Panx1 regulates neural stem and progenitor cell behaviours associated with cytoskeletal dynamics and interacts with multiple cytoskeletal elements.
Pannexins (Panxs) are relatively newly discovered large-pore ion and metabolite permeable channels. Although no proteomics-based interactome has yet been published, Panx1 has been demonstrated to interact with actin in an ectopic expression system. This interaction affects both Panx1 plasma membrane stability as well as cytoskeletal remodelling. The current study builds on our recent discovery of Panx1 expression in ventricular zone (VZ) neural stem and progenitor cells (NSC/NPCs), and on the demonstrated interaction of Panx1 with the cytoskeleton. Here we demonstrate that Panx1 also plays roles in two additional cell behaviours associated with neurogenesis, including cell migration and neurite extension. Furthermore, we confirm an endogenous interaction between actin and Panx1, and identify a new interaction with actin-related protein 3, an actin cytoskeleton-modulating protein. This study further establishes the importance of Panx1 in the cell biology of NSC/NPCs and strengthens and expands our knowledge of Panx1 interactions with the cytoskeleton.


Palliative therapy for stage IV rectal adenocarcinoma: how frequently is it used?
Palliative care is associated with decreased cost and improved quality of life, although its use in stage IV rectal cancer is understudied. Stage IV rectal cancer patients (2004-2011) who did not undergo surgery with curative intent were identified within the National Cancer Database. Patients receiving palliative therapy were stratified by the type of intervention, as were patients undergoing chemotherapy that was not designated as palliative. Logistic regression was used to identify factors associated with the receipt of palliative therapy. A total of 11,245 patients were analyzed, of which 2314 (20.6%) received palliative therapy. Use of palliative therapy as a category of treatments did not change significantly from 2004-2012 (19.4%-23.0%; P = 0.14), but the use of palliative chemotherapy nearly doubled (4.7%-8.7%; P < 0.001). Factors associated with the use of palliative therapy included age >60 y and increasing chronic comorbidities; these subgroups also had lower odds of receiving chemotherapy that was not designated as palliative. Differences in gender and race were not associated with variations in the receipt of palliative therapy. For stage IV rectal cancers managed without curative intent, use of palliative therapies remains consistently low, with a preference for sicker patients.


[Hip Joint phylogenesis. Phenotypic plasticity. Lamarckian or Darwinian paradigm? Part II].
The aim of this work is to analyse the origin of phenotypic plastic changes into a biologic structure, in this case the hip. As a hypothesis of the work, the possibility that changes could be explained following the Lamarckian paradigm, opposed to the Darwinian paradigm, is shown. The section material and methods of this work have been published in part I. Studies in plants and fish have been added. Results showed that the ball-and-socket design of the hip joint remains unchanged. Phenotype in the elements that form the hip joint tissues showed significant plastic changes. Interpretation of our results suggest that changes in phenotype plasticity of the hip joint are immanent to phenotype and cannot be explained by following Lamarck's or Darwin's paradigm.


Psychological coping styles and cortisol over the day in healthy older adults.
Patterns of psychological coping are associated with a variety of health outcomes but the underlying pathways are not yet established. The purpose of this study was to assess the relationship between salivary cortisol output over the course of a day and coping style. Data were available from 350 men and 192 women with an average age of 60.9 years. Participants were drawn from the Whitehall II cohort, and had no history of cardiovascular disease. Individuals who were taking medication that might affect cortisol levels were also excluded. Saliva samples were provided on waking, then 0.5, 2.5, 8 and 12h after waking, and just before the participant went to sleep. Coping style was measured with a standard instrument, the COPE, and data were factor analysed to generate three factors: seeking social support, problem engagement and problem avoidance. The relationships between these factors and the cortisol awakening response (CAR), the slope of cortisol change over the day and total cortisol output over the day (excluding the waking period) were assessed using multiple linear regression. Cortisol output over the day was inversely associated with coping with stress by seeking social support (p=0.034) and by problem engagement (p=0.003), independently of age, gender, body mass index, smoking, depression, self-rated health, time of waking and income. Individuals who coped by problem engagement and seeking support had lower cortisol levels. Additionally, gender, BMI, smoking, self-rated health and time of waking were independently related to cortisol output over the day. There were no significant associations between coping and the CAR or cortisol slope over the day. The results indicate that adaptive coping styles are related to low levels of cortisol over the day, suggesting that neuroendocrine pathways may partly mediate relationships between psychological coping and health.


Fluoride inhibition of polymorphonuclear leukocytes.
Significant inhibition of PMN metabolic activity by F- occurred at 0.1, 0.5 and 0.0 mM F- for O2- generation, 1-C14 CO2 release labeled glucose and NBT-reduction respectively. This inhibition resulted primarily from F- suppression of nonoxidative glucose metabolism. As the concentration of F- in the O2- generating system increased beyond 10 mM, a rise in production of O2- anion occurred, peaking at 20 mM F-, followed by a rapid decline.


Toward establishing an empirical basis for the diagnosis of oppositional defiant disorder.
(1) To determine the frequency of occurrence of oppositional defiant behaviors in the general population with a view to establishing empirical frequency cutoffs for the evaluation of oppositional defiant disorder (ODD). (2) To examine the effects of changes in the definition of ODD between DSM-III-R and DSM-IV. The Great Smoky Mountains Study is a general population study of 9-, 11-, and 13-year-olds. Subjects and their parents were interviewed with the Child and Adolescent Psychiatric Assessment at baseline and again 1 year later. Ninetieth percentile frequency cutoffs for ODD symptoms are given. Although rates of ODD were little different between DSM-III-R and DSM-IV, fewer than half of those who met criteria by one or the other definition met criteria according to both. DSM-IV defined a more disturbed group of children than did DSM-III-R. Requiring only two or three ODD symptoms plus impairment identified children with substantial evidence of disturbance who did not otherwise meet criteria for any diagnosis. The DSM-IV criteria represent an improvement over DSM-III-R. However, a reduction in the number of ODD symptoms required for diagnosis is indicated. Symptom frequency criteria for ODD symptoms are suggested for clinical use.


Protein associated with the sensory cell layer of the rainbow trout saccular macula.
A protein has been detected that is associated with the saccular hair cell layer of the rainbow trout, Salmo gairdnerii R. By one- and two-dimensional SDS polyacrylamide gel electrophoresis, the molecular weight and isoelectric point of this protein are estimated to be 13.6 and 8.8 kDa, respectively. The 13.6 kDa protein cannot be detected electrophoretically in brain, gill, liver, and fractions containing the basal lamina, non-sensory epithelium, and saccular nerve. This protein does not bind antibodies to bovine myelin basic protein, while trout myelin basic proteins in the same molecular weight range do. In addition, the protein does not bind concanavalin A or react with the periodic acid-Schiff reagent. The 13.6 kDa band represents about 1% of the total protein in saccular sensory epithelium, and may be a marker protein for the hair cell layer.


Role of serotonin in the blockade of muricidal behavior by tricyclic antidepressants.
Dose-response curves for the ability of three tricyclic antidepressants, imipramine, desmethylimipramine and amitriptyline to inhibit muricidal behavior were measured after treatment with a tryptophan-free diet and after administration of p-chloroamphetamine. Both treatments, which have been reported to specifically reduce central levels of serotonin, decreased the ability of the drugs to inhibit muricide. The results suggest that all three antidepressants block muricide in part through their effects on serotonin.


Quantifying national biomechanics day's impact on student perceptions toward biomechanics: A multisite pilot study.
National Biomechanics Day (NBD) is an international celebration of biomechanics that seeks to increase the awareness and appreciation of biomechanics among the high school community. Initial research supports the positive effects of NBD on students' attitudes toward the field of biomechanics; however, quantitative evidence remains scarce. The purpose of this study was to quantify changes in high school students' perceptions toward biomechanics after participating in NBD events to better understand the impact of NBD. Data were collected at two locations during the 2019 NBD season. Surveys were collected before and after NBD events for 112 high school students from Montana and North Carolina. Paired pre- versus post-NBD surveys for the aggregate sample population suggest that students perceived biomechanics as more appealing (p = 0.050), exciting (p = 0.007), and important (p = 0.018) following the NBD events. Students did not report a change in whether they could see themselves in a biomechanics-related career (p = 0.49). These findings further support the ability for NBD events to positively impact students' perceptions toward biomechanics, although opportunities persist to increase student career interest in biomechanics. This paper presents and discusses the study's results, interpretations, limitations, and implications for future research on biomechanics outreach activities.


Inhibitors of sterol synthesis. Metabolism of [2,4-3H]5 alpha-cholest-8(14-)-en-3 beta-ol-15-one after intravenous administration to a nonhuman primate.
The metabolism of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one, a potent inhibitor of cholesterol synthesis with marked hypocholesterolemic activity, has been studied after the intravenous administration of a mixture of [2,4-3H]5 alpha-cholest-8(14)-en-3 beta-ol-15-one and [4-14C] cholesterol to a baboon. The levels of 3H in plasma which was associated with the free 15-ketosterol decreased very rapidly (T1/2 approximately 9 min) after injection of the labeled sterol. By 4 h, the level of the [3H]15-ketosterol in plasma was negligible. The rapid decrease in the levels of the free 15-ketosterol was associated with rapid formation of fatty acid esters of the 15-ketosterol. The maximum level of 3H-labeled 15-ketosteryl esters was observed at 20 min after the injection of the 15-ketosterol. Thereafter, the levels of the 15-ketosteryl esters decreased rapidly with an apparent T1/2 of approximately 3.5-4.0 h. The results also indicated rapid formation of 3H-labeled cholesterol and cholesteryl esters. Substantial formation of [3H]cholesterol was observed at 20 min after the injection of the 15-ketosterol and reached a maximum level in plasma at 2 h. The maximum levels of [3H]cholesteryl esters in plasma were observed much later. These and other findings indicated that the observed slow clearance of total 3H from plasma is a consequence of metabolism of the 15-ketosterol to cholesterol and cholesteryl esters, normal constituents of plasma whose turnover in the whole animal is known to be relatively slow.


Students with disabilities in higher education - perceptions of support needs and received support: a pilot study.
Students with disabilities in higher education frequently need support to succeed in their studies. Perceived problems in managing studies and everyday life may be the same for students with different disabilities, although the reasons for support may vary between them. In this pilot study, a questionnaire aimed to survey everyday functioning in students with disabilities was tested. Thirty-four students with Asperger syndrome, motor disabilities or deafness/hearing impairments were asked 55 close-ended and open-ended questions on participation restrictions and available support programmes. One aim of this study was to test the usefulness of the questionnaire, and another aim was to identify students' perceptions of their everyday student life and the support they are offered, with a special focus on comparing perceptions of needs and support between students with Asperger syndrome and other student groups. The results indicate the need to plan recruitment of participants carefully and that the questionnaire was useful. The descriptive analyses indicated that the groups primarily reported the same difficulties; however, the open-ended comments indicated that the reasons for the problems vary between the groups. It indicates that Likert-type responses to questions concerning perceived difficulties need to be supplemented by open-ended questions on the perceived reasons to problems.


Robot-assisted intraocular surgery: development of the IRISS and feasibility studies in an animal model.
The aim of this study is to develop a novel robotic surgical platform, the IRISS (Intraocular Robotic Interventional and Surgical System), capable of performing both anterior and posterior segment intraocular surgery, and assess its performance in terms of range of motion, speed of motion, accuracy, and overall capacities. To test the feasibility of performing 'bimanual' intraocular surgical tasks using the IRISS, we defined four steps out of typical anterior (phacoemulsification) and posterior (pars plana vitrectomy (PPV)) segment surgery. Selected phacoemulsification steps included construction of a continuous curvilinear capsulorhexis and cortex removal in infusion-aspiration (I/A) mode. Vitrectomy steps consisted of performing a core PPV, followed by aspiration of the posterior hyaloid with the vitreous cutter to induce a posterior vitreous detachment (PVD) assisted with triamcinolone, and simulation of the microcannulation of a temporal retinal vein. For each evaluation, the duration and the successful completion of the task with or without complications or involuntary events was assessed. Intraocular procedures were successfully performed on 16 porcine eyes. Four eyes underwent creation of a round, curvilinear anterior capsulorhexis without radialization. Four eyes had I/A of lens cortical material completed without posterior capsular tear. Four eyes completed 23-gauge PPV followed by successful PVD induction without any complications. Finally, simulation of microcannulation of a temporal retinal vein was successfully achieved in four eyes without any retinal tears/perforations noted. Robotic-assisted intraocular surgery with the IRISS may be technically feasible in humans. Further studies are pending to improve this particular surgical platform.


Recent advances in the study of Kaposi's sarcoma-associated herpesvirus replication and pathogenesis.
It has now been over twenty years since a novel herpesviral genome was identified in Kaposi's sarcoma biopsies. Since then, the cumulative research effort by molecular biologists, virologists, clinicians, and epidemiologists alike has led to the extensive characterization of this tumor virus, Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 (HHV-8)), and its associated diseases. Here we review the current knowledge of KSHV biology and pathogenesis, with a particular emphasis on new and exciting advances in the field of epigenetics. We also discuss the development and practicality of various cell culture and animal model systems to study KSHV replication and pathogenesis.


Survival of patients with acute renal failure requiring dialysis after open heart surgery: early prognostic indicators.
We analyzed pre- and postoperative data from 36 consecutive patients, who developed acute renal failure requiring hemodialysis after open heart surgery, to determine which factors predicted survival. Seventeen patients (47%) survived. Age, sex, preoperative renal dysfunction, severity of underlying heart disease, perioperative myocardial infarction, cardiopulmonary bypass time, and oliguria did not influence outcome (by univariate analysis). However, the number and type of postoperative complications, before the first hemodialysis and 48 hours thereafter, were found to be significant predictors of outcome. Univariate as well as multivariate analysis showed that the highest mortality rate was associated with the presence of respiratory failure, central nervous system dysfunction, hypotension, and infection (48 hours after first hemodialysis). Thirty-three (92%) of the 36 patients were correctly classified as survivors or nonsurvivors based on the presence or absence of any one of three prognostic indicators (three or more complications before the first hemodialysis and persisting 48 hours later; hypotension before the first dialysis and persisting 48 hours later; or central nervous system dysfunction 48 hours after hemodialysis was initiated). We conclude that an assessment of prognosis can be made in such patients as early as 48 hours after the first hemodialysis based on the number and type of complications.


Phagocytosis of Dictyostelium discoideum studied by the particle-tracking method.
Single phagocytic events of cellular slime mold Dictyostelium discoideum were studied by the method of particle tracking. A 2-microm polystyrene bead, which had been covalently coated with folate, was attached to the advancing edge of a Dictyostelium ameba with the aid of an optical trap. The bead was transported backward on the cell surface. Forty-five percent of the transported beads were internalized. The bead motion was analyzed by determining every 33 ms the x-y coordinate of the centroid of the phase-contrast image of the bead. The x(t) and y(t) traces were smoothed over 1 s and the difference between the smoothed (x(t) and y(t)) and the original traces, delta(x) identical with x(t) - x(t) and delta(y) identical with y(t) - y(t), were calculated, which represented relatively rapid components of the bead motion. The plot of delta(2) = (delta(x)(2) + delta(y)(2)) against time could be divided into three phases on the basis of the variance of delta(2). Comparison of the plot with the video sequence indicated that the first phase corresponded to the transport, the second phase to the internalization, and the third phase to the postinternalization process (intracellular movement). Cytochalasin A at 5 microM completely inhibited phagocytosis without affecting the binding of bead to the cell surface, indicating the importance of actin cytoskeleton in all the phases. At 1 microM cytochalasin A the variance of the postinternalization process decreased, and the duration of the transport phase increased. At 0.25 microM cytochalasin A the duration of the internalization phase exhibited a significant increase, but other parameters did not change appreciably. The complex and differential effects of cytochalasin A on the parameters characterizing the three phases in the phagocytic process indicate that various aspects of actin dynamics are involved in the individual process of phagocytosis.


Genetic loci of major antigenic protein genes of Edwardsiella tarda.
Seven antigenic proteins of Edwardsiella tarda were identified by using a rabbit polyclonal antiserum. Four of these proteins also reacted with a Japanese flounder antiserum. The amino acid sequences had identity to lipoproteins, periplasmic proteins, and exported and secreted proteins with roles in transport of metabolites across the cell membrane, stress response, and motility. These genes and their products are useful for developing DNA or recombinant subunit vaccines to control edwardsiellosis.


Macroecology of habitat choice in long-distance migratory birds.
Patterns of habitat choice in ecological communities are not only influenced by present-day selective forces but also by historical processes, such as the biogeographical history of the lineages they are composed of. Nevertheless, it has been very difficult to test historical factors. The possible tropical origin of long-distance migratory birds provides an opportunity for such a test. If habitat choice of long-distance migrants is inherited from their tropical ancestors then Nearctic long-distance migrants might have acquired their habitat choice from Neotropical forest species and European long-distance migrants from African savannah species. Here we use a macroecological approach to show that this hypothesis can be confirmed. Long-distance migrants in the Nearctic are found in forested habitat types, while those in Europe are found in open ones. In comparison, the habitat choice of residents and short-distance migrants (in genera without long-distance migration) does not differ between the Nearctic and Europe. These results demonstrate that habitat choice in temperate bird communities can be explained by the tropical history of long-distance migrants. Thus, habitat choice seems to be shaped not only by local mechanisms, but also by processes acting on much larger spatial and temporal scales.


Shaping polyploid wheat for success: Origins, domestication, and the genetic improvement of agronomic traits.
Bread wheat (Triticum aestivum L., AABBDD, 2n = 6x = 42), which accounts for most of the cultivated wheat crop worldwide, is a typical allohexaploid with a genome derived from three diploid wild ancestors. Bread wheat arose and evolved via two sequential allopolyploidization events and was further polished through multiple steps of domestication. Today, cultivated allohexaploid bread wheat has numerous advantageous traits, including adaptive plasticity, favorable yield traits, and extended end-use quality, which have enabled its cultivation well beyond the ranges of its tetraploid and diploid progenitors to become a global staple food crop. In the past decade, rapid advances in wheat genomic research have considerably accelerated our understanding of the bases for the shaping of complex agronomic traits in this polyploid crop. Here, we summarize recent advances in characterizing major genetic factors underlying the origin, evolution, and improvement of polyploid wheats. We end with a brief discussion of the future prospects for the design of gene cloning strategies and modern wheat breeding.


The use of intradermal tests and relevance of negative controls in patients with negative or equivocal modified RAST test scores to inhalant allergens.
Patients with suspected inhalant allergy that demonstrate a Modified RAST Test (MRT) Class 0 and 1 (equivocal) may demonstrate positive infradermal (ID) skin whealing to suspect allergens. This whealing may be due, however, to an irritant reaction from glycerin used as a preservative in the extract. The purpose of this study is to establish the incidence of allergy as demonstrated by ID testing in patients with MRT Class 0 or 1 and to reinforce the importance of negative controls during ID testing. Fifty-five consecutive patients evaluated for allergy with MRT Classes 0 or 1 were studied. Intradermal testing with 1:500 wt/vol concentrations of allergenic extracts and a 2% glycerin control were performed. Thirty-eight patients (69%) were found to have ID whealing to allergenic extracts greater than the negative glycerin controls. We conclude that ID allergen testing of patients with MRT Class 0 or 1, when using a glycerin control, identifies additional allergens to be considered for immunotherapy.


The YUMM lines: a series of congenic mouse melanoma cell lines with defined genetic alterations.
The remarkable success of immune therapies emphasizes the need for immune-competent cancer models. Elegant genetically engineered mouse models of a variety of cancers have been established, but their effective use is limited by cost and difficulties in rapidly generating experimental data. Some mouse cancer cell lines are transplantable to immunocompetent host mice and have been utilized extensively to study cancer immunology. Here, we describe the Yale University Mouse Melanoma (YUMM) lines, a comprehensive system of mouse melanoma cell lines that are syngeneic to C57BL/6, have well-defined human-relevant driver mutations, and are genomically stable. This will be a useful tool for the study of tumor immunology and genotype-specific cancer biology.


[Procedural skills of students qualifying as a doctor - towards blended learning].
Medical students feel that their ability to carry out procedures is lower than desired. Whereas supervised learning is easily arranged at scheduled appointment clinics, experience in emergency procedures often accumulates only during practical training. A large part of the students had turned to the internet in search for advice or repetition about typical emergency procedures. With the growing yearly intake by the faculties it will be difficult to increase contact teaching at the clinical stage, but it is possible to improve its quality through flipped classroom. Procedural videos found in the internet are well suited for stimuli prior to contact teaching.


Thrombus architecture is influenced by the antiplatelet loading treatment in patients with acute myocardial infarction.
Intracoronary thrombus formation is a main cause of acute myocardial infarction triggered by platelet activation. However, there are no data on the impact of different treatment strategies with antiplatelet agents before percutaneous coronary intervention (PCI) on histological characteristics of thrombus formation. In this study, we investigate the impact of preinterventional administration of the P2Y12-inhibitors clopidogrel and prasugrel on thrombus composition, highlighting significant changes associated with the antiplatelet pre-treatment. We prospectively enrolled 104 consecutive patients with ST-segment elevation myocardial infarction (STEMI) undergoing immediate PCI and thrombus aspiration by immunohistochemical staining along with RNA-sequencing employing Nanostring analysis. Fifty-two patients were treated with either prasugrel loading (60 mg) or clopidogrel loading (600 mg) prior to PCI, respectively. In Patients with STEMI, intracoronary thrombus architecture was significantly altered between patients pre-treated with prasugrel when compared to clopidogrel. Fibrin content of thrombi was significantly decreased (41.8 % versus 66.7 %, p = 0.009) after pre-treatment with prasugrel compared to clopidogrel. Furthermore, levels of MPO positive cells in intracoronary thrombi were significantly decreased in patients with prasugrel pre-treatment (90.5 versus 201.1, p = 0.014) indicating an association of antiplatelet pre-treatment and the inflammatory responses during thrombus formation. Most strikingly, we observed significant differences among both pre-treatment groups regarding altered RNA expression and signaling pathways of thrombo-inflammatory processes within the thrombotic material, which were independently associated with antiplatelet strategies. Our study elucidates the impact of antiplatelet pre-treatment on thrombus remodeling and architecture, thereby lowering the risk of recurrent adverse cardiovascular events in prasugrel-treated patients.


Electron Microprobe and Raman Spectroscopy Investigation of an Oxygen-Bearing Pt-Fe-Pd-Ni-Cu Compound from Nurali Chromitite (Southern Urals, Russia).
One grain, about 100×80 μm in size, occurring in chromitite associated with the layered sequence of the Nurali mafic-ultramafic complex (Southern Urals, Russia) was investigated by electron-microprobe analyses and Raman spectroscopy. The grain is characterized by a spotty, rugged appearance and chemical zoning from which two compositions were calculated: (Pt(0.35)Pd(0.26)Fe(0.22)Cu(0.01)Ni(0.05))(0.98)O(1.02) and (Fe(0.90)Pt(0.58)Ni(0.28)Pd(0.13)Cu(0.08)Rh(0.01))(1.98)O(1.02). In the lack of X-ray data, Raman spectroscopy established the presence of a diffuse 500-700 band and a sharp peak at 657 cm⁻¹ of relative wavenumber that strongly resemble the Raman spectra of synthetic PtO and PdO (palladinite). It is concluded that the Nurali grain probably represents a platinum group element (PGE) oxide, and does not consist of a mixture of PGE alloys with Fe oxide or hydroxide as reported for other natural PGE-O compounds.


Evaluation of serological anti-SARS-CoV-2 chemiluminescent immunoassays correlated to live virus neutralization test, for the detection of anti-RBD antibodies as a relevant alternative in COVID-19 large-scale neutralizing activity monitoring.
The Spike-Receptor Binding Domain (S-RBD) is considered the most antigenic protein in SARS-CoV-2 and probably the key player in SARS-CoV-2 immune response. Quantitative immunoassays may help establish an anti-RBD Abs threshold as an indication of protective immunity. Since different immunoassays are commercial, the standard reference method for the neutralizing activity is the live Virus Neutralization Test (VNT). In this study, anti-RBD IgG levels were detected with two chemiluminescent immunoassays in paucisymptomatic, symptomatic and vaccinated subjects, and their neutralizing activity was correlated to VNT titer, using SARS-CoV-2 original and British variant strains. Both immunoassays confirmed higher anti-RBD Abs levels in vaccinated subjects. Furthermore, despite different anti-RBD Abs median concentrations between the immunoassays, a strong positive correlation with VNT was observed. In conclusion, although the SARS-CoV-2 immune response heterogeneity, the use of immunoassays can help in large-scale monitoring of COVID-19 samples, becoming a valid alternative to VNT test for diagnostic routine laboratories.


Intermale and maternal aggression in adult rats tested at different ages.
In Experiment 1, rat colonies consisting of two males and one female were established when the animals were either 100, 200, or 300 days old. All colony members were reared from weaning in small, stable isosexual groups prior to colony formation. Males that were 200 days old engaged in significantly more fighting at colony formation, and, three weeks later, were more likely to wound an intruder during a 24 hr aggression test than either younger or older animals. These findings demonstrate that colony aggression in male rats varies markedly as a function of age when reared under housing conditions that are employed in most laboratories. In Experiment 2, colony females were individually housed after their second pregnancy and their response to a male intruder was evaluated for a 24 hr period after nine days of lactation. Maternal aggression occurred at all ages, indicating that age may be of lesser importance in nest defense of females than intermale conflict. However, maternal aggression was ineffective in preventing the destruction of a high proportion of the litters by intruders in the three maternal age groups.


Delay in Presentation, Diagnosis and Treatment for Colorectal Cancer Patients in Jordan.
Colorectal cancer (CRC) ranked first among cancers reported in males and second among cancers reported in females in Jordan in 2010. There has been no specific CRC-control programme in Jordan. Additionally, there has been no published study from Jordan or its neighbours on patient delays in presentation, diagnosis or treatment. Therefore, we conducted this study to assess these important quality indicators aiming to improve prognosis for CRC and to provide baseline data for future health promotion programmes for CRC in Jordan. This project was a cross-sectional study on CRC patients at Al Bashir Hospital, Ministry of Health, and at the Military Oncology Centre of the Jordanian Royal Medical Services. The total number of participants was 189. The proportion of patients with presentation delay, diagnosis delay or treatment delay was 33.9, 68.1 and 32.6%, respectively. The main reasons reported for delay in presentation were lack of knowledge that symptoms were suggestive of cancer (58.5%), misdiagnosis by physicians or pharmacists (38.4%) or the patient did not want to visit a doctor (3.1%). Predictors of delay and mean time for presentation, diagnosis and treatment were identified. Our results revealed that CRC patients in Jordan experience delays in presentation, Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation diagnosis, and, to a lesser degree, in treatment. This could justify the advanced stages at diagnosis and poor outcomes for CRC patients. Our findings provide baseline information for future CRC-control programmes in Jordan. We recommend that CRC prevention programmes in Jordan focus on early detection of CRC and target both patients and physicians.


Bassoon contributes to tau-seed propagation and neurotoxicity.
Tau aggregation is a defining histopathological feature of Alzheimer's disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer's disease and progressive supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies.


Skull base reconstruction using various types of galeal flaps.
Failure of skull base reconstruction is a life-threatening issue. This study describes surgical techniques utilising various types of galeal flaps and reports on outcome of these procedures for skull base reconstruction. Clinical records of 136 patients (75 men, 61 women; mean age, 50.0 years) who required skull base reconstruction with galeal flaps were reviewed retrospectively. Patients had undergone skull base surgeries with simultaneous reconstruction for benign tumours in 77 patients, malignant tumours in 53, and other lesions in 6. We repaired dural defects using a fascial patch, and covered the skull base defects using various types of galeal flap according to the size and location of the skull base defects. Routine spinal drainage was not used in any patients. Reconstruction was performed as planned in all patients. We utilised a galea frontalis flap in 17 patients, temporoparietal galeal flap in 95, temporoparietal galeal flap with calvarial bone in 9, and bipedicled temporoparietal galeal flap in 15. Postoperative complications included scalp wound necrosis in 8 patients (5.9%), transient leakage of cerebrospinal fluid in 3 (2.2%), and intracranial infection in 2 (1.5%). Necrosis of the galeal flaps was not encountered. Galea is a well-vascularised tissue with homogenous thickness. Since the galeal layer covers the entire head area, various types of galeal flap can be elevated to cover any size and location of skull base defect.


[Construction and toxicity the recombinant SpltMNPV expressing the scorpion toxin gene].
To develop a high toxic recombinant Spodoptera litura multicapsid nucleopolyhedroviruse (SpltMNPV) insecticide. We constructed a recombinant transfer vector that was characterized by disrupting of ecdysterioid UDP-glucosyltransferase (egt) gene and expressing the mature peptide of the Chinese scorpion, B. martensi Karsch (BmK ITal) gene at the control of ie-1 promoter. The transfer vector and the SpltMNPV II DNA cotransfected the SpLi cells. Recombinant viruses were purified by the end point dilution and fluorescent spot purification. We successfully screened the recombinant SpltMNPV-deltaegt-Pph-egfp-ie-1-BmK ITal of which the egt gene was knocked out and expressed the mature peptide of the BmK ITal gene at the control of ie-1 promoter. Bioassays showed that, compared to the wide-type SpltMNPV, the speed of the recombinant virus killing the S. litura (LT50) increased by 0.7-0.8 days. The insecticidal effect of SpltNPV could be increased by inserting the foreign gene, which provided a further opportunity to develop the SpltNPV into commercially viable products to control the S. litura.


Size and structure of the bird genome. II. Repetitive DNA and sequence organization.
1. Highly repetitive, middle repetitive and single copy DNA were evaluated in 19 species of birds, belonging to nine orders, by means of a reassociation kinetics method. 2. A rather uniform pattern is present in all the species studied (single copy = 60-75%; middle repetitive = 13-20% and highly repetitive 10-20%). 3. Reassociation kinetics of fragments of different length confirms the presence of a long period interspersion pattern. 4. Among different orders, no significant differences are observed. 5. DNA sequence organization seems to be related to genome size, with an inverse correlation between DNA nuclear content and amount of interspersed repetitive sequences.


Spinocerebellar projections in the turtle. Observations on their origin and terminal organization.
Spinocerebellar projections were studied in the turtle, Pseudemys scripta elegans, by both anterograde (injections of 35S-methionine into various spinal segments) and retrograde (injections of horseradish peroxidase into the cerebellar cortex) tracing techniques. After unilateral HRP injections, labeled neurons were found on both sides of the spinal cord. The total number of retrogradely labeled spinocerebellar tract neurons was relatively small and neuronal aggregations were not observed. Most spinocerebellar tract neurons were found in the ventral horn, dorsal to the motoneuronal cell group. Some cells lay in the spinal intermediate zone and in the dorsal horn. The fibers mainly ascended in the lateral funiculus, some in the ventral and possibly some in the dorsal funiculi. Spinal projections terminated within the cerebellar granular layer. The spinocerebellar target area extended along the whole medio-lateral extent and covered about the rostral four fifths of the cerebellar plate. Individual target areas, separated from each other, as are the anterior and posterior spinocerebellar target areas of higher vertebrates, could not be identified. Similar to mammals, however, the terminal field in the turtle was not a homogenous one but consisted of zones of mossy fiber terminations of varying sizes and intensities.


Current understanding of the pathogenesis and management of chronic recurrent multifocal osteomyelitis.
Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory disorder that primarily affects children. Its hallmark is recurring episodes of sterile osteomyelitis. The clinical presentation is insidious onset of bone pain with or without fever. Laboratory studies typically reveal nonspecific evidence of inflammation. Radiologic imaging and histologic appearance resemble those of infectious osteomyelitis. There is a strong association with inflammatory disorders of the skin and intestinal tract in affected individuals and their close relatives, suggesting a shared pathophysiology and supporting a genetic component to disease susceptibility. Two genetic syndromes have CRMO as a prominent phenotype-Majeed syndrome and deficiency of the interleukin-1 receptor antagonist-and suggest that interleukin-1 may be a key cytokine in disease pathogenesis. This review briefly summarizes the main clinical and radiologic aspects of the disease and then focuses on genetics and pathophysiology and provides an update on treatment.


Associations of long-term exposure to air pollution with prevalence of pulmonary nodules: A cross-sectional study in Shijiazhuang, China.
A complete understanding of the associations of ambient air pollution with prevalence of pulmonary nodule is lacking. We aimed to investigate the associations of ambient air pollutants with prevalence of pulmonary nodule. A total of 9991 health examination participants was enrolled and 3166 was elected in the final in Shijiazhuang between April 1st, 2018, and December 31st, 2018. 107 participants were diagnosed in pulmonary nodule while 3059 participants were diagnosed in non-pulmonary (named control). The individual exposure of participants was evaluation by Empirical Bayesian Kriging model according to their residential or work addresses. The pulmonary nodules were found and diagnosed by health examination through chest x-ray detection. Our results suggested that there were positive associations between prevalence of pulmonary nodules and PM2.5 (OR = 1.06, 95% CI: 1.02, 1.11) as well as O3 (OR = 1.49, 95% CI: 1.35, 1.66) levels. The platelet count (PLT) acted as the mediator of pulmonary nodules related with the PM2.5 exposure, while the neutrophil-to-lymphocyte ratio (NLR) as well as platelet-to-lymphocyte ratio (PLR) were the mediators of pulmonary nodules related with the O3 exposure. This study suggests that long-term exposure to PM2.5 and O3 may significantly associated with prevalence of pulmonary nodules, and the above associations are mediated by PLT, NLR and PLR.


Development of a computerized adaptive test for assessing activities of daily living in outpatients with stroke.
An efficient, reliable, and valid measure for assessing activities of daily living (ADL) function is useful to improve the efficiency of patient management and outcome measurement. The purpose of this study was to construct a computerized adaptive testing (CAT) system for measuring ADL function in outpatients with stroke. Two cohort studies were conducted at 6 hospitals in Taiwan. A candidate item bank (44 items) was developed, and 643 outpatients were interviewed. An item response theory model was fitted to the data and estimated the item parameters (eg, difficulty and discrimination) for developing the ADL CAT. Another sample of 51 outpatients was interviewed to examine the concurrent validity and efficiency of the CAT. The ADL CAT, as the outcome measure, and the Barthel index (BI) and Frenchay Activities index (FAI) were administered on the second group of participants. Ten items did not satisfy the model's expectations and were deleted. Thirty-four items were included in the final item bank. Two stopping rules (ie, reliability coefficient >.9 and maximum test length of 7 items) were set for the CAT. The participants' ADL scores had an average reliability of .93. The CAT scores were highly associated with those of the full 34 items (Pearson r=.98). The scores of the CAT were closely correlated with those of the combined BI and FAI (r=.82). The time required to complete the CAT was about one fifth of the time used to administer both the BI and FAI. The participants were outpatients living in the community. Further studies are needed to cross-validate the results. The results demonstrated that the ADL CAT is quick to administer, reliable, and valid in outpatients with stroke.


Performance of the Emergency Surgery Score (ESS) for nonelective infrainguinal open revascularization procedures (NEIOR).
The Emergency Surgery Score has been previously validated as a reliable; tool to predict postoperative outcomes in emergency general surgery. The purpose of this study was to assess the performance of the Emergency Surgery Score for infrainguinal open revascularization procedures in the nonelective setting. The American College of Surgeons' National Surgical Quality Improvement Program database was retrospectively analyzed for patients undergoing infrainguinal open revascularization procedures in the nonelective setting between 2015 and 2019. The performance of the Emergency Surgery Score in predicting mortality in each procedure was assessed using receiver operating characteristic analyses. A total of 5,027 patients underwent infrainguinal open revascularization procedures in the nonelective setting with median age 68 (±11.66 standard deviation), with 1,666 females (33.1%). The 30-day mortality rate was 2.7%. The Emergency Surgery Score correlated with 30-day mortality (area under the curve was 0.738). The Emergency Surgery Score also predicted risk of death/discharge to hospice (area under the curve 0.756), discharge to rehab (area under the curve 0.643), renal failure (area under the curve 0.741), postintervention ventilation requirement (0.684), stroke (0.717), cardiopulmonary arrest (0.657), and septic shock (0.697). A cumulative frequency table of mortality with Emergency Surgery Score was used to partition patients into quartiles of Emergency Surgery Score ≤5, Emergency Surgery Score of 6, Emergency Surgery Score of 7 or 8, and Emergency Surgery Score ≥9. A Cochran-Armitage test showed linear trend toward increased 30-day mortality among the quartiles with increasing Emergency Surgery Score (P < .001), with quartile 4 (Emergency Surgery Score ≥10) having 13 times odds of increased 30-day mortality compared to reference quartile 1 (Emergency Surgery Score ≤4). Emergency Surgery Score performance accurately predicts mortality for infrainguinal open revascularization procedures in the nonelective setting procedures. It may be useful for preoperative risk stratification and for national benchmarking after nonelective open lower extremity procedures.


Age-dependent variations in serum 1,25-dihydroxyvitamin D in childhood.
Circulating 1,25-dihydroxyvitamin D (1,25-(OH)2D) was measured in 87 children aged 3 months to 15 years, and in 11 adolescents 16-19 years of age. A positive correlation to growth velocity was observed, indicating that the biologically active vitamin D metabolite is an important physiological factor in the regulation of growth and development of the skeleton.


Ethanol and aloe emodin alter the p53 mutational spectrum in ultraviolet radiation-induced murine skin tumors.
Mutations in the p53 tumor-suppressor gene contribute to the development of skin cancer, and the spectrum of mutations in this gene correlates with specific physical and chemical carcinogens in the environment. Cosmetics may contain alcohols and/or aloe emodin (AE). Although these compounds are not carcinogenic when applied to the skin, they may increase the carcinogenicity of ultraviolet (UV) radiation. We investigated whether ethanol (EtOH) and AE alone or combined with UV radiation cause mutations in the p53 gene. In the absence of UV radiation, C3H/HeN mice chronically treated for up to 33 wk with AE in 25% EtOH-in-water vehicle or vehicle alone failed to develop tumors and had no mutations in exons 4-8 of the p53 gene. UV radiation alone induced skin tumors, which had mutations predominantly in p53 exons 5 and 8. In contrast, mutations arising in UV + EtOH-or UV + AE-treated groups were more broadly distributed throughout the p53 gene. Mutations were found in exons 4, 6, and 7, as well as in exons 5 and 8. This altered distribution of mutations across the p53 DNA sequence more closely resembles the pattern observed in TP53 from human skin tumors at sun-exposed sites than that in the p53 gene of mice treated with UV alone. Thus, treatment with UV radiation in combination with two chemicals not thought to be carcinogenic, alcohol, and AE results in a broader distribution of mutations in a critical tumor-suppressor gene.


Benefits and risks of using bacterial- and plant-produced nano-silver for Japanese quail hatching-egg sanitation.
This research compared how bacterial-, plant-produced silver nanoparticles (Ag-NPs) and TH4 affected the eggshells microbial load and quail chicks' liver structure, embryonic mortality, and features related to hatchability. Ag-NPs were sensitized by bacterial and plant methods, and then identified by UV-visible spectroscopy, TEM, and FTIR spectroscopy. B-Ag-NPs were found in spherical shapes in size ranging from 7.09 to 18.1 nm versus multi-shape with size range of 25.0-78.1 nm for P-Ag-NPs. A total number of 624 eggs (in three equal groups) of Japanese quail flock were sprayed with TH4 as control, B-Ag-NPs and P-Ag-NPs. Thereafter, three eggs were sampled randomly from each group for determining important microbial groups. The remaining eggs were incubated according to the recommended incubation conditions. On the day of hatching, the percentages of hatchability and embryonic mortality were measured. Besides, five chicks from each treatment were slaughtered and the livers were utilized for ICP and histological tests. The effects of all three treatments on the microbial count in eggshells were comparable, according to the results. In addition, there was no negative effect on either hatchability percentage or embryonic mortality rate. The liver structure from both B-Ag-NPs and P-Ag-NPs treatments exhibited severe and moderate degeneration of hepatocytes, which may indicate possible hazardous effects of using nanoparticles. Using TH4 did not cause liver structure abnormality. In conclusion, using Ag-NPs for sanitizing hatching eggs effectively reduces the eggshell microbial count without affecting the hatchability percentage. Nevertheless, histological changes are appropriate to be considered as a safety parameter in Ag-NPs applications.


Rational design of visible light panchromatic absorption laser dye molecules: The first principle study.
Laser dye molecules play an important role in tunable lasers due to enhancing the laser radiation intensity and increasing the laser adjustable range. The broad spectral bandwidth and visible light absorption allows for the evaluation of multiple fluorescence quenching mechanisms such as excition formation, photoinduced electron transfer, and excited-state proton transfer. A series of organic dye molecules (LD1-4、LA2-5、LU1-5、LV1-4、LI1-4) consisting of simple electron donor (D), conjugated bridge (π) and electron acceptor (A) units were designed using first-principles calculations in order to evaluate their potential for applications in tunable lasers. Furthermore, the optical and electronic properties of the dye molecules are analyzed in detail using density functional theory (DFT) and time-dependent density functional theory (TDDFT), including spectral parameters, energy levels and orbital contributions of organic dye molecules. The results indicate that LI1-3 show high molar extinction coefficient, visible light full color absorption and obvious red-shifted compared to the experimentally synthesized dye LA3. In particular, the newly designed LI3 exhibits not only a 190 nm red-shifted and a higher molar extinction coefficient with an increment of 19%, but also has an extremely broad absorption spectrum covering entire visible absorption spectrum from 380 to 750 nm compared to LD1. We also find that the dyes with dithiophene groups and naphthalene group as the electron donors are better absorption spectrum than dyes with double bond group and benzene group. These calculated results will hopefully contribute to the further development of novel laser dye molecules and further provide scientific support and theoretical guidance for subsequent related research.


Economic barriers to implementation of innovations in health care: is the long run-short run efficiency discrepancy a paradox?
Favourable cost-effectiveness of innovative technologies is more and more a necessary condition for implementation in clinical practice. But proven cost-effectiveness itself does not guarantee successful implementation. The reason for this is a potential discrepancy between long run efficiency, on which cost-effectiveness is based, and short run efficiency. Long run and short run efficiency is dependent upon economies of scale. This paper addresses the potential discrepancy between long run and short run efficiency of innovative technologies in healthcare, explores diseconomies of scale in Dutch hospitals and suggests what strategies might help to overcome hurdles to implement innovations due to that discrepancy.


Mapping in a radon-prone area in Adamawa region, Cameroon, by measurement of radon activity concentration in soil.
The radon-prone area of the Adamawa region in Cameroon is characterized by high natural radiation background resulting from the high concentrations of radium-226, thorium-232, and indoor radon. To produce a radon-risk map, radon measurements in soil were carried out in the city of Ngaoundere. The radon activity concentration in soil gas ranged from 256 to 166 kBq m-3 with a mean of 80 kBq m-3 and a standard deviation of 38 kBq m-3. The area is mostly classified as high risk (80%) according to the Swedish classification, and 20% as medium risk. A low-risk area was not observed. Granite-like geology sites were characterized by higher radon concentration. A ratio of about 295:1 was obtained for soil radon gas to indoor radon concentrations, with a positive correlation (R = 0.40), and a transfer factor of 3 per mil. These results demonstrate that in situ measurements of radon concentration in soil can provide accurate information on the level of indoor radon concentrations. Geostatistical and deterministic interpolation techniques have been used to obtain a radon map by comparing the suitability of ordinary kriging and inverse-distance-weighted (IDW) interpolation methods. It turned out that there is not much difference in the prediction errors of the two techniques (Root Mean Square Error = 34.4 for ordinary kriging and 34.3 for IDW). It is concluded that both methods give acceptable results. In situ measurements and geostatistical analysis allow assessment of expected indoor radon exposure in a given area at reduced costs and time required. However, for the investigated area, more research is needed to produce reliable radon-risk maps.


Exons 16 and 17 of the amyloid precursor protein gene in familial inclusion body myopathy.
Accumulation of beta-amyloid protein (A beta) occurs in some muscle fibers of patients with inclusion body myopathy and resembles the type of amyloid deposits seen in the affected tissues of patients with Alzheimer's disease and cerebrovascular amyloidosis. Because mutations in exons 16 and 17 of the beta-amyloid precursor protein (beta APP) gene on chromosome 21 have been identified in patients with early-onset familial Alzheimer's disease and Dutch-type cerebrovascular amyloidosis, we searched for mutations of the same region in patients with familial inclusion body myopathy. Sequencing of both alleles in 8 patients from four unrelated families did not reveal any mutations in these exons. The amyloid deposition in familial forms of inclusion body myopathy may be either due to errors in other gene loci, or it is secondary reflecting altered beta APP metabolism or myocyte degeneration and cell membrane degradation.


Synthesis, Characterization, and Evaluation of a Novel Molecularly Imprinted Polymer (MIP) for Selective Quantification of Curcumin in Real Food Sample by UV-Vis Spectrophotometry.
Curcumin is the main colorant of the curcuma longa plant, a food with many benefits for human health. This work aims to synthesize a novel molecularly imprinted polymer (MIP) for the selective detection of curcumin in real samples obtained from the local market of Peru. MIPs were synthesized via bulk polymerization using curcumin, acrylamide, ethylene glycol dimethacrylate, ABCV, and acetonitrile. FTIR spectra showed equal spectra for MIP and NIP. N2 physisorption analysis presented a higher value BET surface for the MIP (28.5 m2 g-1) compared to the NIP (18.5 m2 g-1). The adsorption capacity of the MIP was evaluated using UV-vis spectrophotometry in the band around 430 nm. The adsorption kinetics found were of pseudo-second-order and a Qe value of 16.2 mg g-1. Furthermore, the adsorption process resembles the Freundlich adsorption model with a heterogeneity factor of less than 1 (0.61) and Kf greater for MIP (1.97). The selectivity test indicated that MIP is more selective for curcumin (Q = 13.20 mg g-1) than against interferents (Q = 2.19 mg g-1). The specific selectivity factor (S) obtained for the interferents was greater than 1 which indicates a good selectivity. Finally, the application of MIP in real samples using UV-vis spectrophotometry yielded a recovery value greater than 70%.


Project RedDE: Cluster Randomized Trial to Reduce Missed or Delayed Abnormal Laboratory Value Actions.
Failure of timely abnormal laboratory result follow-up is relatively common and may lead to harm. This study hypothesized that a quality improvement collaborative (QIC) could reduce the frequency of missed or delayed action on abnormal laboratory values. A national cohort of pediatric practices was cluster-randomized to sequentially receive a QIC intervention: video conferences, transparent data sharing, a "focus on failures," QI coaching, and tools to help reduce missed or delayed action on abnormal laboratory values. Practices recorded the percentage of patients with 5 specific abnormal laboratory values who received an appropriate provider action (control), and then, during an 8-month intervention phase, implemented QI strategies to reduce errors (intervention). Subsequently, practices collected data on laboratory errors while working to reduce unrelated second (sustain phase), and third (maintenance phase) errors. Generalized mixed-effects regression models compared the mean percentage of patients with appropriate actions. We randomized 43 practices, of which 31 were included in analyses. Control and intervention phases included 1,357 and 1,426 patients with abnormal laboratory values, respectively. The mean percentage of patients who received appropriate actions did not change comparing control and intervention phases [risk difference (RD) 1%; 95% CI -1%, 3%]. In post-hoc analyses, practices significantly improved comparing control to sustain (RD 3%; 95% CI 0.3%, 6%) and maintenance phases (RD 6%; 95% CI 3%, 9%). Implementation of a QIC did not reduce the frequency of abnormal laboratory errors in the initial 8-month intervention phase. A significant reduction was appreciated comparing sustain and maintenance phases (months 9-24) to the control phase.


Characterisation of SB-221420-A - a neuronal Ca(2+) and Na(+) channel antagonist in experimental models of stroke.
For progression to clinical trials in stroke, putative neuroprotective compounds should show robust efficacy post-ischaemia in several experimental models of stroke. This paper describes the characterisation of (+)(1S, 2R)-cis-1-[4-(1-methyl-1-phenylethyl)phenoxy]-2-methylamino indane hydrochloride (SB-221420-A), a Ca(2+) and Na(+) channel antagonist. SB-221420-A inhibited (IC(50)=2.2 microM) N-type voltage-operated Ca(2+) channel currents in cultured superior cervical ganglion neurons, which were pretreated with 10 microM nimodipine to block L-type voltage-operated Ca(2+) channel currents. In dorsal root ganglion neurons pretreated with 1 microM omega-conotoxin GVIA to block N-type voltage-operated Ca(2+) channel currents, SB-221420-A inhibited the residual Ca(2+) current with an IC(50) of 7 microM. SB-221420-A also inhibited Na(+) currents in dorsal root ganglion neurons with an IC(50) of 8 microM. In rats, the pharmacokinetic profile of SB-221420-A shows that it has a half-life of 6.4 h, a high volume of distribution, is highly brain penetrating, and has no persistent metabolites. Following bilateral carotid artery occlusion in gerbils, SB-221420-A significantly reduced the level of ischaemia-induced hyperlocomotor activity and the extent of hippocampal CA1 cell loss compared to the ischaemic vehicle-treated group. SB-221420-A was also effective in focal models of ischaemia. In the mouse permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously, post-ischaemia significantly (P<0.05) reduced lesion volume compared to the ischaemic vehicle-treated group. In the normotensive rat permanent middle cerebral artery occlusion model, SB-221420-A (10 mg/kg) administered intravenously over 1 h, beginning 30 min postmiddle cerebral artery occlusion, significantly (P<0.05) reduced lesion volume from 291+/-16 to 153+/-30 mm(3), compared to ischaemic vehicle-treated controls when measured 24 h postmiddle cerebral artery occlusion. Efficacy was maintained when the same total dose of SB-221420-A was infused over a 6-h period, beginning 30 min postmiddle cerebral artery occlusion. SB-221420-A also significantly (P<0.05) reduced lesion volume following transient middle cerebral artery occlusion in normotensive rats and permanent middle cerebral artery occlusion in spontaneously hypertensive rats (SHR). Investigation of the side effect profile using the Irwin screen in mice revealed that, at neuroprotective doses, there were no overt behavioural or cardiovascular changes. These data demonstrate that robust neuroprotection can be seen post-ischaemia with SB-221420-A in both global and focal ischaemia with no adverse effects at neuroprotective doses, and indicate the potential utility of a mixed cation blocker to improve outcome in cerebral ischaemia.


Acetogen and acetogenesis for biological syngas valorization.
The bioconversion of syngas using (homo)acetogens as biocatalysts shows promise as a viable option due to its higher selectivity and milder reaction conditions compared to thermochemical conversion. The current bioconversion process operates primarily to produce C2 chemicals (e.g., acetate and ethanol) with sufficient technology readiness levels (TRLs) in process engineering (as midstream) and product purification (as downstream). However, the economic feasibility of this process could be improved with greater biocatalytic options in the upstream phase. This review focuses on the Wood-Ljungdahl pathway (WLP) which is a biological syngas-utilization pathway, redox balance and ATP generation, suggesting that the use of a specific biocatalysts including Eubacterium limosum could be advantageous in syngas valorization. A pertinent strategy to mainly produce chemicals with a high degree of reduction is also provided with examples of flux control, mixed cultivation and mixotrophy. Finally, this article presents future direction of industrial utilization of syngas fermentation.


Pathophysiology of gait disturbance in neurologic disorders and clinical presentations.
Ambulation requires significant motor coordination. Because of inherent differences in body proportions, level of coordination, motivation, and other factors, each individual gait pattern is unique. However, despite the existence of these individual differences that contribute to each person's own unique walking style, there are highly repeatable gait sequences, allowing characterization of normal gait patterns and identification of gait disturbance. This article briefly reviews neural control of human ambulation, basic kinematics, and kinetics of normal human gait, and describes the pathophysiology and clinical presentations of spastic hemiparetic and paraparetic, ataxic, and Parkinsonian gait patterns.


Wetting phase connectivity and irreducible saturation in simple granular media.
We present drainage simulations that allow trapping of wetting phase in a simple but nontrivial granular medium, a dense random packing of equal spheres. The basis for the simulations is a network model derived directly from the known locations and dimensions of pore space features. This provides a means of evaluating the morphology of trapped wetting phase. The possible morphologies depend on the assumed connectivity of the wetting phase. At one extreme, we assume that the entire wetting phase except for pendular rings is connected. At the opposite extreme, we illustrate a low level of connectivity by assuming that pendular rings are trapped as soon as the pores surrounding them are drained; any wetting phase not yet drained from pore throats connecting these pores is also assumed to be trapped. Finally we consider a set of criteria involving larger neighborhoods within the network, which allows trapping in individual pores. Irreducible wetting phase saturations obtained in the latter case agree with experimental data. The numbers of pendular rings and liquid bridges are also consistent with observations. Because the agreement does not involve adjustable parameters, we conclude that a relatively simple, local evaluation of trapping criteria can yield physically representative wetting phase configurations.


Perimenopause and cognition.
The impact of perimenopause on cognition seems to be characterized by an absence of improved scores rather than a decline. In the SWAN, the perimenopausal decrement in cognitive performance was not accounted for; however, increases in anxiety and depressive symptoms had independent, unfavorable effects on performance. Estradiol has been found to protect against changes resulting from serotonin withdrawal and defend against changes from cholinergic depletion. There is support for the critical timing hypothesis--that estrogen benefits cognitive function when instituted early, but not later. The menopausal transition may affect cognitive function in older age owing to worsened cardiovascular risk factors.


Simple squaramide receptors for highly efficient anion binding in aqueous media and transmembrane transport.
A family of acyclic squaramide receptors (L1-L5) have been synthesised with the aim to bind anions in a competitive solvent mixture and to evaluate how the presence of additional H-bond donor groups on the squaramide scaffold could affect the affinity towards anions and the transmembrane transport ability.


The role of viruses in squamous cell carcinoma of the oropharyngeal mucosa.
The development of squamous cell carcinomas of the oropharyngeal mucosa may involve many factors, including viruses. This review examines the evidence that viruses could be involved in the etiology of oral cancer, and shows that the evidence for a role of different viruses varies from very weak to very persuasive. Papillomaviruses are probably involved in the etiology of some carcinomas, particularly those of the oropharynx, and some herpes viruses may be involved as well. On the other hand some viruses can cause cancer in experimental situations but not in humans. Thus the importance of viruses in oral cancer is not always clear and must be evaluated with care. Those viruses that are associated with the disease provide targets for therapy and for diagnostic assays.


Sustainable lamb production: Evaluation of factors affecting lamb growth using hierarchical, cross classified and multiple memberships models.
In light of current concerns about the sustainability of red meat production in a world with increasing global demand for food from animal origin there is a need for a better understanding of factors that influence the growth rate and feed conversion efficiency of animals on commercial farms. The primary objective of this observational study was to use longitudinal data to quantify the simultaneous effects of multiple ewe and lamb factors on lamb growth rate. A secondary aim was to evaluate model structures that specifically account for lamb grouping effects during the growth period and compare these to classical hierarchical growth rate models. A total of 4172 weight recordings from 805 lambs and data on disease events were collected over a 6-month period from a commercial pedigree sheep flock. Three mixed model structures were compared, hierarchical, cross classified and multiple membership, and final estimates determined within a Bayesian framework. The multiple membership structure provided the best model fit and was used for final inference; taking account of the effect of lamb grouping over time provided the best estimates of lamb growth rate. Ewe lameness and mastitis cases had a deleterious impact on lamb growth. Lambs from ewes identified with mastitis during lactation were on average 3.0 (standard error (SE) 1.6) kg lighter during the four month growth period than lambs from unaffected ewes. Lambs from ewes that were not lame during pregnancy were 3.0 (SE 1.2) kg heavier at eight weeks of age than lambs from ewes with a least one lameness case during the same period. Lambs from ewes lame either during the first 4 weeks or between 4-8 weeks of a lamb's life (but not lame during pregnancy) were also significantly heavier at 56 days of age, than lambs reared by ewes that were lame during pregnancy (2.8 (SE 1.2) and 3.4 (SE 1.2) kg respectively). Cases of pneumonia and bacterial arthritis in lambs had a significant negative impact on lamb growth with affected lambs being on average 5.5 (SE 1.1) kg and 2.2 (SE 1.2) kg less than non-affected lambs respectively after the disease event. Prior to a case of lameness or pneumonia, lambs were significantly heavier than unaffected lambs suggesting a possible trade-off between growth and immune function. Overall, the study provides evidence that that a combination of ewe and lamb characteristics and disease events play an important role in determining lamb growth rate and that heavier lambs may be more susceptible to disease.


Biodegradation of chlorobenzoic acids by ligninolytic fungi.
We investigated the abilities of several perspective ligninolytic fungal strains to degrade 12 mono-, di- and trichloro representatives of chlorobenzoic acids (CBAs) under model liquid conditions and in contaminated soil. Attention was also paid to toxicity changes during the degradation, estimated using two luminescent assay variations with Vibrio fischeri. The results show that almost all the fungi were able to efficiently degrade CBAs in liquid media, where Irpex lacteus, Pycnoporus cinnabarinus and Dichomitus squalens appeared to be the most effective in the main factors: degradation and toxicity removal. Analysis of the degradation products revealed that methoxy and hydroxy derivatives were produced together with reduced forms of the original acids. The findings suggest that probably more than one mechanism is involved in the process. Generally, the tested fungal strains were able to degrade CBAs in soil in the 85-99% range within 60 days. Analysis of ergosterol showed that active colonization is an important factor for degradation of CBAs by fungi. The most efficient strains in terms of degradation were I. lacteus, Pleurotus ostreatus, Bjerkandera adusta in soil, which were also able to actively colonize the soil. However, in contrast to P. ostreatus and I. lacteus, B. adusta was not able to significantly reduce the measured toxicity.


Frequency of iron deficiency anemia in type 2 diabetes - Insights from tertiary diabetes care centres across India.
To study the frequency of iron deficiency anemia (IDA) in individuals with type 2 diabetes mellitus (T2DM) seen at tertiary diabetes care centres across India. This is a retrospective study (January 1, 2017-December 31, 2019), which included 1137 individuals with T2DM, aged ≥18 years, for whom data on glycemic, lipid and haematological parameters were available. Anthropometric measurements were done using standardized techniques. Biochemical investigations included fasting plasma glucose[FPG], post prandial plasma glucose, HbA1c, lipids and serum ferritin and iron wherever feasible. Of the 1137 individuals included for the study, 117 (10.3%) were categorized as no 'iron deficiency' (ID) group [normal hemoglobin: male ≥13 g/dl, female ≥12 g/dl and normal serum ferritin ≥70 μg/L], 123 (10.8%) as ID group [normal hemoglobin and low serum ferritin <70 μg/L)], 447 (39.3%) as IDA group [low haemoglobin: male <13 g/dl, female <12 g/dl and low serum ferritin] and 450 (39.6%) as 'anemia of chronic disease' (ACD) group [low hemoglobin and normal serum ferritin]. The percentage of women having ID (57.7%) and IDA (65.3%) was significantly higher than their male counterparts. ID was most prevalent (61.7%) in the individuals with duration of diabetes <5 years whereas ACD was most prevalent (50.5%) in individuals with long standing diabetes (>10 years). Independent risk factors for IDA were female gender (OR 3.3,95% CI:1.75-6.23, p < 0.001), duration of diabetes (OR 1.05, 95% CI 1.01-1.11, p = 0.028) and FPG (OR 1.01, 95% CI 0.99-1.00, p = 0.018). There is a need of identifying and monitoring iron status and anemia in patients with T2DM.


Alpha-1-antitrypsin in serum exosomes and pericardial fluid exosomes is associated with severity of rheumatic heart disease.
Rheumatic heart disease (RHD) is an autoimmune sequel of pharyngitis and rheumatic fever that leads to permanent heart valve damage, especially the mitral valves. The mitral valves, which are responsible for the binding of auto-antibodies during immune response generation, lead to valve scarring and eventually valves dysfunction. Recently, exosomes (EXOs), the nano-sized vesicles, which range in size from 30 to 150 nm, are reported in various cardiovascular physiological and pathological processes. These vesicles are found in several body fluids such as plasma, serum, and also in cell culture media. Exosomal cargo contains proteins, which are taken up by the recipient cells and modulate the cellular characteristics. The role of exosomal proteins in RHD is still obscure. Hence, the present study has been designed to unveil the exosomal proteins in disease severity during RHD. In this study, the exosomes were isolated from biological fluids (serum and pericardial fluid) of RHD patients as well as from their respective controls. Protein profiling of these isolated exosomes revealed that alpha-1 antitrypsin is up-regulated in the biological fluids of RHD patients. The enhanced levels of exosomal alpha-1 antitrypsin, were further, validated in biological samples and mitral valve tissues of RHD patients, to correlate with the disease severity. These findings suggest an association of increased levels of exosomal alpha-1 antitrypsin with the RHD pathogenesis.


The association between depression and later educational attainment in children and adolescents: a systematic review protocol.
Depression represents a major public health concern for children and adolescents, and is thought to negatively impact subsequent educational attainment. However, the extent to which depression and educational attainment are directly associated, and whether other factors play a role, is uncertain. Therefore, we aim to systematically review the literature to provide an up-to-date estimate on the strength of this association, and to summarise potential mediators and moderators on the pathway between the two. To identify relevant studies, we will systematically search Embase, PsycINFO, PubMed, Education Resources Information Centre and British Education Index, manually search reference lists and contact experts in the field. Studies will be included if they investigate and report on the association between major depression diagnosis or depressive symptoms in children and adolescents aged 4-18 years (exposure) and later educational attainment (outcome). Two independent reviewers will screen titles, abstracts and full texts according to eligibility criteria, perform data extraction and assess study quality according to a modified version of the Newcastle-Ottawa Scale. If sufficiently homogeneous studies are identified, summary effect estimates will be pooled in meta-analysis, with further tests for study heterogeneity, publication bias and the effects of moderators using meta-regression. Because this review will make use of already published data, ethical approval will not be sought. The review will be submitted for publication in a peer-reviewed journal, presented at practitioner-facing conferences, and a lay summary will be written for non-scientific audiences such as parents, young people and teachers. The work will inform upcoming investigations on the association between child and adolescent mental health and educational attainment. CRD42019123068.


Polybutadiene Functionalization via an Efficient Avenue.
We introduce a facile and quantitative postpolymerization functionalization methodology for 1,4-polybutadienes, allowing us to decorate their pendent alkene functionalities with bromine and alkoxyether motifs carrying an array of functional groups ranging from tetrazoles to pyrenes. Specifically, the approach makes use of a mild, metal-free, electrophilic cascade reaction employing N-bromosuccinimide (NBS), a cyclic ether (i.e., THF), and a functional carboxylic acid. Detailed NMR, SEC, and ATR-IR studies confirm the successful modification.


Neurodevelopmental outcomes in very preterm infants: The role of severity of Bronchopulmonary Dysplasia.
Bronchopulmonary dysplasia is a chronic respiratory disease that still affects preterm neonates; its association with neurodevelopmental (ND) impairment is already known. Different studies investigated neurodevelopmental outcomes in infants with BPD, often using the old dichotomous definition (BPD vs Non-BPD). This retrospective study aims to evaluate the role of different BPD severity grades on ND outcomes at 24 months of corrected age (CA). All preterm infants born between 2011 and 2015 in the study hospital with a gestational age (GA) ≤ 30 weeks and discharged from our NICU were included and were divided in infants with and without BPD. Infants with BPD were divided into three severity groups as defined by NICHD/NHLBI Workshop in 2001, and were compared to their Non-BPD peers, matching them according to the same GA and year of birth. At 24 months postmenstrual age, we assessed general outcomes (growth and hospital readmissions) and neurodevelopmental outcomes (motor, developmental and sensory outcomes) with a standardized assessment. We enrolled 89 patients affected by BPD of different grades of severity and a control group of 89 preterm infants without BPD. Infants with Moderate and Severe BPD showed a significantly higher corrected odds ratio (OR) for cognitive impairment compared to controls. Within the group of infants without severe disability (regarding Griffiths' scales), infants with Moderate and Severe BPD as well as infants with Mild BPD showed a significantly higher risk of a lower total Developmental Quotient (DQ) score, even after correction for confounding factors. Our study evidenced that not only Severe BPD infants, but also Moderate ones showed a higher risk of overall cognitive impairment at 24 months CA. Within the group of infants without severe disability, also those with Mild BPD had lower Griffiths DQ scores than those without. This would suggest that infants with BPD, regardless of severity, warrant neurodevelopmental follow-up.


Reward and immune responses in adolescent females following experimental traumatic brain injury.
The pathology of traumatic brain injury (TBI) adversely affects many brain regions, often resulting in the development of comorbid psychiatric disorders including substance use disorders (SUD). Although traditionally thought to be an epidemic that predominantly affects males, recent clinical studies report females have higher rates of concussions and longer recovery times than males. Yet, how neurotrauma, particularly deep within the brain, between the sexes is differentially manifested remains largely unknown. The risk of TBI peaks during adolescence when neuronal networks that regulate reward behaviors are not fully developed. Previously, using the conditioned place preference (CPP) assay, we found that adolescent TBI increased susceptibility to the rewarding effects of cocaine in male mice. Further, we observed augmented inflammatory profiles, increased microglial phagocytosis of neuronal proteins, and decreased neuronal spine density in the NAc. Notably, the extent of sex differences in SUD susceptibility following TBI has not be investigated. Thus, here we ask the central question of whether the adolescent TBI-induced neuroinflammatory profile at reward centers is divergent in a sex-dependent manner. Using the CPP assay, we found that female mice with high levels of female sex hormones at the time of adolescent TBI demonstrated neuroprotection against increased sensitivity to the rewarding effects of cocaine. These studies also provide evidence of significantly reduced microglial activation and phagocytosis of neuronal proteins within the NAc of females. Overall, our results offer crucial insight into how adolescent TBI impacts the reward pathway in a sex depending manner that could explain a vulnerability to addiction-like behavior.


Two-piece inflatable and semi-rigid penile implants: an effective alternative?
Penile prostheses (PPs) are an excellent treatment to be considered for patients suffering from erectile dysfunction (ED), refractory to oral medications, or unwilling to consider intracavernosal injections or other therapeutic strategies. Nowadays the market is dominated by three-piece inflatable penile prosthesis (IPP), which are considered the best option available. However, in some specific cases three-piece IPP may be superseded by semi-rigid penile prosthesis (SRPP) and two-piece IPP. Despite the advantages of these implants, the literature is quite scarce, not robust and rarely takes into consideration the partner's satisfaction. This clearly affects the strength of our conviction. Most of the studies confirm that SRPPs and two-piece IPPs can be considered a valid alternative in patients with hand dexterity issues, refractory ischaemic priapism, neophallus and in cases of complex anatomies. In addition, the ease of placement and the high confidence level of surgeons make them a powerful tool in the armamentarium of urologists.


Migraine and defense mechanisms: psychophysiological relationships in young females.
Two psychological defense mechanisms, repression and self aggression, were studied in 23 young female migraine patients who had not been receiving treatment for their complaints and in 23 relatively headache free matched controls. All subjects were psychology students. Each subject was classified as high or low on repression and self aggression using the defense mechanism inventory. During three separate sessions: adaptation, intelligence test and real-life stress (an examination which was part of the psychology curriculum) pulse amplitudes of the temporal and digital arteries, frontal, temporal and corrugator EMGs, forehead temperature, skin conductance, and heart and respiration rate were measured. The migraine patients showed a trend towards more repression of their emotions and significantly more self aggression than the controls. Self aggression appeared to be positively associated with the headache frequency in the migraine group. With regard to the physiological measurements, in both groups repressors showed a modest tendency to enhanced sympathetic activity. Self aggression was not found to be related to any physiological measure of sympathetic activity, but, instead, related to less temporal blood flow. In general, associations were found between psychological defense mechanisms and physiological activity, which is suggestive of the existence of physiological pathways along which emotional inhibition might contribute to an attack of migraine after a stressful situation.


Purification and evaluation of 2, 4-di-tert butylphenol (DTBP) as a biocontrol agent against phyto-pathogenic fungi.
A fungal strain, Marasmiellus sp (PUK64), isolated from the mangrove forests in Muthupet, Tamil Nadu, East coast of India, along with others were screened for the search of potent bioactive compounds. A phenolic compound, 2,4-di-tert-butylphenol (DTBP), was isolated from the most promising strain PUK64 and its chemical structure was ascertained. DTBP demonstrated remarkable antifungal activity against the phytopathogenic fungi Aspergillus oryzae, Curvularia lunata and Fusarium verticillioides. In an in-vitro experimental setup, DTBP suppressed the growth of all three fungi, among which F. verticillioides was found to be highly susceptible. This effect relates with the inhibition of spore germination and hyphal growth that we observed. DTBP showed high affinity with the F. verticillioides's β-tubulin protein (determined by ligand-protein docking) as compared to the standard fungicide carbendazim (CBZ). Molecular docking and simulation studies of DTBP with target β-tubulin further confirmed the potential of β-tubulin binding in F. verticillioides. To our knowledge, this is the first report on DTBP-mediated biocontrol of phytopathogenic fungi, produced by Marasmiellus sp. PUK64 that can be potent inhibitor of β-tubulin protein of F. verticillioides.


Over-expression of apoptosis-related proteins contributes to muscular damage in the obstructed ureter of the rat.
To determine the role of apoptosis-related proteins (Myc, Bax, Bcl-2, and Bcl-X(L)) in muscular damage in obstructed rat ureters. The in situ end-labelling of DNA fragments and the expression of apoptosis-related proteins were assessed, using immunohistochemistry, in 54 female Sprague-Dawley rats in which unilateral ureteric obstruction was caused by ureteric ligation. The severity of ureteric damage increased during the period of obstruction. Apoptotic cells and the expression of Bax were detected in the smooth muscle layer from 14 days after ligation. The percentage of apoptotic cells and the expression of Bax in the smooth muscle layer increased and reached a peak 21 days after ligation, and then declined. The expression of Myc was also detected in the smooth muscle layer 14 days after ligation but reached a peak at 28 days. The expressions of Bcl-2 and Bcl-X(L) in the smooth muscle layer were only detected 21 and 28 days after ligation. The numbers of apoptotic cells in the smooth muscle layer correlated significantly with the expressions of Myc and Bax (r = 0.7360 and 0.7432, respectively; both P < 0.005), and with the expression index of Bax/Bcl-2 and Bax/Bcl-X(L) (r = 0.8909 and 0.8592, respectively; both P < 0.001). Apoptosis-related proteins might be important in regulating cell apoptosis in ureteric damage during the development of obstructive uropathy.


Study on the networks of "Nature-Family-Component" of Chinese medicinal herbs based on association rules mining.
To explore appropriate methods for the research of the theory of Chinese medicine nature property and find the relationship between Nature-Family-Component of Chinese herbs. From perspective of systems biology, we used Associate Network to identify useful relationships among "Nature-Family-Component" of Herbs. In this work, Associate Network combines association rules mining method and network construction method to evaluate the complicate relationship among "Nature-Family-Component" of herbs screened. The results of association rules mining showed that the families had a close relationship with nature properties of herbs. For example, the families of Magnoliaceae, Araceae had a close relationship with hot nature with confidence of 100%, the families of Cucurbitaceae has a close relationship to cold nature with confidence of 90.91%. Moreover, the results of constructed Associate Network implied that herbs belonging to the same families generally had the same natures. In addition, some herbs belonging to different families may also have same natures when they contain the same main components. These results implied that the main components of herbs might affect their natures; the relationships between families and natures were based on the main compounds of herbs.


Determining the optimal system-specific cut-off frequencies for filtering in-vitro upper extremity impact force and acceleration data by residual analysis.
The fundamental nature of impact testing requires a cautious approach to signal processing, to minimize noise while preserving important signal information. However, few recommendations exist regarding the most suitable filter frequency cut-offs to achieve these goals. Therefore, the purpose of this investigation is twofold: to illustrate how residual analysis can be utilized to quantify optimal system-specific filter cut-off frequencies for force, moment, and acceleration data resulting from in-vitro upper extremity impacts, and to show how optimal cut-off frequencies can vary based on impact condition intensity. Eight human cadaver radii specimens were impacted with a pneumatic impact testing device at impact energies that increased from 20J, in 10J increments, until fracture occurred. The optimal filter cut-off frequency for pre-fracture and fracture trials was determined with a residual analysis performed on all force and acceleration waveforms. Force and acceleration data were filtered with a dual pass, 4th order Butterworth filter at each of 14 different cut-off values ranging from 60Hz to 1500Hz. Mean (SD) pre-fracture and fracture optimal cut-off frequencies for the force variables were 605.8 (82.7)Hz and 513.9 (79.5)Hz, respectively. Differences in the optimal cut-off frequency were also found between signals (e.g. Fx (medial-lateral), Fy (superior-inferior), Fz (anterior-posterior)) within the same test. These optimal cut-off frequencies do not universally agree with the recommendations of filtering all upper extremity impact data using a cut-off frequency of 600Hz. This highlights the importance of quantifying the filter frequency cut-offs specific to the instrumentation and experimental set-up. Improper digital filtering may lead to erroneous results and a lack of standardized approaches makes it difficult to compare findings of in-vitro dynamic testing between laboratories.


Decitabine Enhances Acute Myeloid Leukemia Cell Apoptosis through SH3BGRL Upregulation.
SH3-domain-binding glutamic acid-rich protein-like protein (SH3BGRL) is downregulated in acute myeloid leukemia (AML). Clinically, DNA demethylating drug decitabine (DAC) combined with traditional chemotherapies reveals better efficacy on AML patients than the conventional chemotherapies alone. Our previous results revealed that human SH3-domain-binding glutamic acid-rich protein-like protein (SH3BGRL) plays a tumor suppressive role in AML but whether there is a connection between DAC and SH3BGRL expression remains elusive. Here, we tentatively treated AML cell lines U937, MV4, and HL-60 with DAC and Western Blots, RT-PCR was used to detect the expression of SH3BGRL. Cell proliferation and apoptosis were determined using Annexin V/7- AAD staining. Real-time RT-PCR and Western blot were used to determine the expression of SH3BGRL mRNA and protein. Methylation-specific PCR was used to quantify the DNA methylation in AML cell lines. DAC had cytotoxicity in HL-60, MV4, and U937. In U937 cell lines, treatment with DAC showed the upregulation of cleaved caspase3, PARP, and SH3BGRL. Upon treatment, up-regulation of SH3BGRL mRNA and protein was dose-dependent and this activity was partially inhibited in endogenous SH3BGRL knockdown cell lines. Thus, our results demonstrated a possibly cytotoxic role of DAC on AML cells by upregulation of SH3BGRL expression at epigenetic modulation level and the methylation status in the SH3BGRL promoter region could be a supplemental diagnostic marker to the precise administration of DAC to AML patients.


Unnecessary removal of vascular access devices due to suspected infection in Australian intensive care units.
Vascular access devices suspected of infection are often removed unnecessarily and frequently require replacement. The aim of this study was to identify the prevalence and economic impact of premature, unnecessary device removal due to suspected infection in adult patients admitted to the intensive care unit. Secondary data analysis of a prospectively collected data set detailing central venous catheters and peripheral arterial catheters in 1458 adult patients was conducted in nine Australian intensive care units. Data extracted from the parent database included patient demographics, device, and infection-specific data including the reason for device removal. Cost estimates were based on a recently published review of device utilisation and associated costs in Queensland public hospitals. A total of 6144 central venous catheter days and 4696 arterial catheter days were studied. Median device dwell time was 7.2 (interquartile range: 5.6-9.0) days for central venous catheters and 6.5 (interquartile range: 4.8-8.5) days for arterial catheters. Device removal due to suspected infection occurred at a rate of 25.7 and 15.3 episodes/1000 catheter days in central venous and arterial catheters, respectively. Central venous and arterial catheter-related bloodstream infections occurred at a rate of 1.8 and 0.2 episodes/1000 catheter days, respectively. Central line-associated bloodstream infection occurred at a rate of 3.3 episodes/1000 catheter days. Local central venous and arterial catheter infection occurred at 0.16 and 0.02 episodes/1000 catheter days, respectively. The difference in incidence between devices suspected of infection and those responsible for infection resulted in AUD$67,087 unnecessarily spent on device replacement. Unnecessary device removal due to suspected infection presents a substantial clinical problem which is costly for the healthcare organisation and time-consuming for clinicians and places the patient at an increased risk of iatrogenic complications. There is a need for robust evidence and clinical practice guidelines to inform clinical decision-making to reduce unnecessary device removal.


Predictors of treatment failures during chemotherapy: A prospective study on 110 older cancer patients.
Several instruments have been proposed to improve treatment decisions in elderly cancer patients, but evidence of their impact in clinical practice is limited. The aim of this study was to analyze the role of clinical and functional factors in predicting serious adverse events, including death, severe toxicity or treatment interruption, during chemotherapy in elderly cancer patients. The survey evaluated elderly with lung or colon or breast cancer treated with chemotherapy, followed by S. Giovanni Battista Hospital. We enrolled 110 consecutive patients older than 70 years of age with lung (n=45), colon (n=50) and breast (n=15) cancer between October 2004 and October 2005. Overall, 73/110 patients (66.4%) experienced adverse events as death (n=14), grades III and IV toxicity (n=40), or treatment interruption for other reasons (n=19). The variables with stronger predictivity were advanced stage, toxicity of treatment, level of comorbidity and Karnofsky performance status (KPS). instrumental activities of daily living (IADL) index and age itself were not independent predictors. In conclusion our results confirm the need of a careful selection of elderly patients suitable for chemotherapy, giving more weight to comorbidity and KPS scores than to age itself. The potential role of other functional evaluations need to be further assessed in randomized controlled trials.


A novel inhibitor of inducible nitric oxide synthase, ONO-1714, does not ameliorate hypoxia-induced pulmonary hypertension in rats.
A recent study showed that long-term administration of the inducible nitric oxide synthase (iNOS) inhibitor L-NIL reduced the development of pulmonary hypertension. The purpose of the present study was to identify the effect of an another iNOS inhibitor, ONO-1714, on the development of pulmonary hypertensive vascular changes in chronic hypoxic pulmonary hypertension in rats. ONO-1714 was administered to rats exposed to hypobaric hypoxia (air at 380 mmHg) for 10 days. Muscularization of normally nonmuscular peripheral arteries and medial hypertrophy of normally muscular arteries were assessed by light microscopy. iNOS mRNA and protein levels of the lung were assessed in normal and hypoxic rats. Chronic hypoxia induced pulmonary hypertension, right ventricular hypertrophy, and hypertensive pulmonary vascular changes. Although an acute single injection of ONO-1714 induced a significant increase in mean pulmonary artery pressure in chronic hypoxic pulmonary hypertensive rats, the increase was slight and transient. There were no significant differences among rats with and without long-term administration of ONO-1714 in pulmonary artery pressure, right ventricular hypertrophy, medial wall thickness of muscular arteries, and the percentage of muscularized arteries at the alveolar wall and duct levels. Although there was a significantly increased expression of iNOS as assessed with the reverse-transcription polymerase chain reaction in rats that were exposed to 10 days of hypobaric hypoxia, we could not detect a significant level of iNOS protein by Western blotting. ONO-1714 does not have a therapeutic role in preventing the development of chronic hypoxic pulmonary hypertension.


A critique of the molecular target-based drug discovery paradigm based on principles of metabolic control: advantages of pathway-based discovery.
Contemporary drug discovery and development (DDD) is dominated by a molecular target-based paradigm. Molecular targets that are potentially important in disease are physically characterized; chemical entities that interact with these targets are identified by ex vivo high-throughput screening assays, and optimized lead compounds enter testing as drugs. Contrary to highly publicized claims, the ascendance of this approach has in fact resulted in the lowest rate of new drug approvals in a generation. The primary explanation for low rates of new drugs is attrition, or the failure of candidates identified by molecular target-based methods to advance successfully through the DDD process. In this essay, I advance the thesis that this failure was predictable, based on modern principles of metabolic control that have emerged and been applied most forcefully in the field of metabolic engineering. These principles, such as the robustness of flux distributions, address connectivity relationships in complex metabolic networks and make it unlikely a priori that modulating most molecular targets will have predictable, beneficial functional outcomes. These same principles also suggest, however, that unexpected therapeutic actions will be common for agents that have any effect (i.e., that complexity can be exploited therapeutically). A potential operational solution (pathway-based DDD), based on observability rather than predictability, is described, focusing on emergent properties of key metabolic pathways in vivo. Recent examples of pathway-based DDD are described. In summary, the molecular target-based DDD paradigm is built on a naïve and misleading model of biologic control and is not heuristically adequate for advancing the mission of modern therapeutics. New approaches that take account of and are built on principles described by metabolic engineers are needed for the next generation of DDD.