Metabolism and toxicity of 2-methylpropene (isobutene)--a review.
2-Methylpropene (MP) or isobutene is a gaseous chemical used on a large scale in the synthetic rubber industry. The present review covers the rather scarce literature on MP with respect to its metabolic fate and toxicity in laboratory animals and humans. It has been shown both in vivo and in vitro that MP is metabolized to the primary metabolite 2-methyl-1,2-epoxypropane (MEP) by rodent and human liver tissue. The formation of this reactive epoxide intermediate is catalyzed by CYP2E1, while epoxide hydrolase and glutathione S-transferase appear to be involved in its inactivation. In rats, the capacity to absorb and metabolize MP is saturable. MP is oxidized to compounds that are mainly excreted in urine. Data indicate that rodents can tolerate low levels of MP without apparent toxicity. The primary metabolite MEP, however, is able to produce genetic damage in both prokaryotic and eukaryotic cells in vitro. MP is thus not toxic per se but elicits metabolic activation to become potentially harmful. Consequently, the balance between formation and detoxification of MEP plays a key role in determining the potential toxicity of the parent compound. Obviously, further research, including repeated exposure toxicity studies, is required before an estimation of the risk for man can be made.


Telemedicine for pathology.
Telemedicine for pathology, this is pathology in which the specimen is digitally transmitted and examined by a pathologist at a distance. In another words, telemedicine for pathology, or simply telepathology, is a branch of telemedicine and pathology that consists in the exchange of pathology images through telecommunication with the purposes of diagnosis, consultation, research and/or education. The use of telepathology is of great importance in management of patients since it allows fast diagnosis and inter-consultations among specialist pathologists located in every part of the world.


The pedagogic evolution in Surgery: the University at the centre of a training which becomes territorialized The model of the region Marche.
We want to show a new organisational model of General Surgery training, in act in Università Politecnica delle Marche, which sees its strength in the territorial formative network. In our Athenaeum, this organization is not a recent realization, but the firsts to have benefited completely of this system are the four residents who have completed the General Surgery formation in March 2014, for this reason we report their experience. The four residents benefited of the two years in the peripheral structures, two also performed a period in a foreign country, two chose to spend other 6 months in the peripheral structure to prepare the thesis of specialization; surgical activity has been, for each resident, of 400 interventions on average as first operator (237-476) distributed in great surgery 44 (13-80), middle 172 (129-268) and small 209 (70-378). The Formative NETWORK becomes an essential strength at the service of the academic world, the network foresees a continuous update, it can be easily standardized for every resident and it doesn't raise barriers to the foreign countries experiences. With the purpose to conform the model of specialistic formation in General Surgery, we propose a new tailored italian organizational model, tested the lasts 6 years, which seems to give good results and conform to the european standard of surgical training. Formative network, General Surgery, Resident, Training.


Transport properties of carbon dioxide and methane from molecular dynamics simulations.
Transport properties of carbon dioxide and methane are predicted for temperatures between (273.15 and 573.15) K and pressures up to 800 MPa by molecular dynamics simulations. Viscosities and thermal conductivities were obtained through the Green-Kubo formalism, whereas the Einstein relation was used to provide self-diffusion coefficient estimates. The differences in property predictions due to the force field nature and parametrization were investigated by the comparison of seven different CO2 models (two single-site models, three rigid three-site models, and two fully flexible three-site models) and three different CH4 models (two single-site models and one fully flexible five-site model). The simulation results show good agreement with experimental data, except for thermal conductivities at low densities. The molecular structure and force field parameters play an important role in the accuracy of the simulations, which is within the experimental deviations reported for viscosities and self-diffusion coefficients considering the most accurate CO2 and CH4 models studied. On the other hand, the molecular flexibility does not seem to improve accuracy, since the explicit account of vibrational and bending degrees of freedom in the CO2 flexible models leads to slightly less accurate results. Nonetheless, the use of a correctional term to account for vibrational modes in rigid models generally improves estimations of thermal conductivity values. At extreme densities, the caging effect observed with single-site representations of the molecules restrains mobility and leads to an unphysical overestimation of viscosities and, conversely, to the underestimation of self-diffusion coefficients. This result may help to better understand the limits of applicability of such force fields concerning structural and transport properties of dense systems.


Leprosy at the edge of Europe-Biomolecular, isotopic and osteoarchaeological findings from medieval Ireland.
Relatively little is known of leprosy in Medieval Ireland; as an island located at the far west of Europe it has the potential to provide interesting insights in relation to the historical epidemiology of the disease. To this end the study focuses on five cases of probable leprosy identified in human skeletal remains excavated from inhumation burials. Three of the individuals derived from the cemetery of St Michael Le Pole, Golden Lane, Dublin, while single examples were also identified from Ardreigh, Co. Kildare, and St Patrick's Church, Armoy, Co. Antrim. The individuals were radiocarbon dated and examined biomolecularly for evidence of either of the causative pathogens, M. leprae or M. lepromatosis. Oxygen and strontium isotopes were measured in tooth enamel and rib samples to determine where the individuals had spent their formative years and to ascertain if they had undertaken any recent migrations. We detected M. leprae DNA in the three Golden Lane cases but not in the probable cases from either Ardreigh Co. Kildare or Armoy, Co. Antrim. M. lepromatosis was not detected in any of the burals. DNA preservation was sufficiently robust to allow genotyping of M. leprae strains in two of the Golden Lane burials, SkCXCV (12-13th century) and SkCCXXX (11-13th century). These strains were found to belong on different lineages of the M. leprae phylogenetic tree, namely branches 3 and 2 respectively. Whole genome sequencing was also attempted on these two isolates with a view to gaining further information but poor genome coverage precluded phylogenetic analysis. Data from the biomolecular study was combined with osteological, isotopic and radiocarbon dating to provide a comprehensive and multidisciplinary study of the Irish cases. Strontium and oxygen isotopic analysis indicate that two of the individuals from Golden Lane (SkCXLVIII (10-11th century) and SkCXCV) were of Scandinavian origin, while SkCCXXX may have spent his childhood in the north of Ireland or central Britain. We propose that the Vikings were responsible for introducing leprosy to Ireland. This work adds to our knowledge of the likely origins of leprosy in Medieval Ireland and will hopefully stimulate further research into the history and spread of this ancient disease across the world.


Exclusive dependence of IL-10Rα signalling on intestinal microbiota homeostasis and control of whipworm infection.
The whipworm Trichuris trichiura is a soil-transmitted helminth that dwells in the epithelium of the caecum and proximal colon of their hosts causing the human disease, trichuriasis. Trichuriasis is characterized by colitis attributed to the inflammatory response elicited by the parasite while tunnelling through intestinal epithelial cells (IECs). The IL-10 family of receptors, comprising combinations of subunits IL-10Rα, IL-10Rβ, IL-22Rα and IL-28Rα, modulates intestinal inflammatory responses. Here we carefully dissected the role of these subunits in the resistance of mice to infection with T. muris, a mouse model of the human whipworm T. trichiura. Our findings demonstrate that whilst IL-22Rα and IL-28Rα are dispensable in the host response to whipworms, IL-10 signalling through IL-10Rα and IL-10Rβ is essential to control caecal pathology, worm expulsion and survival during T. muris infections. We show that deficiency of IL-10, IL-10Rα and IL-10Rβ results in dysbiosis of the caecal microbiota characterised by expanded populations of opportunistic bacteria of the families Enterococcaceae and Enterobacteriaceae. Moreover, breakdown of the epithelial barrier after whipworm infection in IL-10, IL-10Rα and IL-10Rβ-deficient mice, allows the translocation of these opportunistic pathogens or their excretory products to the liver causing organ failure and lethal disease. Importantly, bone marrow chimera experiments indicate that signalling through IL-10Rα and IL-10Rβ in haematopoietic cells, but not IECs, is crucial to control worm expulsion and immunopathology. These findings are supported by worm expulsion upon infection of conditional mutant mice for the IL-10Rα on IECs. Our findings emphasize the pivotal and complex role of systemic IL-10Rα signalling on immune cells in promoting microbiota homeostasis and maintaining the intestinal epithelial barrier, thus preventing immunopathology during whipworm infections.


Experiences of Screening for Human Immunodeficiency Virus, Viral Hepatitis B, and Viral Hepatitis C Infections at a Hospital in Thailand: Test Utilization and Outcomes.
BACKGROUND To prevent the transmission of HIV and hepatitis B and C viruses, early detection is necessary; however, in the early stage, most infected people are symptomless. Screening for these infections should be targeted to certain clinical settings to increase the early detection rate. MATERIAL AND METHODS This retrospective study was conducted by analyzing data from patients' medical records to determine how the screening tests for these viral infections were utilized and what the clinical outcomes from the test utilization were. RESULTS From 11 676 collected records, the screening tests for HIV, HBV, and HCV infections were utilized in 871, 556, and 236 cases, respectively. The tests for HIV and HCV were utilized the most in people with chronic non-infectious diseases, while the test for HBV infection was utilized the most in pregnant women. The positive results of these tests were highly found in the group of patients with acute non-infectious diseases. HIV infection was newly detected in 1.38% of patients, and HBV and HCV infections were newly detected in 5.58% and 2.12%, respectively. CONCLUSIONS Screening for HIV and HBV infections was performed according to the guidelines of the national HIV and HBV programs. The Outpatient Department (OPD) and medical ward may be the most appropriate clinical settings for HIV screening because most patients are there and blood tests are often ordered there, too. The national programs helped slow the rates of HIV and HBV infections in this community.


Plasmodial pigmentation of placenta and outcome of pregnancy in West African mothers.
In a region where falciparum malaria is endemic and where pregnant women traditionally receive only curative treatment for parasitaemias and no chemoprophylaxis 65 placental biopsy specimens were examined histologically for malaria pigment. Twenty seven placentas had pigment, but parasitaemias had been diagnosed antenatally in only 12 of these women despite their frequent attendance at antenatal and other clinics. The incidence of parasitaemia in pregnant primigravidas was 17.7%, seven times greater than that in lactating primiparous mothers; pregnant primigravidas also had the highest incidence (67%) of pigmented placentas. First born babies with pigmented placentas had a mean (SD) birth weight of 2580 (260) g, significantly less than the 3150 (400) g of unaffected first babies. All babies weighing less than 2500 g at birth had pigmented placentas. Pigmentation was associated with parasitaemias in the second half of pregnancy, and, although some recovery from early parasitaemias may occur, the fetoplacental unit is inadequately protected by curative treatment alone. Chemoprophylaxis currently remains the procedure of choice.


Cyclic AMP and prostaglandins in periodontal disease.
Since inflamed gingiva contain significantly higher levels of endogenous PGs (8) and cAMP than normal gingiva and since exogenous PGs have been shown to stimulate endogenous cAMP synthesis in gingiva in vitro, we suggest that the increase in the endogenous cAMP levels found in the inflamed tissue may be attributable to the increase in endogenous PGs. Cyclic AMP has been reported to stabilize the lysosomal membranes of inflammatory cells; hence, the increase in cAMP formation in inflammation seems to be associated with an endogenous compensatory protective mechanism which is able to stop immune or allergic reactions (9, 10).


Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study.
Long-term follow-up of prospective studies comparing allogeneic transplantation to autologous transplantation in multiple myeloma is few and controversial. This is an update at a median follow-up of 96 months of the European Group for Blood and Marrow Transplantation Non-Myeloablative Allogeneic stem cell transplantation in Multiple Myeloma (NMAM)2000 study that prospectively compares tandem autologous/reduced intensity conditioning allogeneic transplantation (auto/RICallo) to autologous transplantation alone (auto). There are 357 myeloma patients up to age 69 years enrolled. Patients with an HLA-identical sibling were allocated to auto/RICallo (n = 108) and those without to auto alone (n = 249). At 96 months progression-free survival (PFS) and overall survival (OS) were 22% and 49% vs 12% (P = .027) and 36% (P = .030) with auto/RICallo and auto respectively. The corresponding relapse/progression rate (RL) was 60% vs 82% (P = .0002). Non-relapse mortality at 36 months was 13% vs 3% (P = .0004). In patients with the del(13) abnormality corresponding PFS and OS were 21% and 47% vs 5% (P = .026), and 31% (P = .154). Long-term outcome in patients with multiple myeloma was better with auto/RICallo as compared with auto only and the auto/RICallo approach seemed to overcome the poor prognostic impact of del(13) observed after autologous transplantation. Follow up longer than 5 years is necessary for correct interpretation of the value of auto/RICallo in multiple myeloma.


Ecophysiology of Chloromonas hindakii sp. nov. (Chlorophyceae), Causing Orange Snow Blooms at Different Light Conditions.
Slowly melting snowfields in mountain and polar regions are habitats of snow algae. Orange blooms were sampled in three European mountain ranges. The cysts within the blooms morphologically resembled those of Chloromonas nivalis (Chlorophyceae). Molecular and morphological traits of field and cultured material showed that they represent a new species, Chloromonas hindakii sp. nov. The performance of photosystem II was evaluated by fluorometry. For the first time for a snow alga, cyst stages collected in a wide altitudinal gradient and the laboratory strain were compared. The results showed that cysts were well adapted to medium and high irradiance. Cysts from high light conditions became photoinhibited at three times higher irradiances (600 µmol photons m-2 s-1) than those from low light conditions, or likewise compared to cultured flagellates. Therefore, the physiologic light preferences reflected the conditions in the original habitat. A high content of polyunsaturated fatty acids (about 60% of total lipids) and the accumulation of the carotenoid astaxanthin was observed. They are regarded as adaptations to cope with extreme environmental conditions of snow that include low temperatures, freeze-thaw cycles, and variable light intensity. The intraspecific ability of adaptation of the photosynthetic apparatus to different irradiance regimes seems to be advantageous for thriving in different snow habitats.


[Effect of weightlessness and hypokinesia on the velocity-strength properties of human muscles].
Before and after exposure to short- and long-term microgravity and prolonged bed rest velocity and strength parameters of leg muscles were measured by isokinetic dynamometry. It was found that long-term exposure to microgravity produced a more distinct decline of muscle strength than short-term exposure. At the same time prolonged bed rest led to greater strength losses than microgravity of comparable duration. After long-term flights individual variability of changes was twice as high as after prolonged bed rest. A comparable analysis of the above exposures demonstrated that the changes observed after long-duration exposures were associated with atrophic changes due to disuse while those seen after short-term effects were induced, as shown previously, by reflex tonic shifts related to support unloading.


The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells.
Glioblastomas (GBMs) maintain their cellular heterogeneity with glioma stem cells (GSCs) producing a variety of tumor cell types. Here we interrogated the oncogenic roles of Lim domain only 2 (LMO2) in GBM and GSCs in mice and human. High expression of LMO2 was found in human patient-derived GSCs compared with the differentiated progeny cells. LMO2 is required for GSC proliferation both in vitro and in vivo, as shRNA-mediated LMO2 silencing attenuated tumor growth derived from human GSCs. Further, LMO2 is sufficient to induce stem cell characteristics (stemness) in mouse premalignant astrocytes, as forced LMO2 expression facilitated in vitro and in vivo growth of astrocytes derived from Ink4a/Arf null mice and acquisition of GSC phenotypes. A subset of mouse and human GSCs converted into vascular endothelial-like tumor cells both in vitro and in vivo, which phenotype was attenuated by LMO2 silencing and promoted by LMO2 overexpression. Mechanistically, the action of LMO2 for induction of glioma stemness is mediated by transcriptional regulation of Jagged1 resulting in activation of the Notch pathway, whereas LMO2 directly occupies the promoter regions of the VE-cadherin gene for a gain of endothelial cellular phenotype. Subsequently, selective ablation of human GSC-derived VE-cadherin-expressing cells attenuated vascular formation in mouse intracranial tumors, thereby significantly prolonging mouse survival. Clinically, LMO2 expression was elevated in GBM tissues and inversely correlated with prognosis of GBM patients. Taken together, our findings describe novel dual roles of LMO2 to induce tumorigenesis and angiogenesis, and provide potential therapeutic targets in GBMs.


Peri- and Postpartum Management of Patients With Factor XI Deficiency.
Factor XI (FXI) deficiency is an uncommon autosomal disorder with variable bleeding phenotype, making peripartum management challenging. We describe our experience in pregnant women with FXI deficiency and identify strategies to minimize the use of hemostatic agents and increase utilization of neuraxial anesthesia. Electronic records of 28 pregnant women with FXI deficiency seen by a hematology service in an academic medical center from January 2006 to August 2018 were reviewed. Data on bleeding, obstetric history, peripartum management, and FXI activity were collected. Partial FXI deficiency was defined as >20 IU/dL and severe <20 IU/dL. Median FXI activity was 42 IU/dL (range <1-73 IU/dL), and median activated partial thromboplastin time was 32.2 seconds (range: 27.8-75 seconds). There were 64 pregnancies: 53 (83%) live births and 11 (17%) pregnancy losses. Postpartum hemorrhage occurred in 9 (17%) pregnancies. Antifibrinolytic agents and fresh frozen plasma were used only in women with severe deficiency (42% with bleeding and 17% with no bleeding phenotype, respectively). Neuraxial anesthesia was successfully administered in 32 (59%) deliveries. Most women with FXI deficiency have uncomplicated pregnancies and deliveries with minimal hemostatic support. Neuraxial anesthesia can be safely administered in most women.


Evidence for reduced copying fidelity of DNA polymerases alpha, delta, and epsilon from Novikoff hepatoma cells.
To investigate whether or not DNA polymerases alpha, delta, and epsilon from tumor cells have acquired properties that might be responsible for mutations found in tumor development, we investigated copying fidelities of DNA polymerases alpha, delta, and epsilon from the highly malignant Novikoff hepatoma cells and compared them to the corresponding enzymes from normal rat liver. DNA polymerases were purified more than 300-fold by three chromatographic steps. Copying fidelity was studied using steady-state kinetics and an 18-mer oligonucleotide primed with a 12-mer (13-mer for extension experiments) as DNA primer-template. Three experimental approaches were chosen: i) extension of DNA primers with mismatched 3'-OH ends opposite dGMP, ii) DNA insertion of nucleotides opposite m6G in the template and iii) extension of DNA primers with mismatched 3'-OH ends opposite m6G. i) Extension of DNA primers with mismatched 3'-OH ends opposite dGMP. DNA primer templates containing G:T and G:A mispairs at the 3'-OH position of the primer were easily extended by DNA polymerases alpha, delta and epsilon from both normal rat liver and Novikoff hepatoma cells. The G:G mismatch was elongated with low efficiency. Notably, DNA polymerase alpha from Novikoff hepatoma cells extended G:A and G:G mismatches significantly faster than the enzyme from normal cells. ii) Insertion of nucleotides opposite m6G. DNA polymerases alpha, delta, and epsilon from normal rat liver preferably catalyzed incorporation of dAMP opposite m6G at dNTP concentrations < 100 microM. When dNTP concentrations were raised to > or = 100 microM, dCMP (DNA polymerases delta and epsilon) and dTMP (DNA polymerase alpha) were also incorporated. The same insertion characteristics were found for the enzymes from Novikoff cells, however, insertion efficiencies of dAMP and dCMP were significantly higher for polymerases delta and epsilon. iii) Extension of primers with mismatched 3'-OH ends opposite m6G. Only m6G:dAMP and m6G:dCMP mismatches were extended by DNA polymerases alpha, delta and epsilon from both sources. No differences in extension efficiency were observed between the enzymes from normal and hepatoma cells. Taken together, our results suggest that DNA polymerases alpha, delta, and epsilon from Novikoff cells catalyzed incorporation of the wrong nucleotides more readily and extended mismatches more easily. These results may provide a rationale why numerous mutations accumulate during tumor development.


Multiplex peptide-MHC tetramer staining using mass cytometry for deep analysis of the influenza-specific T-cell response in mice.
Antigen-specific T cells play a crucial role for the host protective immunity against viruses and other diseases. The use of mass cytometry together with a combinatorial multiplex tetramer staining has successfully been applied for probing and characterization of multiple antigen-specific CD8+ T cells in human blood samples. The present study shows that this approach can also be used to rapidly assess the magnitude of influenza-specific CD8+ T cell epitope dominance across lymph nodes and lungs in a murine model of a highly pathological influenza infection. Moreover, we show feasibility of extending this approach to include concurrent identification of virus-specific CD4+ T cells. By using a double coding approach, we probed for five influenza-specific MHCI-peptide complexes as well as one influenza-specific MHCII-peptide complex in the presence of irrelevant control peptides and show that this approach is capable of tracking antigen-specific T cells across individual lymph nodes and lungs. The simultaneous staining with 26 surface maker molecules further facilitated an in-depth characterization of T cells reacting with influenza epitopes and revealed tissue specific phenotypic differences between CD4+ T cells targeting the same pathogenic epitope. In conclusion, this approach provides the possibility for a rapid and comprehensive analysis of antigen-specific CD8+ and CD4+ T cells in different disease settings that might be advantageous for subsequent vaccine formulation strategies.


A global synthesis reveals biodiversity-mediated benefits for crop production.
Human land use threatens global biodiversity and compromises multiple ecosystem functions critical to food production. Whether crop yield-related ecosystem services can be maintained by a few dominant species or rely on high richness remains unclear. Using a global database from 89 studies (with 1475 locations), we partition the relative importance of species richness, abundance, and dominance for pollination; biological pest control; and final yields in the context of ongoing land-use change. Pollinator and enemy richness directly supported ecosystem services in addition to and independent of abundance and dominance. Up to 50% of the negative effects of landscape simplification on ecosystem services was due to richness losses of service-providing organisms, with negative consequences for crop yields. Maintaining the biodiversity of ecosystem service providers is therefore vital to sustain the flow of key agroecosystem benefits to society.


Phylogenetic analysis of Ganoderma based on nearly complete mitochondrial small-subunit ribosomal DNA sequences.
Characteristics and structures of mt SSU rDNA were investigated for the phylogenetic study of Ganoderma. Phylogenetic information was concentrated mostly in the V1, V4, V5, V6 and V9 variable domains, but informative sites in conserved domains also significantly contributed in resolving phylogenetic relationships between Ganoderma groups. Secondary structure information of variable domains was found to be a useful marker in delineation of phylogenetic groups. Strains of Ganoderma species used in this study were divided into six monophyletic groups. Ganoderma colossus made a distinct basal lineage from other Ganoderma species and Tomophagus, created for G. colosuss, appeared to be a valid genus. Ganoderma applanatum and G. lobatum classified in subgenus Elfvingia made a monophyletic group. Ganoderma tsugae from North America and G. valesiacum from Europe, both living on conifers, were closely related. Ganoderma oregonense and strains labeled G. lucidum from Europe and Canada were grouped with G. tsugae and G. valesiacum. Strains labeled G. lucidum living on hardwoods from the United States and Taiwan were grouped with G. resinaceum, G. pfeifferi and G. subamboinense var. laevisporum, and they all produced chlamydospores. Two strains labeled G. lucidum and three strains labeled G. resinaceum from America were concluded to be conspecific. Strains labeled G. lucidum from Korea and Japan were monophyletic and were distinguished from strains labeled G. lucidum from Europe and North America. Host relationships and the presence of chlamydospores in culture proved to be important characteristics in the systematics as well as the phylogenetic relationships of Ganoderma.


Efficacy and safety of tolazoline for treatment of severe hypoxemia in extremely preterm infants.
To determine the efficacy of tolazoline as a rescue treatment for hypoxemia in preterm infants with respiratory distress syndrome. Retrospective chart review on case series of infants weighing < 750 g at birth who received tolazoline during a severe hypoxemic episode while receiving maximal ventilator support for respiratory distress syndrome. A slow bolus infusion of low dose tolazoline (0.5 mg-2 mg/kg) mixed with plasmanate or normal saline (10 mL/kg) was administered. Outcome measures evaluated included an increase in PaO(2) > or =20 mm Hg from pretreatment value and an increase in oxygen saturation to > or =90%. Forty-three infants with a mean gestational age and birth weight of 24 weeks and 581 g, respectively, received tolazoline. All infants were mechanically ventilated and required a fraction of inspired oxygen of 1.0. Oxygenation improved in 72% (31/43) of infants with a tolazoline dose of 0.5 to 1.0 mg/kg. Of those who responded, PaO(2) values (mean +/- standard deviation) pretolazoline and posttolazoline were 32 +/- 7.5 mm Hg and 156 +/- 114.9 mm Hg, respectively. In all responders, oxygen saturation increased to > or =90% within 30 minutes of tolazoline administration. Improvement in pH, pCO(2), oxygenation index, and mean airway pressure was also noted. Among nonresponders, pH decreased and pCO(2) increased after tolazoline. Minimal change in blood pressure was noted in both responders and nonresponders. Heart rate decreased by 19 beats per minute among nonresponders compared with an increase of 3 beats per minute in those who responded to tolazoline. Tolazoline is an effective treatment of severe resistant hypoxemia in preterm infants who are already on vigorous ventilatory support.


Immune cell impact of three differently coated lipid nanocapsules: pluronic, chitosan and polyethylene glycol.
Lipid nanocapsules (NCs) represent promising tools in clinical practice for diagnosis and therapy applications. However, the NC appropriate functionalization is essential to guarantee high biocompatibility and molecule loading ability. In any medical application, the immune system-impact of differently functionalized NCs still remains to be fully understood. A comprehensive study on the action exerted on human peripheral blood mononuclear cells (PBMCs) and major immune subpopulations by three different NC coatings: pluronic, chitosan and polyethylene glycol-polylactic acid (PEG) is reported. After a deep particle characterization, the uptake was assessed by flow-cytometry and confocal microscopy, focusing then on apoptosis, necrosis and proliferation impact in T cells and monocytes. Cell functionality by cell diameter variations, different activation marker analysis and cytokine assays were performed. We demonstrated that the NCs impact on the immune cell response is strongly correlated to their coating. Pluronic-NCs were able to induce immunomodulation of innate immunity inducing monocyte activations. Immunomodulation was observed in monocytes and T lymphocytes treated with Chitosan-NCs. Conversely, PEG-NCs were completely inert. These findings are of particular value towards a pre-selection of specific NC coatings depending on biomedical purposes for pre-clinical investigations; i.e. the immune-specific action of particular NC coating can be excellent for immunotherapy applications.


Inactivation of voltage-gated delayed potassium current in molluscan neurons. A kinetic model.
Voltage-gated delayed potassium current in molluscan neurons is characterized by a marked inactivation. Inactivation can accumulate between repetitive pulses, giving rise to current patterns in which the maximum current during a second voltage pulse is less than the current at the end of the preceding pulse (cumulative inactivation). Other features of inactivation of this current include an onset time-course that can be characterized by the sum of two exponential processes and an early minimum in the recovery-vs.-time curve. A simple four-state model is developed that can, when supplied with rate constants derived from voltage-clamp experiments, reproduce these features of inactivation. The model incorporates state-dependent inactivation rates. Upon depolarization, both open and closed channels can be inactivated, although inactivation of closed channels is much faster. Upon repolarization, recovery from inactivated states is sufficiently slow that little recovery occurs during a short interpulse interval. Cumulative inactivation comes about as a result of fast inactivation during the second pulse, further limiting the peak current from the level at the end of the previous pulse.


SIRT1 is a critical regulator of K562 cell growth, survival, and differentiation.
Inhibition of histone deacetylases (HDACi) has emerged as a promising approach in the treatment of many types of cancer, including leukemias. Among the HDACs, Class III HDACs, also known as sirtuins (SIRTs), are unique in that their function is directly related to the cell's metabolic state through their dependency on the co-factor NAD(+). In this study, we examined the relation between SIRTs and the growth, survival, and differentiation of K562 erythroleukemia cells. Using a mass spectrometry approach we previously developed, we show that SIRT expression and deacetylase activity in these cells changes greatly with differentiation state (undifferentiated vs. megakaryocytic differentiation vs. erythroid differentiation). Moreover, SIRT1 is crucially involved in regulating the differentiation state. Overexpression of wildtype (but not deacetylase mutant) SIRT1 resulted in upregulation of glycophorin A, ~2-fold increase in the mRNA levels of α, γ, ε, and ζ-globins, and spontaneous hemoglobinization. Hemin-induced differentiation was also enhanced by (and depended on) higher SIRT1 levels. Since K562 cells are bipotent, we also investigated whether SIRT1 modulation affected their ability to undergo megakaryocytic (MK) differentiation. SIRT1 was required for commitment to the MK lineage and subsequent maturation, but was not directly involved in polyploidization of either K562 cells or an already-MK-committed cell line, CHRF-288-11. The observed blockage in commitment to the MK lineage was associated with a dramatic decrease in the formation of autophagic vacuoles, which was previously shown to be required for K562 cell MK commitment. Autophagy-associated conversion of the protein LC3-I to LC3-II was greatly enhanced by overexpression of wildtype SIRT1, further suggesting a functional connection between SIRT1, autophagy, and MK differentiation. Based on its clear effects on autophagy, we also examined the effect of SIRT1 modulation on stress responses. Consistent with results of prior studies, we found that SIRT1 silencing modestly promoted drug-induced apoptosis, while overexpression was protective. Furthermore, pan-SIRT inhibition mediated by nicotinamide pre-treatment substantially increased imatinib-induced apoptosis. Altogether, our results suggest a complex role for SIRT1 in regulating many aspects of K562 cell state and stress response. These observations warrant further investigation using normal and leukemic primary cell models. We further suggest that, ultimately, a well-defined mapping of HDACs to their substrates and corresponding signaling pathways will be important for optimally designing HDACi-based therapeutic approaches.


[Osteogenesis imperfecta and aortic incompetence. One case with pathological findings. Review of the literature (author's transl)].
Cardiovascular manifestations of Lobstein's disease are rare, probably unrecognized, and determining factors for the final prognosis, the most frequent lesion being aortic incompetence. The eleventh case to be reported with pathological findings in the literature is described. This complication is usually found in men, blood regurgitation being large in amount, symptomatic, and progressive. Its mechanism is related less to dilatation of the aorta and its ring than to valvular changes, they being frequently bicuspid and dysplasic. Histological findings, not however pathognomonic, are myxoid degeneration in the valves and parietal cystic necrosis in the aortic wall. Apart from the absence of an aneurysm and aortic dissection, macro- and microscopic lesions are similar to those observed in Marfan's syndrome and osteogenesis imperfecta. Operative therapy was employed in all eleven cases, with three postoperative deaths and three later deaths. Certain complications arise from uncontrollable severe hemorrhage, which justifies the use of valve heterografts not requiring antivitamin K administration.


Structured reporting has the potential to reduce reporting times of dual-energy x-ray absorptiometry exams.
In recent years, structured reporting has been shown to be beneficial with regard to report completeness and clinical decision-making as compared to free-text reports (FTR). However, the impact of structured reporting on reporting efficiency has not been thoroughly evaluted yet. The aim of this study was to compare reporting times and report quality of structured reports (SR) to conventional free-text reports of dual-energy x-ray absorptiometry exams (DXA). FTRs and SRs of DXA were retrospectively generated by 2 radiology residents and 2 final-year medical students. Time was measured from the first view of the exam until the report was saved. A random sample of DXA reports was selected and sent to 2 referring physicians for further evaluation of report quality. A total of 104 DXA reports (both FTRs and SRs) were generated and 48 randomly selected reports were evaluated by referring physicians. Reporting times were shorter for SRs in both radiology residents and medical students with median reporting times of 2.7 min (residents: 2.7, medical students: 2.7) for SRs and 6.1 min (residents: 5.0, medical students: 7.5) for FTRs. Information extraction was perceived to be significantly easier from SRs vs FTRs (P < 0.001). SRs were rated to answer the clinical question significantly better than FTRs (P < 0.007). Overall report quality was rated significantly higher for SRs compared to FTRs (P < 0.001) with 96% of SRs vs 79% of FTRs receiving high or very high-quality ratings. All readers except for one resident preferred structured reporting over free-text reporting and both referring clinicians preferred SRs over FTRs for DXA. Template-based structured reporting of DXA might lead to shorter reporting times and increased report quality.


Microtektites and mass extinctions: evidence for a late devonian asteroid impact.
Glass spherules, similar to microtektites, have been found near the Frasnian-Famennian boundary (F/F) (Upper Devonian) at Senzeilles, Belgium, contemporaneous with one of the largest marine mass extinctions of the Phanerozoic. These spherules exhibit a wide range of compositions and display teardrop, dumbbell, and compound morphologies analogous to microtektites. In addition, they lack crystallites, have few or no vesicles, and have a low content of volatile material. These characteristics are supportive of an impact origin. The Siljan Ring (Sweden) and Charlevoix structure (Quebec,Canada) are candidate craters of this age. The presence of microtektites near the F/F boundary supports the hypothesis that an impact caused the Upper Devonian worldwide benthic mass extinctions.


How to reach linguistic consensus: a proof of convergence for the naming game.
In this paper we introduce a mathematical model of naming games. Naming games have been widely used within research on the origins and evolution of language. Despite the many interesting empirical results these studies have produced, most of this research lacks a formal elucidating theory. In this paper we show how a population of agents can reach linguistic consensus, i.e. learn to use one common language to communicate with one another. Our approach differs from existing formal work in two important ways: one, we relax the too strong assumption that an agent samples infinitely often during each time interval. This assumption is usually made to guarantee convergence of an empirical learning process to a deterministic dynamical system. Two, we provide a proof that under these new realistic conditions, our model converges to a common language for the entire population of agents. Finally the model is experimentally validated.


Combined low-saturated fat intake and high fitness may counterbalance diabetogenic effects of obesity: the DR's EXTRA Study.
We report associations of saturated fat (SF) intake with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), concurrent IFG+IGT and type 2 diabetes (T2DM) at different levels of cardiorespiratory fitness and body mass index (BMI). In a population-based sample (n=1261, age 58-78 years), oral glucose tolerance, 4-day food intake and maximal oxygen uptake were measured. High intake of SF (>11.4 E%) was associated with elevated risk for IFG (4.36; 1.93-9.88), concurrent IFG+IGT (6.03; 1.25-29.20) and T2DM (4.77; 1.93-11.82) in the category of high BMI (>26.5) and high fitness, whereas there was no significantly elevated risk in individuals reporting low intake of SF. Concurrent high BMI and low fitness were associated with elevated risks. In general, SF intake and fitness did not differentiate the risk of abnormal glucose metabolism among subjects with low BMI. Limited intake of SF may protect from diabetogenic effects of adiposity, but only in individuals with high level of fitness.


The effects of age on the neural correlates of feedback processing in a naturalistic gambling game.
We examined age-related differences in the spatiotemporal distribution of event-related brain potentials (ERPs) related to feedback processing in a virtual blackjack game. The behavioral data revealed that older adults were less risk seeking than younger adults both within and across trials. Age-related differences were observed in the amplitude of several ERP components (P2-FN-P3a, P3a, slow wave activity) related to feedback processing. These components were localized to the anterior and posterior cingulate, the occipital cortex, and the inferior and medial frontal cortices. The effects of aging on the ERPs ranged from 200-2,000 ms after feedback onset. Our findings indicate that aging affects the activity of a distributed neural network that underpins processing the valence and motivational significance of feedback related to risky decisions.


Statistical models of acute mountain sickness.
Acute mountain sickness (AMS) is caused by exposure to altitudes exceeding 2500 m and often resolves by acclimatization without further ascent. Statistical models of AMS score and the probability of an AMS diagnosis were developed to allow the combination of dissimilar exposures for simultaneous analysis. The study population was 302 trekkers from a previous investigation who provided self-reported symptoms upon arrival at 3840 m during hikes through altitudes of 1500 to 6200 m. AMS score (Hackett scale) was estimated by linear regression and the probability of an AMS diagnosis (Lake Louise criteria) by logistic regression. AMS score or probability was significantly associated with exposure day and altitude. Increased altitude over the prior 3 days resulted in higher estimated AMS score or probability and decreased altitude in lower score or probability. The odds ratio (OR) of AMS was 3.6 if not on acetazolamide. Females appeared slightly more susceptible than males (1.5 OR). The approach offers the advantages of (1) improved statistical power by combining exposures, (2) insight into the dose-response relationship of altitude exposure and AMS risk, (3) quantitative tests for the significance of factors that might affect AMS susceptibility, and (4) practical tools to track individual climbers and plan operational ascents.


Papilledema and tumours of the cauda equina: a case report.
Bilateral papilledema is a rare symptom of cauda equina tumours. The authors report a case of neurinoma of cauda equina, which had a bilateral papilledema among its initial symptoms. A 28 years old man showed the presence of a bilateral papilledema; a cerebral MRI did not show any endocranial pathology. After three months the patient started suffering, especially at night, of right-leg-sciatica. A lumbar MRI showed a neurinoma of the cauda equina. The patient was operated and after surgery the papilledema slowly shrank. The tumours of cauda equina could cause endocranial hypertension and consequently a papilledema because of hyperproteinorachia. If there is a bilateral papilledema and the cerebral MRI does not show any endocranial pathology, there is the need for the examination of any spinal disorders.


Virus-induced autoimmunity: monoclonal antibodies that react with endocrine tissues.
Mice infected with reovirus type 1 develop an autoimmune polyendocrine disease. Spleen cells from these mice were fused with myeloma cells and the culture fluids were screened by indirect immunofluorescence for autoantibodies reactive with normal mouse tissues. A large panel of cloned, stable antibody-producing hybridomas has been obtained. Fourteen of the hybridomas make autoantibodies that react with cells in the islets of Langerhans, 24 with cells in the anterior pituitary, 11 with cells in gastric mucosa, and 5 with nuclei. Except for the antibodies to nuclei, the monoclonal autoantibodies are organ-specific. Some, however, show broad cross-species reactivity, recognizing similar antigenic determinants in mouse, rat, pig, and human organs, whereas other recognize determinants only in rodent tissues. Several of the antigens recognized by these monoclonal autoantibodies have been identified as hormones (for example, glucagon, growth hormone, and insulin).


Synthesis and Structure Determination of Large-Pore Zeolite SCM-14.
SCM-14 (Sinopec Composite Material No. 14), a new stable germanosilicate zeolite with a 12×8×8-ring channel system, was synthesized using commercially available 4-pyrrolidinopyridine as organic structure-directing agents (OSDAs) in fluoride medium. The framework structure of SCM-14 was determined using rotation electron diffraction (RED), and refined against synchrotron X-ray powder diffraction (SXPD) data for both as-made and calcined materials. The framework structure of SCM-14 is closely related to that of three known zeolites: mordenite (MOR), GUS-1 (GON), and IM-16 (UOS). SCM-14 has the same projection as that of mordenite and GUS-1 when viewed along the 12-ring channels, and possesses two more straight 8-ring channels running perpendicular to the 12-ring channels. The structure of SCM-14 can be constructed by either the same layers as that of GUS-1 or the same columns as that of IM-16. Based on their structural relationship, three topologically reasonable hypothetical zeolites were predicted.


Optimisation in fluoroscopy.
Optimisation of radiation protection in fluoroscopy is important since the procedure could lead to relatively high absorbed doses both in patients and personnel resulting in acute radiation injury. Optimisation procedures include adjustment of the fluoroscopy equipment such as exposure factors as well as proper use of automatic brightness control and pulsed fluoroscopy. It is also important to gain the benefits of image processing and the higher sensitivity of flat panel detectors as compared to image intensifier-TV systems.Proper positioning of the patient with respect to detector and X-ray tube is of fundamental importance to image quality and radiation dose to the patient. Both image quality and radiation dose are also affected by the methodology used with parameters such as magnification factor, increased filtration, use of last-image-hold and the use of a grid.There is a direct relation between patient dose and the absorbed dose to the personnel since this is mostly due to scattered radiation from the patient. If the correct methodology and the correct radiation protection devices are used, the absorbed dose to the personnel could be minimised to acceptable levels even for those working with complex procedures.In order to have an organised review of all aspects of optimisation, it is recommendable to have an active quality system at the department. This system should define responsibilities and tasks for persons involved.


[Psychogenically-induced lumbar pain].
Diseases of the column and some psychic disturbances (e.g. neuroses) form the causes of transitory or chronic invalidity. From a psychological point of view, the lumbar region plays an important role in the polarisation of certain psychological conflicts: sexuality, aggressiveness, depression, frustration, exaggerated submission, etc. In consideration of this sensitivity of the lumbar region to certain psychic disturbances we have subjected a great number of women and men to a special neurological and clinical examination. Only in one per cent of the patients operated on no organic change was found, which underlines the importance and necessity of an appraisal of the personality of the patients with chronic, psychically caused pain. When this appraisal of the personality is omitted, diagnostic errors may occur that cannot be made good again.


Mean macronuclear DNA contents are variable in the ciliate Tetrahymena.
Using cytophotometry the mean macronuclear DNA content of the ciliate Tetrahymena was found to be variable in two cell lines examined. While environmental changes (different culture fluids, temperature shifts) influence the mean DNA content of at least one of the two cell lines, spontaneous changes of the means are observed in both lines. The mean DNA contents of cultures maintained permanently in defined medium at various temperatures suggest the existence of a lower (7.5 pg) and an upper (13.6 pg) limit of the mean macronuclear DNA contents. Greatly differing means, either below or above those limits, were only occasionally found in cultures shifted to different temperatures for periods of less than 3 days. Eventually, the G2 mean macronuclear DNA contents of these cultures differed greatly from the doubled G1 mean value (maximum: mean G2 value equalling four times the G1 mean). Analysis of the maximum and minimum G1 DNA contents found in any culture indicates no absolute macronuclear DNA content triggering the regulation of macronuclear DNA content. There is no stringent correlation between the average cell volume and the average macronuclear DNA content. The data are discussed with reference to reported mechanisms of regulation of macronuclear DNA content.


Planning the Safety of Atrial Fibrillation Ablation Registry Initiative (SAFARI) as a Collaborative Pan-Stakeholder Critical Path Registry Model: a Cardiac Safety Research Consortium "Incubator" Think Tank.
Atrial fibrillation (AF) is a major public health problem in the United States that is associated with increased mortality and morbidity. Of the therapeutic modalities available to treat AF, the use of percutaneous catheter ablation of AF is expanding rapidly. Randomized clinical trials examining the efficacy and safety of AF ablation are currently underway; however, such trials can only partially determine the safety and durability of the effect of the procedure in routine clinical practice, in more complex patients, and over a broader range of techniques and operator experience. These limitations of randomized trials of AF ablation, particularly with regard to safety issues, could be addressed using a synergistically structured national registry, which is the intention of the SAFARI. To facilitate discussions about objectives, challenges, and steps for such a registry, the Cardiac Safety Research Consortium and the Duke Clinical Research Institute, Durham, NC, in collaboration with the US Food and Drug Administration, the American College of Cardiology, and the Heart Rhythm Society, organized a Think Tank meeting of experts in the field. Other participants included the National Heart, Lung and Blood Institute, the Centers for Medicare and Medicaid Services, the Agency for Healthcare Research and Quality, the Society of Thoracic Surgeons, the AdvaMed AF working group, and additional industry representatives. The meeting took place on April 27 to 28, 2009, at the US Food and Drug Administration headquarters in Silver Spring, MD. This article summarizes the issues and directions presented and discussed at the meeting.


No-fault malparactice insurance. Proximate cause and the quality of medical care.
No-fault medical malpractice insurance has been proposed as an alternative to the present tort liability approach. Statistical examination of the concept of proximate cause reveals not only that the question of acceptable care, and therefore of fault, is unavoidable in identifying patients deserving compensation, but also that specifying fault in an individual case is scientifically untenable. A simple formula for a Coefficient of Causality clarifies the question of proximate cause in existing trial practices and suggests that many of the threats associated with malpractice suits arise from the structure of the tort-insurance system rather than from professional responsibility for medical injury. The concepts could provide the basis for a revised claims and compensation procedure.


[Determination of trace elements Cu, Zn, Mg, Cr, Mn in serum of people with hepatoma, cirrhosis, hepatapstema disease].
Using AAS method, we detected serum Zn, Cu, Mn, Cr, Mg in the people with hepatoma, cirrhosis and hepatophyma disease. The results showed that the level of serum Cu of people with hepatoma and cirrhosis were significantly higher than those in the healthy control and with hepatophyma disease (P < 0.01). The levels of serum Mn, Cr of those with hepatoma and cirrhosis disease were significantly lower than those with hepatophyma and the healthy control (P < 0.01). It is concluded that determination of Cu, Mn, Cr may be one of the methods to diagnose hepatoma and cirrhosis disease.


Lysine-Based Small Molecules That Disrupt Biofilms and Kill both Actively Growing Planktonic and Nondividing Stationary Phase Bacteria.
The emergence of bacterial resistance is a major threat to global health. Alongside this issue, formation of bacterial biofilms is another cause of concern because most antibiotics are ineffective against these recalcitrant microbial communities. Ideal future antibacterial therapeutics should possess both antibacterial and anti-biofilm activities. In this study we engineered lysine-based small molecules, which showed not only commendable broad-spectrum antibacterial activity but also potent biofilm-disrupting properties. Synthesis of these lipophilic lysine-norspermidine conjugates was achieved in three simple reaction steps, and the resultant molecules displayed potent antibacterial activity against various Gram-positive (Staphylococcus aureus, Enterococcus faecium) and Gram-negative bacteria (Escherichia coli) including drug-resistant superbugs MRSA (methicillin-resistant S. aureus), VRE (vancomycin-resistant E. faecium), and β-lactam-resistant Klebsiella pneumoniae. An optimized compound in the series showed activity against planktonic bacteria in the concentration range of 3-10 μg/mL, and bactericidal activity against stationary phase S. aureus was observed within an hour. The compound also displayed about 120-fold selectivity toward both classes of bacteria (S. aureus and E. coli) over human erythrocytes. This rapidly bactericidal compound primarily acts on bacteria by causing significant membrane depolarization and K(+) leakage. Most importantly, the compound disrupted preformed biofilms of S. aureus and did not trigger bacterial resistance. Therefore, this class of compounds has high potential to be developed as future antibacterial drugs for treating infections caused by planktonic bacteria as well as bacterial biofilms.


An information-rich CGG repeat primed PCR that detects the full range of fragile X expanded alleles and minimizes the need for southern blot analysis.
(CGG)(n) repeat expansion in the FMR1 gene is associated with fragile X syndrome and other disorders. Current methods for FMR1 molecular testing rely on Southern blot analysis to detect expanded alleles too large to be PCR-amplified and to identify female homozygous alleles that often confound interpretations of PCR data. A novel, single-tube CGG repeat primed FMR1 PCR technology was designed with two gene-specific primers that flank the triplet repeat region, as well as a third primer that is complementary to the (CGG)(n) repeat. This PCR was evaluated with 171 unique DNA samples, including a blinded set of 146 clinical specimens. The method detected all alleles reported by Southern blot analysis, including full mutations in 66 clinical samples and comprised up to 1300 CGG. Furthermore, a blinded cohort of 42 female homozygous and heterozygous specimens, including 21 with full mutation alleles, was resolved with 100% accuracy. Last, AGG interrupter sequences, which may influence the risk of (CGG)(n) expansion in the children of some carriers, were each correctly identified in 14 male and female clinical samples as referenced to DNA sequencing. As a result, this PCR provides robust detection of expanded alleles and resolves allele zygosity, thus minimizing the number of samples that require Southern blot analysis and producing more comprehensive FMR1 genotyping data than other methods.


Association of Radiotherapy Boost for Ductal Carcinoma In Situ With Local Control After Whole-Breast Radiotherapy.
The use of a radiotherapy (RT) boost to the tumor bed after whole-breast RT (WBRT) for ductal carcinoma in situ (DCIS) is largely extrapolated from invasive cancer data, but robust evidence specific to DCIS is lacking. To compare ipsilateral breast tumor recurrence (IBTR) in women with DCIS treated with vs without the RT boost after breast-conserving surgery and WBRT. This retrospective analysis pooled deidentified patient-level data from 10 academic institutions in the United States, Canada, and France from January 1, 1980, through December 31, 2010. All patients had newly diagnosed pure DCIS (no microinvasion), underwent breast-conserving surgery, and received WBRT with or without the boost with a minimum of 5 years of follow-up required for inclusion in the analysis. Given the limited events after WBRT, an a priori power analysis was conducted to estimate the DCIS sample size needed to detect the anticipated benefit of the boost. Data were uniformly recoded at the host institution and underwent primary and secondary reviews before analysis. Sample size calculations (ratio of patients who received the boost dose to those who did not, 2:1; α = .05; power = 80%) estimated that 2982 cases were needed to detect a difference of at least 3%. The final analysis included 4131 patients (2661 in the boost group and 1470 in the no-boost group) with a median follow-up of 9 years and media boost dose of 14 Gy. Data were collected from July 2011 through February 2014 and analyzed from March 2014 through August 2015. Radiotherapy boost vs no boost. Ipsilateral breast tumor recurrence. The analysis included 4131 patients (median [SD] age, 56.1 [10.9] years; range, 24-88 years). Patients with positive margins, unknown estrogen receptor status, and comedo necrosis were more likely to have received an RT boost. For the entire cohort, the boost was significantly associated with lower IBTR (hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01) and with IBTR-free survival (boost vs no-boost groups) of 97.1% (95% CI, 0.96-0.98) vs 96.3% (95% CI, 0.95-0.97) at 5 years, 94.1% (95% CI, 0.93-0.95) vs 92.5% (95% CI, 0.91-0.94) at 10 years, and 91.6% (95% CI, 0.90-0.93) vs 88.0% (95% CI, 0.85-0.91) at 15 years. On multivariable analysis accounting for confounding factors, the boost remained significantly associated with reduced IBTR (HR compared with no boost, 0.68; 95% CI, 0.50-0.91; P = .01) independent of age and tamoxifen citrate use. This patient-level analysis suggests that the RT boost confers a statistically significant benefit in decreasing IBTR across all DCIS age groups, similar to that seen in patients with invasive breast cancer. These findings suggest that a DCIS RT boost to the tumor bed could be considered to provide an added incremental benefit in decreasing IBTR after a shared discussion between the patient and her radiation oncologist.


Platelet gene therapy improves hemostatic function for integrin alphaIIbbeta3-deficient dogs.
Activated blood platelets mediate the primary response to vascular injury. Although molecular abnormalities of platelet proteins occur infrequently, taken collectively, an inherited platelet defect accounts for a bleeding diathesis in ≈1:20,000 individuals. One rare example of a platelet disorder, Glanzmann thrombasthenia (GT), is characterized by life-long morbidity and mortality due to molecular abnormalities in a major platelet adhesion receptor, integrin αIIbβ3. Transfusion therapy is frequently inadequate because patients often generate antibodies to αIIbβ3, leading to immune-mediated destruction of healthy platelets. In the most severe cases allogeneic bone marrow transplantation has been used, yet because of the risk of the procedure it has been limited to few patients. Thus, hematopoietic stem cell gene transfer was explored as a strategy to improve platelet function within a canine model for GT. Bleeding complications necessitated the use of a mild pretransplant conditioning regimen; therefore, in vivo drug selection was used to improve engraftment of autologously transplanted cells. Approximately 5,000 αIIbβ3 receptors formed on 10% of platelets. These modest levels allowed platelets to adhere to αIIbβ3's major ligand (fibrinogen), form aggregates, and mediate retraction of a fibrin clot. Remarkably, improved hemostatic function was evident, with ≤135-fold reduced blood loss, and improved buccal bleeding times decreased to 4 min for up to 5 y after transplant. One of four transplanted dogs developed a significant antibody response to αIIbβ3 that was attenuated effectively with transient immune suppression. These results indicate that gene therapy could become a practical approach for treating inherited platelet defects.


Neurilemmoma Mimicking a Multilocular Cystic Lesion of the Liver.
Neurilemmomas are benign tumors arising from the sheaths of peripheral nerves. They appear rarely in the abdominal cavity. We herein report an 80-year-old man with a multilocular cystic neurilemmoma mimicking a liver lesion. Preoperative images showed a lesion in the porta hepatis. Although a preoperative diagnosis was difficult, surgery was undertaken because of the possibility of malignancy. Histologically, the tumor consisted of spindle-shaped cells with positivity for S-100 protein. The final diagnosis was a neurilemmoma. Porta hepatic neurilemmomas are rare. When we encounter a multilocular cystic lesion of the liver, neurilemmoma should be considered in the differential diagnosis.


Anthropometry, carbohydrate and lipid metabolism in the East Flanders Prospective Twin Survey: linkage of candidate genes using two sib-pair based variance components analyses.
Insulin resistance and obesity are underlying causes of type 2 diabetes and therefore much interest is focused on the potential genes involved. A series of anthropometric and metabolic characteristic were measured in 240 MZ and 112 DZ twin pairs recruited from the East Flanders Prospective Twin Survey. Microsatellite markers located close to ABCC8, ADIPOQ, GCK, IGF1, IGFBP1, INSR, LEP, LEPR, PPARgamma and the RETN gene were genotyped. Univariate single point variance components linkage analyses were performed using two methods: (1) the standard method, only comprising the phenotypic and genotypic data of the DZ twin pairs and (2) the extended method, also incorporating the phenotypic data of the MZ twin pairs. Suggestive linkages (LOD > 1) were observed between the ABCC8 marker and waist-to-hip ratio and HDL-cholesterol levels. Both markers flanking ADIPOQ showed suggestive linkage with triglycerides levels, the upstream marker also with body mass and HDL-cholesterol levels. The IGFBP1 marker showed suggestive linkage with fat mass, fasting insulin and leptin levels and the LEP marker showed suggestive linkage with birth weight. This study suggests that DNA variants in ABCC8, ADIPOQ, IGFBP1 and LEP gene region may predispose to type 2 diabetes. In addition, the two methods used to perform linkage analyses yielded similar results. This was however not the case for birth weight where chorionicity seems to be an important confounder.


Revisiting deficits in threat and safety appraisal in obsessive-compulsive disorder.
Current behavioural treatment of obsessive-compulsive disorder (OCD) is informed by fear conditioning and involves iteratively re-evaluating previously threatening stimuli as safe. However, there is limited research investigating the neurobiological response to conditioning and reversal of threatening stimuli in individuals with OCD. A clinical sample of individuals with OCD (N = 45) and matched healthy controls (N = 45) underwent functional magnetic resonance imaging. While in the scanner, participants completed a well-validated fear reversal task and a resting-state scan. We found no evidence for group differences in task-evoked brain activation or functional connectivity in OCD. Multivariate analyses encompassing all participants in the clinical and control groups suggested that subjective appraisal of threatening and safe stimuli were associated with a larger difference in brain activity than the contribution of OCD symptoms. In particular, we observed a brain-behaviour continuum whereby heightened affective appraisal was related to increased bilateral insula activation during the task (r = 0.39, pFWE = .001). These findings suggest that changes in conditioned threat-related processes may not be a core neurobiological feature of OCD and encourage further research on the role of subjective experience in fear conditioning.


Automated detection of lung nodules in CT scans: effect of image reconstruction algorithm.
We have investigated the effect of computed tomography (CT) image reconstruction algorithm on the performance of our automated lung nodule detection method. Commercial CT scanners offer a choice of several algorithms for the reconstruction of projection data into transaxial images. Different algorithms produce images with substantially different properties that are apparent not only quantitatively, but also through visual assessment. During some clinical thoracic CT examinations, patient scans are reconstructed with multiple reconstruction algorithms. Thirty-eight such cases were collected to form two databases: one with patient projection data reconstructed with the "standard" reconstruction algorithm and the other with the same patient projection data reconstructed with the "lung" reconstruction algorithm. The automated nodule detection method was applied to both databases. This method is based on gray-level-thresholding techniques to segment the lung regions from each CT section to create a segmented lung volume. Further gray-level-thresholding techniques are applied within the segmented lung volume to identify a set of lung nodule candidates. Rule-based and linear discriminant classifiers are used to differentiate between lung nodule candidates that correspond to actual nodules and those that correspond to non-nodules. The automated method that was applied to both databases was exactly the same, except that the classifiers were calibrated separately for each database. For comparison, the classifier then was trained on one database and tested independently on the other database. When applied to the databases in this manner, the automated method demonstrated overall a similar level of performance, indicating an encouraging degree of robustness.


Bimolecular fluorescence complementation (BiFC) analysis as a probe of protein interactions in living cells.
Protein interactions are a fundamental mechanism for the generation of biological regulatory specificity. The study of protein interactions in living cells is of particular significance because the interactions that occur in a particular cell depend on the full complement of proteins present in the cell and the external stimuli that influence the cell. Bimolecular fluorescence complementation (BiFC) analysis enables direct visualization of protein interactions in living cells. The BiFC assay is based on the association between two nonfluorescent fragments of a fluorescent protein when they are brought in proximity to each other by an interaction between proteins fused to the fragments. Numerous protein interactions have been visualized using the BiFC assay in many different cell types and organisms. The BiFC assay is technically straightforward and can be performed using standard molecular biology and cell culture reagents and a regular fluorescence microscope or flow cytometer.


tRNA is entrapped in similar, but distinct, nuclear and cytoplasmic ribonucleoprotein complexes, both of which contain vigilin and elongation factor 1 alpha.
Vigilin, which is found predominantly in cells and tissues with high levels of protein biosynthesis, was isolated in its native form from human HEp-2 cells (A.T.C.C. CCL23) by immunoaffinity chromatography. Here we demonstrate that vigilin is part of a novel large tRNA-binding ribonucleoprotein complex (tRNP), found not only in the cytoplasm, but also in the nuclei of human cells. Compositional differences in the protein pattern were detected between the nuclear and cytoplasmic tRNPs, although some properties of the purified nuclear tRNP, such as tRNA protection against nuclease attack, were identical with those of the cytoplasmic tRNP. By using either a pool of total human nuclear RNA or radioactively labelled yeast tRNAAsp in rebinding experiments, we could show that tRNA is specifically recaptured by the RNA-depleted, vigilin-containing nuclear complex. We could also show that vigilin is capable of binding tRNA in vitro. Another tRNA-binding protein is elongation factor 1 alpha, which appears to be enriched in the cytoplasmic and nuclear tRNP complexes. This suggests that the cytoplasmic tRNP may be involved in the channelled tRNA cycle in the cytoplasm of eukaryotic cells. Our results also suggest that the nuclear vigilin-containing tRNP may be related to the nuclear export of tRNA.


The relation between body fat distribution and cardiovascular risk factors in patients with schizophrenia: a cross-sectional pilot study.
Obesity has recently become a concern for physicians treating schizophrenic patients. Obesity is associated with hypertension, dyslipidemia, and diabetes mellitus. In this pilot study, we investigate which anthropometric measurement, body mass index or waist circumference, is a better predictor of cardiovascular risk factors in patients with schizophrenia. This cross-sectional study, conducted from January 2001 to January 2002, examined body fat distribution and its relation to cardiovascular risk factors in 62 patients with schizophrenia (DSM-IV) recruited from an outpatient psychiatric clinic. Chi-square analysis revealed that an increased waist circumference was associated with dyslipidemia (p < .01), hypertension (p < .05), and abnormal serum glucose (p < .05), whereas an increased body mass index was only associated with dyslipidemia (p < .05). In logistic regression analysis, after controlling for age, gender, race, ethnicity, smoking, and body mass index, increased waist circumference remained significantly associated with dyslipidemia (odds ratio = 2.08, 95% CI = 1.01 to 1.15, p < .05) and hypertension (odds ratio = 2.05, 95% CI = 1.02 to 1.17, p < .05). Waist circumference revealed a stronger correlation than body mass index to cardiovascular risk factors in patients with schizophrenia. We propose the measurement of waist circumference as a screening tool for cardiovascular risk factors in this population. Waist circumference measurement can provide an opportunity for primary prevention of coronary heart disease and diabetes mellitus in patients with schizophrenia.


Risk For Postpartum Depression Among Immigrant Arabic Women in the United States: A Feasibility Study.
Postpartum depression (PPD) affects approximately 14% of women in the United States and 10% to 37% of Arabic women in the Middle East. Evidence suggests that immigrant women experience higher rates, but information on PPD among immigrant women of Arabic descent in the United States is nonexistent. A cross-sectional descriptive feasibility study was conducted to assess the practicality of implementing a larger proposed research study to examine predictors of PPD in US immigrant women of Arabic descent residing in Dearborn, Michigan. Fifty women were recruited from an Arab community center and completed demographic data, the Arabic version of the Edinburgh Postpartum Depression Scale (EPDS), and the Postpartum Depression Predictors Inventory-Revised (PDPI-R). Among participants, 36% were considered at high risk for developing PPD. Lack of social support, antenatal anxiety, antenatal depression, maternity blues (feeling depressed during the first 4 weeks postpartum), and life stress were significantly related to risk for PPD. Multiple regression analysis revealed that social support (t = -3.77, P < .0001) and maternity blues (t = 2.19, P = .03) were the only significant predictors for postpartum depressive symptoms. Findings of this study describe the prevalence of PPD in a sample of US immigrant women of Arabic descent and support the feasibility of a larger and more in-depth understanding of their immigration and acculturation experiences. Study participants reported high risk for PPD. Maternity blues and lack of social support were significant predictors to the risk for PPD. Future research tailored to this minority group is recommended.


[Sensitivity and specificity of blood amylase, amylase and creatinine clearance ratio and urinary amylase/urinary creatinine ratio in the diagnosis of acute pancreatitis].
The sensitivity and specificity of amylasemia, the ratios of amylase/creatinine clearance and amylasuria/creatininuria were determined in four groups of patients: a control group (n = 43), patients with acute pancreatitis detected on computed tomography (n = 30, 25 cases of alcoholic pancreatitis), patients with an acute surgical abdomen without pancreatitis (n = 25), and patients with renal failure (n = 20). Sensitivity was defined for the acute pancreatitis group and specificity for the other groups. When amylasemia was greater than 20 UI/dl and the amylasuria/creatininuria ratio greater than 100, sensitivity was 98 per cent. The specificity of these two results in patients with an acute surgical abdomen was 98 per cent. When the ratio amylase/creatinine clearance ratio was greater than 4 sensitivity was 73 per cent and specificity in patients with acute surgical abdomen was 75 per cent. These two values were lower than those of the two preceding tests (p less than 0.01). Sensitivity of the association of an amylasemia greater than 13 UI/dl (m + 2SD) with a clearance ratio greater than 4 was 73 per cent. The amylase/creatinine clearance ratio did not seem to be reliable since its change was delayed with respect to the increase of amylasemia and amylasuria. This ratio has a poor specificity as it increased when the clearance of creatinine decreased in the group with an acute surgical abdomen associated with functional or organic renal failure. In these two groups, the correlation between the amylase/creatinine clearance ratio and creatininemia was significant. This suggested that the clearance of creatinine fell more rapidly than the clearance of amylase as renal failure increased.


Microwave-assisted synthesis and antimicrobial evaluation of novel spiroisoquinoline and spiropyrido[4,3-d]pyrimidine derivatives.
Bromination of N-substituted homophthalimides and tetrahydropyrido[4,3-d]- pyrimidine-5,7-diones produces 4,4-dibromohomophthalimide and 8,8-dibromo-tetrahydropyrido[4,3-d]pyrimidine-5,7-dione derivatives, respectively, that can be used as precursors for spiro derivatives. The dibromo derivatives react with different binucleophilic reagents to produce several spiroisoquinoline and spirotetrahydropyrido[4,3-d]- pyrimidine-5,7-dione derivatives, respectively. Reaction of the dibromo derivatives with malononitrile produces dicyanomethylene derivatives which react with different binucleophiles to produce new spiro derivatives. All new compounds are prepared by using the usual chemical conditions and microwave assisted conditions. The latter conditions improved the reaction yields, reduced reaction times and ameliorated the effects on the surrounding environment as the reactions are carried out in closed systems. Structures of the newly synthesized compounds are proved using spectroscopic methods such as IR, MS, 1H-NMR and 13C-NMR and elemental analyses. Some of the newly synthesized compounds were tested for their antimicrobial activities, whereby four of them showed moderate activities and the rest showed low or no activities towards the investigated species.


Effect of replacement of the amino and the carboxyl termini of rat testis fructose 6-phosphate, 2-kinase:fructose 2,6-bisphosphatase with those of the liver and heart isozymes.
Fru 6-P,2-kinase:Fru 2,6-Pase is a bifunctional enzyme, consisting of highly conserved catalytic domains and variable regulatory domains. The regulatory domains reside in either the N- or the C-terminus, depending upon the isozyme. The rat testis enzyme (RT2K) lacks the regulatory domain, but the rat liver and the bovine heart enzymes contain phosphorylation site(s) in the N- and the C-termini, respectively. In order to determine whether the regulatory domains can be swapped, we have constructed mutant enzymes in which the N- or the C-terminal tail of the testis enzyme was replaced with that of either the liver or the heart enzyme. The substitution with the N-terminus of the liver enzyme (RLN-RT2K) resulted in a small change in the kinetic properties of Fru 6-P,2-kinase, but that with the heart enzyme increased the KFru 6-P 18-fold without affecting the Vmax. The substitution with the C-terminus of the heart enzyme had little effect. The phosphorylation of RLN-RT2K increased KFru 6-P fivefold as in the liver enzyme but did not affect the Fru 2,6-Pase, unlike the liver enzyme. All these mutant enzymes were more thermally labile than the wild type testis enzyme. RLN-RT2K was more sensitive to the denaturant. These results suggest that the N-terminus of the liver enzyme could interact with the kinase domain of the testis enzyme, regulating the kinase activity but was unable to affect the phosphatase domain. These differences could be explained by the large differences in net charges of the terminal tails.


A Machine Learning Approach for Sex and Age Classification of Paediatric EEGs.
Electroencephalography (EEG) is an important investigation of childhood seizures and other brain disorders. Expert visual analysis of EEGs can estimate subjects' age based on the presence of particular maturational features. The sex of a child, however, cannot be determined by visual inspection. In this study, we explored sex and age differences in the EEGs of 351 healthy male and female children aged between 6 and 10 years. We developed machine learning-based methods to classify the sex and age of healthy children from their EEGs. This preliminary study based on small EEG numbers demonstrates the potential for machine learning in helping with age determination in healthy children. This may be useful in distinguishing developmentally normal from developmentally delayed children. The model performed poorly for estimation of biological sex. However, we achieved 66.67% accuracy in age prediction allowing a 1 year error, on the test set.


Application of a Human Blood Brain Barrier Organ-on-a-Chip Model to Evaluate Small Molecule Effectiveness against Venezuelan Equine Encephalitis Virus.
The blood brain barrier (BBB) is a multicellular microenvironment that plays an important role in regulating bidirectional transport to and from the central nervous system (CNS). Infections by many acutely infectious viruses such as alphaviruses and flaviviruses are known to impact the integrity of the endothelial lining of the BBB. Infection by Venezuelan Equine Encephalitis Virus (VEEV) through the aerosol route causes significant damage to the integrity of the BBB, which contributes to long-term neurological sequelae. An effective therapeutic intervention strategy should ideally not only control viral load in the host, but also prevent and/or reverse deleterious events at the BBB. Two dimensional monocultures, including trans-well models that use endothelial cells, do not recapitulate the intricate multicellular environment of the BBB. Complex in vitro organ-on-a-chip models (OOC) provide a great opportunity to introduce human-like experimental models to understand the mechanistic underpinnings of the disease state and evaluate the effectiveness of therapeutic candidates in a highly relevant manner. Here we demonstrate the utility of a neurovascular unit (NVU) in analyzing the dynamics of infection and proinflammatory response following VEEV infection and therapeutic effectiveness of omaveloxolone to preserve BBB integrity and decrease viral and inflammatory load.


Human herpesviruses in chronic fatigue syndrome.
We have conducted a double-blind study to assess the possible involvement of the human herpesviruses (HHVs) HHV6, HHV7, Epstein-Barr virus (EBV), and cytomegalovirus in chronic fatigue syndrome (CFS) patients compared to age-, race-, and gender-matched controls. The CFS patient population was composed of rigorously screened civilian and Persian Gulf War veterans meeting the Centers for Disease Control and Prevention's CFS case definition criteria. Healthy control civilian and veteran populations had no evidence of CFS or any other exclusionary medical or psychiatric condition. Patient peripheral blood mononuclear cells were analyzed by PCR for the presence of these HHVs. Using two-tailed Fisher's exact test analyses, we were unable to ascertain any statistically significant differences between the CFS patient and control populations in terms of the detection of one or more of these viruses. This observation was upheld when the CFS populations were further stratified with regard to the presence or absence of major axis I psychopathology and patient self-reported gradual versus acute onset of disease. In tandem, we performed serological analyses of serum anti-EBV and anti-HHV6 antibody titers and found no significant differences between the CFS and control patients.


Chronic inactivation of a neural circuit enhances LTP by inducing silent synapse formation.
Chronic inactivation of a neural network is known to induce homeostatic upregulation of synaptic strength, a form of synaptic plasticity that differs from Hebbian-type synaptic plasticity in that it is not input-specific, but involves all synapses of an individual neuron. However, it is unclear how homeostatic and Hebbian synaptic plasticity interact in the same neuron. Here we show that long-term potentiation (LTP) at Schaffer collateral-CA1 synapses is greatly enhanced in cultured mouse hippocampal slices after chronic (60 h) network-activity blockade with tetrodotoxin (TTX). This increase in LTP is not due to an altered synaptic NMDA receptor composition or presynaptic function. Instead, we found that silencing neural network activity not only increases the abundance of both AMPA and NMDA receptors at existing synapses as previously described, but also promotes the presence of new glutamatergic synapses that contain only NMDA receptors-a class of synapses that are functionally silent due to the absence of AMPA receptors. Induction of LTP in TTX-treated neurons leads to insertion of AMPA receptors into the silent synapses, thereby "switching on" these silent synapses, which produces the observed enhancement of LTP magnitude. Our findings suggest that homeostatic synaptic plasticity manifests not only in the adjustment of the strength of existing synapses, but also in the modulation of new synapse formation/maintenance. Moreover, presence of new but functionally silent synapses enables more robust LTP to occur through rapid conversion of silent synapses to active synapses, resulting in a stronger input-specific modulation of synapses following prolonged network silencing.


Chemical computing with reaction-diffusion processes.
Chemical reactions are responsible for information processing in living organisms. It is believed that the basic features of biological computing activity are reflected by a reaction-diffusion medium. We illustrate the ideas of chemical information processing considering the Belousov-Zhabotinsky (BZ) reaction and its photosensitive variant. The computational universality of information processing is demonstrated. For different methods of information coding constructions of the simplest signal processing devices are described. The function performed by a particular device is determined by the geometrical structure of oscillatory (or of excitable) and non-excitable regions of the medium. In a living organism, the brain is created as a self-grown structure of interacting nonlinear elements and reaches its functionality as the result of learning. We discuss whether such a strategy can be adopted for generation of chemical information processing devices. Recent studies have shown that lipid-covered droplets containing solution of reagents of BZ reaction can be transported by a flowing oil. Therefore, structures of droplets can be spontaneously formed at specific non-equilibrium conditions, for example forced by flows in a microfluidic reactor. We describe how to introduce information to a droplet structure, track the information flow inside it and optimize medium evolution to achieve the maximum reliability. Applications of droplet structures for classification tasks are discussed.


Workflow for the Quantification of Soluble and Insoluble Carbohydrates in Soybean Seed.
Soybean seed composition has a profound impact on its market value and commercial use as an important commodity. Increases in oil and protein content have been historically pursued by breeders and genetic engineers; consequently, rapid methods for their quantification are well established. The interest in complete carbohydrate profiles in mature seeds, on the other hand, has recently increased due to numerous attempts to redirect carbohydrates into oil and protein or to offer specialty seed with a specific sugar profile to meet animal nutritional requirements. In this work, a sequential protocol for quantifying reserve and structural carbohydrates in soybean seed was developed and validated. Through this procedure, the concentrations of soluble sugars, sugar alcohols, starch, hemicellulose, and crystalline cellulose can be determined in successive steps from the same starting material using colorimetric assays, LC-MS/MS, and GC-MS. The entire workflow was evaluated using internal standards to estimate the recovery efficiency. Finally, it was successfully applied to eight soybean genotypes harvested from two locations, and the resulting correlations of carbohydrate and oil or protein are presented. This methodology has the potential not only to guide soybean cultivar optimization processes but also to be expanded to other crops with only slight modifications.


Conservation genetics and evolution in an endangered species: research in Sonoran topminnows.
Conservation genetics of endangered species has primarily focused on using neutral markers to determine units of conservation and estimating evolutionary parameters. Because the endangered Sonoran topminnow can be bred in the laboratory and has a relatively short generation length, experiments to examine both detrimental and adaptive variations are also possible. Here, we discuss over two decades of empirical and experimental observations in the Sonoran topminnow. Results from this research have been used to determine species and evolutionary significant units using neutral markers, document inbreeding and outbreeding depression and genetic load using experimental crosses, and measure adaptive differences in fitness-related traits and variation in pathogen resistance among populations and major histocompatibility complex genotypes. In addition, both premating and postmating reproductive isolation between Gila and Yaqui topminnows have been experimentally determined, and the predicted and observed ancestry of these two species in experimental crosses has been examined over time. Although some have suggested that endangered species are unsuitable for experimentation because of both practical and ethical considerations, these results demonstrate that in this case an endangered species can be employed to examine fundamental questions in conservation and evolution.


Diethylene glycol poisoning in Gurgaon, India, 1998.
To discover the cause of acute renal failure in 36 children aged 2 months to 6 years who were admitted to two hospitals in Delhi between 1 April and 9 June 1998. Data were collected from hospital records, parents and doctors of the patients, and district health officials. Further information was obtained from house visits and community surveys; blood and stool samples were collected from other ill children, healthy family members and community contacts. Samples of drinking-water and water from a tube-well were tested for coliform organisms. Most of the children (26/36) were from the Gurgaon district in Haryana or had visited Gurgaon town for treatment of a minor illness. Acute renal failure developed after an episode of acute febrile illness with or without watery diarrhoea or mild respiratory symptoms for which the children had been treated with unknown medicines by private medical practitioners. On admission to hospital the children were not dehydrated. Median blood urea concentration was 150 mg/dl (range 79-311 mg/dl) and median serum creatinine concentration was 5.6 mg/dl (range 2.6-10.8 mg/dl). Kidney biopsy showed acute tubular necrosis. Thirty-three children were known to have died despite being treated with peritoneal dialysis and supportive therapy. Cough expectorant manufactured by a company in Gurgaon was found to be contaminated with diethylene glycol (17.5% v/v), but a sample of acetaminophen manufactured by the same company tested negative for contamination when gas-liquid chromatography was used. Thus, poisoning with diethylene glycol seems to be the cause of acute renal failure in these children.


Epistatic association mapping for alkaline and salinity tolerance traits in the soybean germination stage.
Soil salinity and alkalinity are important abiotic components that frequently have critical effects on crop growth, productivity and quality. Developing soybean cultivars with high salt tolerance is recognized as an efficient way to maintain sustainable soybean production in a salt stress environment. However, the genetic mechanism of the tolerance must first be elucidated. In this study, 257 soybean cultivars with 135 SSR markers were used to perform epistatic association mapping for salt tolerance. Tolerance was evaluated by assessing the main root length (RL), the fresh and dry weights of roots (FWR and DWR), the biomass of seedlings (BS) and the length of hypocotyls (LH) of healthy seedlings after treatments with control, 100 mM NaCl or 10 mM Na2CO3 solutions for approximately one week under greenhouse conditions. A total of 83 QTL-by-environment (QE) interactions for salt tolerance index were detected: 24 for LR, 12 for FWR, 11 for DWR, 15 for LH and 21 for BS, as well as one epistatic QTL for FWR. Furthermore, 86 QE interactions for alkaline tolerance index were found: 17 for LR, 16 for FWR, 17 for DWR, 18 for LH and 18 for BS. A total of 77 QE interactions for the original trait indicator were detected: 17 for LR, 14 for FWR, 4 for DWR, 21 for LH and 21 for BS, as well as 3 epistatic QTL for BS. Small-effect QTL were frequently observed. Several soybean genes with homology to Arabidopsis thaliana and soybean salt tolerance genes were found in close proximity to the above QTL. Using the novel alleles of the QTL detected above, some elite parental combinations were designed, although these QTL need to be further confirmed. The above results provide a valuable foundation for fine mapping, cloning and molecular breeding by design for soybean alkaline and salt tolerance.


Forskolin, adenylate cyclase, and cell physiology: an overview.
The potential of forskolin as a research tool is just beginning to be realized. Its use has revealed further subtleties to the control of cyclic AMP generation by adenylate cyclase in both solubilized and membrane preparations and in intact cells. It appears that an effect of forskolin will become one of the criteria for implicating adenylate cyclase in any physiological or biochemical response or, conversely, in ruling out an involvement of cyclic AMP. Clinical applications of forskolin as a hypotensive, spasmolytic, lipolytic, or antithrombotic agents or for the treatment of glaucoma or cardiac insufficiency remain other challenges for the future.


Exploring relationships among psychosocial status, dietary quality, and measures of placental development during the first trimester in low-income women.
To examine the relationships between maternal psychosocial factors and dietary quality and explore the relationships among dietary quality and selected biomarkers of nutrition and placental development. A cross-sectional design in 18 low-income, pregnant women. Partner support was positively related to vegetable intake (r = .54) and negatively related to intake of iron (r = -.68) and grains (r = -.67). Emotional eating in response to anger was negatively related to intake of iron-(r /it> = -.53) and folate-rich (r = -.75) foods, and emotional eating in response to anxiety was negatively related to intake of folate-rich foods (r = -.51). Depressed women had an increased intake of calcium-rich foods (r = .60). Levels of vascular endothelial growth factor (VEGF) were negatively related to depression (r = -.56) and intake of foods high in calcium (r = -.53) and iron (r = -.34) but positively related to serum calcium levels (r = .60). VEGF was negatively relationship to soluble fms-like tyrosine kinase 1 (sFlt-1; r = -.56). Placental growth factor had a negative relationship with maternal serum levels of albumin (r = -.61) and calcium (r = -.65). Low-income pregnant women who eat to cope with anger and anxiety may have an inadequate intake of nutrients that contribute to positive pregnancy outcomes. Placental development in the early weeks of pregnancy may be influenced by maternal psychosocial and nutritional status. More research is needed to explore the relationship of dietary quality and placental development in the first trimester of pregnancy.


Synthesis and Characterization of Biopolyol-Based Waterborne Polyurethane Modified through Complexation with Chitosan.
In this study, a series of castor oil-based anionic waterborne polyurethane (CWPU) systems, which it has been suggested may be suitable for use as green elastomers with diverse applications in films and coatings, was prepared by modified with O-carboxymethyl chitosan (CS) as not only a reinforcing filler, but a chain-extender of polyurethane prepolymer to enhance the properties of polyurethanes. Moreover, not only was the system obtained with castor oil-based polyol in the absence of a catalyst, but it was maintained with low viscosity by using acetone instead of toxic methyl ethyl ketone (MEK) during the synthesis process. The sizes, zeta potential, chemical formation, and morphology of the CWPU-CS composites had been investigated by dynamic light scattering (DLS), infrared spectroscopy (IR), and scanning electron microscopy (SEM). Moreover, the results show that the modification allows to enhance storage/loss modulus, tensile properties, thermal stability at high temperature, and biocompatibility of CWPU and CWPU/CS nanocomposites according to various contents of CS.


Zebrafish genomic instability mutants and cancer susceptibility.
Somatic loss of tumor suppressor gene function comprising the second hit of Knudson's two-hit hypothesis is important in human cancer. A genetic screen was performed in zebrafish (Danio rerio) to find mutations that cause genomic instability (gin), as scored by Streisinger's mosaic-eye assay that models this second hit. The assay, based on a visible test for loss of wild-type gene function at a single locus, golden, is representative of genomewide events. Twelve ENU-induced genomic instability (gin) mutations were isolated. Most mutations showed weak dominance in heterozygotes and all showed a stronger phenotype in homozygotes. Trans-heterozygosity for 7 of these mutations showed greatly enhanced instability. A variety of spontaneous tumors were found in heterozygous adults from all gin lines, consistent with the expectation that genomic instability (mutator) mutations can accelerate carcinogenesis. The incidence of spontaneous cancer at 30-34 months was increased 9.6-fold in heterozygotes for the mutant with the strongest phenotype, gin-10. Tumors were seen in skin, colon, kidney, liver, pancreas, ovary, testis, and neuronal tissues, with multiple tumors in some fish. The study of these mutants will add to our understanding of the mechanisms of somatic loss of gene function and how those mechanisms contribute to cancer susceptibility.


Thermodiffusion anisotropy under a magnetic field in ionic liquid-based ferrofluids.
Ferrofluids based on maghemite nanoparticles (NPs), typically 10 nm in diameter, are dispersed in an ionic liquid (1-ethyl 3-methylimidazolium bistriflimide - EMIM-TFSI). The average interparticle interaction is found to be repulsive by small angle scattering of X-rays and of neutrons, with a second virial coefficient A2 = 7.3. A moderately concentrated sample at Φ = 5.95 vol% is probed by forced Rayleigh scattering under an applied magnetic field (up to H = 100 kA m-1) from room temperature up to T = 460 K. Irrespective of the values of H and T, the NPs in this study are always found to migrate towards the cold region. The in-field anisotropy of the mass diffusion coefficient Dm and that of the (always positive) Soret coefficient ST are well described by the presented model in the whole range of H and T. The main origin of anisotropy is the spatial inhomogeneities of concentration in the ferrofluid along the direction of the applied field. Since this effect originates from the magnetic dipolar interparticle interaction, the anisotropy of thermodiffusion progressively vanishes when temperature and thermal motion increase.