenbaum's Self-Control Schedule (SCS) (Behav Ther 1980; 11: 109-121) to weight loss following a self-control program. Twenty-two women signed up for the 5-week self-control program. Participants' weight was recorded at the first and final session of the program, and at a 4-week follow-up. Results indicated that low resourceful women were more likely to drop out of the self-control program than high resourceful women. Although both the high and low resourceful women who completed the program lost the same amount of weight, only the high resourceful subjects continued to lose weight at follow-up. In contrast, the low resourceful women regained lost weight. Results point to the importance of learned resourcefulness for maintenance of weight loss following a self-control weight program.


New polyurethane compositions able to bond high amounts of both albumin and heparin. Part I.
In order to prepare polymers provided with better haemocompatibility with respect both to the coagulative cascade and to platelet aggregation and activation, we have synthesized new polyurethanes containing in the chain-extender [di(2-hydroxyethyl)hexadecylamine] both a long chain alkyl group (able to bond albumin) and a tertiary ammonium group able, after suitable quaternization reaction, to bind ionically significant amounts of heparin. The amounts of heparin and albumin bonded to the polymer films were determined spectrophotometrically. A biological in vitro evaluation of the heparinized and albuminized films was also carried out with respect to blood coagulation factors (by activated partial thromboplastin time measurements) and to platelet adhesion and activation (by platelet count and scanning electron microscopy examination). It was seen that the type of adsorption sequence for albumin and heparin, respectively, onto the various homo- and copolymer films, plays an important role on their biological properties; the possible mechanisms involved are also discussed on the basis of X-ray photoelectron spectroscopy and attenuated transmission reflectance evaluation of the polymer surfaces.


Magnetic resonance imaging of the liver: true fast imaging with steady state free precession sequence facilitates rapid and reliable distinction between hepatic hemangiomas and liver malignancies.
To assess the capability of the true fast imaging with steady state free precession (true FISP) sequence in the distinction between hemangiomas and malignant liver lesions. Sixty-eight patients with 45 hemangiomas and 51 liver malignancies were included in this study. A 1.5-T magnetic resonance system and a phased-array body coil were used. In addition to true FISP, breath-hold and fat-suppressed, T2-weighted, half-Fourier single-shot turbo spin echo (HASTE) and both unenhanced and gadolinium (Gd)-enhanced T1-weighted sequences were acquired. Two radiologists evaluated the magnetic resonance images independently in a blinded fashion. Interobserver variations with true FISP and HASTE were determined. Lesion contrast-to-noise ratios were calculated from true FISP images. With true FISP, readers 1 and 2 made a correct distinction between hemangiomas and liver malignancies in 43 of 45 (96%) cases and 40 of 45 (89%) cases, respectively. The kappa value was 0.65. With HASTE, the success rates were 40 of 45 cases (89%) and 36 of 45 cases (80%), respectively, and the kappa value was 0.33. With a Gd-enhanced T1-weighted sequence, the correct classifications were 35 of 45 cases (78%) and 37 of 45 cases (82%), respectively. All hemangiomas appeared as bright and well-demarcated lesions on true FISP images. Malignant liver foci were heterogeneous with unsharp margins and nearly isointense relative to liver. The specificities of true FISP in lesion differentiation were 100% and 98% for readers 1 and 2, respectively. The mean contrast to noise ratio value of hemangiomas was 21.2 (standard deviation [SD] = 9.2), and that of malignant lesions was 4.9 (SD = 3.9). This difference was highly significant (P < 0.0001). Noninvasive, rapid, and reliable differentiation between hemangiomas and malignant liver lesions is possible by using the true FISP sequence.


Study of the Dynamics of Biofilm Formation and Elastase Activity of Pseudomonas aeruginosa in the Presence of Dodecanoyl-Homoserine Lactone.
We studied the effect of early accumulation of N-3-oxo-dodecanoyl-homoserine lactone on the suppression of Pseudomonas aeruginosa reproduction, biofilm formation, and elastase activity. N-3-oxo-dodecanoyl-homoserine lactone in various concentrations was added to the P. aeruginosa culture, and changes in the concentration of bacteria and the formation of biofilms were studied in dynamics. N-3-oxo-dodecanoyl-homoserine lactone in a concentration of 25 μM, decelerated proliferation of bacterial cells during the first 6 h of culturing (p<0.05) and stimulated biofilm formation after 18 h of culturing. Elastase activity of P. aeruginosa increased significantly after addition of N-3-oxo-dodecanoyl-homoserine lactone in a concentration of 0.75 μM.


Genetic and epidemiological analysis of ESBL-producing Klebsiella pneumoniae in three Japanese university hospitals.
We aimed to clarify the genetic background and molecular epidemiology of extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae (K. pneumoniae) at three geographically separated university hospitals in Japan. From January 2014 to December 2016, 118 ESBL-producing K. pneumoniae (EPKP) strains that were detected and stored at three university hospitals were collected. Molecular epidemiological analysis was performed using enterobacterial repetitive intergenic consensus (ERIC)-polymerase chain reaction (PCR) and multi-locus sequence typing (MLST). The ESBL type was determined using the PCR-sequence method. The presence of plasmid-mediated fluoroquinolone resistance (PMQR) genes was analyzed by PCR. We compared the relationships between PMQR gene possession/quinolone resistance-determining region (QRDR) mutation and levofloxacin (LVFX)/ciprofloxacin (CPFX) susceptibility. The detection rate of EPKP was 4.8% (144/2987 patients). MLST analysis revealed 62 distinct sequence types (STs). The distribution of STs was diverse, and only some EPKP strains had the same STs. ERIC-PCR showed discriminatory power similar to that of MLST. The major ESBL genotypes were CTX-M-15-, CTX-M-14-, and SHV-types, which were detected in 47, 30, and 27 strains, respectively. Ninety-one out of 118 strains had PMQR genes and 14 out of 65 strains which were not susceptible to CPFX had QRDR mutations, and the accumulation of PMQR genes and QRDR mutations tended to lead to higher minimum inhibitory concentrations (MICs) of LVFX. At three geographically separated university hospitals in Japan, the epidemiology of EPKP was quite diverse, and no epidemic strains were found, whereas CTX-M-14 and CTX-M-15 were predominant.


Survival and complications of zirconia-based fixed dental prostheses: a systematic review.
Evidence is limited on the efficacy of zirconia-based fixed dental prostheses. The purpose of this systemic review was to assess zirconia-based FDPs in terms of survival and complications. Searches performed in PubMed databases were enriched by hand searches to identify suitable publications. The keywords used were: "zirconia" and "fixed dental prosthesis," "zirconia" and "crown," "zirconia" and "fixed partial denture" and "humans," "zirconia" and "crown" and "humans," "crown" and "all-ceramics," and "fixed partial denture" and "all-ceramics". Titles and abstracts were read to identify literature that fulfilled the inclusion criteria. Only peer reviewed clinical studies published in the English language from January 1999 through June 2011 were included. Twelve clinical studies based on zirconia, framework design, and porcelain veneering technique met the inclusion criteria. Of the studies identified, 1 was a randomized clinical study with 3-year follow-up results; the others were cohort prospective studies. Clinical complications included chipping of veneering porcelain, abutment failure, and framework fracture. One study investigated pressed ceramics as the veneering material and found no chipping of veneering porcelain after 3 years. Short term clinical data suggest that zirconia-based fixed dental prostheses may serve as an alternative to metal ceramic fixed dental prostheses in the anterior and posterior dentition.


Rhythmic discharges in the perfused isolated brainstem preparation of adult guinea pig.
An isolated brainstem preparation of adult guinea pig was used for an in vitro electrophysiological study of rhythmic neuronal discharge patterns. More than half of the spontaneously active neurons (40/71) exhibited a rhythmic discharge. Rhythmic discharges were recorded dorsally in the nucleus tractus solitarius and ventrally in the ambiguus and paragigantocellular reticular nuclei. Three types of rhythmic patterns of discharge were identified in these areas: repetitive single discharge, repetitive bursting discharge and spontaneous periodic discharge. No rhythmic patterns were recorded in other explored parts of the brainstem. Comparison of these data with those from brainstem slices shows that spontaneous periodic discharges may require extended networks within the brainstem.


Antibacterial Properties and Efficacy of LL-37 Fragment GF-17D3 and Scolopendin A2 Peptides Against Resistant Clinical Strains of Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii In Vitro and In Vivo Model Studies.
Pseudomonas aeruginosa, Staphylococcus aureus, and Acinetobacter baumannii have emerged as major clinical threats owing to the increasing prevalence of ventilator-associated pneumonia caused by multidrug-resistant or extensively drug-resistant strains. The present study aimed to assess the antibacterial effects and efficacy of LL-37 fragment GF-17D3 and synthetic Scolopendin A2 peptides against resistant clinical strains in vitro and in vivo models. P. aeruginosa, S. aureus, and A. baumannii were isolated from clinical infections. Their antibiotic resistance and minimum inhibitory concentration were assessed. LL-37 fragment GF-17D3 peptide was selected from available databases. Scolopendin A2 peptide's 6th amino acid (proline) was substituted with lysine and peptides and MICs were determined. The biofilm inhibitory activity was quantified at sub MIC concentrations. Synergetic effects of Scolopendin A2 and imipenem were assessed by checkerboard. After mice nasal infection with P. aeruginosa, peptides LD50 was determined. Isolates harbored complete resistance toward the majority of antibiotics and MIC values ranged between 1 and > 512 µg/ml. The majority of isolates exhibited strong biofilm activity. Synthetic peptides showed lower MIC values than antibiotic agents and the lowest MIC values were obtained for synthetic peptides in combination with antibiotics. The Synergisms effect of Scolopendin A2 with imipenem was also determined. Scolopendin A2 was found to have antibacterial efficacy against P. aeruginosa, S. aureus, and A. baumannii with MIC 64 µg/ml, 8 µg/ml, and 16 µg/ml, respectively, and LL37 showed antibacterial efficacy against P. aeruginosa, S. aureus, and A. baumannii with MIC 128 µg/ml, 32 µg/ml, and 32 µg/ml, respectively. Both AMPs decreased biofilms by ≥ 96% at 1 × MIC. The biofilm inhibitory activity was measured at sub MIC concentrations of the peptides and the results demonstrated that Scolopendin A2 exhibited anti-biofilm activity at 1/4 × MIC and 1/2 × MIC concentrations was 47.9 to 63.8%, although LL37 among 1/4 × MIC and 1/2 × MIC concentrations was 21.3 to 49.6% against three pathogens. The combination of Scolopendin A2 and antibiotics demonstrated synergistic activity-resistant strains with FIC values ≤ 0.5 for three pathogens, while LL37 and antibiotics showed synergistic activity FIC values ≤ 0.5 for only P. aeruginosa. Infection model Scolopendin A2 with Imipenem (2 × MIC) was efficacious in vivo, with a 100% survival rate following treatment at 2 × MIC after 120 h. The mRNA expression of biofilm-related genes was decreased for both peptides. Synthesis Scolopendin A2 decreased the expression of biofilm formation genes compared to the control group. Synthetic Scolopendin A2 exhibits antimicrobial activity without causing toxicity on the human epithelial cell line. Based on our findings, it seems that synthetic Scolopendin A2 is an appropriate antimicrobial source. That could be a promising option in combination with antibiotics for a topical medication and in the prevention of acute and chronic infections caused by multidrug-resistant bacteria. Nevertheless, additional experiments are required to assess another potential of this novel AMP.


Familial Klippel-Trenaunay syndrome: a case report.
We present a case of familial occurrence of Klippel-Trenaunay syndrome (thought to be the first such reported in a family from the UK), and the results of an investigation into associated abnormalities in related family members. The findings are compatible with recent suggestions that the syndrome may be inherited, and that isolated naevi flammei may, at least in some instances, have a similar genetic basis, possibly representing a forme fruste of the syndrome.


Changes in Adult BMI and Waist Circumference Are Associated with Increased Risk of Advanced Colorectal Neoplasia.
Waist circumference (WC) is a stronger predictor of colon cancer (CRC) risk than body mass index (BMI). However, how well change in either WC or BMI predicts risk of advanced colorectal neoplasia (AN) is unclear. To determine the relationship between change in BMI and WC from early adulthood to later age and the risk of AN and which change measure is a stronger predictor. In 4500 adults, ages 50-80, with no previous neoplasia and undergoing screening colonoscopy, BMI and WC at age 21 and at time of screening were reported. Changes in BMI and WC were defined using universal risk cutoffs. Known CRC risk factors were controlled in the logistic models. Overall, model statistics showed WC change (omnibus test χ 2 = 10.15, 2 DF, p value = 0.006) was a statistically stronger predictor of AN than BMI change (omnibus test χ 2 = 5.66, 5 DF, p value = 0.34). Independent of BMI change, participants who increased WC (OR 1.44; 95% CI 1.05-1.96) or maintained a high-risk WC (OR 2.50; 95% CI 1.38-4.53) at age 21 and at screening had an increased risk of AN compared to those with a low-risk WC. Study participants who were obese at age 21 and at screening had an increased risk of AN (OR 1.87; 95% CI 1.08-3.23) compared to those who maintained a healthy BMI. Maintaining an overweight BMI or increasing BMI was not associated with AN. Maintaining an unhealthy BMI and WC throughout adult life may increase risk of AN. WC change may be a better predictor of AN than BMI change.


Block and Lock HIV Cure Strategies to Control the Latent Reservoir.
The HIV latent reservoir represents the major challenge to cure development. Residing in resting CD4+ T cells and myeloid cells at multiple locations in the body, including sanctuary sites such as the brain, the latent reservoir is not eliminated by ART and has the ability to reactivate virus replication to pre-therapy levels when ART is ceased. There are four broad areas of HIV cure research. The only successful cure strategy, thus far, is stem cell transplantation using naturally HIV resistant CCR5Δ32 stem cells. A second potential cure approach uses gene editing technology, such as zinc-finger nucleases and CRISPR/Cas9. Another two cure strategies aim to control the HIV reservoir, with polar opposite concepts; The "shock and kill" approach, which aims to "shock" or reactivate the latent virus and then "kill" infected cells via targeted immune responses. Lastly, the "block and lock" approach, which aims to enhance the latent virus state by "blocking" HIV transcription and "locking" the HIV promoter in a deep latent state via epigenetic modifications. "Shock and kill" approaches are a major focus of cure studies, however we predict that the increased specificity of "block and lock" approaches will be required for the successful development of a sustained HIV clinical remission in the absence of ART. This review focuses on the current research of novel "block and lock" approaches being explored to generate an HIV cure via induction of epigenetic silencing. We will also discuss potential future therapeutic delivery and the challenges associated with progressing "block and lock" cure approaches as these move toward clinical trials.


An improved portmanteau test for autocorrelated errors in interrupted time-series regression models.
A new portmanteau test for autocorrelation among the errors of interrupted time-series regression models is proposed. Simulation results demonstrate that the inferential properties of the proposed Q(H-M) test statistic are considerably more satisfactory than those of the well known Ljung-Box test and moderately better than those of the Box-Pierce test. These conclusions generally hold for a wide variety of autoregressive (AR), moving averages (MA), and ARMA error processes that are associated with time-series regression models of the form described in Huitema and McKean (2000a, 2000b).


Mindfulness-based stress reduction for menopausal symptoms after risk-reducing salpingo-oophorectomy (PURSUE study): a randomised controlled trial.
To assess the short- and long-term effects of mindfulness-based stress reduction (MBSR) on the resulting quality of life, sexual functioning, and sexual distress after risk-reducing salpingo-oophorectomy (RRSO). Randomised controlled trial. A specialised family cancer clinic of the university medical center Groningen. Sixty-six women carriers of the BRCA1/2 mutation who developed at least two moderate-to-severe menopausal symptoms after RRSO. Women were randomised to an 8-week MBSR training programme or to care as usual (CAU). Change in the Menopause-Specific Quality of Life Questionnaire (MENQOL), the Female Sexual Function Index, and the Female Sexual Distress Scale, administered from baseline at 3, 6, and 12 months. Linear mixed modelling was applied to compare the effect of MBSR with CAU over time. At 3 and 12 months, there were statistically significant improvements in the MENQOL for the MBSR group compared with the CAU group (both P = 0.04). At 3 months, the mean MENQOL scores were 3.5 (95% confidence interval, 95% CI 3.0-3.9) and 3.8 (95% CI 3.3-4.2) for the MBSR and CAU groups, respectively; at 12 months, the corresponding values were 3.6 (95% CI 3.1-4.0) and 3.9 (95% CI 3.5-4.4). No significant differences were found between the MBSR and CAU groups in the other scores. Mindfulness-based stress reduction was effective at improving quality of life in the short- and long-term for patients with menopausal symptoms after RRSO; however, it was not associated with an improvement in sexual functioning or distress. Mindfulness improves menopause-related quality of life in women after risk-reducing salpingo-oophorectomy.


Evaluation of a First-Year Veterinary Surgical Skills Laboratory: A Retrospective Review.
A retrospective review of the first-year surgical skills competency-based assessment was performed at the Western College of Veterinary Medicine (WCVM) using 6 years of data from 475 students. The cumulative pass rate was 88.2% on first attempt and 99.2% upon remediation. Student gender did not influence overall pass/fail rates, with a failure rate of 11.1% for female students and 10.5% for male students (p = 0.88). Significantly decreased pass rates were associated with identification of the Mayo scissors (p = 0.03), explanation of using Allis tissue forceps (p = 0.002), and performance of a Lembert suture pattern (p < 0.01). An increased pass rate was observed for the cruciate pattern (p < 0.01). No differences were found in pass/fail rates for hand ties (p = 0.80) or instrument ties (p = 0.60). The most common errors occurred with half hitch ties: hand ties (53%) and instrument ties (38%). The most common errors were also recognized for instrument handling (31%) and needle management (20%) during the suture pattern section. The veterinary medical education community may benefit from the evidence-based findings of this research, in terms of understanding student performance across competencies, identifying areas requiring additional mentoring, and determining appropriate competencies for first-year veterinary students.


Metabolic enhancement and increase of alveolar macrophages induced by ozone.
Male Wistar rats were exposed to 0.2 ppm ozone (O3) for 14 days and at intervals alveolar macrophages were collected by bronchoalveolar lavage to examine the effects of O3. The specific activities of glucose-6-phosphate dehydrogenase and glutathione peroxidase of alveolar macrophages increased to 1.6-fold (on the 3rd day) and 1.5-fold (on the 5th day), respectively, those of the control values. Similarly, the specific activities of pyruvate kinase, lactate dehydrogenase, and hexokinase also increased to 1.6-fold, 1.4-fold, and 1.2-fold, respectively, those of the control values on the 3rd day. The activities of all enzymes tested were maintained at significantly higher levels until the 14th day. Furthermore, the incorporation of [14C]thymidine into alveolar macrophages increased twice the control values on the 1st and 3rd days and was almost completely inhibited by the addition of 1.23 x 10(-4) M aphidicolin, a competitive inhibitor of DNA polymerase alpha. The number of alveolar macrophages collected from exposed animals also increased to 1.5-fold that of the control value on the 3rd day and was maintained at significantly higher level until the 14th day. It was noted that alveolar macrophages of small size preferentially increased between the 5th and 14th days. These results show that exposures to 0.2 ppm O3 induced a metabolic enhancement of the peroxidative metabolism, glycolysis, and DNA synthesis in alveolar macrophages and increased the macrophages of small size.


Eimeria lancasterensis (Apicomplexa: Eimeriidae) from the eastern fox squirrel, Sciurus niger (Rodentia: Sciuridae), in north-central Texas.
Eimeria lancasterensis Joseph, 1969, is reported for the first time from the feces of 10 of 11 (91%) eastern fox squirrels, Sciurus niger ludovicianus, in Dallas and Johnson counties, Texas. Oocyst measurements were similar to those reported previously from the eastern gray squirrel, Sciurus carolinensis carolinensis, in Massachusetts. Except for our observation of a substieda body, oocyst morphology was identical to the original description of E. lancasterensis.


Leonardo da Vinci: the Lady with an Ermine enigma.
"Lady with an Ermine" (1489-1490) is an oil on walnut portrait by the Italian artist Leonardo da Vinci. The portrait's subject is Cecilia Gallerani, the favorite mistress of Ludovico Sforza, known as "il Moro", Duke of Milan. It was painted around the time of Cecilia's pregnancy with Ludovico's illegitimate son. Leonardo's paintings are famous for hiding mysteries; thus, the truth about the "Lady with an Ermine" is still unclear. However, the solution to this enigma could be more evident than expected. Our hypothesis is that Cecilia might have suffered from pregnancy-induced Cushing syndrome.


Noncoding SNP at rs1663689 represses ADGRG6 via interchromosomal interaction and reduces lung cancer progression.
A previous genome-wide association study (GWAS) revealed an association of the noncoding SNP rs1663689 with susceptibility to lung cancer in the Chinese population. However, the underlying mechanism is unknown. In this study, using allele-specific 4C-seq in heterozygous lung cancer cells combined with epigenetic information from CRISPR/Cas9-edited cell lines, we show that the rs1663689 C/C variant represses the expression of ADGRG6, a gene located on a separate chromosome, through an interchromosomal interaction of the rs1663689 bearing region with the ADGRG6 promoter. This reduces downstream cAMP-PKA signaling and subsequently tumor growth both in vitro and in xenograft models. Using patient-derived organoids, we show that rs1663689 T/T-but not C/C-bearing lung tumors are sensitive to the PKA inhibitor H89, potentially informing therapeutic strategies. Our study identifies a genetic variant-mediated interchromosomal interaction underlying ADGRG6 regulation and suggests that targeting the cAMP-PKA signaling pathway may be beneficial in lung cancer patients bearing the homozygous risk genotype at rs1663689.


Determination of phenprocoumon in plasma and urine using at-line solid-phase extraction-capillary electrophoresis.
The use of capillary electrophoresis (CE) for the analysis of biological samples is rather problematic because of the large number of interferences present in the matrix. One of the possibilities to solve such problems is to couple solid-phase extraction (SPE) at-line with CE, a technique developed in our laboratory. In this study at-line SPE-CE is performed for the determination of the anticoagulant phenprocoumon in biological fluids. Plasma samples are injected after the addition of 1 vol.% of formic acid to release the drug from binding proteins, while urine samples can be directly injected. The procedure is linear between 0.2 and 30 microg ml(-1) with a correlation coefficient, r2, of 0.9996. The detection limit in plasma is 0.1 microg ml(-1), which is fully adequate in view of the concentrations, that have to be dealt with in practice. The phenprocoumon concentration in a plasma sample of a patient treated with the anticoagulant was 3.8 microg ml(-1).


Relationship between cytosolic calcium and oxygen consumption in isolated rat hearts.
Maximum oxygen consumption was attained in isolated perfused rat hearts using high perfusate calcium and/or isoproterenol, or phenylephrine. The amplitude of calcium transients was directly related to oxygen consumption until oxygen consumed per beat reached maximum. At saturating oxygen consumption the amplitude of [Ca2+]i transients continued to increase, indicative of a calcium overload. In all cases +dP/dt correlated proportionately with +dCa2+/dt. Augmented developed pressure, related to isoproterenol-induced increase in cytosolic cAMP, cannot be attributed totally to elevated levels of [Ca2+]i transients. Adenosine (10(-5) M) added to the medium containing isoproterenol (10(-6) M) negated the isoproterenol-induced increase in cAMP and returned cardiac performance, oxygen consumption, and amplitude of [Ca2+]i transients to control state.


A neuronal receptor, neuropilin-1, is essential for the initiation of the primary immune response.
The initiation of a primary immune response requires contact between dendritic cells (DCs) and resting T cells. However, little is known about the proteins that mediate this initial contact. We show here that neuropilin-1, a receptor involved in axon guidance, was expressed by human DCs and resting T cells both in vitro and in vivo. The initial contact between DCs and resting T cells led to neuropilin-1 polarization on T cells. DCs and resting T cells specifically bound soluble neuropilin-1, and resting T cells formed clusters with neuropilin-1-transfected COS-7 cells in a neuropilin-1-dependent manner. Functionally, preincubation of DCs or resting T cells with blocking neuropilin-1 antibodies inhibited DC-induced proliferation of resting T cells. These data suggest that neuropilin-1 mediates interactions between DCs and T cells that are essential for initiation of the primary immune response and show parallels between the nervous and immune systems.


Effect of a specific serine protease inhibitor on the rat pancreas: systemic administration of camostate and exocrine pancreatic secretion.
Camostate, a synthetic serine protease inhibitor, specifically inhibits the trypsin activity in vitro. Immediately after intravenous administration of camostate (5, 2.5, 0.5, and 0.1 mg/kg body weight/h) the trypsin activity in the biliary-pancreatic juice was diminished dose-dependently in anaesthetized rats. The amylase release was not influenced. Camostate and its metabolites were detected by high-pressure liquid chromatography in the pancreatic juice and tissue; in plasma, only the metabolites were found. Therefore, the inhibitory action of camostate on the trypsin activity in the biliary-pancreatic juice may be due to penetration of camostate into the juice.


Catheter squeeze technique to solve urinary catheter drainage problem.
Urinary catheter insertion is one of the basic techniques used in patient care to drain the bladder. Around 30 million urinary catheters are inserted annually in the USA alone.2 Often, when inserting a urinary catheter, it is noticed that urine does not drain right away. This article will discuss the 'urinary catheter squeeze' technique that can help healthcare providers resolve this problem. We have a simple solution called the 'catheter squeeze technique' to address the problem of urine not draining. The clinician who inserts the catheter can assess the outcome of this technique immediately, as it provides immediate results. There are several theories regarding why urine may not properly drain into a catheter after it is inserted, and various methods are employed to address this issue. Our "catheter squeeze technique" is a simple approach that requires no tools or assistance, and its effectiveness can be observed immediately after insertion.


An AIE active monoimidazolium skeleton: high selectivity and fluorescence turn-on for H₂PO₄⁻ in acetonitrile and ClO₄⁻ in water.
We disclose herein a monoimidazolium skeleton 1 with an aggregation-induced emission (AIE) characteristic. This fluorogenic skeleton exhibited high selectivity and fluorescence turn-on for H2PO4(-) in acetonitrile and ClO4(-) in water.


From metabolic connectivity to molecular connectivity: application to dopaminergic pathways.
This study aims to reveal the feasibility and potential of molecular connectivity based on neurotransmission in comparison with the metabolic connectivity with an application to dopaminergic pathways. For this purpose, we propose to compare the neurotransmission connectivity findings using 123I-FP-CIT SPECT and 18F-FDOPA PET with the metabolic connectivity findings using 18F-FDG PET. 18F-FDG PET and 123I-FP-CIT SPECT images from 47 subjects and 18F-FDOPA PET images from 177 subjects, who had no neurological or psychiatric disorders, were studied. Interregional correlation analyses were performed at the group level to determine the midbrain's connectivity via glucose metabolic rate using 18F-FDG PET and via dopaminergic binding potential using 123I-FP-CIT SPECT and 18F-FDOPA PET. SPM-T maps of each radiotracer were generated, and masks used to highlight the significant differences obtained among the imaging modalities and targets. The three dopaminergic pathways (i.e., nigrostriatal, mesolimbic, and mesocortical) were identified by 18F-FDG PET (1599 voxels, with a Tmax value of 12.6), 123I-FP-CIT SPECT (1120 voxels, with Tmax value of 5.1), and 18F-FDOPA PET (6054 voxels, with Tmax value of 11.7) for a T voxel threshold of 5.10, 2.80, and 5.10, respectively. Using the same T voxel threshold of 5.10, 18F-FDOPA PET showed more specific findings than 18F-FDG PET with less voxels identified outside these pathways (- 9323 voxels), whereas no significant voxels were obtained with 123I-FP-CIT SPECT at this threshold. The present study illustrates the feasibility and interest in using molecular connectivity with 18F-FDOPA PET for dopaminergic pathways. Such analyses could be applied to specific diseases involving the dopaminergic system.


Photo-induced interaction of thioglycolic acid (TGA)-capped CdTe quantum dots with cyanine dyes.
The photo-induced interaction of three different sizes of thioglycolic acid (TGA)-capped CdTe quantum dots (CdTe QDs) with two monomethine cyanine dyes belonging to the thiazole orange (TO) family has been studied. Positively charged cyanines interact with QDs surface which is negatively charged due to capping agent carboxylate ions. The energy transfer parameters including Stern-Volmer constant, Ksv, number of binding sites, n, quenching sphere radius, r, the critical energy transfer distance, R0, and energy transfer efficiencies, E have been calculated. The effect of structure and the number of aggregating molecules have been studied as a function of CdTe QDs particle size. Combining organic and inorganic semiconductors leads to increase of the effective absorption cross section of the QDs which can be utilized in novel nanoscale designs for light-emitting, photovoltaic and sensor applications. A synthesized triplet emission of the studied dyes was observed using CdTe QDs as donors and this is expected to play a potential role in molecular oxygen sensitization and in photodynamic therapy (PDT) applications.


3'-Deoxy-3'-[18F]Fluorothymidine Uptake Is Related to Thymidine Phosphorylase Expression in Various Experimental Tumor Models.
We recently reported that high thymidine phosphorylase (TP) expression is accompanied by low tumor thymidine concentration and high 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) uptake in four untreated lung cancer xenografts. Here, we investigated whether this relationship also holds true for a broader range of tumor models. Lysates from n = 15 different tumor models originating from n = 6 institutions were tested for TP and thymidylate synthase (TS) expression using western blots. Results were correlated to [18F]FLT accumulation in the tumors as determined by positron emission tomography (PET) measurements in the different institutions and to previously published thymidine concentrations. Expression of TP correlated positively with [18F]FLT SUVmax (ρ = 0.549, P < 0.05). Furthermore, tumors with high TP levels possessed lower levels of thymidine (ρ = - 0.939, P < 0.001). In a broad range of tumors, [18F]FLT uptake as measured by PET is substantially influenced by TP expression and tumor thymidine concentrations. These data strengthen the role of TP as factor confounding [18F]FLT uptake.


Combination of the PI3K inhibitor Idelalisib with the conventional cytostatics cytarabine and dexamethasone leads to changes in pathway activation that induce anti-proliferative effects in B lymphoblastic leukaemia cell lines.
The introduction of combined conventional cytostatics and pathway-specific inhibitors has opened new treatment options for several cancer types including hematologic neoplasia such as leukaemias. As the detailed understanding of the combination-induced molecular effects is often lacking, the identification of combination-induced molecular mechanisms bears significant value for the further development of interventional approaches. Combined application of conventional cytostatic agents (cytarabine and dexamethasone) with the PI3K-inhibitor Idelalisib was analysed on cell-biologic parameters in two acute pro-B lymphoblastic leukaemia (B-ALL) cell lines. In particular, for comparative characterisation of the molecular signatures induced by the combined and mono application, whole transcriptome sequencing was performed. Emphasis was placed on pathways and genes exclusively regulated by drug combinations. Idelalisib + cytostatics combinations changed pathway activation for, e.g., "Retinoblastoma in cancer", "TGF-b signalling", "Cell cycle" and "DNA-damage response" to a greater extent than the two cytostatics alone. Analyses of the top-20 regulated genes revealed that both combinations induce characteristic gene expression changes. A specific set of genes was exclusively deregulated by the drug combinations, matching the combination-specific anti-proliferative cell-biologic effects. The addition of Idelalisib suggests minor synergistic effects which are rather to be classified as additive.


Antigenic mapping of human low density lipoprotein with monoclonal antibodies.
Monoclonal anti-LDL antibodies were produced in a mouse spleen-myeloma system and purified by affinity chromatography on insolubilized low density lipoprotein (LDL). Five antibodies with different specificities could be distinguished by their immunoreactivities with chemically modified LDL preparations, and by their competition for binding to LDL. One of the antibodies inhibited the binding of (125)I-labeled LDL to the apoB,E receptors of cultured human fibroblasts. The same degree of inhibition was achieved using isolated Fab fragments. This antibody may bind to an antigenic site located near the cellular binding site of LDL-apoB.-Tikkanen, M. J., R. Dargar, B. Pfleger, B. Gonen, J. M. Davie, and G. Schonfeld. Antigenic mapping of human low density lipoprotein with monoclonal antibodies.


Potential protection of curcumin against hypoxia-induced decreases in beta-III tubulin content in rat prefrontal cortical neurons.
The central nervous system (CNS) is highly dependent on adequate supply of oxygen and is sensitive to hypoxia. It is known that hypoxia induces injuries on the brain tissue and the neuronal activity. Curcumin, a yellow pigment obtained from the rhizome of C. longa Linn., has been regarded as a multi-functional drug with antioxidative activity. In the present study, we first demonstrated a significant decrease in the content of beta-III tubulin protein in rat prefrontal cortex (PFC) tissues induced by repeated hypoxia, but not in rat cerebellum tissue. These suggest a relatively higher sensitivity and probably a higher vulnerability of rat PFC tissue to hypoxia in vivo. We reconfirmed the effect of hypoxia to primary cultured neurons from rat PFC and found a significant decrease in the contents of beta-III tubulin protein after chronic exposure to hypoxia. Moreover, we demonstrated that the hypoxia-induced decrease in beta-III tubulin protein content could be restored by curcumin, suggesting a potential protection of curcumin against hypoxia-induced decreases in beta-III tubulin content in rat PFC neurons.


In vitro studies on the self-differentiating capacities of quail adenohypophysis epithelium.
Isolated epithelial rudiments of 3--4 days quail embryo adenohypophysis were cultivated in vitro. Differentiation of glandular cells occurred when culture conditions allowed the formation of explants characterized by the presence of a fibroblastic sheet and of an epithelial roof surrounding a central cavity. Differentiation did not occur when culture conditions did not allow the fibroblastic sheet to be established or resulted in the absence of a cavity. The importance of the explant structure in differentiation is also indicated by the location of glandular cells. In vitro they differentiate near the cavity derived from Rathke's pouch lumen while in situ they first appear at the periphery of the rudiment, near the basement membrane. The results of this study show that the adenohypophyseal primordium can differentiate without any mesenchymal influence. The observed differentiation seems to be correlated with fibroblast-secreted material, and this hypothesis is discussed.


Is there an association between otitis media and nasal polyposis?
The association between otitis media with effusion (OME) and nasal polyposis (NP) is poorly described. However, two different approaches to this problem seem to come from the few studies concerning both otitis media and NP in the literature. One study was based on the assessment of a population of patients presenting with NP, with the authors interested in patients among the studied population who complained of ear-related symptoms and developed OME (rhinologic approach). Other studies were based on the assessment of a population of patients developing a particular OME, with the authors interested in characterizing this condition they named eosinophilic otitis media (otologic approach). The article reviews currents concepts in the relationship between OME and NP. It appears that regardless of the approach to the problem of interest (rhinologic or otologic approach), OME and NP seem to be closely related. Moreover, some striking similarities can be noted between the different entities described in the different studies reviewed, and all authors seem to agree that the middle ear has a central role in the concept of united airways inflammatory disease. Otologists and rhinologists should work together on a single approach that allows for better management of inflammatory disease leading to the formation of polyps, development of concurrent asthma, appearance of aspirin intolerance, and finally involvement of the middle ear.


Formula-feeding practice and associated factors among urban and rural mothers with infants 0-6 months of age: a comparative study in Jimma zone Western Ethiopia.
Infants are in a state of rapid development and maturation; the growth rate is most rapid during the first 4 to 6 months of life. Few studies indicated that in developing countries including Ethiopia the prevalence and duration of breastfeeding is declining and being replaced by formula milk. Therefore, this study aimed to assess the formula-feeding practice and its associated factors among urban and rural mothers with infants 0-6 months of age in the Jimma Zone, Western Ethiopia. A community-based cross-sectional study was conducted from November 7, 2015, to January 10, 2016, in the Jimma Zone. The quantitative data were collected from a sample of 714 respondents using a multistage sampling technique. Data were collected through a structured questionnaire and the multivariate logistic regression model was used to show predictors of the formula-feeding practice among mothers with infants 0-6 months of age. The proportion of mothers who feed their baby formula-based was 47.2%, of which 34.5% were living in rural areas and 65.5% were living in urban areas. Among the mothers living in urban areas, the likelihood of formula-feeding was significantly associated with maternal educational status and attitude towards formula-feeding. On the other hand, being attended by relatives/friends and the traditional birth attendant was significantly associated with the formula-feeding practice among mothers who live in rural areas. Nearly half of the mothers in the study area practice formula-feeding for their infant. Therefore, sustained community based nutritional health education is recommended for pregnant and lactating mothers to reduce the practice of formula-feeding for infants.


Restenosis: the cost to society.
Restenosis occurs in 20% to 55% of arteries subjected to percutaneous intervention procedures and is an important cause of recurrent symptomatic angina. More than half of the patients in whom angiographically defined restenosis develops will require an additional revascularization procedure within 6 months, and as many as 80% of patients with angiographically defined restenosis will need to undergo repeat revascularization within 6 years. It has been calculated that a treatment that would reduce the risk of restenosis by 25% would save $1400 per patient in hospital, procedural, and professional fees, and a 33% risk reduction would save $2000 per patient. An economic analysis of the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial results has demonstrated that the 26% reduction in the 6-month rate of restenosis achieved with c7E3 treatment translated into a saving per patient of more than $1000 in medical costs, not counting the cost of the drug, which reflects a reduced incidence of rehospitalization and substantial declines in the need for repeat angioplasty and bypass surgery. Although few other therapies have been subjected to a prospective cost analysis in several thousand patients, future and past therapies should be initially evaluated with use of the same methods. According to an economic analysis of a small sample of patients in the Stent Restenosis Study (STRESS) trial, similar cost savings may be achieved by stent implantation.


Seeding role of spectrin in polymerization of skeletal muscle actin.
The effect of spectrin on the polymerization of muscle actin has been investigated by hydrodynamic methods and electron microscopy. Spectrin markedly accelerated polymerization of actin. The effect was more easily observed in lower concentrations of KCl (e.g. 24 mM) where spontaneous polymerization was negligibly small. Similarly large acceleration was observed for polymerization in MgCl2 or CaCl2. The rate of polymerization of actin was proportionally increased with the concentration of spectrin added to a fixed concentration of action. The stationary level of specific viscosity also increased with the spectrin concentration, but at larger concentrations it became smaller. The flow birefringence and electron microscope measurements indicated that actin polymers formed under the influence of spectrin were shorter than those of control F-actin filaments. The structural viscosity and electron microscope observations suggested that the interaction between F-actin fibers was not increased by spectrin. These data strongly suggest a seeding role of spectrin in the polymerization of actin. Spectrin accelerates formation of the nuclei for polymerization. The more the nuclei are formed, the larger the number of the grown polymers are and this leads to rapid formation of shorter polymers since the amount of actin is limited. The acceleration activity was found only in freshly prepared spectrin from fresh ghosts taken from freshly drawn blood.


Biomarkers for pancreatic cancer: promising new markers and options beyond CA 19-9.
Pancreatic adenocarcinoma accounts for nearly 90-95% of exocrine malignant tumors of the pancreas. Traditionally, overexpressed proteins/epitopes such as CA 19-9, CA-50, CEA, and many others were being used as pancreatic cancer tumor markers. The main utility of these biomarkers was in the diagnosis of pancreatic cancer as well as to assess response to chemotherapy and to determine prognosis and to predict tumor recurrence. However, these markers had significant limitations such as lack of sensitivity, false-negative results in certain blood groups, as well as false-positive elevation in the presence of obstructive jaundice. To circumvent these limitations, an extraordinary amount of research is being performed to identify an accurate tumor marker or a panel of markers that could aid in the management of the pancreatic cancer. Although this research has identified a large number and different variety of biomarkers, few hold future promise as a preferred marker for pancreatic cancer. This review provides an insight into exciting new areas of pancreatic biomarker research such as salivary, pancreatic juice, and stool markers that can be used as a noninvasive test to identify pancreatic cancer. This manuscript also provides a discussion on newer biomarkers, the role of microRNAs, and pancreatic cancer proteomics, which have the potential to identify a preferred tumor marker for pancreatic adenocarcinoma. This review further elaborates on important genetic changes associated with the development and progression of pancreatic cancer that holds the key for the identification of a sensitive biomarker and which could also serve as a therapeutic target.