Treatment of buffalo (Bubalus bubalis) donor cells with trichostatin A and 5-aza-2'-deoxycytidine alters their growth characteristics, gene expression and epigenetic status and improves the in vitro developmental competence, quality and epigenetic status of cloned embryos.
We examined the effects of treating buffalo skin fibroblast donor cells with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, and 5-aza-2'-deoxycytidine (5azadC), a DNA methyltransferase (DNMT) inhibitor, on the cells and embryos produced by hand-made cloning. Treatment of donor cells with TSA or 5azadC resulted in altered expression levels of the HDAC1, DNMT1, DNMT3a, P53, CASPASE3 and CASPASE9 genes and global levels of acetylation of lysine at position 9 or 14 in histone 3 (H3K9/14ac), acetylation of lysine at position 5 in histone 4 (H4K5ac), acetylation of lysine at position 18 in histone 3 (H3K18ac) and tri-methylation of lysine at position 27 in histone 3 (H3K27me3). Moreover, global levels of DNA methylation and activity of DNMT1 and HDAC1 were decreased, while global acetylation of H3 and H3K9 was significantly increased in comparison to untreated cells. Simultaneous treatment of donor cells with TSA (50nM) and 5azadC (7.5nM) resulted in higher in vitro development to the blastocyst stage, reduction of the apoptotic index and the global level of H3K27 me3 and altered expression levels of HDAC1, P53, CASPASE3, CASPASE9 and DNMT3a in cloned blastocysts. Transfer of cloned embryos produced with donor cells treated with TSA led to the birth of a calf that survived for 21 days. These results show that treatment of buffalo donor cells with TSA and 5azadC improved developmental competence and quality of cloned embryos and altered their epigenetic status and gene expression, and that these beneficial effects were mediated by a reduction in DNA and histone methylation and an increase in histone acetylation in donor cells.


Overexpression of a pea DNA helicase (PDH45) in peanut (Arachis hypogaea L.) confers improvement of cellular level tolerance and productivity under drought stress.
Peanut, a major edible oil seed crop globally is predominantly grown under rainfed conditions and suffers yield losses due to drought. Development of drought-tolerant varieties through transgenic technology is a valid approach. Besides superior water relation traits like water mining, intrinsic cellular level tolerance mechanisms are important to sustain the growth under stress. To achieve this objective, the focus of this study was to pyramid drought adaptive traits by overexpressing a stress responsive helicase, PDH45 in the background of a genotype with superior water relations. PCR, Southern, and RT-PCR analyses confirmed stable integration and expression of the PDH45 gene in peanut transgenics. At the end of T₃ generation, eight transgenic events were identified as promising based on stress tolerance and improvement in productivity. Several transgenic lines showed stay-green phenotype and increased chlorophyll stability under stress and reduced chlorophyll retardation under etherel-induced simulated stress conditions. Stress-induced root growth was also substantially higher in the case of transformants. This was reflected in increased WUE (low Δ¹³C) and improved growth rates and productivity. The transgenics showed 17.2 and 26.75 % increase in yield under non-stress and stress conditions over wild type ascertaining the feasibility of trait pyramiding strategy for the development of drought-tolerant peanut.


Effect of branched conjugation structure on the optical, electrochemical, hole mobility, and photovoltaic properties of polythiophenes.
Four branched polythiophenes (PTs) with different ratios of conjugated terthiophene-vinylene side chains, PT-TThV10 to PT-TThV40, were synthesized by Stille coupling reaction. The polymers exhibited reversible p-doping/dedoping (oxidation/re-reduction) and n-doping/dedoping (reduction/reoxidation) processes. The absorption spectra, hole mobility, and photovoltaic properties of the polymers were much improved in comparison with the PT derivative without the terthiophene-vinylene side chain and were influenced by the content of the conjugated side chains. With the increase of the content of the conjugated side chains, the absorption peak of the branched PTs enhanced and blue-shifted. The maximum hole mobility reached 6.35 x 10(-4) cm2/V.s (SCLC method) and the maximum power conversion efficiency of the polymer solar cell reached 1.91% under the illumination of AM 1.5, 100 mW/cm2, for the polymer with 20% terthiophene-vinylene side chains. The results indicate that the branched PTs with suitable content of the terthiophene-vinylene side chains could be promising photovoltaic materials.


Acute liver failure in pregnancy associated with maternal MCAD deficiency.
In recent years the association between severe pregnancy complications and fetal fatty acid oxidation (FAO) disorders has been reported. However, there are few descriptions of a maternal FAO disorder leading to these complications. We describe acute liver failure associated with an undiagnosed maternal medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. The previously healthy proband presented at the 39th week with an itchy rash, palmar erythema and trace proteinuria; she was admitted onto a maternity ward. Acute fatty liver was suspected from the blood tests and a Caesarean section was performed, delivering a healthy boy. Cord blood samples were taken at delivery as part of an ongoing research project. The analysis of the cord blood sample showed a high concentration of octanoylcarnitine of 2.3 micromol/L (reference <0.1), suggesting a possible fatty acid oxidation disorder. However, subsequent acylcarnitine analyses of the baby's blood showed a normal pattern. The proband was further evaluated by urine organic acids and acylcarnitine profile. Elevated concentrations of hexanoylglycine in urine and octanoylcarnitine in blood spots were found, consistent with a diagnosis of MCAD deficiency. Mutation analyses confirmed that she was homozygous for c.985A>G (K329E). Even though these pregnancy complications are rare and it is not possible to affirm that the proband's acute liver failure was secondary to an undiagnosed MCAD deficiency, it seems likely.


Prevalence of plasma autoantibody against cancer testis antigen NY-ESO-1 in HTLV-1 infected individuals with different clinical status.
Detection of specific immune responses against cancer/testis antigen NY-ESO-1 was recently reported in patients with adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-infected asymptomatic carriers (ACs). However, the relationship of the responses with the HTLV-1 proviral load (PVL) and the levels of viral gene expression remain unclear. We measured plasma levels of autoantibodies to NY-ESO-1 immunogenic tumor antigen in HTLV-1-infected individuals with different clinical status, and in healthy controls. Data were compared to tax and HBZ mRNA levels, and PVL. Plasma anti-NY-ESO-1 antibody was detectable in 13.7% (7/51) of ACs, 29.2% (38/130) of patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), and 18.9% (10/53) of patients with ATL. Anti-NY-ESO-1 plasma levels were significantly higher in patients with HAM/TSP than in patients with ATL or ACs. Anti-NY-ESO-1 levels were not associated with PVL or the expression levels of tax and HBZ mRNA among HTLV-1-infected individuals, regardless of clinical status. The present results indicate the strong humoral immune response against NY-ESO-1 in natural HTLV-1 infection, irrespective of the clinical status. The higher immunoreactivity against NY-ESO-1 is not simply associated with the levels of both HTLV-1 gene expression and the number of infected cells in vivo. Rather, it might reflect chronic and generalized immune activation in infected individuals.


Pesticide residues in eggs and chicks from laying hens fed low levels of several chlorinated hydrocarbon pesticides.
Eighty-four Single-Comb While Leghorn laying hens housed individually in laying cages were fed rations containing less than 0.1 p.p.m. of dieldrin, DDT, heptachlor and mirex individually or in combination for 7 days and in combination for 15 weeks. DDT residues in egg yolk reached 0.043 p.p.m. by 7 days when fed in combination with the other pesticides. None of the residues were above FDA action level at 7 days and all had declined to below trace levels by 8 weeks after termination of pesticide feeding. Residues in eggs from hens fed all four pesticides for 15 weeks increased steadily for the first few weeks and then reached a plateau or increased only slightly until pesticide feeding was terminated. By the end of the 5th week of pesticide feeding all pesticides except DDT had exceeded FDA action levels for pesticides in eggs. DDT residues reached a level of 0.139 p.p.m. by 8 weeks and did not increase thereafter. Traces of the pesticides were still present 24 weeks after termination of pesticide feeding. The pesticides tested did not affect fertility of hatchability of eggs collected during the 14th and 15th weeks of pesticide feeding. Total carcass fat of chicks hatched from these eggs had 0.024 p.p.m. dieldrin, .049 p.p.m. DDT, .001 p.p.m. heptachlor epoxide and, 0.47 mirex at 1 day of age.


Modulation of inflammatory pathways, medicinal uses and toxicities of Uvaria species: potential role in the prevention and treatment of inflammation.
The therapeutic efficacy of the contemporary anti-inflammatory drugs are well established; however, prolonged use of such can often lead to serious and life-threatening side effects. Natural product-based anti-inflammatory compounds with superior efficacy and minimum toxicity can serve as possible therapeutic alternatives in this scenario. Genus Uvaria is a part of Annonaceae family, while the majority of its species are widely distributed in tropical rain forest regions of South East Asia. Uvaria species have been used extensively used as traditional medicine for treating all sorts of inflammatory diseases including catarrhal inflammation, rheumatism, acute allergic reactions, hemorrhoids, inflammatory liver disease and inflamed joints. Phytochemical analysis of Uvaria species has revealed flavones, flavonoids, tannins, saponins, polyoxygenated cyclohexene and phenolic compounds as major phyto-constituents. This review is an attempt to highlight the anti-inflammatory activity of Uvaria species by conducting a critical appraisal of the published literature. The ethnopharmacological relevance of Uvaria species in the light of toxicological studies is also discussed herein. An extensive and relevant literature on anti-inflammatory activity of Uvaria species was collected from available books, journals and electronic databases including PubMed, ScienceDirect, Scopus, Proquest and Ovid. Extracts and isolates of Uvaria species exhibited significant anti-inflammatory activity through various mechanisms of action. 6,7-di-O-Methyl-baicalein, flexuvarol B, chrysin, (-)-zeylenol, 6-hydroxy-5,7-dimethoxy-flavone, and pinocembrin were the most potent anti-inflammatory compounds with comparable IC50 with positive controls. Therefore, it is suggested that further research should be carried out to determine the pharmacokinetics, pharmacodynamics and toxicity of these therapeutically significant compounds, to convert the pre-clinical results into clinical data for drug development and design.


The k-space origins of scattering in Bi2Sr2CaCu2O8+x.
We demonstrate a general, computer automated procedure that inverts the reciprocal space scattering data (q-space) that are measured by spectroscopic imaging scanning tunnelling microscopy (SI-STM) in order to determine the momentum space (k-space) scattering structure. This allows a detailed examination of the k-space origins of the quasiparticle interference (QPI) pattern in Bi2Sr2CaCu2O8+x within the theoretical constraints of the joint density of states (JDOS). Our new method allows measurement of the differences between the positive and negative energy dispersions, the gap structure and an energy dependent scattering length scale. Furthermore, it resolves the transition between the dispersive QPI and the checkerboard ([Formula: see text] excitation). We have measured the k-space scattering structure over a wide range of doping (p ∼ 0.22-0.08), including regions where the octet model is not applicable. Our technique allows the complete mapping of the k-space scattering origins of the spatial excitations in Bi2Sr2CaCu2O8+x, which allows for better comparisons between SI-STM and other experimental probes of the band structure. By applying our new technique to such a heavily studied compound, we can validate our new general approach for determining the k-space scattering origins from SI-STM data.


Comparison of oocyte-activating agents for mouse cloning.
Since somatic cell components are unable to activate oocytes following injection or fusion, enucleated oocytes receiving adult somatic cells during the cloning process must be activated artificially for their development. We compared the efficiency of four types of oocyte-activating agents: strontium, ethanol, single electric pulse, and spermatozoa. Although strontium was the best in supporting preimplantation development of reconstructed mouse oocytes, there was no significant difference among the four agents with respect to the rate of postimplantation embryo development and the birth of live offspring.


Influence of synthesis pH and oxidative strength of the catalyzing acid on the morphology and chemical structure of hydrothermal carbon.
A specific control of the morphology and chemical structure of hydrothermal carbon (HTC) is of crucial importance for its application, both in catalyst supports or electrochemical devices. Here we show how the morphology, that is, particles size and homogeneity, and the distribution of functional groups can be controlled by the control of the synthesis pH of the hydrothermal carbonization. A complementary analysis of liquid byproducts by HPLC provides useful information on the nature of the polymeric species produced during the poly-condensation in the hydrothermal process and reveals the potential implementation of the process into the biorefinery concept. The acidic byproducts levulinic acid and formic acid determine the hydrothermal carbonization autocatalytically by additional supply of protons to the reaction medium. Thus, for a starting pH>3, only minor structural differences can be detected for HTC. The use of oxidizing acids favors higher yields of HTC and improves carbonization towards higher condensed carbon domains. Scaling up the process in a stirred 2 L batch reactor favors carbonization leading to higher condensed carbonaceous products. The relative trends of pH variation are maintained.


An Event-Driven Classifier for Spiking Neural Networks Fed with Synthetic or Dynamic Vision Sensor Data.
This paper introduces a novel methodology for training an event-driven classifier within a Spiking Neural Network (SNN) System capable of yielding good classification results when using both synthetic input data and real data captured from Dynamic Vision Sensor (DVS) chips. The proposed supervised method uses the spiking activity provided by an arbitrary topology of prior SNN layers to build histograms and train the classifier in the frame domain using the stochastic gradient descent algorithm. In addition, this approach can cope with leaky integrate-and-fire neuron models within the SNN, a desirable feature for real-world SNN applications, where neural activation must fade away after some time in the absence of inputs. Consequently, this way of building histograms captures the dynamics of spikes immediately before the classifier. We tested our method on the MNIST data set using different synthetic encodings and real DVS sensory data sets such as N-MNIST, MNIST-DVS, and Poker-DVS using the same network topology and feature maps. We demonstrate the effectiveness of our approach by achieving the highest classification accuracy reported on the N-MNIST (97.77%) and Poker-DVS (100%) real DVS data sets to date with a spiking convolutional network. Moreover, by using the proposed method we were able to retrain the output layer of a previously reported spiking neural network and increase its performance by 2%, suggesting that the proposed classifier can be used as the output layer in works where features are extracted using unsupervised spike-based learning methods. In addition, we also analyze SNN performance figures such as total event activity and network latencies, which are relevant for eventual hardware implementations. In summary, the paper aggregates unsupervised-trained SNNs with a supervised-trained SNN classifier, combining and applying them to heterogeneous sets of benchmarks, both synthetic and from real DVS chips.


New Directions in Health Sciences Libraries in Canada: Research and Evidence based Practice Are Key.
This article is the second in a new series in this regular feature. The intention of the series is to look at important global developments in health science libraries. These articles will serve as a road map, describing the key changes in the field and exploring factors driving these changes. The present article by two Canadian librarians identifies important national developments which are shaping the profession such as the centralisation of health care services, the challenge of providing consumer health information in the absence of a national strategy, government recognition of the need to recognise and respond to the health needs of indigenous peoples and the growing emphasis on managing research data. Although their profession is strong, health science librarians must find ways of providing enhanced services with fewer staff and demonstrate value to organisations. JM.


Generation of HLA-Universal iPSC-Derived Megakaryocytes and Platelets for Survival Under Refractoriness Conditions.
Platelet (PLT) transfusion is indispensable to maintain homeostasis in thrombocytopenic patients. However, PLT transfusion refractoriness is a common life-threatening condition observed in multitransfused patients. The most frequent immune cause for PLT transfusion refractoriness is the presence of alloantibodies specific for human leukocyte antigen (HLA) class I epitopes. Here, we have silenced the expression of HLA class I to generate a stable HLA-universal induced pluripotent stem cell (iPSC) line that can be used as a renewable cell source for the generation of low immunogenic cell products. The expression of HLA class I was silenced by up to 82% and remained stable during iPSC cultivation. In this study, we have focused on the generation of megakaryocytes (MK) and PLTs from a HLA-universal iPSC source under feeder- and xeno-free conditions. On d 19, differentiation rates of MKs and PLTs with means of 58% and 76% were observed, respectively. HLA-universal iPSC-derived MKs showed polyploidy with DNA contents higher than 4n and formed proPLTs. Importantly, differentiated MKs remained silenced for HLA class I expression. HLA-universal MKs produced functional PLTs. Notably, iPSC-derived HLA-universal MKs were capable to escape antibody-mediated complement- and cellular-dependent cytotoxicity. Furthermore, HLA-universal MKs were able to produce PLTs after in vivo transfusion in a mouse model indicating that they might be used as an alternative to PLT transfusion. Thus, in vitro produced low immunogenic MKs and PLTs may become an alternative to PLT donation in PLT-based therapies and an important component in the management of severe alloimmunized patients.


RNAi-based GM plants: food for thought for risk assessors.
RNA interference (RNAi) is an emerging technology that offers new opportunities for the generation of new traits in genetically modified (GM) plants. Potential risks associated with RNAi-based GM plants and issues specific to their risk assessment were discussed during an international scientific workshop (June 2014) organized by the European Food Safety Authority (EFSA). Selected key outcomes of the workshop are reported here.


Selection of Phototransduction Genes in Homo sapiens.
We investigated the evidence of recent positive selection in the human phototransduction system at single nucleotide polymorphism (SNP) and gene level. SNP genotyping data from the International HapMap Project for European, Eastern Asian, and African populations was used to discover differences in haplotype length and allele frequency between these populations. Numeric selection metrics were computed for each SNP and aggregated into gene-level metrics to measure evidence of recent positive selection. The level of recent positive selection in phototransduction genes was evaluated and compared to a set of genes shown previously to be under recent selection, and a set of highly conserved genes as positive and negative controls, respectively. Six of 20 phototransduction genes evaluated had gene-level selection metrics above the 90th percentile: RGS9, GNB1, RHO, PDE6G, GNAT1, and SLC24A1. The selection signal across these genes was found to be of similar magnitude to the positive control genes and much greater than the negative control genes. There is evidence for selective pressure in the genes involved in retinal phototransduction, and traces of this selective pressure can be demonstrated using SNP-level and gene-level metrics of allelic variation. We hypothesize that the selective pressure on these genes was related to their role in low light vision and retinal adaptation to ambient light changes. Uncovering the underlying genetics of evolutionary adaptations in phototransduction not only allows greater understanding of vision and visual diseases, but also the development of patient-specific diagnostic and intervention strategies.


Comparison of three different approaches in treatment of mandibular condylar fractures - Our experience.
The principal transfacial routes described to approach condylar process fractures are preauricular, retromandibular, high submandibular, and their various modifications. The selection of a specific surgical approach mainly depends on the level of condylar fracture, displacement/dislocation of the proximal segment and time elapsed from the date of trauma. Not too many studies proclaim a unanimous consensus on "gold standard" approaches for particular levels of fracture. This study was conducted with the aim to lay down guidelines for determining the ideal surgical approach for treating different condylar fractures based on different clinical situations. This prospective study was conducted on 60 patients that underwent open reduction internal fixation of condylar fractures according to preset study design. Inclusion criteria were fracture displacement more than 10 degrees, dislocation, shortening of ramal height more than 2 mm. Patients having maxillofacial fractures other than mandible and condylar fractures in edentulous patients were excluded from this study. The risk of facial nerve injury was more in endaural group and parotid fistula was more evident in retromandibular subparotid group but there was no statistical difference between the groups. The surgical scar was inconspicuous in all three groups. Excellent results were achieved in the other parameters such as mouth opening, range of motion, bite force, and occlusion with all the three approaches. Postoperative CT scan showed satisfactory anatomical reduction. This study concludes that the decision-making on the approach to be selected for any particular condylar fracture depends on the level of fracture, presence of fracture dislocation, and time elapsed from the date of trauma.


Communication about Suicide, Perceived Social Support, and Suicidal Intention in Korean Adults.
The present study investigates indirect effects of communication about suicide in interpersonal relationships and patient-provider relationships on suicidal intention via attitude, descriptive norm, injunctive norm, and self-efficacy in committing suicide among Korean adults, using longitudinal survey data. Moderation effects of perceived social support are also tested. As a result of path analysis (N = 984), communication about suicide with family, friends, and coworkers is significantly related to pro-suicide descriptive norm and pro-suicide injunctive norm. Positive attitude toward suicide, pro-suicide injunctive norm, and high self-efficacy in committing suicide are significantly related to suicidal intention. Interpersonal communication is positively related to pro-suicide injunctive norm, which in turn links to suicidal intention. Communication about suicide with healthcare professionals, however, did not show significant direct and indirect effects. Moderation effects of perceived social support are detected between interpersonal communication and pro-suicide attitude and pro-suicide injunctive norm, as well as between patient-provider communication and pro-suicide attitude.


Perioperative lumbar injection of Ringer's lactate solution in chronic subdural hematomas: a series of 100 cases.
A series of 100 patients underwent surgical treatment for chronic subdural hematomas between 1979 and 1987. The procedure consisted of craniectomy with a 30-mm trephine, irrigation and drainage of the hematoma, laceration of the outer and inner membranes, and lumbar intrathecal injection of Ringer's lactate solution for immediate cerebral reexpansion (average injection, 130 ml). This technique gave the following results: 2% mortality, 2% moderate morbidity, and 96% recovery. The recovery of the patients was rapid, and good outcome was achieved in Grade 3 and Grade 4 cases (Markwalder's classification).


Hierarchical ordering with partial pairwise hierarchical relationships on the macaque brain data sets.
Hierarchical organizations of information processing in the brain networks have been known to exist and widely studied. To find proper hierarchical structures in the macaque brain, the traditional methods need the entire pairwise hierarchical relationships between cortical areas. In this paper, we present a new method that discovers hierarchical structures of macaque brain networks by using partial information of pairwise hierarchical relationships. Our method uses a graph-based manifold learning to exploit inherent relationship, and computes pseudo distances of hierarchical levels for every pair of cortical areas. Then, we compute hierarchy levels of all cortical areas by minimizing the sum of squared hierarchical distance errors with the hierarchical information of few cortical areas. We evaluate our method on the macaque brain data sets whose true hierarchical levels are known as the FV91 model. The experimental results show that hierarchy levels computed by our method are similar to the FV91 model, and its errors are much smaller than the errors of hierarchical clustering approaches.


Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease.
Traumatic brain injury (TBI) has acute and chronic sequelae, including an increased risk for the development of Alzheimer's disease (AD). TBI-associated neuroinflammation is characterized by activation of brain-resident microglia and infiltration of monocytes; however, recent studies have implicated beta-amyloid as a major manipulator of the inflammatory response. To examine neuroinflammation after TBI and development of AD-like features, these studies examined the effects of TBI in the presence and absence of beta-amyloid. The R1.40 mouse model of cerebral amyloidosis was used, with a focus on time points well before robust AD pathologies. Unexpectedly, in R1.40 mice, the acute neuroinflammatory response to TBI was strikingly muted, with reduced numbers of CNS myeloid cells acquiring a macrophage phenotype and decreased expression of inflammatory cytokines. At chronic time points, macrophage activation substantially declined in non-Tg TBI mice; however, it was relatively unchanged in R1.40 TBI mice. The persistent inflammatory response coincided with significant tissue loss between 3 and 120 days post-injury in R1.40 TBI mice, which was not observed in non-Tg TBI mice. Surprisingly, inflammatory cytokine expression was enhanced in R1.40 mice compared with non-Tg mice, regardless of injury group. Although R1.40 TBI mice demonstrated task-specific deficits in cognition, overall functional recovery was similar to non-Tg TBI mice. These findings suggest that accumulating beta-amyloid leads to an altered post-injury macrophage response at acute and chronic time points. Together, these studies emphasize the role of post-injury neuroinflammation in regulating long-term sequelae after TBI and also support recent studies implicating beta-amyloid as an immunomodulator.


Excess mortality between 2007 and 2014 among patients with Clostridium difficile infection: a French health insurance database analysis.
The impact of Clostridium difficile infection (CDI) on mortality is controversial. To assess excess mortality due to CDI in France. Two cohorts of patients with CDI and a cohort of matched controls were extracted from a 1% representative sample of subjects covered by the general health insurance system in France (Echantillon Généraliste de Bénéficiaires database, 660,000 patients). The CDI patients were hospitalized with CDI as a principal diagnosis or an associated diagnosis between 2007 and 2014, but not in 2006. Controls were patients hospitalized between 2007 and 2014 but not hospitalized with CDI between 2006 and 2014. The one-year incidence of deaths between 2007 and 2014 was estimated and compared with that of a propensity score (PS)-matched control group with no CDI (two controls per case). The PS was calculated with the following variables: age; sex; Charlson Comorbidity Index score; duration of stay; year of index stay; and main comorbidities. Cox and Poisson models were used to estimate the increased risk of death while adjusting for PS. Sensitivity analyses (timeframe, diarrhoea, recurrent hospitalization for CDI) were used to explore the robustness of the results. In total, 482 patients who had been infected with C. difficile were matched with 964 controls. A significantly higher risk of death was observed among the subjects with CDI, with a non-adjusted hazard ratio of 1.65 [95% confidence interval (CI) 1.33-2.04] and an adjusted ratio of 1.58 (95% CI 1.27-1.97). The adjusted relative risk of death was 1.78 (95% CI 1.18-2.70]) at 28 days, 1.52 (95% CI 1.17-1.98) at three months, 1.52 (95% CI 1.20-1.93) at six months and 1.64 (95% CI 1.32-2.03) at 12 months. Sensitivity analyses produced similar results; the hazard ratio ranged from 1.53 to 1.86, and was always statistically significant. CDI is responsible for excess mortality after taking age, sex, comorbidities and length of hospital stay into account.


Role for formin-like 1-dependent acto-myosin assembly in lipid droplet dynamics and lipid storage.
Lipid droplets (LDs) are cellular organelles specialized in triacylglycerol (TG) storage undergoing homotypic clustering and fusion. In non-adipocytic cells with numerous LDs this is balanced by poorly understood droplet dissociation mechanisms. We identify non-muscle myosin IIa (NMIIa/MYH-9) and formin-like 1 (FMNL1) in the LD proteome. NMIIa and actin filaments concentrate around LDs, and form transient foci between dissociating LDs. NMIIa depletion results in decreased LD dissociations, enlarged LDs, decreased hydrolysis and increased storage of TGs. FMNL1 is required for actin assembly on LDs in vitro and for NMIIa recruitment to LDs in cells. We propose a novel acto-myosin structure regulating lipid storage: FMNL1-dependent assembly of myosin II-functionalized actin filaments on LDs facilitates their dissociation, thereby affecting LD surface-to-volume ratio and enzyme accessibility to TGs. In neutrophilic leucocytes from MYH9-related disease patients NMIIa inclusions are accompanied by increased lipid storage in droplets, suggesting that NMIIa dysfunction may contribute to lipid imbalance in man.


Pulmonary embolism in a patient with Klippel-Trenaunay-Weber syndrome.
Klippel-Trenaunay-Weber syndrome (KTWS) is a congenital disorder characterized by cutaneous capillary malformations, venous-lymphatic anomalies, hypertrophy of soft tissue and bone in the area of increased vascularity and arteriovenous fistulas with shunting. In this article we report the case of a 25 year old man with KTWS who had multiple surgical operations because of arteriovenous malformations. He admitted with pulmonary embolism attack to the hospital although he was taking prophylactic heparin treatment. We evaluate the risk of pulmonary embolism in patients with KTWS, being aware of the risk of deep venous thrombosis in progress of the disease and the importance of early diagnosis in prognosis.


Age-dependent basal insulin patterns in children with type 1 diabetes treated with continuous subcutaneous insulin infusion.
Identifying age-dependent basal rates in type 1 diabetic children treated with continuous subcutaneous insulin infusion (CSII). CSII-treated children with type 1 diabetes exhibiting insulin requirement > 0.5 U/kg and glycated haemoglobin (HbA1c) < 8%. The study population was composed of 198 Caucasian children (111 girls) with mean age of 9.8 +/- 3.8 years, mean duration of diabetes of 4.3 +/- 3.1 years and mean HbA1c value of 6.7 +/- 0.7%. Data were evaluated for four age groups (0-6; 6-9; 9-12, 12-18 years). Basal rates records were downloaded from pump memory. HbA1c, weight, height were measured at scheduled visits. Significant differences in the average hourly basal rate between groups were observed: I gr. 0.14 versus II gr. 0.24 versus III gr. 0.39 versus IV gr. 0.72 units/h; p < 0.0001. The average hourly basal rate correlated with age, body weight, BMI, diabetes duration and total insulin daily dose. Insulin peaks were observed for: I gr. - before midnight, II gr. - before midnight and in the early morning, gr. III and IV - in the early morning. Basal insulin infusion rate profiles in well-controlled paediatric patients on CSII reflect the age-dependent amount of basal insulin (20-40%) and affect circadian distribution of insulin needs.


Associations of menopausal vasomotor symptoms with fracture incidence.
Vasomotor symptoms (VMS) are common. Whether VMS are associated with fracture incidence or bone mineral density (BMD) levels is unknown. This study aimed to examine associations of baseline VMS with fracture incidence and BMD. This was a prospective observational study with mean (SD) followup of 8.2 (1.7) years (1993-2005). Forty United States clinical centers. We examined data from Women's Health Initiative Clinical Trial participants (n = 23 573) age 50-79 years not using menopausal hormone therapy, and 4,867 participants of the BMD sub-study. None. We measured baseline VMS, incident adjudicated fractures, and BMD (baseline, annual visits 1, 3, 6, and 9). After adjustment for baseline age, body mass index, race/ethnicity, smoking, and education, the hazard ratio for hip fracture among women with baseline moderate/severe VMS (vs no VMS) was 1.78 (95% confidence interval [CI], 1.20-2.64; P = .01). There was no association between VMS and vertebral fracture. VMS severity was inversely associated with BMD during followup (P = .004 for femoral neck, P = .045 for lumbar spine). In repeated measures models, compared with women who reported no VMS, women with moderate/severe VMS had 0.015 g/cm(2) lower femoral neck BMD (95% CI, -0.025--0.005) and 0.016 g/cm(2) lower lumbar spine BMD (95% CI, -0.032--0.004). Women with moderate/severe VMS have lower BMD and increased hip fracture rates. Elucidation of the biological mechanisms underlying these associations may inform the design of preventive strategies for at-risk women prior to occurrence of fracture.


Additional Clinical Value for PET/MRI in Oncology: Moving Beyond Simple Diagnosis.
Initial clinical research comparing the diagnostic performance of PET/MRI and PET/CT has largely shown equivalent diagnostic capabilities for these modalities in oncology. These uncertainties about the magnitude of diagnostic benefit are compounded by the considerable health economic challenges associated with clinical implementation. Therefore, there is a need to identify ways to extend the use of this technology beyond simple diagnosis so that PET/MRI can add sufficient clinical value beyond PET/CT or MRI alone and become a cost-effective imaging modality in clinical practice. A major advantage of PET/MRI over other imaging modalities is the ability to generate multiple quantitative images from a single examination. This article describes how a multiparametric PET/MRI approach not only can add clinical value through contributing to precision medicine but also can establish PET/MRI as a potentially cost-effective imaging modality in oncology.


Ribonuclease E is involved in the processing of 5-S rRNA from a number of rRNA transcription units.
Strains of Escherichia coli having a thermosensitive RNase E produce a number of 5-S ribosomal RNA precursors at a non-permissive temperature. One of these precursors, 9-S RNA, was reported earlier [Ghora, B.K. and Apirion, D. (1978) Cell, 15, 1055-1066]. Here we show the existence of additional precursors to 5-S rRNA, originating from a number of rRNA genes. All the precursors are very similar in the first 200 nucleotides and the last part of this sequence contains the mature 5-S rRNA. Precursors that contain only these nucleotides (8-S RNA) accumulate. They probably originate from the rrn genes C, D and F which contain trailer tRNAs. The 9-S RNA precursors contain in addition a termination stem and loop structure and are derived from genes which do not contain trailer tRNA (Singh and Apirion, unpublished results). In addition, a 10-S precursor was identified. It contains distal to the 5-S rRNA a trailer tRNA, tRNAAsp, and a transcription termination signal. It is derived from the rrnF gene. The accumulation of an RNA precursor containing an RNase P site in an rne mutant suggests that the efficiency of one RNA processing enzyme depends on the activity of other RNA processing enzymes.


A novel beta 1 integrin-dependent mechanism of leukocyte adherence to apoptotic cells.
Adherence of leukocytes to cells undergoing apoptosis has been reported to be dependent on a variety of recognition pathways. These include alpha V beta 3 (CD51/CD61, vitronectin receptor), CD36 (thrombospondin receptor), macrophage class A scavenger receptor, phosphatidylserine translocated to the outer leaflet of apoptotic cell membranes, and CD14 (LPS-binding protein). We investigated the mechanism by which leukocytes adhere to apoptotic endothelial cells (EC). Peripheral blood mononuclear leukocytes and U937 monocytic cells adhered to human or bovine aortic EC induced to undergo apoptosis by withdrawal of growth factors, treatment with the promiscuous protein kinase inhibitor staurosporine, with the protein synthesis inhibitor and protein kinase activator anisomycin, or with the combination of cycloheximide and TNF-alpha. Expression of endothelial adherence molecules such as CD62E (E-selectin), CD54 (ICAM-1), and CD106 (VCAM-1) was not induced or increased by these treatments. A mAb to alpha V beta 3, exogenous thrombospondin, or blockade of phosphatidylserine by annexin V did not inhibit leukocyte adherence. Further, leukocyte binding to apoptotic EC was completely blocked by treatment of leukocytes but not EC with mAb to beta 1 integrin. These results define a novel pathway for the recognition of apoptotic cells.


[Obesity, a main risk factor for endometrial cancer].
obesity is a well-known risk factor for endometrial cancer, and both diseases are rising in Mexico. However, in our country some data indicates low influence of obesity on this neoplasm, and this is contradictory. Therefore, we explore the prevalence of obesity on women affected with this malignant tumor. this was a pilot case-control study in a general hospital at Mexico City. The analysis involved obesity (a body mass index ≥ 30 kg/m(2)) diabetes mellitus and systemic arterial hypertension. the sample was of 66 women: 22 cases and 44 controls. In cases, obesity occurred in 77 % (odds ratio [OR] 8.1, 95 % confidence interval [CI] 2.46-26.6); diabetes mellitus in 41 % (OR 4.3, CI 1.31-14.7); and systemic arterial hypertension in 41 % (OR 2.3, CI 0.78-7.1). these preliminary results suggested that obesity was the most frequent risk factor for these women with endometrial cancer.


Biocompatible Soft Nanoparticles with Multiple Morphologies Obtained from Nanoprecipitation of Amphiphilic Graft Copolymers in a Backbone-Selective Solvent.
Stealth nanocarriers are a promising technology for the treatment of diseases. However, the preparation and characterization of well-defined soft nanoparticulate systems remain challenging. Here we describe a platform of amphiphilic graft copolymers leading to nanoparticles with multiple morphologies and the role of the hydrophilic backbone in their interaction with a model protein. The amphiphilic graft copolymers platform was composed of hydrophilic backbone poly(2-methyl-2-oxazoline-co-2-pentyl-2-oxazoline) (P(MeOx-co-PentOx)), prepared via cationic ring-opening polymerization. Hydrophobic poly(d,l-lactide) (PLA) chains were grafted on the backbone via Huisgen 1,3-dipolar cycloaddition. The "click" copper-catalyzed cycloaddition reactions of azides with alkynes (CuAAC) were successfully carried out, and a series of amphiphilic copolymers were prepared containing a backbone with a number-average molecular weight of 14.2 × 103 g mol-1 and different hydrophobic PLA grafts with various molecular weights (2.8 × 103-12.4 × 103 g mol-1). These original architectures of copolymers, when nanoprecipitated in water, the backbone-selective solvent, allowed us to obtain various structures of nanoparticles with a hydrodynamic diameter in the range of 65-99 nm. More interestingly, a plurality of morphologies going from unilamellar, multilamellar, and large compound vesicles to core-shell nanoparticles and depending on the PLA molecular weights were evidenced by combining cryo-transmission electron microscopy (cryo-TEM) and small-angle neutron scattering (SANS) studies. A first evaluation of their stealthiness by studying the stability and the interaction of these nano-objects with a model protein revealed the role played by the P(MeOx-co-PentOx) in these interactions, demonstrating the utility of this amphiphilic graft copolymers platform with well-defined architectures for the design of nanocarriers in drug delivery applications.


Quality Improvement Capacity in a Department of Family Medicine: A Mixed-Methods Study.
Quality improvement capacity is defined as ongoing commitment to sustained quality improvement (QI) and requires knowledge of QI methods and commitment to QI activities from practice leadership and staff. The aim of this project was to identify the major facilitators and barriers to developing quality improvement capacity in a teaching practice of a department of family medicine. We conducted an exploratory, sequential, mixed-methods study, inviting key informants to participate in qualitative interviews and then conducting a survey of faculty, resident physicians, and staff at a community residency teaching practice affiliated with an academic medical center in the Midwest United States. Among 12 qualitative key informant interviewees, facilitators of QI capacity included a strong motivation to provide high-quality care and a desire to leverage team-based care in QI interventions. Barriers included competing clinical and educational priorities, lack of faculty expertise in quality and scholarship, and lack of infrastructure to turn QI into scholarship. The survey response rate was 75% (48 of 64 total team members). The most common motivation for participation in QI work was "making a difference" (41, 85%), while the biggest barriers were prioritization of patient care (25, 53%), and teaching (19, 40%). This mixed-methods study identified key barriers and facilitators to QI capacity, of which addressing competing priorities, improving QI training, and creating infrastructure for scholarship may improve QI capacity.


Linguistic features of stuttering during spontaneous speech.
Previous work shows that linguistic features (e.g., word length, word frequency) impact the predictability of stuttering events. Most of this work has been conducted using reading tasks. Our study examined how linguistic features impact the predictability of stuttering events during spontaneous speech. The data were sourced from the FluencyBank database and consisted of interviews with 35 adult stutterers (27,009 words). Three logistic regression mixed models were fit as the primary analyses: one model with four features (i.e., initial phoneme, grammatical function, word length, and word position within a sentence), a second model with six features (i.e., the features from the previous model plus word frequency and neighborhood density), and a third model with nine features (i.e., the features from the previous model plus bigram frequency, word concreteness, and typical age of word acquisition). We compared our models using the Area Under the Curve statistic. The four-feature model revealed that initial phoneme, grammatical function, and word length were predictive of stuttering events. The six-feature model revealed that initial phoneme, word length, word frequency, and neighborhood density were predictive of stuttering events. The nine-feature model was not more predictive than the six-feature model. Linguistic features that were previously found to be predictive of stuttering during reading were predictive of stuttering during spontaneous speech. The results indicate the influence of linguistic processes on the predictability of stuttering events such that words associated with increased planning demands (e.g., longer words, low frequency words) were more likely to be stuttered.


Toxicity and chemical composition of commercial road palliatives versus oil and gas produced waters.
Across the United States, road palliatives are applied to roads for maintenance operations that improve road safety. In the winter, solid rock salts and brine solutions are used to reduce the accumulation of snow and ice, while in the summer, dust suppressants are used to minimize fugitive dust emissions. Many of these products are chloride-based salts that have been linked to freshwater salinization, toxicity to aquatic organisms, and damage to infrastructure. To minimize these impacts, organic products have been gaining attention, though their widespread adoption has been limited due to their higher cost. In some states, using produced water from conventionally drilled oil and gas wells (OGPWs) on roads is permitted as a cost-effective alternative to commercial products, despite its typically elevated concentrations of heavy metals, radioactivity, and organic micropollutants. In this study, 17 road palliatives used for winter and summer road maintenance were collected and their chemical composition and potential human toxicity were characterized. Results from this study demonstrated that liquid brine solutions had elevated levels of trace metals (Zn, Cu, Sr, Li) that could pose risks to human and environmental health. The radium activity of liquid calcium chloride products was comparable to the activity of OGPWs and could be a significant source of radium to the environment. The organic fractions of evaluated OGPWs and chloride-based products posed little risk to human health. However, organic-based dust suppressants regulated toxicity pathways related to xenobiotic metabolism, lipid metabolism, endocrine disruption, and oxidative stress, indicating their use could lead to environmental harm and health risks to operators handing these products and residents living near treated roads.


Thyroid dysfunction induced by immune checkpoint inhibitors and tumor progression during neoadjuvant therapy of non‑small cell lung cancer: A case report and literature review.
Immune checkpoint inhibitors (ICIs) have a demonstrable treatment response in patients with resectable non-small cell lung cancer (NSCLC). However, immune-related adverse events and tumor progression in patients administered ICIs are of great concern. The present case study is of a 59-year-old male with NSCLC (squamous, stage IIIA) who received neoadjuvant immunotherapy combined with chemotherapy before surgery. The patient first developed hyperthyroidism and then hypothyroidism, indicating that ICI-related thyroid dysfunction had occurred. Furthermore, the patient suffered from tumor progression and could not undergo resection. The present case called attention to the prevention and management of irAEs, and the precaution that should be taken with regard to tumor progression. The case also suggested that the development of ICI-related thyroid dysfunction may not predict an improved response to ICI therapies, which needs further evidence to illustrate.


Observation of large Kerr nonlinearity at low light intensities.
We report an experimental observation of large Kerr nonlinearity with vanishing linear susceptibilities in coherently prepared four-level rubidium atoms. Quantum coherence and interference manifested by electromagnetically induced transparency suppress the linear susceptibilities and greatly enhance the nonlinear susceptibilities at low light intensities. The measured Kerr nonlinearity is comparable in magnitude to the linear dispersion in a simple two-level system and is several orders of magnitude greater than the Kerr nonlinearity of a conventional three-level scheme under similar conditions.


A quest for the stereo-electronic requirements for selective agonism for the neurotrophin receptors TrkA and TrkB in 17-spirocyclic-dehydroepiandrosterone derivatives.
The neurotrophin system plays a pivotal role in the development, morphology, and survival of the nervous system, and its dysregulation has been manifested in numerous neurodegenerative and neuroinflammatory diseases. Neurotrophins NGF and BDNF are major growth factors that prevent neuronal death and synaptic loss through binding with high affinity to their specific tropomyosin-related kinase receptors namely, TrkA and TrkB, respectively. The poor pharmacokinetic properties prohibit the use of neurotrophins as therapeutic agents. Our group has previously synthesized BNN27, a prototype small molecule based on dehydroepiandrosterone, mimicking NGF through the activation of the TrkA receptor. To obtain a better understanding of the stereo-electronic requirements for selective activation of TrkA and TrkB receptors, 27 new dehydroepiandrosterone derivatives bearing a C17-spiro-dihydropyran or cyclobutyl moiety were synthesized. The new compounds were evaluated for their ability (a) to selectively activate the TrkA receptor and its downstream signaling kinases Akt and Erk1/2 in PC12 cells, protecting these cells from serum deprivation-induced cell death, and (b) to induce phosphorylation of TrkB and to promote cell survival under serum deprivation conditions in NIH3T3 cells stable transfected with the TrkB receptor and primary cortical astrocytes. In addition the metabolic stability and CYP-mediated reaction was assessed. Among the novel derivatives, six were able to selectively protect PC12 cells through interaction with the TrkA receptor and five more to selectively protect TrkB-expressing cells via interaction with the TrkB receptor. In particular, compound ENT-A025 strongly induces TrkA and Erk1/2 phosphorylation, comparable to NGF, and can protect PC12 cells against serum deprivation-induced cell death. Furthermore, ENT-A065, ENT-A066, ENT-A068, ENT-A069, and ENT-A070 showed promising pro-survival effects in the PC12 cell line. Concerning TrkB agonists, ENT-A009 and ENT-A055 were able to induce phosphorylation of TrkB and reduce cell death levels in NIH3T3-TrkB cells. In addition, ENT-A076, ENT-A087, and ENT-A088 possessed antiapoptotic activity in NIH-3T3-TrkB cells exclusively mediated through the TrkB receptor. The metabolic stability and CYP-mediated reaction phenotyping of the potent analogs did not reveal any major liabilities. We have identified small molecule selective agonists of TrkA and TrkB receptors as promising lead neurotrophin mimetics for the development of potential therapeutics against neurodegenerative conditions.


Role and knowledge of critical care nurses in the assessment and management of hypophosphataemia and refeeding syndrome. A descriptive exploratory study.
To assess the perceived and actual role of critical care nurses in nutritional care, and their knowledge regarding the identification and management of hypophosphataemia and refeeding syndrome. Data were collected in one intensive care unit in Israel, from a self-administered questionnaire completed by 42 critical care nurses. The questionnaire was designed to assess their perceived and actual roles in the administration of nutritional care, and knowledge regarding electrolyte monitoring, hypophosphataemia and refeeding syndrome, including risk factors, consequences, and treatment. The majority participants that dieticians are solely responsible for nutrition care and follow-up. Most agreed that the measurement of phosphate levels was not important and that patients should receive full nutrition upon admission, while important risk factors for the development of refeeding syndrome were not recognised or considered. This informed their actual practice. A correlation was found between nurses' knowledge and their actual practice so that the greater the nurses' knowledge, the more they adhered to current nutrition guidelines (p < 0.05). This study revealed critical care nurses' lack of clarity of their role and lack of knowledge regarding nutrition care. We suggest that this complex task is best managed by a multidisciplinary team, including nurses and dieticians, with clear role definitions.


Independent component analysis for source localization of EEG sleep spindle components.
Sleep spindles are bursts of sleep electroencephalogram (EEG) quasirhythmic activity within the frequency band of 11-16 Hz, characterized by progressively increasing, then gradually decreasing amplitude. The purpose of the present study was to process sleep spindles with Independent Component Analysis (ICA) in order to investigate the possibility of extracting, through visual analysis of the spindle EEG and visual selection of Independent Components (ICs), spindle "components" (SCs) corresponding to separate EEG activity patterns during a spindle, and to investigate the intracranial current sources underlying these SCs. Current source analysis using Low-Resolution Brain Electromagnetic Tomography (LORETA) was applied to the original and the ICA-reconstructed EEGs. Results indicated that SCs can be extracted by reconstructing the EEG through back-projection of separate groups of ICs, based on a temporal and spectral analysis of ICs. The intracranial current sources related to the SCs were found to be spatially stable during the time evolution of the sleep spindles.


The circulating alarin level was elevated in infertile women with poor ovarian reserve.
We aimed to reveal the association of serum alarin level with POR status of the infertile women in the present study. The eligibility criteria for this prospective cross-sectional study included a total of 92 infertile women attending the Hitit University Hospital, and all participant women were categorized into two main groups of ovarian reserve: (i) Poor ovarian reserve (POR) group (n = 40) based on ESHRE consensus and (ii) Control group (NOR) (n = 52). The mean adjusted-ages and BMI values of the NOR and POR groups were statistically comparable (p = .057 and p = .600, respectively). The mean E2, FSH, and LH levels were elevated in the POR group (p < .001, for all). The mean AFC and AMH concentration were significantly reduced in the POR group (p < .001, for both). In addition, there was a significant increase in the serum alarin level in the POR group (p < .001). Pearson's analysis revealed that the mean BMI value of the POR group had a weak and negative correlation (r = 0.318, p = .046). Also, there was no correlation between serum alarin with E2 and FSH levels in both study groups. A weak and positive correlation was found between serum alarin and LH concentration only in the POR group (r = 0.318, p = .045). The mean AMH and AFC values were not significantly correlated with serum alarin levels. The circulating alarin level was significantly elevated in infertile women with POR patterns. In addition, the alarin level was significantly correlated with the serum LH concentration in the POR pattern.


The missing links to link ubiquitin: Methods for the enzymatic production of polyubiquitin chains.
Attachment of ubiquitin (Ub) as monoUb and polyUb chains of different lengths and linkages to proteins plays a dominant role in very different regulatory mechanisms. Therefore, the study of polyUb chains has assumed a central interest in biochemistry and structural biology. An essential step necessary to allow in vitro biochemical and structural studies of polyUbs is the production of their chains in high quantities and purity. This is not always an easy task and can be achieved both enzymatically and chemically. Previous reviews have covered chemical cross-linking exhaustively. In this review, we concentrate on the different approaches developed so far for the enzymatic production of different Ub chains. These strategies permit a certain flexibility in the production of chains with various linkages and lengths. We critically describe the available methods and comment on advantages and limitations. It is clear that the field is mature to study most of the possible links, but some more work needs to be done to complete the picture and to exploit the current methodologies for understanding in full the Ub code.


Effect of cyasterone on intestinal flora in a BRAFV600E-mutant mouse model of colorectal cancer.
BRAF V600E-mutated colorectal cancer (CRC) is very aggressive and responds poorly to standard treatment. In this study, BRAFV600E-mutant mice with CRC were treated with intragastric cyasterone, a compound commonly used in traditional Chinese herbal medicine, for 21 days. Microbial DNA was extracted from mouse intestinal contents for 16S ribosomal RNA gene amplicon sequencing and analyzed. Our results indicated that cyasterone enhanced the diversity of the gut microbiota. The abundance of beneficial bacteria, such as Prevotellaceae, Muribaculaceae, and Ruminococcaceae was significantly higher in cyasterone-treated mice than controls. The abundance of Erysipelotrichaceae, a family of bacteria that promotes inflammation in the gut, was significantly positively correlated with tumor weight. Cyasterone is a potential inhibitor of BRAFV600E-mutant CRC via its effects on intestinal flora.


Safety assessment of dairy microorganisms: the Lactobacillus genus.
Lactobacilli are Gram positive rods belonging to the Lactic Acid Bacteria (LAB) group. Their phenotypic traits, such as each species' obligate/facultative, homo/heterofermentation abilities play a crucial role in souring raw milk and in the production of fermented dairy products such as cheese, yoghurt and fermented milk (including probiotics). An up to date safety analysis of these lactobacilli is needed to ensure consumer safety. Lactobacillus genus is a heterogeneous microbial group containing some 135 species and 27 subspecies, whose classification is constantly being reshuffled. With the recent use of advanced molecular methods it has been suggested that the extreme diversity of the Lactobacillus genomes would justify recognition of new subgeneric divisions. A combination of genotypic and phenotypic tests, for example DNA-based techniques and conventional carbohydrate tests, is required to determine species. Pulsed-Field gel Electrophoresis (PFGE) has been successfully applied to strains of dairy origin and is the most discriminatory and reproducible method for differentiating Lactobacillus strains. The bibliographical data support the hypothesis that the ingestion of Lactobacillus is not at all hazardous since lactobacillemia induced by food, particularly fermented dairy products, is extremely rare and only occurs in predisposed patients. Some metabolic features such as the possible production of biogenic amines in fermented products could generate undesirable adverse effects. A minority of starter and adjunct cultures and probiotic Lactobacillus strains may exceptionally show transferable antibiotic resistance. However, this may be underestimated as transferability studies are not systematic. We consider that transferable antibiotic resistance is the only relevant cause for caution and justifies performing antibiotic-susceptibility assays as these strains have the potential to serve as hosts of antibiotic-resistance genes, with the risk of transferring these genes to other bacteria. However, as a general rule, lactobacilli have a high natural resistance to many antibiotics, especially vancomycin, that is not transferable. Safety assessment requirements for Lactobacillus strains of technological interest should be limited to an antibiotic profile and a study to determine whether any antibiotic resistance(s) of medical interest detected is (or are) transferable. This agrees with the recent EFSA proposal suggesting attribution of a QPS status for 32 selected species of lactobacilli.


Inhibitory action of palatinose and its hydrogenated derivatives on the hydrolysis of alpha-glucosylsaccharides in the small intestine.
This study was conducted to investigate the inhibitory effects of palatinose and Palatinit, which are disaccharides (or disaccharide alcohol) connected through an alpha-1,6-glucosyl linkage, on the hydrolysis of other carbohydrates, using an enzyme extract from the rat small intestine and a purified sucrase-isomaltase complex. Palatinose and its hydrogenated product, Palatinit, an equimolar mixture of alpha-O-D-glucopyranosyl-1,6-D-sorbitol (GPS) and alpha-O-D-glucopyranosyl-1,6-D-mannitol (GPM), inhibited the hydrolysis of sucrose and maltose. Palatinose and Palatinit also inhibited the hydrolysis of dextrin and soluble starch. Kinetic analysis of the enzymatic inhibition by GPS and GPM on sucrose hydrolysis revealed that both GPS and GPM competitively inhibit sucrase catalytic activity. These results suggest that disaccharides with an alpha-1,6-glucosyl linkage competitively inhibit intestinal alpha-glucosidases and may reduce the rate of hydrolysis of sucrose and other alpha-glucosylsaccharides.


[Advanced practice nursing implementation strategies in hospital: a review of the literature].
Objective: To analyse the factors of success and the obstacles to implementation of advanced practice nursing in the French health system. Methods: Review of the international literature concerning implementation of advanced practice nursing published between 2010 and 2016. Results: Of the 503 articles reviewed, 14 were included in this analysis, which showed that obstacles to implementation can be potentially transformed into advantages. Only one guideline was identified, the PEPPA (Participatory, Evidence-based, Patient-focused process for Advanced Practice Nursing (APN) role development). Four factors of successful implementation and evaluation of advanced practice nursing were identified: involvement of medical and paramedical personnel, supervisor and material support from administrative authorities, implementation of policies and regulation mechanisms and postgraduate university training. Conclusion: Implementation of advanced practice nursing in France should take into account the PEPPA guidelines used in Canada, in order to promote the success of these new roles in clinical practice.


Modeling molecular transport in slit pores.
We examine the transport of methane in microporous carbon by performing equilibrium and nonequilibrium molecular dynamics simulations over a range of pore sizes, densities, and temperatures. We interpret these simulation results using two models of the transport process. At low densities, we consider a molecular flow model, in which intermolecular interactions are neglected, and find excellent agreement between transport diffusion coefficients determined from simulation, and those predicted by the model. Simulation results indicate that the model can be applied up to fluid densities of the order to 0.1-1 nm(-3). Above these densities, we consider a slip flow model, combining hydrodynamic theory with a slip condition at the solid-fluid interface. As the diffusion coefficient at low densities can be accurately determined by the molecular flow model, we also consider a model where the slip condition is supplied by the molecular flow model. We find that both density-dependent models provide a useful means of estimating the transport coefficient that compares well with simulation.


Economic Evaluation for Benign Prostatic Hyperplasia in Iran: Surgical Treatment or Dutasteride.
Benign prostatic hyperplasia is a common chronic disease that is age-dependent. There are two main types of interventional treatment, transurethral resection of prostate as a gold standard (TURP) and open prostatectomy (OP); also, there are two pharmacological groups for managing BPH: alpha-blockers and 5-alpha-reductase inhibitors (5-ARIs). In this economic evaluation study, one 5-ARIs, dutasteride and two main surgical treatments are compared as alternatives for treating moderate BPH in Iran. A cost-utility study with an Iranian health provider perspective was conducted. Markov model in a cohort of 1000 patients with BPH with annual cycle length and ten years' time horizon was developed by using MS EXCEL 2013. The effectiveness measure was an improvement in the IPSS score and transformed to the utility. The transition probabilities, utilities and adverse events were extracted from published clinical trials. The direct medical costs were measured in the 2017 US Dollar. One way sensitivity analysis and scenario analysis were conducted.For treating moderate BPH, seventy-year-old men, in the base case scenario, the utility of pharmacotherapy is 18 QALY less than surgery, and the cost of pharmacotherapy is 136,301.1 $ less than surgery. ICER for pharmacotherapy was 7,572.3 $ compared to surgery. In the sensitivity analysis, the model is not sensitive to most variables but the unit cost of dutasteride. Based on scenario analysis conducted for different age groups, pharmacotherapy with dutasteride is preferred to surgery in patients over 60 years of age in Iran. However, for younger adult men between 40-60 years old, surgery is a cost-effective alternative.


Systemic allergic contact dermatitis associated with allergy to intraoral metals.
Contact (allergic) dermatitis is a skin disorder related to natural exposure to various allergens. Systemic contact dermatitis (SCD) describes a cutaneous eruption in response to systemic exposure to an allergen. The exact pathologic mechanism remains uncertain. Herein we describe a 36-year-old woman with symmetric systemic allergic contact dermatitis, unresponsive to conventional treatment, associated with dental alloy-contact hypersensitivity. We did skin patch testing and the blood lymphocyte transformation test (LTT) from the dental allergen series to assess contact allergy to restorative dental materials. On patch testing, positive allergic contact dermatitis reactions to metals occurred (nickel, potassium dichromate, and gold). Nickel hypersensitivity was confirmed by LTT, which also revealed silver-amalgam sensitization. Our case report highlights the need to consider adverse reactions to base-metal dental alloys in the differential diagnosis of cases of systemic allergic contact dermatitis.


Design, synthesis and characterization of poly (methacrylic acid-niclosamide) and its effect on arterial function.
We have found that niclosamide induced relaxation of constricted artery. However, niclosamide is insoluble, the low bioavailability and the resultant low plasma concentration limit its potential exertion in vivo. The aim of the present study is to synthesize a soluble poly (methacrylic acid-niclosamide) polymer (PMAN) and study the effects of PMAN on arterial function in vitro and the blood pressure and heart rate of rats in vivo. We synthesized the poly (methacrylic acid-niclosamide) polymer (PMAN), the chemical structure of which was identified by FTIR and 1H NMR spectra. The average molecular weight and polydispersity index of PMAN were 5138 and 1.193 respectively. Compared with niclosamide, the water solubility of niclosamide in PMAN was significantly increased. PMAN showed dose-dependent vasorelaxation effect on rat mesenteric arteries with intact or denuded endothelium in phenylephrine (PE) and high K+ (KPSS)-induced vasoconstriction models in vitro. The efficacy of vasorelaxant effect and the cytotoxic effect of PMAN on vascular smooth muscle cells (A10) were lower than that of niclosamide. The LD50 of PMAN in mice (iv) was 80mg/kg. Venous injection of PMAN (equivalent 5mg niclosamide per kg) showed acute reduction of the rat blood pressure and heart rate in vivo. In conclusion, the solubility of niclosamide was increased in the way of poly (methacrylic acid-niclosamide) polymer, which relaxes the constricted arteries in vitro and reduces the rat blood pressure and heart rate in vivo, indicating that modifying niclosamide solubility through polymerization is a feasible approach to improve its pharmacokinetic profiles for potential clinic application.


Evaluation of coronal microleakage of four different glass-ionomer cements in endodontically treated teeth.
Four different glass-ionomer materials were evaluated for coronal microleakage in permanent lingual access restorations of endodontically treated anterior teeth. Forty extracted human anterior teeth were randomly divided into four groups following chemomechanical preparations and obturations with gutta-percha and sealer. Logobond, Aqua Ionobond, Ionoseal and Ketac-Cem were placed in 2 mm thickness over the gutta-percha obturation from cemento-enamel junction. Eight teeth were used as negative and positive controls. The teeth were thermocycled, coated with nail varnish and paraffin except around the access preparation. Next they were placed in dye and cleared to allow visualization of dye penetration. There was a tendency for the Ketac-Cem group to lack least but there were no statistically differences among the groups.


Enforced SOCS1 and SOCS3 expression attenuates Lck-mediated cellular transformation.
Lck is an Src family protein tyrosine kinase with predominant T cell expression. Aberrant expression or activation of Lck kinase has been reported in both lymphoid and non-lymphoid malignancies. We showed previously that the signal transduction pathway involving Janus kinase (JAK) and signal transducer and activator of transcription (STAT) is constitutively activated and contributes to Lck-mediated oncogenesis. Under normal physiological conditions, active STAT proteins induce the expression of suppressor of cytokine signaling (SOCS) family proteins to inhibit further JAK/STAT signaling. It is not fully understood whether and how SOCS-mediated negative feedback control is dysregulated in Lck-transformed cells. Here we report that two SOCS family members, SOCS1 and SOCS3, are not expressed in Lck-transformed LSTRA leukemia. While SOCS1 gene is silenced by DNA hypermethylation, loss of SOCS3 expression is through a mechanism independent of epigenetic silencing by DNA methylation. Furthermore, ectopic expression of SOCS1 or SOCS3 leads to reduced cell proliferation and increased apoptosis in Lck-transformed cells. This is consistent with the attenuation of Lck kinase activity by exogenous SOCS1 or SOCS3 expression. Downstream STAT5 activity is also inhibited as shown by reduced STAT5 tyrosine phosphorylation and in vitro DNA binding. All together, our data highlight the importance of silencing multiple SOCS genes in tumorigenesis and support the roles of SOCS1 and SOCS3 as tumor suppressors toward oncogenic Lck kinase.


The Deazidoalkoxylation: Sequential Nucleophilic Substitutions with Diazidated Diethyl Malonate.
Diazidated malonamides derived from amines and diazidated diethyl malonate react with lithiated alcohols through nucleophilic substitution reactions where azide acts as an unconventional leaving group. This deazidoalkoxylation leads to the formal construction of N, O-acetals, and the remaining azide functionality is a useful entry point for further functionalizations through, for example, standard cycloaddition chemistry. Thus, the presented chemistry provides an easy route toward densely functionalized molecules: Amines, alcohols, and alkynes can be attached onto the small malonate core unit in a sequential manner.


Copper is taken up efficiently from albumin and alpha2-macroglobulin by cultured human cells by more than one mechanism.
Ionic copper entering blood plasma binds tightly to albumin and the macroglobulin transcuprein. It then goes primarily to the liver and kidney except in lactation, where a large portion goes directly to the mammary gland. Little is known about how this copper is taken up from these plasma proteins. To examine this, the kinetics of uptake from purified human albumin and alpha(2)-macroglobulin, and the effects of inhibitors, were measured using human hepatic (HepG2) and mammary epithelial (PMC42) cell lines. At physiological concentrations (3-6 muM), both cell types took up copper from these proteins independently and at rates similar to each other and to those for Cu-dihistidine or Cu-nitrilotriacetate (NTA). Uptakes from alpha(2)-macroglobulin indicated a single saturable system in each cell type, but with different kinetics, and 65-80% inhibition by Ag(I) in HepG2 cells but not PMC42 cells. Uptake kinetics for Cu-albumin were more complex and also differed with cell type (as was the case for Cu-histidine and NTA), and there was little or no inhibition by Ag(I). High Fe(II) concentrations (100-500 microM) inhibited copper uptake from albumin by 20-30% in both cell types and that from alpha(2)-macroglobulin by 0-30%, and there was no inhibition of the latter by Mn(II) or Zn(II). We conclude that the proteins mainly responsible for the plasma-exchangeable copper pool deliver the metal to mammalian cells efficiently and by several different mechanisms. alpha(2)-Macroglobulin delivers it primarily to copper transporter 1 in hepatic cells but not mammary epithelial cells, and additional as-yet-unidentified copper transporters or systems for uptake from these proteins remain to be identified.


[Multiprofessional intermittent psychiatric treatment of children in preschool age and their parents in a family day clinic].
Psychiatric treatment of children in preschool age (0-6 years) and their parents is an expanding field of research due to its high clinical significance. Specific family psychiatric treatment programs have been developed to meet the demands of this young age group, but are little known. A multiprofessional intermittent treatment approach sensitive to developmental and family context has been established in the Preschool Family Day Hospital for Infants, Toddlers and Preschoolers and their Families at Münster University Hospital, Germany. Group and individual therapeutic interventions for both children and parents, video-based parent-child-interaction therapy, psychiatric and psychotherapeutic treatments of parents and family therapeutic interventions integrating siblings are supporting and enhancing each other in an innovative and integrated family psychiatric program. First results of evaluation studies are reported that show that this treatment is effective.


Updates on the Current Technologies for microRNA Profiling.
MicroRNAs are RNA molecules of ~22 nt length that regulate gene expression posttranscriptionally. The role of miRNAs has been reported in many cellular processes including apoptosis, cell differentiation, development and proliferation. The dysregulated expression of miRNAs has been proposed as a biomarker for the diagnosis, onset and prognosis of human diseases. The utility of miRNA profiles to identify and discriminate patients from healthy individuals is highly dependent on the sensitivity and specificity of the technologies used for their detection and the quantity and quality of starting material. In this review, we present an update of the current technologies for the extraction, QC assessment and detection of miRNAs with special focus to the most recent methods, discussing their advantages as well as their shortcomings.


Role of C-reactive protein in deciding duration of antibiotic therapy in neonatal septicemia.
In this study serum C-reactive protein (CRP) levels were used to evaluate the duration of antibiotic therapy in 50 consecutive neonates with suspected septicemia. In 44 percent of cases therapy was stopped on 3rd day, as CRP was normal. In 8 percent antibiotics could be stopped within 5-7 days as CRP values returned to normal and in 48 percent therapy was extended beyond 7th day, as CRP values were high or rising persistently. Negative predictive value of serial CRP was 100 percent in deciding duration of antibiotic therapy in suspected neonatal septicemia up to 7 days. The correlation between positive CRP, raised micro ESR and positive blood culture was significant (p < 0.005).


[Icteric cholestasis as an early symptom in Hodgkin's disease].
Initial symptoms in a hitherto healthy 23-year-old man were jaundice (bilirubin 21.7 mg/dl) and pruritus, but extensive radiological, endoscopical, microbiological and laboratory investigations failed to reveal the cause. Stool culture positive for Salmonella agona suggested intrahepatic cholestasis resulting from a Salmonella cholangitis. However, antibiotic treatment was not successful. As he was in generally good health the patient declined further investigations. He returned two years later because of fatigue, lack of appetite and weight loss. Further tests now revealed lymphogranulomatosis in stage IVb of the nodular sclerosing type. The case demonstrates that cholestasis as an isolated early symptom of Hodgkin's disease can precede by years any further signs of the disease.


Patterns in melting snow and vapor deposited layers.
We have observed a natural periodic pattern occurring in partially melted snow lying on the ground under certain atmospheric conditions. We explain this phenomenon quantitatively by considering heat flow through this layer coexisting in two phases (snow and water). Our model equations exhibit a range of patterns depending on the average density of snow. Strikingly similar patterns have been observed by Plass and co-workers in monolayer depositions of Pb on heated PbCu substrates. We argue that the physics of the two phenomena, differing in length scales by 7 orders of magnitude, is similar.


Traumatic brain injury disrupts cerebrovascular tone through endothelial inducible nitric oxide synthase expression and nitric oxide gain of function.
Traumatic brain injury (TBI) has been reported to increase the concentration of nitric oxide (NO) in the brain and can lead to loss of cerebrovascular tone; however, the sources, amounts, and consequences of excess NO on the cerebral vasculature are unknown. Our objective was to elucidate the mechanism of decreased cerebral artery tone after TBI. Cerebral arteries were isolated from rats 24 hours after moderate fluid‐percussion TBI. Pressure‐induced increases in vasoconstriction (myogenic tone) and smooth muscle Ca2+ were severely blunted in cerebral arteries after TBI. However, myogenic tone and smooth muscle Ca2+ were restored by inhibition of NO synthesis or endothelium removal, suggesting that TBI increased endothelial NO levels. Live native cell NO, indexed by 4,5‐diaminofluorescein (DAF‐2 DA) fluorescence, was increased in endothelium and smooth muscle of cerebral arteries after TBI. Clamped concentrations of 20 to 30 nmol/L NO were required to simulate the loss of myogenic tone and increased (DAF‐2T) fluorescence observed following TBI. In comparison, basal NO in control arteries was estimated as 0.4 nmol/L. Consistent with TBI causing enhanced NO‐mediated vasodilation, inhibitors of guanylyl cyclase, protein kinase G, and large‐conductance Ca2+‐activated potassium (BK) channel restored function of arteries from animals with TBI. Expression of the inducible isoform of NO synthase was upregulated in cerebral arteries isolated from animals with TBI, and the inducible isoform of NO synthase inhibitor 1400W restored myogenic responses following TBI. The mechanism of profound cerebral artery vasodilation after TBI is a gain of function in vascular NO production by 60‐fold over controls, resulting from upregulation of the inducible isoform of NO synthase in the endothelium.


Modulation of poly-N-acetylglucosamine accumulation within mature Staphylococcus epidermidis biofilms grown in excess glucose.
PNAG is a major component of Staphylococcus epidermidis biofilms involved in intercellular adhesion as well as in the interaction of the biofilm with components of the host immune response. Synthesis of PNAG has been found to be regulated by several environmental factors. In the present study, the effect of glucose metabolism-dependent culture medium acidification in PNAG accumulation was evaluated. Established S. epidermidis biofilms were allowed to grow in excess glucose with or without maintained pH conditions. PNAG accumulation in these biofilms was determined by flow cytometry and fluorescence microscopy using wheat germ agglutinin as a fluorescent probe. Biofilms grown in maintained pH conditions presented significantly higher amounts of this polymer as well as higher icaA expression than biofilms grown in acidic pH conditions. Moreover, PNAG accumulation in biofilms grown in non-maintained pH conditions occurred in association with cell death. Overall, we show that glucose metabolism by decreasing the culture pH affects biofilm physiology in respect to PNAG production and cell death. The reported in vitro modulation of PNAG accumulation within S. epidermidis biofilms further highlights the role of environment on determining the biofilm physiological state.


Effects of rapid evolution on species coexistence.
Increasing evidence for rapid evolution suggests that the maintenance of species diversity in ecological communities may be influenced by more than purely ecological processes. Classic theory shows that interspecific competition may select for traits that increase niche differentiation, weakening competition and thus promoting species coexistence. While empirical work has demonstrated trait evolution in response to competition, if and how evolution affects the dynamics of the competing species-the key step for completing the required eco-evolutionary feedback-has been difficult to resolve. Here, we show that evolution in response to interspecific competition feeds back to change the course of competitive population dynamics of aquatic plant species over 10-15 generations in the field. By manipulating selection imposed by heterospecific competitors in experimental ponds, we demonstrate that (i) interspecific competition drives rapid genotypic change, and (ii) this evolutionary change in one competitor, while not changing the coexistence outcome, causes the population trajectories of the two competing species to converge. In contrast to the common expectation that interspecific competition should drive the evolution of niche differentiation, our results suggest that genotypic evolution resulted in phenotypic changes that altered population dynamics by affecting the competitive hierarchy. This result is consistent with theory suggesting that competition for essential resources can limit opportunities for the evolution of niche differentiation. Our finding that rapid evolution regulates the dynamics of competing species suggests that ecosystems may rely on continuous feedbacks between ecology and evolution to maintain species diversity.


Review of the partitioning of chemicals into different plastics: Consequences for the risk assessment of marine plastic debris.
Marine plastic debris are found worldwide in oceans and coastal areas. They degrade only slowly and contain chemicals added during manufacture or absorbed from the seawater. Therefore, they can pose a long-lasting contaminant source and potentially transfer chemicals to marine organisms when ingested. In order to assess their risk, the contaminant concentration in the plastics needs to be estimated and differences understood. We collected from literature plastic water partition coefficients of various organic chemicals for seven plastic types: polydimethylsiloxane (PDMS), high-density, low-density and ultra-high molecular weight polyethylene (LDPE, HDPE, UHMWPE), polystyrene (PS), polypropylene (PP), and polyvinyl chloride (PVC). Most data was available for PDMS (1060) and LDPE (220), but much less for the remaining plastics (73). Where possible, regression models were developed and the partitioning was compared between the different plastic types. The partitioning of chemicals follows the order of LDPE≈HDPE≥PP>PVC≈PS. Data describing the impact of weathering are urgently needed.


Insights into the absorption of carbon dioxide by zinc substrates: isolation and reactivity of di- and tetranuclear zinc complexes.
The heptadentate Schiff base H(3)L can react with zinc acetate to form the discrete dinuclear complex Zn(2)L(OAc)(H(2)O), 1.H(2)O. The reaction of 1.H(2)O with NMe(4)OH.5H(2)O both in air and under an argon stream has been investigated. On one hand, this reaction in air yields the tetranuclear complex (Zn(2)L)(2)(CO(3))(H(2)O)(6), 2.5H(2)O, by spontaneous absorption of adventitious carbon dioxide. This process can be reverted in an acetic acid medium, whereas the treatment of 2.5H(2)O with methanoic acid yields crystals of [Zn(2)L(HCOO)].0.5MeCN.1.25MeOH.2H(2)O, 3.0.5MeCN.1.25MeOH.2H(2)O. On the other hand, the interaction under an argon atmosphere of 1.H(2)O with NMe(4)OH.5H(2)O in methanol allows the isolation of the dinuclear complex Zn(2)L(OMe)(H(2)O)(4), 4.4H(2)O. Recrystallisations of 1.H(2)O, 2.5H(2)O and 4.4H(2)O, in different solvents, yielded single crystals of 1.MeCN.2.5H(2)O, 2.4MeOH and 4.3MeOH.H(2)O, respectively. The crystal structure of 2.4MeOH can be understood as resulting from an unusual asymmetric tetranuclear self-assembly from two dinuclear units, and shows three different geometries around the four zinc atoms.


Subtotal reconstruction of the orbit after destruction by benign tumour.
We present five cases of reconstruction of the orbital walls after destruction by tumours. Treatment is based upon wide exposure through a bicoronal scalp incision and immediate reconstruction with autogenous iliac bone grafts. we do not recommend using foreign materials for reconstructing the orbit.


The expression of murine Hox-2 genes is dependent on the differentiation pathway and displays a collinear sensitivity to retinoic acid in F9 cells and Xenopus embryos.
In this paper we describe experiments that detail the response of murine Hox-2 genes to cellular differentiation and retinoic acid in cell culture. Hox-2 genes are transiently activated in differentiating ES cells even in the absence of retinoic acid (RA), indicating that their induction is a normal aspect of differentiation. Furthermore, in the continuous presence of RA F9 teratocarcinoma cells show a differential ability to maintain Hox-2 expression depending upon whether the cells follow a visceral or parietal endoderm pathway. These data suggest a clear dependence of Hox-2 expression on the degree and type of differentiation in different cells. However, RA also has dramatic differentiation independent effects on Hox-2 regulation. In ES cells the levels of Hox expression are greatly enhanced by exposure to RA, and in F9 cells of the visceral or parietal phenotype the continuous presence of RA is required to maintain these high levels. Nuclear run-on experiments illustrate that Hox-2 genes are active in F9 stem cells and that a large portion of the RA induction is mediated by post-transcriptional mechanisms. Therefore RA exerts its effects on Hox-2 expression by upregulating or modulating genes which are already active, rather than by turning-on silent genes. All nine Hox-2 genes are induced in F9 cells by RA and there is a direct correlation (collinearity) between gene order and the relative dose response of each gene to RA. In Xenopus embryos treated with RA, homologues of the Hox-2 genes also displayed a temporal and dose response collinearity with gene organisation. Together these findings suggest that the collinear response to RA is highly conserved in vertebrates and combined with the ability of RA to modify expression during cellular differentiation could be an important feature of the Hox-2 cluster itself used to generate the spatially-restricted patterns of gene expression in embryogenesis.


[A case report of innominate and carotid artery aneurysms causing cerebral embolism].
Brachiocephalic aneurysms are relatively rare in Japan. A case with tandem aneurysms of innominate and right carotid artery was experienced and its successful surgical treatment was reported. A 54-year-old female patient had an attack of cerebral infarction with left hemiparesis. Computed tomography and angiogram revealed aneurysms of innominate and right carotid artery causing cerebral embolisms. Aneurysmectomy and replacement with Dacron prosthesis was performed. A temporary shunt was utilized between ascending aorta and common carotid artery during clamping carotid artery. She had no problems after operation, and her postoperative course was uneventful.


[Production of an erythrocyte preparation for detection of herpes antibody in the hemagglutination reaction].
A method for obtaining an erythrocyte diagnostic preparation for detection and titration of herpetic antibody in the passive hemagglutination test is reported. The use of this preparation for quantitative assay of herpetic antibody in sera from herpes simplex patients detected antibody in 100% of cases. Considerably less frequent findings of herpetic antibody were in human sera from diseases of other etiologies and in donor sera. Titers of antibody detected in the PHA test were 2--10 times higher than in the CFT. However, no differences between the PHA test and the CFT were found in per sent of seroconversions and in increase of antibody titers. The method is simple, sensitive and easy to perform in any clinical laboratory.


Is the preoperative neutrophil-to-lymphocyte ratio a predictive value for postoperative mortality in orthogeriatric patients who underwent proximal femoral nail surgery for pertrochanteric fractures?
Hip fractures in the orthogeriatric population are a health problem that causes mortality and morbidity, with an increasing frequency. The present study aims to investigate whether the preoperative neutrophil-to-lymphocyte ratio (NLR) is a predictive value for the postoperative mortality risk in patients who underwent only proximal femoral nail (PFN) surgery due to pertrochanteric fractures (PTF). To our knowledge, there is not any study conducted with a similar population in the litertaure. Fifty-five patients who were operated on by two National Board-certified surgeons with the PFN method were included in our retrospective study. The patients were divided into two groups. Group A included the patients who lost their lives within the postoperative first year (n=13), while Group B included the survivors (n=42). Preoperative NLR data, demographic information, duration of hospitalization, postoperative intensive care requirements (ICU) and comorbid diseases of all patients were recorded. In our study with a maximum follow-up period of 27 months, no statistically significant difference was found between the groups concerning age, gender, body mass index, preoperative American Society of Anesthesiologists scores (ASA), types of fractures, ICU requirements, duration of hospitalization (p>0.05). However, the NLR was significantly higher in Group A (p<0.01), with a cut-off value of 5.25, sensitivity of 84.6% and specificity of 78.6%. We believe that the preoperative NLR is a predictive variable for orthopedic surgeons in assessing the postoperative mortality risk in orthogeriatric patients who presented to the emergency room due to PTF and were planned to undergo PFN surgery.


Hearing aid evaluation based on measures of benefit, use, and satisfaction.
A comprehensive follow-up protocol was designed and utilized to assess benefit, use, and satisfaction from hearing aids. The benefit assessments included functional gain measures, and speech intelligibility in quiet and in noise. Hearing aid use was evaluated based on a questionnaire which asked for an estimate of daily use in hours and also an accounting of times when the aid was not in use during the day. Two use values were derived, an absolute daily use value and an adjusted percentage of use value. Satisfaction also was assessed using a questionnaire. The subjects were asked to indicate their general satisfaction with the aid on a seven-point scale. Two communication assessment questionnaires were used to assess communication handicap. Data are provided on 45 subject. The subjects were categorized into groups according to both low- and high-frequency hearing. These preliminary mean scores by group can be used as target goals for benefit, use, and satisfaction on persons fit with hearing aids. The protocol as used can provide considerable evaluative clinical information in a reasonable amount of time.


[Clinical classification of ALS patients based on the total course of ALS--proposal of respiratory motor paralysis-preceded type and its significance].
Since the motor paralysis occurs in all motor systems in ALS, the clinicopathological findings and care of the patients living beyond the development of respiratory failure must be considered. We have divided the efferent motor systems into four groups, i.e., limb, bulbar, respiratory, and external ocular. In this study, 37 ALS patients were followed for more than two years with respirator, and the onset of motor paralysis in all four systems was observed in each patient. First, we classified the patients into three groups according to the number of paralyzed motor systems observed within six months from the onset of the first motor paralysis, and we discuss the patient's prognosis after the first motor paralysis. Twenty-one patients with paralysis of the respiratory motor system alone were categorized as respiratory paralysis-preceded type ALS (R-type ALS), four patients with paralysis of the bulbar motor system alone as bulbar paralysis-preceded type ALS (B-type ALS), and 12 patients with simultaneous paralysis of two or more motor systems as combined motor system paralysis type ALS (C-type ALS). The results showed that the prognosis of R-type ALS is slow progression and that of C-type ALS, rapid progression. Next, we investigated the time of occurrence of the first motor paralysis of the four motor systems in 37 patients, and we discuss the most vulnerable motor functions in ALS, i.e., the initial clinical presentations in ALS. The most frequent first motor paralysis was of the respiratory motor system, and the initial clinical manifestations in ALS were impairment of fine discriminating voluntary respiratory and limb motor functions. These findings could be explained by the rule of ALS involvements, according to which onto-genetically newer motor functions are lost earlier than the older ones. Based on the findings in this study, we concluded that ALS initially involves the ontogenetically new motor functions in "the first system" proposed by G. Holstege, whose anatomical structure is composed of pre-motoneurons and motoneurons in the brain stem and spinal cord.


Spatiotemporally separated cardiac neural crest subpopulations that target the outflow tract septum and pharyngeal arch arteries.
We used lacZ-retrovirus labeling combined with neural crest ablation in chick embryos to determine whether the cardiac neural crest cells constitute one group of multipotent cells, or they emigrate from the neural tube in time-dependent groups with different fates in the developing cardiovascular system. We demonstrated that early-migrating cardiac neural crest cells (HH9-10) massively target the aorticopulmonary septum and pharyngeal arch arteries, while the late-migrating cardiac neural crest cells (HH12) are restricted to the proximal part of the pharyngeal arch arteries. These results suggest a prominent role for early-migrating cells in outflow tract septation, and a function for late-migrating cells in pharyngeal arch artery remodeling. We demonstrated in cultures of neural tube explants an intrinsic difference between the early and late populations. However, by performing heterochronic transplantations we showed that the late-migrating cardiac neural crest cells were not developmentally restricted, and could contribute to the condensed mesenchyme of the aorticopulmonary septum when transplanted to a younger environment. Our findings on the exact timing and migratory behavior of cardiac neural crest cells will help narrow the range of factors and genes that are involved in neural crest-related congenital heart diseases.