Enhanced development of porcine embryos cloned from bone marrow mesenchymal stem cells.
In the present study, we have characterized an isolated population of porcine bone marrow mesenchymal stem cells (MSCs) for multilineage commitment and compared the developmental potential of cloned embryos with porcine MSCs and fetal fibroblasts (FFs). MSCs exhibited robust alkaline phosphatase activity and later transformed into mineralized nodules following osteoinduction. Furthermore, MSCs underwent adipogenic and chondrogenic differentiation by producing lipid droplets and proteoglycans, respectively. Primary cultures of FFs from a female fetus at ~30 day of gestation were established. Donor cells at 3-4 passage were employed for nuclear transfer (NT). Cell cycle analysis showed that the majority of MSCs in confluence were in the G0/G1 stage. Cumulus-oocyte complexes were matured and fertilized in vitro (IVF) as control. The cleavage rate was significantly (P<0.05) higher in IVF than in NT embryos with MSCs and FFs (84.54.6% vs. 52.25.4% and 50.85.2%, respectively). However, blastocyst rates in IVF and NT embryos derived from MSCs (20.62.5% and 18.43.0%) did not differ, but were significantly (P<0.05) higher than NT derived from FFs (9.52.1%). Total cell number and the ratio of ICM to total cells among blastocysts cloned from MSCs (34.45.2 and 0.380.08, respectively) were significantly (P<0.05) higher than those from FFs (22.65.5 and 0.180.12, respectively). Proportions of TUNEL positive cells in NT embryos from FFs (7.31.8%) were significantly (P<0.05) higher than in MSCs (4.61.3%) and IVF (2.50.9%). The results clearly demonstrate that multipotent bone marrow MSCs have a greater potential as donor cells than FFs in achieving enhanced production of cloned porcine embryos.


Quantum chemical MP2 results on some hydrates of cytosine: binding sites, energies and the first hydration shell.
A detailed quantum chemical investigation was undertaken to obtain the structure and energetics of cytosine hydrates Cyt·nH2O, with n = 1 to 7. The MP2(fc)/aug-cc-pVDZ level was used as the standard, with some DFT (B3LYP) and coupled cluster calculations, as well as calculations with the aug-cc-pVTZ basis set added for comparison. In a systematic search for microhydrated forms of cytosine, we have found that several structures have not yet been reported in the literature. The energies of different isomers, as well as binding energies are compared. When predicting the stability of a complex, we suggest using a scheme where the water molecules are extracted from a finite model of bulk water. Finally, based on energetic data, we suggest a rational definition of the first hydration shell; with this definition, it contains just six water molecules.


The importance of lattice defects in katanin-mediated microtubule severing in vitro.
The microtubule-severing enzyme katanin uses ATP hydrolysis to disrupt noncovalent bonds between tubulin dimers within the microtubule lattice. Although its microtubule severing activity is likely important for fundamental processes including mitosis and axonal outgrowth, its mechanism of action is poorly understood. To better understand this activity, an in vitro assay was developed to enable the real-time observation of katanin-mediated severing of individual, mechanically unconstrained microtubules. To interpret the experimental observations, a number of theoretical models were developed and compared quantitatively to the experimental data via Monte Carlo simulation. Models that assumed that katanin acts on a uniform microtubule lattice were incompatible with the in vitro data, whereas a model that assumed that katanin acts preferentially on spatially infrequent microtubule lattice defects was found to correctly predict the experimentally observed breaking rates, number and spatial frequency of severing events, final levels of severing, and sensitivity to katanin concentration over the range 6-300 nM. As a result of our analysis, we propose that defects in the microtubule lattice, which are known to exist but previously not known to have any biological function, serve as sites for katanin activity.


Detection and discrimination capabilities of a multitransducer single-chip gas sensor system.
The performance of a single-chip, three-transducer, complementary metal oxide semiconductor gas sensor microsystem has been thoroughly evaluated. The monolithic gas sensor system includes three polymer-coated transducers, a mass-sensitive cantilever, a thermoelectric calorimetric sensor, and an interdigitated capacitive sensor that are integrated along with all electronic circuits needed to operate these sensors. The system additionally includes a temperature sensor and a serial interface unit so that it can be directly connected to, for example, a microcontroller. Several multitransducer chips have been coated with various partially selective polymers and then have been exposed to different volatile organic compounds. The sensitivities of the three different polymer-coated transducers to defined sets of gaseous analytes have been determined. The obtained sensitivity values have then been normalized with regard to the partition coefficients of the respective analyte/polymer combination to reveal the transducer-specific effects. The results of this investigation show that the three different transducers respond to fundamentally different molecular properties, such as the analyte molecular mass (mass-sensitive), its dielectric coefficient (capacitive), and its sorption heat (calorimetric) so that correlations between the determined sensitivity values and the different molecular properties of the absorbed analytes could be established. The information as provided by the system, hence, represents a body of orthogonal data that can serve as input to appropriate signal processing and pattern recognition techniques to address issues such as the quantification of analytes in mixtures.


Nalpha-acetylfusarinines: isolation, characterization, and properties.
The isolation, purification, and structural elucidation of a new group of naturally occurring hydroxamic acids are described. These compounds are produced by an unidentified species of Penicillium when grown on iron deficient medium. They are closely related structurally to the fusarinines, whose basic structure contains Ndelta-(cis-5-hydroxy-3-methylpent-2-enoyl)-Ndelta-hydroxy-L-ornithine, but the alpha-amino groups in the new compounds are protected by Nalpha acetyl groups. The most complex of the compounds is N,N',N"-triacetylfusarinine C, or N,N'N"-triacetylfusigen, a cyclic triester composed of three molecules on Nalpha-acetylfusarinine. The trimer has growth factor activity for Arthrobacter JG-9 about equal to fusarinine C itself. The monohydroxamate, Nalpha-acetylfusarinine, is more active than the trimer. The greater chemical stability of these compounds compared to the unacetylated fusarinines reconciles the utilization of otherwise unstable amino acid esters as iron transport agents.


A new intellectual framework for psychiatry.
In an attempt to place psychiatric thinking and the training of future psychiatrists more centrally into the context of modern biology, the author outlines the beginnings of a new intellectual framework for psychiatry that derives from current biological thinking about the relationship of mind to brain. The purpose of this framework is twofold. First, it is designed to emphasize that the professional requirements for future psychiatrists will demand a greater knowledge of the structure and functioning of the brain than is currently available in most training programs. Second, it is designed to illustrate that the unique domain which psychiatry occupies within academic medicine, the analysis of the interaction between social and biological determinants of behavior, can best be studied by also having a full understanding of the biological components of behavior.


Environmental monitoring using autonomous vehicles: a survey of recent searching techniques.
Autonomous vehicles are becoming an essential tool in a wide range of environmental applications that include ambient data acquisition, remote sensing, and mapping of the spatial extent of pollutant spills. Among these applications, pollution source localization has drawn increasing interest due to its scientific and commercial interest and the emergence of a new breed of robotic vehicles capable of operating in harsh environments without human supervision. The aim is to find the location of a region that is the source of a given substance of interest (e.g. a chemical pollutant at sea or a gas leakage in air) using a group of cooperative autonomous vehicles. Motivated by fast paced advances in this challenging area, this paper surveys recent advances in searching techniques that are at the core of environmental monitoring strategies using autonomous vehicles.


Running for exercise mitigates age-related deterioration of walking economy.
Impaired walking performance is a key predictor of morbidity among older adults. A distinctive characteristic of impaired walking performance among older adults is a greater metabolic cost (worse economy) compared to young adults. However, older adults who consistently run have been shown to retain a similar running economy as young runners. Unfortunately, those running studies did not measure the metabolic cost of walking. Thus, it is unclear if running exercise can prevent the deterioration of walking economy. To determine if and how regular walking vs. running exercise affects the economy of locomotion in older adults. 15 older adults (69 ± 3 years) who walk ≥ 30 min, 3x/week for exercise, "walkers" and 15 older adults (69 ± 5 years) who run ≥ 30 min, 3x/week, "runners" walked on a force-instrumented treadmill at three speeds (0.75, 1.25, and 1.75 m/s). We determined walking economy using expired gas analysis and walking mechanics via ground reaction forces during the last 2 minutes of each 5 minute trial. We compared walking economy between the two groups and to non-aerobically trained young and older adults from a prior study. Older runners had a 7-10% better walking economy than older walkers over the range of speeds tested (p = .016) and had walking economy similar to young sedentary adults over a similar range of speeds (p = .237). We found no substantial biomechanical differences between older walkers and runners. In contrast to older runners, older walkers had similar walking economy as older sedentary adults (p = .461) and ∼ 26% worse walking economy than young adults (p<.0001). Running mitigates the age-related deterioration of walking economy whereas walking for exercise appears to have minimal effect on the age-related deterioration in walking economy.


Chitosan fabricated biogenic silver nanoparticles (Ch@BSNP) protectively modulate the defense mechanism of tomato during bacterial leaf spot (BLS) disease.
Herein, the impact of chitosan fabricated biogenic silver nanoparticles (Ch@BSNP) has been evaluated for the protective management of bacterial leaf spot (BLS) disease in tomatoes caused by Xanthomonas campestris (NCIM5028). The Ch@BSNP originated by the Trichoderma viride (MTCC5661) derived extracellular compounds and subsequent chitosan hybridization. Spherical-shaped Ch@BSNP (30-35 nm) treated diseased plants were able to combat the biotic stress, as evidenced by the decreased elevated response of stress markers viz; anthocyanin (34.02%), proline (45.00%), flavonoids (20.26%), lipid peroxidation (10.00%), guaiacol peroxidase (36.58%), ascorbate peroxidase (41.50%), polyphenol oxidase (25.34%) and phenylalanine ammonia-lyase (2.10 fold) as compared to untreated diseased plants. Increased biochemical content specifically sugar (15.43%), phenolics (49.10%), chlorophyll, and carotenoids were measured in Ch@BSNP-treated diseased plants compared to untreated X. campestris-infested plants. The Ch@BSNP considerably reduced stress by increasing net photosynthetic rate and water use efficiency along with decreased transpiration rate and stomatal conductance in comparison to infected plants. Additionally, the expression of defense-regulatory genes viz; growth responsive (AUX, GH3, SAUR), early defense responsive (WRKYTF22, WRKY33, NOS1), defense responsive (PR1, NHO1, NPR1), hypersensitivity responsive (Pti, RbohD, OXI1) and stress hormones responsive (MYC2, JAR1, ERF1) were found to be upregulated in diseased plants while being significantly downregulated in Ch@BSNP-treated diseased plants. Furthermore, fruits obtained from pathogen-compromised plants treated with Ch@BSNP had higher levels of health-promoting compounds including lycopene and beta-carotene than infected plant fruits. This nano-enabled and environmentally safer crop protection strategy may encourage a sustainable agri-system towards the world's growing food demand and promote food security.


Utility of in situ sodium alginate/karaya gum gels to facilitate gastric retention in rodents.
Target validation or demonstration of efficacy requires adequate in vivo exposure of tool molecules to determine their activity in order to validate the model or show the potential usefulness of the pharmacophore. Early discovery work is often carried out with compounds which possess undesirable PK properties in small rodents where the discovery formulation scientist is often forced to dose 2-4 times per day. Gastric retentive formulations in small rodents (rats/mice) could enable increased duration of exposure for compounds with narrow absorption windows or increased residence time for compounds with targets located in the GI tract. The aim of this work is to establish an easily administered gastric retentive gel for rodents in situ using a mixture of sodium alginate and karaya gum. Feasibility studies were conducted in Sprague-Dawley rats using barium sulfate as a radio-opaque tracer. The results show that gastric retention of barium was achieved for rats dosed with the gel formulation relative to a barium suspension. The gastric residence time of the gel varied from 1h to >8h (n=3). The data suggest that sodium alginate/karaya gum gels may be a useful tool to achieve gastric retention in rodent studies.


Navigating the course of scholarly productivity: the protégé's role in mentoring.
The importance of mentoring for professional success, including mentoring in writing, has become increasingly emphasized in academic nursing during the past decade. Although much has been published on how to write for publication, as well as the roles of mentors themselves, surprisingly little has been written about how protégés (those who are the recipients of mentoring) can take an active role in assisting themselves to obtain mentorship. How newer faculty can obtain adequate mentoring is often less straightforward. The main goal of this article is to describe some ideas about how faculty can actively help themselves to obtain adequate mentoring, with a particular focus on mentoring in writing. METHOD/DISCUSSION: Five principles are illustrated as follows, with case examples of hypothetical new faculty members: know yourself, develop realistic expectations, reach out and get to know others, negotiate for what is needed, and learn from every experience. We hope that this discussion will foster further exchange among mentors, protégés, and administrators about approaches to seeking mentoring and high-level success in writing for publication along career journeys.


Radon Flux Measurement System.
Disposal of naturally occurring radioactive material (NORM) and technologically enhanced naturally occurring radioactive material (TENORM) waste in the State of Oregon is prohibited unless it can be demonstrated that the material is nonradioactive as defined by its radionuclide content and potential for emission into the environment. It was determined that a radon flux on the surface of the waste no greater than 0.37 Bq m -2 s -1 would meet this requirement. This article provides a method to estimate the radon flux through indirect measurement of the radon mass exhalation rate. It describes a device that consists of a radon accumulation chamber coupled with a continuous radon monitor and software to process the results and calculate the radon mass exhalation rate and radon flux for an unknown sample of approximately 500 g. The chamber system was tested with a uranium ore sample.


Coping with low light under high atmospheric dryness: shade acclimation in a Mediterranean conifer (Abies pinsapo Boiss.).
Plant species living in the understory increase carbon (C) allocation toward leaf production for maximizing light capture at the expense of roots and stems, with negative consequences for the whole-plant hydraulic conductance. Moreover, under some conditions, the high atmospheric evaporative demand occurring in Mediterranean areas may be not well buffered by the canopy, which might be the case for relict conifer Abies pinsapo Boiss. growing in the forest understory. We hypothesized that acclimation to combined understory shade and high atmospheric dryness can be achieved through the adjustment of water losses to cope with the restriction in water transport. The results reveal high structural plasticity in A. pinsapo that allows light harvesting of this species to maximize light capture in the forest understory, and maintain a positive C balance under low light conditions. However, growth in the understory resulted in reduced leaf-specific conductivity, up to approximately four to five times, implying decreased plant capacity to supply water to the leaves. In order to cope with the high atmospheric evaporative demand in the understory, there is an adjustment of the stomatal conductance to the hydraulic conductivity by means of a reduction in the stomatal density in understory individuals, which is due to the almost complete lack of stomata in the adaxial side of the needles. To the extent of our knowledge, such a drastic phenotypic response found in a conifer when growing under shaded conditions had not been previously reported.


Inhibition of hepatitis C virus infection by DNA aptamer against envelope protein.
Hepatitis C virus (HCV) envelope protein (E1E2) is essential for virus binding to host cells. Aptamers have been demonstrated to have strong promising applications in drug development. In the current study, a cDNA fragment encoding the entire E1E2 gene of HCV was cloned. E1E2 protein was expressed and purified. Aptamers for E1E2 were selected by the method of selective evolution of ligands by exponential enrichment (SELEX), and the antiviral actions of the aptamers were examined. The mechanism of their antiviral activity was investigated. The data show that selected aptamers for E1E2 specifically recognize the recombinant E1E2 protein and E1E2 protein from HCV-infected cells. CD81 protein blocks the binding of aptamer E1E2-6 to E1E2 protein. Aptamers against E1E2 inhibit HCV infection in an infectious cell culture system although they have no effect on HCV replication in a replicon cell line. Beta interferon (IFN-β) and IFN-stimulated genes (ISGs) are not induced in virus-infected hepatocytes with aptamer treatment, suggesting that E1E2-specific aptamers do not induce innate immunity. E2 protein is essential for the inhibition of HCV infection by aptamer E1E2-6, and the aptamer binding sites are located in E2. Q412R within E1E2 is the major resistance substitution identified. The data indicate that an aptamer against E1E2 exerts its antiviral effects through inhibition of virus binding to host cells. Aptamers against E1E2 can be used with envelope protein to understand the mechanisms of HCV entry and fusion. The aptamers may hold promise for development as therapeutic drugs for hepatitis C patients.


Does the Fear of Missing Out Moderate the Relationship Between Social Networking Use and Affect? A Daily Diary Study.
Social networking site (SNS) use is common and speculation about the negative impact of SNS use on mental health and psychological well-being is a recurring theme in scientific debates. The evidence for this link, however, is inconclusive. The Fear of Missing Out (FoMO) may assist in understanding the mixed evidence, as individuals who experience FoMO are more driven to keep up with what is happening to avoid missing out. We used a 2-week daily diary study of 408 university students to measure the daily associations between SNS use and negative and positive affect and whether FoMO moderated these associations. Multi-level Bayesian regression analyses revealed that 1) greater SNS use was associated with reductions in successive positive affect, but not increases in negative affect and 2) FoMO moderated the influence of SNS use such that increases in successive negative affect occurred only in those individuals high in trait FoMO.


H/dipeptide absorption across the human intestinal epithelium is controlled indirectly via a functional Na/H exchanger.
For optimal nutrient absorption to occur, the enterocyte must express a range of specialist ion-driven carrier proteins that function cooperatively in a linked and mutually dependent fashion. Thus, absorption via the human intestinal H(+)-coupled di/tripeptide transporter (hPepT1) is dependent on maintenance of the trans-apical driving force (the H(+)-electrochemical gradient) established, in part, by brush-border Na(+)/H(+) exchanger (NHE3) activity. This study aimed to examine whether physiologic regulation of NHE3 activity can limit hPepT1 capacity and, therefore, protein absorption after a meal. hPepT1 and NHE3 activities were determined in intact human intestinal epithelial Caco-2 cell monolayers by measurements of [(14)C]glycylsarcosine transport and uptake, (22)Na(+)-influx, H(+)-influx, and H(+)-efflux. Expression of NHE regulatory factors was determined by reverse-transcriptase polymerase chain reaction. Optimal dipeptide transport was observed in the presence of a transapical pH gradient and extracellular Na(+). At apical pH 6.5, and only in Na(+)-containing media, protein kinase A activation (by forskolin or vasoactive intestinal peptide) or selective NHE3 inhibition (by S1611) reduced transepithelial dipeptide transport and cellular accumulation by a reduction in the capacity (without effect on affinity) of dipeptide uptake. Protein kinase A-mediated modulation of intestinal dipeptide absorption is indirect via effects on the apical Na(+)/H(+) exchanger.


Canine Respiratory Coronavirus: A Naturally Occurring Model of COVID-19?
Discovered in 2003 at the Royal Veterinary College, London, canine respiratory coronavirus (CRCoV) is a betacoronavirus of dogs and major cause of canine infectious respiratory disease complex. Generally causing mild clinical signs of persistent cough and nasal discharge, the virus is highly infectious and is most prevalent in rehoming shelters worldwide where dogs are often closely housed and infections endemic. As the world grapples with the current COVID-19 pandemic, the scientific community is searching for a greater understanding of a novel virus infecting humans. Similar to other betacoronaviruses, SARS-CoV-2 appears to have crossed the species barrier, most likely from bats, clearly reinforcing the One Health concept. Veterinary pathologists are familiar with coronavirus infections in animals, and now more than ever this knowledge and understanding, based on many years of veterinary research, could provide valuable answers for our medical colleagues. Here I review the early research on CRCoV where seroprevalence, early immune response, and pathogenesis are some of the same key questions being asked by scientists globally during the current SARS-CoV-2 pandemic.


Elie Metchnikoff: father of natural immunity.
We celebrate the centenary of the Nobel award to Elie Metchnikoff in 2008, shared with Paul Ehrlich, as respective pioneers of cellular and humoral immunology. Metchnikoff is rightly famous for his recognition of the biological significance of leukocyte recruitment and phagocytosis of microbes in host defence against infection, inflammation and immunity. As a comparative zoologist he utilised a broad range of model organisms for microscopic studies in vivo and in vitro. His work prefigures much of contemporary research in innate immunity. In this brief review, I cover some details of his Europe-wide life in Russia (mainly Odessa) and at the Pasteur Institute in Paris. He had a complex personality, yet his creative genius, imagination and insights justify the title of "Father of natural immunity".


Salmonella infections in the common raccoon (Procyon lotor) in western Pennsylvania.
Ten Salmonella enterica serotypes were isolated from fecal samples collected from anesthetized raccoons (n = 738) trapped in six Pennsylvania counties from 2003 to 2005. Comparison of raccoon pulsed-field gel electrophoresis (PFGE) pulse type data with the Pennsylvania Department of Health PFGE database revealed that the patterns of seven Salmonella serotypes matched those isolated from humans with salmonellosis.


[The significance of alpha-feto-protein (AFP) and human chorionic gonadotrophin (HCG) during the first half of pregnancy (author's transl)].
The determination of AFP and HCG was used as a diagnostic parameter for the functional integrity of the feto-placental unit during the first 20 weeks of normal and disturbed pregnancies. In contrast to HCG which can already be detected very shortly after nidation and reaches a maximum between the 10th and 12th week of gestation, AFP does not begin to rise discernibly before the 8th and 9th week and attains the highest values in the third trimester. The assay of AFP did not contribute relevant data when carried out before the 10th week of pregnancy. Contrary to that, an irreversibly damaged pregnancy has to be expected when lower than normal AFP values are found after the 10th week, even in the presence of a normal level of HCG. Likewise, higher than normal values should be taken as a reliable sign of embryonal demise after the 14th week of pregnancy, as long as a multiple gestation, a previous amniocentesis or a neural tube defect can be excluded. Serum AFP did not only increase markedly in many cases after interruption of pregnancy, but even after amniocentesis or premature rupture of the amniotic sac when fetal cells having a high content of AFP enter the maternal circulation.


Efficacy of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine against acute otitis media and nasopharyngeal carriage in Panamanian children - A randomized controlled trial.
We previously reported 10-valent pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) efficacy in a double-blind randomized trial (ClinicalTrials.gov: NCT00466947) against various diseases, including acute otitis media (AOM). Here, we provide further analyses. In the Panamanian subset, 7,359 children were randomized (1:1) to receive PHiD-CV or control vaccine at age 2/4/6 and 15-18 months. Of these, 2,000 had nasopharyngeal swabs collected. AOM cases were captured when parents sought medical attention for children with AOM symptoms; surveillance was enhanced approximately 2 y into the study through regular telephone calls or home visits by study personnel, who advised parents to visit the clinic if their child had AOM symptoms. Mean follow-up was 31.4 months. Clinical AOM (C-AOM) cases were assessed by physicians and confirmed by otorhinolaryngologists. Middle ear fluid samples, taken from children with C-AOM after specific informed consent, and nasopharyngeal samples were cultured for pathogen identification. For 7,359 children, 2,574 suspected AOM cases were assessed by a primary healthcare physician; 649 cases were C-AOM cases as per protocol definition. From the 503 MEF samples collected, 158 resulted in a positive culture. In the intent-to-treat cohort (7,214 children), PHiD-CV showed VE against first C-AOM (24.0% [95% CI: 8.7, 36.7]) and bacterial (B-AOM) episodes (48.0% [20.3, 66.1]) in children <24 months, which declined thereafter with age. Pre-booster VE against C-AOM was 30.7% [12.9, 44.9]; post-booster, -6.7% [-36.4, 16.6]. PHiD-CV VE was 17.7% [-6.1, 36.2] against moderate and 32.7% [-20.5, 62.4] against severe C-AOM. VE against vaccine-serotype pneumococcal NPC was 31.2% [5.3, 50.3] 3 months post-booster, and 25.6% [12.7, 36.7] across all visits. NTHi colonization rates were low and no significant reduction was observed. PHiD-CV showed efficacy against C-AOM and B-AOM in children younger than 24 months, and reduced vaccine-serotype NPC.


Diagnosis and treatment of cancer in medical textbooks of ancient Iran.
Research shows that ancient Iranians were among the pioneers of medical science, and are therefore admired and praised by non-Iranian scholars for their efforts and accomplishments in this field. Investigations of medical and historical texts indicate that between the 10(th) and the 18(th) century A.D., ancient Iran experienced a golden age of medicine. Great physicians such as Rhazes, al-Ahwazi, Avicenna and others reviewed the medical textbooks of civilizations such as Greece and India, Theories were scientifically criticized, superstitious beliefs were discarded, valuable innovations were added to pre-existing knowledge and the ultimate achievements were compiled as precious textbooks. Alhawi by Rhazes, Cannon by Avicenna, and Kamil al-Sina'ah by al-Ahwazi are among the works that were treasured by domestic and foreign scientists alike, as well as future generations who continued to appreciate them for centuries. The above-mentioned textbooks discuss diseases and conditions related to neurosurgery, ophthalmology, ear, nose and throat, gastroenterology, urology, skeletomuscular system and other specialties, as well as cancer and similar subjects. One of the richest texts on the description, diagnosis, differential diagnosis, and prognosis of cancer and therapeutic approaches is Alhawi by Mohammad ibn Zakarya al Razi (Rhazes). This article presents a brief summary of Rhazes' views about the definition of cancer, types, signs and symptoms, prevalence, complications, medical care, treatment and even surgical indications and contraindications. Moreover, his opinions are compared against the views of other physicians and theories of modern medicine. It is also recommended to review the medical heritage of Iran and evaluate the proposed treatments based on modern methodologies and scientific approaches.


Sudden collapse of a granular cluster.
Single clusters in a vibro-fluidized granular gas in N connected compartments become unstable at strong shaking. They are experimentally shown to collapse very abruptly. The observed cluster lifetime (as a function of the driving intensity) is analytically calculated within a flux model, making use of the self-similarity of the process. After collapse, the cluster diffuses out into the uniform distribution in a self-similar way, with an anomalous diffusion exponent 1/3.


Coupled atomic charge selectivity for optimal ligand-charge distributions at protein binding sites.
Charge optimization as a tool for both analyzing and enhancing binding electrostatics has become an attractive approach over the past few years. An interesting feature of this method for molecular design is that it provides not only the optimal charge magnitudes, but also the selectivity of a particular atomic center for its optimal charge. The current approach to compute the charge selectivity at a given atomic center of a ligand in a particular binding process is based on the binding-energy cost incurred upon the perturbation of the optimal charge distribution by a unit charge at the given atomic center, while keeping the other atomic partial charges at their optimal values. A limitation of this method is that it does not take into account the possible concerted changes in the other atomic charges that may incur a lower energetic cost than perturbing a single charge. Here, we describe a novel approach for characterizing charge selectivity in a concerted manner, taking into account the coupling between the ligand charge centers in the binding process. We apply this novel charge selectivity measure to the celecoxib molecule, a nonsteroidal anti-inflammatory agent binding to cyclooxygenase 2 (COX2), which has been recently shown to also exhibit cross-reactivity toward carbonic anhydrase II (CAII), to which it binds with nanomolar affinity. The uncoupled and coupled charge selectivity profiles over the atomic centers of the celecoxib ligand, binding independently to COX2 and CAII, are analyzed comparatively and rationalized with respect to available experimental data. Very different charge selectivity profiles are obtained for the uncoupled versus coupled selectivity calculations.


Quality and safety of fish curry processed by sous vide cook chilled and hot filled technology process during refrigerated storage.
Fish curry, a traditional Indian dish was prepared from farmed fish Cobia (Rachycentron canadum), packaged by two different cook-chill processes namely, sous vide cook chilled and hot filled technology and held at 2 °C. Biochemical composition revealed that fish curry contained 5% protein and 6% fat. Omega-3 fatty acids, eicosapentaenoic acid (EPA) retained 55.44% while docosahexaenoic acid (DHA) retained 29% during cook-chilling process. The major fatty acids in fish curry were C18:2, C12:0, C16:0 and C18:1. Shelf-life of sous vide cook chilled and hot filled technology processed fish curry were 8 and 12 weeks, respectively. Total bacterial counts were detected after 4 weeks and 12 weeks in sous vide cook chilled and hot filled technology processes, respectively. Total staphylococci were detected in sous vide cook chilled and hot filled technology processed cobia fish curry after 4 and 12 weeks, respectively. Total bacilli, anaerobic sulfite reducing clostridia, Salmonella, and lactic acid bacteria were absent. Hot filled technology process was more efficient and could be applied for chilled fish curry preservation for 12 weeks without any safety problems.


Causality assessment of drug-induced liver injury. Hepatology Working Group.
None of the various methods for drug reaction assessment has been adapted to the well-defined damage of a specific organ. There are disagreements between the parties involved in this issue: practitioners, and experts in drug surveillance either in regulatory agencies or in the pharmaceutical industry. Consensus Meetings were therefore organized in order to answer the three basic questions related to the diagnosis of drug-induced liver injury: (a) is the liver involved? (b) what chronological and clinical criteria suggest a drug-induced reaction? (c) can non-drug-related causes be excluded? On the basis of the method for drug reaction assessment used in France, we describe criteria adapted to the case of acute cytolytic hepatitis, which constitutes only one aspect of the task of the Hepatology Working Group.


Spatiotemporal impact of soil moisture on air temperature across the Tibet Plateau.
The Himalayan Tibet Plateau (HTP) is regarded as the third pole of the globe and is highly sensitive to global climate change. The hydrothermal properties of HTP greatly impacts the water cycle of the HTP and climate change in its surrounding regions. Using the NCEP-CFSR dataset, this study investigated the spatiotemporal pattern of soil moisture (SM) during different seasons considering vegetation types. The response of the evaporation fraction (EF) to SM and the impact of SM on air temperature through evapotranspiration were analyzed. Results showed that the spatial distribution of SM across the HTP was persistent during different seasons. A decreasing SM trend was observed from southeastern to northwestern HTP. Further, results of this study indicated a wetting tendency in past thirty years, espcially in desert region. In addition, the majority of the HTP regions were dominated by persistent transitional SM conditions which could be identified in the Himalayas and the southeastern HTP, whereas a persistent SM deficit in the Qaidam basin. The sensitivity of temperature response to EF was the strongest during spring and summer. Moreover, the spatial distribution of sensitivity was highly consistent with the vegetation regionalization, indicating the remarkable impact of vegetation type on the sensitivity of temperature to EF changes in summer.


Electro- and photochemical H2 generation by Co(ii) polypyridyl-based catalysts bearing ortho-substituted pyridines.
Cobalt(ii) complexes featuring hexadentate amino-pyridyl ligands have been recently discovered as highly active catalysts for the Hydrogen Evolution Reaction (HER), whose high performance arises from the possibility of assisting proton transfer processes via intramolecular routes involving detached pyridine units. With the aim of gaining insights into such catalytic routes, three new proton reduction catalysts based on amino-polypyridyl ligands are reported, focusing on substitution of the pyridine ortho-position. Specifically, a carboxylate (C2) and two hydroxyl substituted pyridyl moieties (C3, C4) are introduced with the aim of promoting intramolecular proton transfer which possibly enhances the efficiency of the catalysts. Foot-of-the-wave and catalytic Tafel plot analyses have been utilized to benchmark the catalytic performances under electrochemical conditions in acetonitrile using trifluoroacetic acid as the proton source. In this respect, the cobalt complex C3 turns out to be the fastest catalyst in the series, with a maximum turnover frequency (TOF) of 1.6 (±0.5) × 105 s-1, but at the expense of large overpotentials. Mechanistic investigations by means of Density Functional Theory (DFT) suggest a typical ECEC mechanism (i.e. a sequence of reduction - E - and protonation - C - events) for all the catalysts, as previously envisioned for the parent unsubstituted complex C1. Interestingly, in the case of complex C2, the catalytic route is triggered by initial protonation of the carboxylate group resulting in a less common (C)ECEC mechanism. The pivotal role of the hexadentate chelating ligand in providing internal proton relays to assist hydrogen elimination is further confirmed within this novel class of molecular catalysts, thus highlighting the relevance of a flexible polypyridine ligand in the design of efficient cobalt complexes for the HER. Photochemical studies in aqueous solution using [Ru(bpy)3]2+ (where bpy = 2,2'-bipyridine) as the sensitizer and ascorbate as the sacrificial electron donor support the superior performance of C3.


Corneal confocal microscopy as a tool for detecting diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes: ADDITION-Denmark.
In this cross-sectional study, we explored the utility of corneal confocal microscopy (CCM) measures for detecting diabetic polyneuropathy (DPN) and their association with clinical variables, in a cohort with type 2 diabetes. CCM, nerve conduction studies, and assessment of symptoms and clinical deficits of DPN were undertaken in 144 participants with type 2 diabetes and 25 controls. DPN was defined according to the Toronto criteria for confirmed DPN. Corneal nerve fiber density (CNFD) was lower both in participants with confirmed DPN (n = 27) and in participants without confirmed DPN (n = 117) compared with controls (P = 0.04 and P = 0.01, respectively). No differences were observed for CNFD (P = 0.98) between participants with and without DPN. There were no differences in CNFL and CNBD between groups (P = 0.06 and P = 0.29, respectively). CNFD was associated with age, height, total- and LDL cholesterol. CCM could not distinguish patients with and without neuropathy, but CNFD was lower in patients with type 2 diabetes compared to controls. Age may influence the level of CCM measures.


Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates.
Neurological manifestations are a significant complication of coronavirus disease (COVID-19), but underlying mechanisms aren't well understood. The development of animal models that recapitulate the neuropathological findings of autopsied brain tissue from patients who died from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are critical for elucidating the neuropathogenesis of infection and disease. Here, we show neuroinflammation, microhemorrhages, brain hypoxia, and neuropathology that is consistent with hypoxic-ischemic injury in SARS-CoV-2 infected non-human primates (NHPs), including evidence of neuron degeneration and apoptosis. Importantly, this is seen among infected animals that do not develop severe respiratory disease, which may provide insight into neurological symptoms associated with "long COVID". Sparse virus is detected in brain endothelial cells but does not associate with the severity of central nervous system (CNS) injury. We anticipate our findings will advance our current understanding of the neuropathogenesis of SARS-CoV-2 infection and demonstrate SARS-CoV-2 infected NHPs are a highly relevant animal model for investigating COVID-19 neuropathogenesis among human subjects.


Porous liquids: a promising class of media for gas separation.
A porous liquid containing empty cavities has been successfully fabricated by surface engineering of hollow structures with suitable corona and canopy species. By taking advantage of the liquid-like polymeric matrices as a separation medium and the empty cavities as gas transport pathway, this unique porous liquid can function as a promising candidate for gas separation. Moreover, such a facile synthetic strategy can be further extended to the fabrication of other types of nanostructure-based porous liquid, opening up new opportunities for preparation of porous liquids with attractive properties for specific tasks.


Accelerated free breathing ECG triggered contrast enhanced pulmonary vein magnetic resonance angiography using compressed sensing.
To investigate the feasibility of accelerated electrocardiogram (ECG)-triggered contrast enhanced pulmonary vein magnetic resonance angiography (CE-PV MRA) with isotropic spatial resolution using compressed sensing (CS). Nineteen patients (59±13 y, 11 M) referred for MR were scanned using the proposed accelerated free breathing ECG-triggered 3D CE-PV MRA sequence (FOV=340×340×110 mm3, spatial resolution=1.5×1.5×1.5 mm3, acquisition window=140 ms at mid diastole and CS acceleration factor=5) and a conventional first-pass breath-hold non ECG-triggered 3D CE-PV MRA sequence. CS data were reconstructed offline using low-dimensional-structure self-learning and thresholding reconstruction (LOST) CS reconstruction. Quantitative analysis of PV sharpness and subjective qualitative analysis of overall image quality were performed using a 4-point scale (1: poor; 4: excellent). Quantitative PV sharpness was increased using the proposed approach (0.73±0.09 vs. 0.51±0.07 for the conventional CE-PV MRA protocol, p<0.001). There were no significant differences in the subjective image quality scores between the techniques (3.32±0.94 vs. 3.53±0.77 using the proposed technique). CS-accelerated free-breathing ECG-triggered CE-PV MRA allows evaluation of PV anatomy with improved sharpness compared to conventional non-ECG gated first-pass CE-PV MRA. This technique may be a valuable alternative for patients in which the first pass CE-PV MRA fails due to inaccurate first pass timing or inability of the patient to perform a 20-25 seconds breath-hold.


A rare case of male breast ductal carcinoma in-situ associated with prolactinoma.
A case of ductal carcinoma in-situ (DCIS) associated with prolactinoma in a male patient is described. A 56-year-old gentleman presented with lethargy and loss of libido. His prolactin at presentation was 3680 mU/l and an MRI scan of the head revealed a pituitary tumour suggestive of prolactinoma. Following 18 months of treatment with cabergoline, the prolactin level reduced to 914 mU/l. However, 3 years later he presented with blood stained nipple discharge, the cytology of which was negative for cancer. Ultrasound scan of his right breast revealed a single dilated mammary duct. Microdochectomy was performed. The histology revealed incompletely excised DCIS. There is increasing evidence of prolactinoma associated with breast cancer with or without DCIS in females. A review of the literature reveals only one previous case report of this association in males. This is the first case of pure DCIS preceded by prolactinoma in a male patient.


Antioxidant and functional properties of protein hydrolysates obtained from squid pen chitosan extraction effluent.
Squid pens were subjected to alkali hydrolysis to extract chitin and chitosan. Proteins present in the alkaline extraction wastewater were recovered at pH 3, 4, 5 and 6, and were subjected to hydrolysis by trypsin, pepsin and a bacterial protease called HT for 1, 2, 4 and 24h. Hydrolysis of the extracted proteins with either trypsin or HT generated more antioxidant activity than hydrolysis with pepsin. Higher ACE-inhibitory activity was generated in the trypsin and pepsin hydrolysates than in the HT hydrolysate. Squid pen protein recovered from chitosan processing waste alkaline solution can be a potential source of bioactive peptides for addition to foods. The antioxidant and ACE-inhibitory activities of the extracted proteins were initially low and increased upon incubation with the proteases. Pepsin generated significantly lower (P<0.05) antioxidant activities compared to trypsin and HT, while trypsin and pepsin hydrolysates exhibited higher ACE-inhibitory activity than HT (P<0.05).


Association between fish consumption and risk of dementia: a new study from China and a systematic literature review and meta-analysis.
To assess the association of fish consumption with risk of dementia and its dose-response relationship, and investigate variations in the association among low-, middle- and high-income countries. A new community-based cross-sectional study and a systematic literature review.SettingsUrban and rural communities in China; population-based studies systematically searched from worldwide literature. Chinese adults aged ≥60 years in six provinces (n 6981) took part in a household health survey of dementia prevalence and risk factors. In addition, 33 964 participants from eleven published and eligible studies were included in the systematic review and meta-analysis. In the new study in China, 326 participants were diagnosed with dementia (4·7 %); those who consumed any amount of fish in the past two years v. those who consumed no fish had reduced risk of dementia (adjusted OR=0·73, 95 % CI 0·64, 0·99), but the dose-response relationship was not statistically significant. The meta-analysis of available data from the literature and the new study showed relative risk (RR) of dementia of 0·80 (95 % CI 0·74, 0·87) for people with fish consumption; the impact was similar among countries with different levels of income. Pooled dose-response data revealed RR (95 % CI) of 0·84 (0·72, 0·98), 0·78 (0·68, 0·90) and 0·77 (0·61, 0·98) in people with low, middle and high consumption of fish, respectively. Corresponding figures for Alzheimer's disease were 0·88 (0·74, 1·04), 0·79 (0·65, 0·96) and 0·67 (0·58, 0·78), respectively. Greater consumption of fish is associated with a lower risk of dementia. Increasing fish consumption may help prevent dementia worldwide regardless of income level.


Comparison of myocardial remodeling between cryoinfarction and reperfused infarction in mice.
Myocardial infarction is associated with inflammatory reaction leading to tissue remodeling. We compared tissue remodeling between cryoinfarction (cMI) and reperfused myocardial infarction (MI) in order to better understand the local environment where we apply cell therapies. Models of closed-chest one-hour ischemia/reperfusion MI and cMI were used in C57/Bl6-mice. The reperfused MI showed rapid development of granulation tissue and compacted scar formation after 7 days. In contrast, cMI hearts showed persistent cardiomyocyte debris and cellular infiltration after 7 days and partially compacted scar formation accompanied by persistent macrophages and myofibroblasts after 14 days. The mRNA of proinflammatory mediators was transiently induced in MI and persistently upregulated in cMI. Tenascin C and osteopontin-1 showed delayed induction in cMI. In conclusion, the cryoinfarction was associated with prolonged inflammation and active myocardial remodeling when compared to the reperfused MI. These substantial differences in remodeling may influence cellular engraftment and should be considered in cell therapy studies.


FamPipe: An Automatic Analysis Pipeline for Analyzing Sequencing Data in Families for Disease Studies.
In disease studies, family-based designs have become an attractive approach to analyzing next-generation sequencing (NGS) data for the identification of rare mutations enriched in families. Substantial research effort has been devoted to developing pipelines for automating sequence alignment, variant calling, and annotation. However, fewer pipelines have been designed specifically for disease studies. Most of the current analysis pipelines for family-based disease studies using NGS data focus on a specific function, such as identifying variants with Mendelian inheritance or identifying shared chromosomal regions among affected family members. Consequently, some other useful family-based analysis tools, such as imputation, linkage, and association tools, have yet to be integrated and automated. We developed FamPipe, a comprehensive analysis pipeline, which includes several family-specific analysis modules, including the identification of shared chromosomal regions among affected family members, prioritizing variants assuming a disease model, imputation of untyped variants, and linkage and association tests. We used simulation studies to compare properties of some modules implemented in FamPipe, and based on the results, we provided suggestions for the selection of modules to achieve an optimal analysis strategy. The pipeline is under the GNU GPL License and can be downloaded for free at http://fampipe.sourceforge.net.


Simple linear model provides highly accurate genotypic predictions of HIV-1 drug resistance.
Drug resistance is a major obstacle to the successful treatment of HIV-1 infection. Genotypic assays are used widely to provide indirect evidence of drug resistance, but the performance of these assays has been mixed. We used standard stepwise linear regression to construct drug resistance models for seven protease inhibitors and 10 reverse transcriptase inhibitors using data obtained from the Stanford HIV drug resistance database. We evaluated these models by hold-one-out experiments and by tests on an independent dataset. Our linear model outperformed other publicly available genotypic interpretation algorithms, including decision tree, support vector machine and four rules-based algorithms (HIVdb, VGI, ANRS and Rega) under both tests. Interestingly, our model did well despite the absence of any terms for interactions between different residues in protease or reverse transcriptase. The resulting linear models are easy to understand and can potentially assist in choosing combination therapy regimens.


Practice of breast self-examination and knowledge of breast cancer among female university students in Korea.
This study examined the practice of breast self-examination and knowledge of breast cancer among female university students in Korea. This was a cross-sectional descriptive study. The participants were 2186 female university students in Korea. The Breast Cancer and Heredity Knowledge Scale was used. The collected data were analyzed through descriptive statistics, χ(2)-test, t-test, ANOVA, and logistic regression. Twenty-seven percent of students reported engaging in breast self-examination. The participants displayed a medium-level score (total score: 5.33 ± 2.70, range: 0-11) on knowledge about breast cancer. Predictors for breast self-examination were age (odds ratio = 1.15, P < 0.001), major (odds ratio = 1.80, P < 0.001), and knowledge of breast cancer (odds ratio = 1.16, P < 0.001). This study was the sole nationwide-scale research that examined the practice of breast self-examination, related factors, and knowledge of breast cancer among female university students, as a representative sample of young Korean women. The results are valuable in developing educational programs that can increase knowledge related to breast cancer, as well as the practice of breast self-examination, to support health promotion among young women.


Dealing with Multiple Requirements in Geometric Arrangements.
Existing algorithms for building layouts from geometric primitives are typically designed to cope with requirements such as orthogonal alignment, overlap removal, optimal area usage, hierarchical organization, among others. However, most techniques are able to tackle just a few of those requirements simultaneously, impairing their use and flexibility. In this work we propose a novel methodology for building layouts from geometric primitives that concurrently addresses a wider range of requirements. Relying on multidimensional projection and mixed integer optimization, our approach arranges geometric objects in the visual space so as to generate well structured layouts that preserve the semantic relation among objects while still making an efficient use of display area. Moreover, scalability is handled through a hierarchical representation scheme combined with navigation tools. A comprehensive set of quantitative comparisons against existing geometry-based layouts and applications on text, image, and video data set visualization prove the effectiveness of our approach.


Inhibition of α-Synuclein contributes to the ameliorative effects of dietary flavonoids luteolin on arsenite-induced apoptotic cell death in the dopaminergic PC12 cells.
Arsenite is a toxic metalloid that may increase the risk of Parkinson's disease by inducing dopaminergic neuronal apoptosis. Luteolin, a common dietary flavonoid, possesses variety of biological functions, but potential effects of luteolin on arsenite toxicity remain elusive. In this study, we demonstrated that luteolin prevented arsenite-induced apoptosis in the dopaminergic PC12 cells. Administration of luteolin to cells attenuated arsenite-induced ROS production, enhanced caspase-3 activity and γ-H2AX expression. Our results further showed the expression of α-Synuclein (α-Syn) was significantly increased in arsenite-treated cells, but co-treatment with luteolin reversed the expression of α-Syn back toward normal level. Inhibition of α-Syn by siRNA remarkably enhanced the beneficial effect of luteolin against arsenite-induced apoptotic cell death. Taken together, these results demonstrate that the ameliorative effects of luteolin against arsenite in the dopaminergic cell may be modulated by α-Syn, and indicating that luteolin may be developed as a chemopreventive supplementary agent to ameliorate dopaminergic cell apoptosis resulting from arsenite exposure.


[Common carotid artery intima-media thickness: the role in evaluation of atherosclerosis progression].
Atherosclerosis is a generalized vascular disease. There are methods to investigate the development of atherosclerosis. Doppler ultrasonography is a noninvasive and safe method. By this method we can see and measure the first stage of atherosclerosis development--thickening of intima-media complex. Measuring intima-media thickness of common carotid artery may be used as an indicator of generalized atherosclerosis. Intima-media thickness is also used to study progression of atherosclerosis and its possible regression during therapy.


Nutritional and Metabolic Derangements in Pancreatic Cancer and Pancreatic Resection.
Pancreatic cancer is an aggressive malignancy with a poor prognosis. The disease and its treatment can cause significant nutritional impairments that often adversely impact patient quality of life (QOL). The pancreas has both exocrine and endocrine functions and, in the setting of cancer, both systems may be affected. Pancreatic exocrine insufficiency (PEI) manifests as weight loss and steatorrhea, while endocrine insufficiency may result in diabetes mellitus. Surgical resection, a central component of pancreatic cancer treatment, may induce or exacerbate these dysfunctions. Nutritional and metabolic dysfunctions in patients with pancreatic cancer lack characterization, and few guidelines exist for nutritional support in patients after surgical resection. We reviewed publications from the past two decades (1995-2016) addressing the nutritional and metabolic status of patients with pancreatic cancer, grouping them into status at the time of diagnosis, status at the time of resection, and status of nutritional support throughout the diagnosis and treatment of pancreatic cancer. Here, we summarize the results of these investigations and evaluate the effectiveness of various types of nutritional support in patients after pancreatectomy for pancreatic adenocarcinoma (PDAC). We outline the following conservative perioperative strategies to optimize patient outcomes and guide the care of these patients: (1) patients with albumin < 2.5 mg/dL or weight loss > 10% should postpone surgery and begin aggressive nutrition supplementation; (2) patients with albumin < 3 mg/dL or weight loss between 5% and 10% should have nutrition supplementation prior to surgery; (3) enteral nutrition (EN) should be preferred as a nutritional intervention over total parenteral nutrition (TPN) postoperatively; and, (4) a multidisciplinary approach should be used to allow for early detection of symptoms of endocrine and exocrine pancreatic insufficiency alongside implementation of appropriate treatment to improve the patient's quality of life.


Neuroprotection induced by post-conditioning following ischemia/reperfusion in mice is associated with altered microRNA expression.
Ischemic preconditioning and ischemic postconditioning (IPostC) represent promising strategies to reduce ischemia-reperfusion (I/R) injury and attenuate the lethal ischemic damage following stroke. However, the mechanism underlying this attenuation remains to be elucidated. It was hypothesized that alterations in microRNA (miRNA) expression in the cerebral cortex and hippocampus of mice following I/R is associated with the functional improvement induced by IPostC. Behavioral changes were assessed in a mouse model of I/R in the absence or presence of IPostC, followed by microarray analyses to investigate the expressional alterations of miRNAs in the cerebral cortex and hippocampus of mice. The results of the present study revealed that IPostC abrogated the neurological impairment and hippocampus‑associated cognitive deficits induced by I/R, and upregulated or downregulated the expression levels of numerous miRNAs. Furthermore, the upregulation of miR‑19a, and the downregulation of miR‑1, let‑7f and miR‑124 expression levels following IPostC was confirmed utilizing reverse transcription‑quantitative polymerase chain reaction. The results of the present study demonstrated that alterations in miRNA expression in the cerebral cortex and hippocampus of mice following I/R was associated with the neuroprotection induced by IPostC.


Dissociation dynamics of sequential ionic reactions: heats of formation of tri-, di-, and monoethylphosphine.
The sequential ethene (C2H4) loss channels of energy-selected ethylphosphine ions have been studied using threshold photoelectron photoion coincidence (TPEPICO) spectroscopy in which ion time-of-flight (TOF) distributions are recorded as a function of the photon energy. The ion TOF distributions and breakdown diagrams have been modeled in terms of the statistical RRKM theory for unimolecular reactions, providing 0 K dissociation onsets, E0, for the ethene loss channels. Three RRKM curves were used to model the five measurements, since two of the reactions differ only by the internal energy of the parent ion. This series of dissociations provides a detailed check of the calculation of the product energy distribution for sequential reactions. From the determined E0's, the heats of formation of several ethylphosphine neutrals and ions have been determined: Delta(f)H degrees 298K[P(C(2)H(5))3] = -152.7 +/- 2.8 kJ/mol, Delta(f)H degrees 298K[P(C(2)H(5))3+] = 571.6 +/- 4.0 kJ/mol, Delta(f)H degrees 298K[HP(C(2)H(5))2] = -89.6 +/- 2.1 kJ/mol, Delta(f)H degrees 298K[HP(C(2)H(5))2+] = 669.9 +/- 2.5 kJ/mol, Delta(f)H degrees 298K[H(2)PC(2)H(5)] = -36.5 +/- 1.5 kJ/mol, Delta(f)H degrees 298K[H(2)PC(2)H(5)+] = 784.0 +/- 1.9 kJ/mol. These values have been supported by G2 and G3 calculations using isodesmic reactions. Coupled cluster calculations have been used to show that the C2H4 loss channel, which involves a hydrogen transfer step, proceeds without a reverse energy barrier.


Defining the "older" crash victim: the relationship between age and serious injury in motor vehicle crashes.
Age is often used as a predictor of injury and mortality in motor vehicle crashes (MVCs), however, the age that defines an "older" occupant in terms of injury-risk remains unclear, as do specific injury patterns associated with increasing age. The objective of this study was to evaluate the relationship between age and serious injury (including injury patterns) for occupants involved in MVCs. This was a retrospective cohort study using a national population-based cohort of adult front-seat occupants involved in MVCs and included in the National Automotive Sampling System Crashworthiness Data System database from 1995 to 2006. The primary outcome was serious injury, defined as an abbreviated injury scale (AIS) score >/=3 in any body region. Anatomic injury patterns were also assessed by age. One hundred thousand one hundred and fifty-six adult front-seat occupants were included in the analysis, of which 14,128 (2%) were seriously injured. Age was a strong predictor of serious injury using a variety of different age covariates (categorical, continuous, and polynomial) in multivariable regression models (p<0.0001 for all). There was evidence of a strong non-linear relationship between age and serious injury (p<0.001 for comparison of non-linear to linear representation of age). There was no age that clearly defined an "older" occupant by injury risk, as the odds of injury increased with increasing age across all age groups. The proportion of serious head and extremity injuries gradually increased with increasing age, while serious chest injuries markedly increased after 60 years. Age is a strong predictor of serious injury from motor vehicle trauma, the risk of which increases in non-linear fashion as age increases. There is no specific age that clearly defines an "older" occupant by injury risk.


Hybridomas specific for carbohydrates; synthetic human blood group antigens for the production, selection, and characterization of monoclonal typing reagents.
A general method for the production of carbohydrate-specific hybridoma antibodies is illustrated by generation of monoclonal antibody to the antigenic determinant of human blood group B. This trisaccharide determinant was chemically synthesized and covalently coupled to bovine serum albumin and human blood group O red cells. Soluble protein antigen and the 'artificial' B red cells were used to immunize BALB/c mice before fusion of spleen cells with the Sp2/0 plasmacytoma cell line. ELISA screening of putative hybrids for B-specific binding activity was facilitated by the availability of a second synthetic conjugate, B-horse hemoglobin. IgM-producing clones were identified by class-specific ELISA reagents and by hemagglutination assay. In this way, clones suitable for blood typing were rapidly identified. The precise antigenic specificity and Ig class of such monoclonal antibodies were defined by inhibition of precipitation and by gel filtration. Hybridoma antibodies were obtained from two separate fusion experiments. One of these, clone 3E-4, was of the IgM class and possessed a binding site that was completely satisfied (100% inhibition) by the trisaccharide determinant of the B blood group. This antibody is shown to be suitable for use in blood typing.


Identification of new process-related impurity in the key intermediate in the synthesis of TCV-116.
Development of safe and effective drugs requires complete impurity evaluation and, therefore, knowledge about the formation and elimination of impurities is necessary. During impurity profiling of a key intermediate during synthesis of candesartan cilexetil (1-(((cyclohexyloxy)carbonyl) oxy)ethyl 1-((2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate, TCV-116), a novel compound, which had not been reported previously, was observed. Structural elucidation of impurity was achieved by liquid chromatography hyphenated to different high resolution mass analyzers. Based on exact mass measurements and fragmentation pattern, a chloro alkyl carbonate ester analogue of the intermediate was identified. Structure of the impurity was confirmed by mass spectro-metric and NMR analyses of the target substance. Identified impurity could represent a hazard if it is transferred to the final API stage and its presence should be kept below allowed limits. Further investigation could reveal whether bis(1-chloroethyl) carbonate is a precursor to impurity formation. Therefore, synthesis should be regulated so as to minimize impurity production. Analysis of the final product indicated that the amount of impurity did not exceed 50 mg L-1, which represents the detection limit, determined according to the signal/noise ratio.


Modified desensitization protocols for a pediatric patient with anaphylactic reaction to deferoxamine.
Thalassemia major is an inherited form of chronic hemolytic anemia that results in iron overload due to regular blood transfusions. Deferoxamine is used as chelating agentfor treatment ofpatients with chronic iron overload worldwide. Anaphylactic reaction to deferoxamine is rare, and the mechanism ofdeferoxamine-induced anaphylaxis is not well understood. Only afewpediatric cases ofsuccessful desensitization for deferoxamine hypersensitivity have been described, and a different protocol has been used in each report. We report a case ofanaphylaxis to deferoxamine in a thirteen-years-old Thai boy with Hemoglobin E/β-thalassemia disease who underwent successful desensitization. He had been receiving blood transfusions since the age often months. At age eleven, the patient began treatment with deferoxamine. Treatment was interrupted after the occurrence ofanaphylaxis, with urticaria, wheezing and gastrointestinal symptoms. A skin prick test was positive, indicating a type 1 hypersensitivity reaction. Deferoxamine desensitization was attempted with various differentprotocols. Finally, the patient could tolerate deferoxamine therapy at the dose previously administered. We proposed this modified subcutaneous desensitization protocolforpediatric cases that develop allergic reactions to deferoxamine.


Glycosyl-phosphatidylinositol-phospholipase type D: a possible candidate for the generation of second messengers.
Membrane associated glycosyl-phosphatidylinositols have been shown to be the precursors of inositol phosphoglycan second messengers. Extraction of human liver membranes and purification by serial thin layer chromatography revealed three glycolipids which co-migrated with glycosyl-phosphatidylinositol from rat liver. These lipidic fractions were partially sensitive to treatment with nitrous acid and to hydrolysis by glycosyl-phosphatidylinositol-specific phospholipase D from bovine serum. In parallel, glycosyl-phosphatidylinositol isolated from rat liver was found to be a substrate for the enzyme generating a biologically active inositol phosphoglycan species (determined by measuring inhibition of protein kinase A activity and stimulation of cell proliferation within the chicken embryo cochleovestibular ganglion). This molecule was recognised by an anti-inositol phosphoglycan antibody. Hence, we propose that glycosyl-phosphatidylinositol-specific phospholipase D could be implicated in cellular signalling.


[Is second course intravesical Bacillus Calmette-Guerin therapy for recurrent carcinoma in situ of the bladder useful?].
We evaluated the usefulness of second course intravesical bacillus Calmette-Guerin (BCG) therapy for carcinoma in situ (CIS) of the bladder that failed to respond to the initial BCG therapy. Between January 1995 and December 2000, 185 patients with CIS of the bladder underwent an initial 6- or 8-week course of intravesical BCG instillation with an average follow-up period of 40.9 months (range: 3.8 to 94.8 months). Of the 185 patients, 160 (86.5%) completely responded to an initial course of BCG therapy. During follow up, 49 (30.6%) of the complete responders had recurrent transitional cell carcinoma. Overall, 9 (36.0%) of the 25 patients who did not respond completely to the initial 6- or 8-week course of BCG therapy and 22 (44.9%) of the 49 who had recurrent tumor after initial complete response, a total of 31 patients received the second course intravesical BCG therapy. Of the 9 incomplete responders, 8 (88.9%) achieved a complete response after the second course BCG therapy. With an average follow-up period of 39.6 months (range: 2.8 to 62.2 months), 2 (22.2%) of the 8 had recurrence. On the other hand, 17 (77.3%) of the 22 with recurrent tumor after the initial complete response developed recurrence with an average follow-up period of 14.1 months (range: 2.8 to 55.2 months). Seven (31.8%) of the 17 patients had disease progression to muscle invasion. Subsequently, cystectomy was done in 10 (58.8%) and radiation in 1 (5.9%). Our results suggest that a selected group of incomplete responders with initial BCG therapy may benefit from continued second course BCG. However, in patients who had recurrence after initial BCG success, the benefits of second course BCG therapy are limited. Careful surveillance and aggressive therapy on optimal timing are mandatory.


Real-space refinement with DireX: from global fitting to side-chain improvements.
Single-particle cryo-electron microscopy (cryo-EM) has become an important tool to determine the structure of large biomolecules and assemblies thereof. However, the achievable resolution varies considerably over a wide range of about 3.5-20 Å. The interpretation of these intermediate- to low-resolution density maps in terms of atomic models is a big challenge and an area of active research. Here, we present our real-space structure refinement program DireX, which was developed primarily for cryo-EM-derived density maps. The basic principle and its main features are described. DireX employs Deformable Elastic Network (DEN) restraints to reduce overfitting by decreasing the effective number of degrees of freedom used in the refinement. Missing or reduced density due to flexible parts of the protein can lead to artifacts in the structure refinement, which is addressed through the concept of restrained grouped occupancy refinement. Furthermore, we describe the performance of DireX in the 2010 Cryo-EM Modeling Challenge, where we chose six density maps of four different proteins provided by the Modeling Challenge exemplifying typical refinement results at a large resolution range from 3 to 23 Å.


The protein tyrosine kinase P59fyn is associated with prolactin (PRL) receptor and is activated by PRL stimulation of T-lymphocytes.
The clonal expansion of antigen-stimulated T-lymphocytes during an immune response is mediated by several lymphokines. Strong evidence now exists that the neuroendocrine hormone PRL is necessary, but not sufficient, for T-cell proliferation. Little is known, however, of the signal transduction mechanisms of the PRL receptor (PRLR) within T-cells. We demonstrate here that PRL stimulation of the T-cell line Nb2 induced the concentration- and time-dependent activation of the protein tyrosine kinase p59fyn, but not of four other src family protein tyrosine kinases. Activation of fyn was also observed in Concanavalin-A-primed peripheral blood lymphocytes stimulated with PRL and in Nb2 cells incubated with anti-PRLR antibodies. The activation of fyn by PRL stimulation correlated with Nb2 cell proliferation. Immunoblot analysis of anti-fyn and anti-PRLR immune complexes revealed an association between each PRLR isoform and p59fyn. These studies demonstrate for the first time an association between the PRLR and a src family protein tyrosine kinase affiliated with signal transduction.


Quantitative phosphoproteomic analyses of the inferior parietal lobule from three different pathological stages of Alzheimer's disease.
Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is clinically characterized by progressive neuronal loss resulting in loss of memory and dementia. AD is histopathologically characterized by the extensive distribution of senile plaques and neurofibrillary tangles, and synapse loss. Amnestic mild cognitive impairment (MCI) is generally accepted to be an early stage of AD. MCI subjects have pathology and symptoms that fall on the scale intermediately between 'normal' cognition with little or no pathology and AD. A rare number of individuals, who exhibit normal cognition on psychometric tests but whose brains show widespread postmortem AD pathology, are classified as 'asymptomatic' or 'preclinical' AD (PCAD). In this study, we evaluated changes in protein phosphorylation states in the inferior parietal lobule of subjects with AD, MCI, PCAD, and control brain using a 2-D PAGE proteomics approach in conjunction with Pro-Q Diamond phosphoprotein staining. Statistically significant changes in phosphorylation levels were found in 19 proteins involved in energy metabolism, neuronal plasticity, signal transduction, and oxidative stress response. Changes in the disease state phosphoproteome may provide insights into underlying mechanisms for the preservation of memory with expansive AD pathology in PCAD and the progressive memory loss in amnestic MCI that escalates to the dementia and the characteristic pathology of AD brain.


Quantification of motor slowness in Parkinson's disease: Correlations between the tapping test and single joint ballistic movement parameters.
The tapping test is used routinely for the quantification of drug effects on motor slowness in Parkinson's disease (FD). This test has not been validated previously using reference methods measuring kinematic parameters of movement. We compared and correlated modifications of the tapping score induced by levodopa with that of kinematic parameters of a single joint ballistic movement in 10 PD patients. Results demonstrate that the modification of the tapping score correlates with the bradykinetic, but not the akinetic, component of motor slowness in PD. Also analyzed are the sensitivity and specificity of different thresholds of the increment of the tapping score for the detection of modifications in amplitude, velocity and acceleration. Using a tapping score threshold of positivity between 10 and 20% of increase, the sensitivity and specificity to detect significant modifications in velocity is 100%.


Association of four HLA class III region genomic markers with HLA haplotypes.
We have studied restriction fragment length polymorphism (RFLP) in the region 300 kb centromeric to the HLA-B locus. Four probes were used: one was genomic DNA derived from the tumor-necrosis factor (TNF)-beta gene, one was a cDNA for the BAT3 gene, and two single-copy genomic probes, R5A and M20A. The order of these markers from HLA-B towards the centromere is M20A, R5A, TNF and BAT3. The BAT3 and TNF-beta probes each detected two allelic bands with Taq I and Nco I digestion, respectively; the R5A and M20A probes each detected three polymorphic allelic bands with BstEII digestion. To determine if these restriction polymorphisms are preferentially associated with certain HLA-B and -DR haplotypes, a total of 153 HLA haplotypes was analyzed. The haplotypes A1, B8, DR3 and A3, B7, DR2 were each associated with a distinct combination of polymorphisms identified at these four sites, thereby demonstrating that the strong linkage disequilibrium characteristic of these haplotypes extends also to this segment of the class III region. In contrast, haplotypes that are not in positive linkage disequilibrium, such as A1,B8,DR4 and A2,B7,DR3, showed no preferential association with any of these polymorphisms. The antigens HLA-B27 and B35 were also found to be in positive linkage disequilibrium with RFLP patterns at three of these sites, and HLA-B14,B35,B44,Bw57 and Bw62 were found preferentially associated with polymorphisms at one or two of these sites, independent of the DR antigen present. These data further demonstrate that genetic linkage disequilibrium in the HLA class III region is complex and variable among different HLA haplotypes.


Advancing Analytic Approaches to Address Key Questions in Mechanisms of Behavior Change Research.
Interest in studying mechanisms of behavior change (MOBCs) in substance use disorder (SUD) treatments has grown considerably in the past two decades. Much of this work has focused on identifying which variables statistically mediate the effect of SUD treatments on clinical outcomes. However, a fuller conceptualization of MOBCs will require greater understanding of questions that extend beyond traditional mediation analysis, including better understanding of when MOBCs change during treatment, when they are most critical to aiding the initiation or maintenance of change, and how MOBCs themselves arise as a function of treatment processes. In the present study, we review why these MOBC-related questions are often minimally addressed in empirical research and provide examples of data analytic methods that may address these issues. We highlight several recent studies that have used such methods and discuss how these methods can provide unique theoretical insights and actionable clinical information. Several statistical approaches can enhance the field's understanding of the timing and development of MOBCs, including growth-curve modeling, time-varying effect modeling, moderated mediation analysis, dynamic systems modeling, and simulation methods. Adopting greater diversity in methods for modeling MOBCs will help researchers better understand the timing and development of key change variables and will expand the theoretical precision and clinical impact of MOBC research. Advances in research design, measurement, and technology are key to supporting these advances.


Exploring the lecturer/practitioner role: individuals perceptions of the lived experience.
This study explored the individual experiences of lecturer practitioners during the development of their role while on secondment to a university. The method was an inductive approach influenced by phenomenology using a sample of six qualified nurses fro m a variety of clinical backgrounds in both the community or hospital settings. Data from the unstructured interviews was collected, recorded and analysed using Burnard's method of Thematic Content Analysis (Burnard 1991). Common themes emerged highligh ting the positive and negative aspects of the lecturer practitioner role; expectations, support, credibility, time-management, and contractual issues. The findings will assist with future role development in the university, provide information for other universities and Trusts considering introduction and development of the role as well as individuals who may be interested in taking up the challenge of the lecturer practitioner post.


The dynamically evolving nematocyst content of an anthozoan, a scyphozoan, and a hydrozoan.
Nematocytes, the stinging cells of cnidarians, are the most evolutionarily ancient venom apparatus. These nanosyringe-like weaponry systems reach pressures of approximately 150 atmospheres before discharging and punching through the outer layer of the prey or predator at accelerations of more than 5 million g, making them one of the fastest biomechanical events known. To gain better understanding of the function of the complex, phylum-specific nematocyst organelle, and its venom payload, we compared the soluble nematocyst's proteome from the sea anemone Anemonia viridis, the jellyfish Aurelia aurita, and the hydrozoan Hydra magnipapillata, each belonging to one of the three basal cnidarian lineages which diverged over 600 Ma. Although the basic morphological and functional characteristics of the nematocysts of the three organisms are similar, out of hundreds of proteins identified in each organism, only six are shared. These include structural proteins, a chaperone which may help maintain venon activity over extended periods, and dickkopf, an enigmatic Wnt ligand which may also serve as a toxin. Nevertheless, many protein domains are shared between the three organisms' nematocyst content suggesting common proteome functionalities. The venoms of Hydra and Aurelia appear to be functionally similar and composed mainly of cytotoxins and enzymes, whereas the venom of the Anemonia is markedly unique and based on peptide neurotoxins. Cnidarian venoms show evidence for functional recruitment, yet evidence for diversification through positive selection, common to other venoms, is lacking. The final injected nematocyst payload comprises a mixture of dynamically evolving proteins involved in the development, maturation, maintenance, and discharge of the nematocysts, which is unique to each organism and potentially to each nematocyst type.


[Interstitial pneumonia in bone marrow transplantation. Preventive and therapeutic aspects. Our experience and review of the literature].
From June/82 through November/85 bone marrow transplant recipients in our Institution were given only trimethoprim-sulfamethoxazole as prophylaxis against interstitial pneumonia. In December/85 we began a program of administration of passive immunoprophylaxis with hyperimmune plasma or cytomegalovirus-specific gamma globulin and transfusion of seronegative blood products to all bone marrow transplant recipients whether they were seropositive or seronegative prior to transplant. Nine of 36 patients in the historical control group and 9 of 32 patients in the study group developed an interstitial pneumonia. Interstitial pneumonia, once established, was treated empirically. The 9 patients in the control group received trimethoprim-sulfamethoxazole +/- adenine arabinoside, acyclovir, amphotericin B and anti-bacterial antibiotics; all died. Post-mortem study was performed in 7 (4 CMV, 3 idiopathic). The 9 patients in the study group received high dose cytomegalovirus-specific gamma globulin + acyclovir or ganciclovir in addition to the above measures. Four were cured, one relapsed and responded to treatment again. Five died (1 CMV, 1 candida, 3 idiopathic). We conclude that the prophylactic measures, as applied at our Institution, were inefficient. By contrast, therapy with specific immunoglobulin + acyclovir or ganciclovir can control a high percentage of patients. We compare this experience with reports from other centers.


ARL6IP1 mediates cisplatin-induced apoptosis in CaSki cervical cancer cells.
Cisplatin has been shown to induce apoptosis in various types of cancer cells. Despite the great efficacy at treating certain kinds of cancers, cisplatin introduced into clinical use shows side effects and the acquisition or presence of resistance to the drug. Thus, it is important that we further understand the anti-cancer mechanism of cisplatin with the goal of enhancing its efficacy. ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1) is an apoptotic regulator. We studied cisplatin-induced apoptosis with suppression of ARL6IP1 expression in CaSki cervical cancer cells. Exogenous expression of ARL6IP1 suppressed cisplatin-induced apoptosis in CaSki cells, and siRNA-induced silencing of ARL6IP1 triggered apoptosis in CaSki cells even in the absence of other apoptotic stimuli. Cisplatin treatment induced caspase-3, -9, p53, Bax, NF-kappaB and MAPK expression, and suppressed Bcl-2 and Bcl-xl expression, whereas cells transfected with pcDNA3.1-ARL6IP1 showed lower levels of cisplatin-induced caspase-3, -9, p53, Bax, NF-kappaB and MAPK up-regulation and higher levels of cisplatin-suppressed Bcl-2 and Bcl-xl down-regulation. These novel findings collectively suggest that ARL6IP1 may play a key role in cisplatin-induced apoptosis in CaSki cervical cancer cells by regulating the expression of apoptosis-associated proteins such as caspase-3, -9, p53, NF-kappaB, MAPK, Bcl-2, Bcl-xl, and Bax.


Counterimmunoelectrophoresis for the diagnosis of bovine mycoplasmosis.
Counterimmunoelectrophoresis (CIE) procedure has been established for mycoplasma identification from cultures, and the specificity and the sensitivity of this technique were evaluated. Preparations of milk samples and clinical and necropsy specimens were used for the technique. From 171 milk samples, 80 (46.8%) were positive by CIE (73 samples with Mycoplasma bovis and 7 with Mycoplasma arginini) and 77 (45%) were positive by biochemical and growth inhibition tests (70 samples with Mycoplasma bovis and 7 with Mycoplasma arginini). From 36 mycoplasma culture-positive clinical and necropsy specimens, CIE identified 5 different mycoplasma species and from 3 mycoplasma culture-positive specimens, the technique identified coinfection by 2 mycoplasma species. The CIE is a reliable, specific, sensitive, and rapid technique for the diagnosis of mycoplasmosis in the bovine.


Importance of hybridization between indigenous and nonindigenous freshwater species: an overlooked threat to North American biodiversity.
Biodiversity of North American freshwaters is among the greatest in the world. However, due to extensive habitat degradation, pollution, and introductions of nonindigenous species, this biodiversity is also among the most endangered. Unlike habitat degradation and pollution, nonindigenous species represent a permanent loss of biodiversity because their removal or control is often impossible. Most species introduced into nonnative North American ranges, however, are not from Eurasia but have been introduced from geographically isolated regions within North America. Although the ecological effects of introduced species have been widely documented, the effects of hybridization, especially between closely related species, represents an equally serious mechanism of extinction but is much less studied. Identification of which species are likely to hybridize after contact is of critical importance to prevent the further loss of native species. Molecular phylogenetics serves as a powerful tool to identify freshwater species at risk of introgression, if we can assume that genetic distance is a good predictor of the potential for hybridization. Although not a thorough review of all cases of hybridization, this article documents the extent and effects of hybridization in fishes, crayfishes, mussels, and other invertebrates in light of the currently accepted phylogenetic relationships. We suggest this approach may be the first step in addressing the potential threat of hybridization between many of the closely related species in North American fresh waters.


Serum immunoglobulins in multiple pregnancy.
The concentrations of immunoglobulins (Ig) G.A.M. and E were determined in paired umbilical cord and maternal sera in 50 twin pregnancies. Mean IgG levels were higher in cord than maternal sera and in most cases the cord IgG level related more closely to that of the other twin than to either maternal level or birthweight, and was in the range for singletons of the same gestational age. The three cases of fetofetal transfusion syndrome were exceptional in the large difference between IgG concentrations in recipient and donor twins. The discrepancy was much greater than that found between the levels of proteins produced by the fetus, suggesting a disturbance in maternofetal placental transfer. IgM was detected in all cord sera, with one exception, and the level was not related to order of birth. IgA was detected in 16% of cord sera, 13% in sera from first borns. IgE was detected in only 8% of cord sera and there was no evidence of placental transfer.


Longitudinal assessment of health related quality of life of HIV infected patients treated for tuberculosis and HIV in a high burden setting.
Assessment of patients receiving treatment for human immunodeficiency virus (HIV) and tuberculosis (TB) using a Health Related Quality of Life (HRQoL) instrument is important to get the subjective view of the patients' wellbeing. We used the Functional Assessment of HIV Infection (FAHI) HRQoL instrument to collect perceived wellness information at baseline, month 3, 6 and 12 from patients enrolled in a pharmacokinetic study between March 2007 and April 2008. Composite domain scores at each time point and their relationship with the rate of adverse events (AEs) and serious adverse events were compared between treatment arms. Out of the 82 patients enrolled, 76 were analysed. There was a significant increase in total score in all groups between baseline, month 3, 6 and 12 (all p values < 0.0001), and over time (p < 0.001). Adjusting for baseline total score, baseline CD4 count had a significant effect on the total score over time (p = 0.002) and the rate of change in total score over time, that is; interaction effect (p < 0.001). There was no difference in each domain scores between participants that received ART with TB treatment and those that received TB treatment only. Respiratory AEs had a significant effect on HRQoL. We found that assessment of HRQoL of participants in TB-HIV treatment using the FAHI instrument was useful in evaluating treatment responses. It showed improvement consistent with decrease in adverse events and signs and symptoms of TB. Number and type of AEs was related to lower HRQoL in spite of TB cure.


The rationality of illusory correlation.
When presented with 2 samples (a smaller sample from a Minority population and a larger sample from a Majority population), where some rare or frequent features occur at exactly the same rate in both samples, people reliably associate the rare feature with the Minority population and the frequent feature with the Majority population. This pattern is referred to as "illusory correlation," reflecting the standard assumption that such associations are fundamentally irrational. In this article we show that this assumption is incorrect, and demonstrate that this pattern of association linking rare features with the Minority and frequent features with the Majority (given a sample where those features occurred at the same proportion in both categories, and no further information) is in fact correct and follows a result in epistemic probability theory known as the "Rule of Succession." Building on this result, we present a new computational model of frequency-based illusory correlation, based on the Rule of Succession. We also discuss the implications of the Rule of Succession for our understanding of various other cognitive biases. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation.
Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is a key process in several pathological conditions, including tumour growth and age-related macular degeneration. Vascular endothelial growth factors (VEGFs) stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells. VEGFR-3 (also known as FLT-4) is present in all endothelia during development, and in the adult it becomes restricted to the lymphatic endothelium. However, VEGFR-3 is upregulated in the microvasculature of tumours and wounds. Here we demonstrate that VEGFR-3 is highly expressed in angiogenic sprouts, and genetic targeting of VEGFR-3 or blocking of VEGFR-3 signalling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching and endothelial cell proliferation in mouse angiogenesis models. Stimulation of VEGFR-3 augmented VEGF-induced angiogenesis and sustained angiogenesis even in the presence of VEGFR-2 (also known as KDR or FLK-1) inhibitors, whereas antibodies against VEGFR-3 and VEGFR-2 in combination resulted in additive inhibition of angiogenesis and tumour growth. Furthermore, genetic or pharmacological disruption of the Notch signalling pathway led to widespread endothelial VEGFR-3 expression and excessive sprouting, which was inhibited by blocking VEGFR-3 signals. Our results implicate VEGFR-3 as a regulator of vascular network formation. Targeting VEGFR-3 may provide additional efficacy for anti-angiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR-2 inhibitors.


The metabolic syndrome: metabolic changes with vascular consequences.
Despite criticism regarding its clinical relevance, the concept of the metabolic syndrome improves our understanding of both the pathophysiology of insulin resistance and its associated metabolic changes and vascular consequences. Free fatty acids (FFA) and tumour necrosis factor-alpha (TNF-alpha) play prominent roles in the development of insulin resistance by impairing the intracellular insulin signalling transduction pathway. Obesity is an independent risk factor for cardiovascular disease and strongly related to insulin resistance. In case of obesity, FFAs and TNF-alpha are produced in abundance by adipocytes, whereas the production of adiponectin, an anti-inflammatory adipokine, is reduced. This imbalanced production of pro- and anti-inflammatory adipokines, as observed in adipocyte dysfunction, is thought to be the driving force behind insulin resistance. The role of several recently discovered adipokines such as resistin, visfatin and retinol-binding protein (RBP)-4 in the pathogenesis of insulin resistance is increasingly understood. Insulin resistance induces several metabolic changes, including hyperglycaemia, dyslipidaemia and hypertension, all leading to increased cardiovascular risk. In addition, the dysfunctional adipocyte, reflected largely by low adiponectin levels and a high TNF-alpha concentration, directly influences the vascular endothelium, causing endothelial dysfunction and atherosclerosis. Adipocyte dysfunction could therefore be regarded as the common antecedent of both insulin resistance and atherosclerosis and functions as the link between obesity and cardiovascular disease. Targeting the dysfunctional adipocyte may reduce the risk for both cardiovascular disease and the development of type 2 diabetes. Although lifestyle intervention remains the cornerstone of therapy in improving insulin sensitivity and its associated metabolic changes, medical treatment might prove to be important as well.


Quantal mechanism of long-term potentiation in hippocampal mossy-fiber synapses.
1. The quantal mechanism underlying the expression of long-term potentiation (LTP) was studied in the mossy-fiber (mf) synapses of the rat hippocampus. Whole-cell recordings were used to measure the excitatory postsynaptic currents (EPSCs) before and after LTP induction in brain slices maintained at 31 +/- 1 degrees C. 2. Evoked EPSCs were recorded from 473 CA3 pyramidal neurons. The mf synapses were stimulated using paired pulses (40-ms interpulse interval) repeated every 2-10 s. At least 400 pairs of mf responses were obtained before and during the expression of LTP, which was produced by high-frequency (100 Hz) mf stimulation. Sufficiently stationary data were obtained from five neurons that exhibited LTP and that also satisfied strict criteria and procedures that are necessary for eliciting and identifying unitary mf responses. 3. Three independent lines of evidence implicated a presynaptic component to the mechanism underlying mf LTP. The first was based on a graphical version of the classical method of variance. The graphical variance (GV) method was evaluated by clamping the cell at two different holding potentials during paired-pulse facilitation (PPF). The results indicated that the GV method can distinguish changes in mean quantal content m and mean quantal size q in rat mf synapses. The same analysis, when applied to PPF before and after LTP induction, indicated that both result from an increase in m. 4. The second line of evidence was based on the classical method of failures. Consistent with the inference that mf LTP is due to an increase in m, there was a statistically significant reduction in the number of quantal release failures.(ABSTRACT TRUNCATED AT 250 WORDS)


Current and emerging options for taxol production.
Paclitaxel (trademark "Taxol") is a plant-derived isoprenoid natural product that exhibits potent anticancer activity. Taxol was originally isolated from the Pacific yew tree in 1967 and triggered an intense scientific and engineering venture to provide the compound reliably to cancer patients. The choices available for production include synthetic and biosynthetic routes (and combinations thereof). This chapter focuses on the currently utilized and emerging biosynthetic options for Taxol production. A particular emphasis is placed on the biosynthetic production hosts including macroscopic and unicellular plant species and more recent attempts to elucidate, transfer, and reconstitute the Taxol pathway within technically advanced microbial hosts. In so doing, we provide the reader with relevant background related to Taxol and more general information related to producing valuable, but structurally complex, natural products through biosynthetic strategies.


[Giant right adrenal myelolipoma].
Adrenal myelolipoma is a rare benign tumor, well limited, variable in size, composed of fatty and hematopoietic tissues, the finding of which is usually incidental. If they reach a big size they may produce the feeling of abdominal mass, pain, neighbour organs compression and acute intratumoral or retroperitoneal hemorrhage. We report the case of a 57-year-old male admitted to the hospital with acute abdominal pain. CT scan with i.v. contrast and adrenal biopsy were performed. Radiological findings: 9 x 10 cm right adrenal mass, well defined, hypodense, with a small calcification in its posterior area. Pathologic findings: benign tumor, encapsulated, with a mixture of mature fatty tissue and hematopoietic cells. The presence of fat within an adrenal mass is essential for the diagnosis. Differential diagnosis should be done with all adrenal tumors with a fat component. When no radiological diagnosis is made, pathologic confirmation is necessary.