Relative biological effectiveness of ionizing radiations determined in tissue (RBE) fails in assessing comparative relative effectiveness in the tissue cells.
The value of the RBE of a test radiation is conventionally determined against a known standard radiation for a chosen response of a selected biological tissue and is expressed as the ratio of tissue absorbed doses at equal effect, or as ratio of magnitudes of the effect at equal absorbed dose. If such an effect is observable as a consequence of responses of individual elements of this tissue, namely the cells, such as induction of cancer that arises from a single cell, the relative biological effectiveness should be expressed as the ratio of the incidences of the effects at equal mean absorbed dose to the cells rather than at equal absorbed dose to tissue. This cell based relative biological effectiveness is here termed the relative local efficiency. Since tissue absorbed dose is a product of the number of energy deposition events in cells of that tissue (N(H)) and the mean absorbed dose to these cells in the exposed tissue (z(1)), per tissue mass equal tissue absorbed doses from different radiation qualities have different values of N(H) and z(1) As a result, for pink mutations in Tradescantia cells, the relative biological effectiveness of 0.43 MeV neutrons is 48 but the relative local efficiency in fact is 2.8.


The oral status of elderly removable partial denture wearers.
A random sample of 1019 elderly home dwelling persons participated in this study. There were 809 dentate respondents, 28.6% of whom wore removable partial dentures. They were examined for coronal and root caries, gingival recession, pocket depth and loss of gingival attachment. The removable partial dentures were also evaluated. Abutment teeth were found to be more likely to have caries and periodontal disease than all other teeth. Using a MANOVA statistical procedure, the analysis indicated that the partial denture itself, irrespective of any professionally determined problems with the denture, appears to affect coronal and root caries on the teeth of partial denture wearers. Partial dentures judged to need repair or adjustment were related to periodontal status. The data on adverse effects of partial dentures suggest a need for patient education by the dentist and through public health measures, and good oral self care and regular professional recall for people who wear removable partial dentures.


mda-9/syntenin: recent insights into a novel cell signaling and metastasis-associated gene.
PDZ (an acronym representing three proteins--postsynaptic density protein PSD95/SAP90, drosophila tumor suppressor DLGA, and tight junction protein ZO-1) domain containing proteins are adapter proteins that play indispensable roles in regulating cell growth, development, and differentiation, predominantly through their capacity to serve as central organizers of protein complexes at the plasma membrane. A recently identified member of this protein family is melanoma differentiation associated gene-9 (mda-9), also known as syntenin, which was first identified as a gene down-regulated during human melanoma differentiation as mda-9 and subsequently recognized as an interacting partner of the cell-surface heparan sulfate syndecans, syntenin. Interest in mda-9/syntenin is intensifying because of its involvement in organization of protein complexes in the plasma membranes, regulation of B cell development, intracellular trafficking and cell surface targeting, cancer metastasis, synaptic transmission, and axonal outgrowth. In this review, we discuss the identification, structure and function of mda-9/syntenin and delineate future studies to address its role in regulating key physiological and pathological processes.


The mechanism of GTP hydrolysis by Ras probed by Fourier transform infrared spectroscopy.
Time-resolved Fourier transform infrared spectroscopy (FTIR) in combination with photo-induced release of (18)O-labeled caged nucleotide has been employed to address mechanistic issues of GTP hydrolysis by Ras protein. Infrared spectroscopy of Ras complexes with nitrophenylethyl (NPE)-[alpha-(18)O(2)]GTP, NPE-[beta-(18)O(4)]GTP, or NPE-[gamma-(18)O(3)]GTP upon photolysis or during hydrolysis afforded a substantially improved mode assignment of phosphoryl group absorptions. Photolysis spectra of hydroxyphenylacyl-GTP and hydroxyphenylacyl-GDP bound to Ras and several mutants, Ras(Gly(12))-Mn(2+), Ras(Pro(12)), Ras(Ala(12)), and Ras(Val(12)), were obtained and yielded valuable information about structures of GTP or GDP bound to Ras mutants. IR spectra revealed stronger binding of GDP beta-PO(3)(2-) moiety by Ras mutants with higher activity, suggesting that the transition state is largely GDP-like. Analysis of the photolysis and hydrolysis FTIR spectra of the [beta-nonbridge-(18)O(2), alphabeta-bridge-(18)O]GTP isotopomer allowed us to probe for positional isotope exchange. Such a reaction might signal the existence of metaphosphate as a discrete intermediate, a key species for a dissociative mechanism. No positional isotope exchange was observed. Overall, our results support a concerted mechanism, but the transition state seems to have a considerable amount of dissociative character. This work demonstrates that time-resolved FTIR is highly suitable for monitoring positional isotope exchange and advantageous in many aspects over previously used methods, such as (31)P NMR and mass spectrometry.


Bis-enaminone based parallel solution-phase synthesis of 1,4-dihydropyridine derivatives.
Two variations of a parallel solution-phase synthesis of N-substituted dimethyl 4-oxo-1,4-dihydropyridine-3,5-dicarboxylates 4 and methyl 3-oxo-3,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxylates 9 from dimethyl acetone-1,3-dicarboxylate (1) were developed. The first synthetic method comprises preparation of the bis-enaminone reagents 2 and 8 and their cyclization with primary amines 3 via double substitution of both dimethylamino groups to give dihydropyridines (DHPs) 4 and 9, respectively. Another variation consists of preparation of the monoenaminone reagents 5 and 10, followed by substitution of the dimethylamino group with primary amines 3, and cyclization of the so formed intermediates 6 with N,N-dimethylformamide dimethylacetal (DMFDMA). In this manner, a library of 46 analytically pure compounds, 24 intermediates 6, 11, and 13, and 22 final dihydropyridines 4 and 9 was obtained employing just a simple filtration workup.


Antigen-agnostic microfluidics-based circulating tumor cell enrichment and downstream molecular characterization.
Circulating tumor cells (CTC) isolated from the peripheral blood of cancer patients by a minimally invasive procedure provide surrogate markers of the tumor that can be repeatedly sampled. However, the selection and enumeration of CTCs by traditional methods based on surface proteins like EPCAM may not detect CTCs with a mesenchymal phenotype. Here, we employed an antibody-agnostic platform, the Parsortix® PR1 system, which enriches CTCs based on cell size and membrane deformability. We evaluated the linearity, sensitivity, and specificity of the Parsortix PR1 system in tandem with 3 downstream molecular characterization techniques using healthy donor blood spiked with cultured cell lines. Signal amplification of mRNA using a QuantiGene 25-gene assay was able to quantitate multiple epithelial genes, including CDH1, EGFR, ERBB2, KRT18, and MUC1, from high numbers of spiked cells and was able to detect KRT18 when only 50 MCF-7 or SUM190 cells were spiked into healthy donor blood. However, target amplification of mRNA by quantitative polymerase chain reaction (qPCR) showed better sensitivity; qPCR without pre-amplification was able to detect CTC-related genes in Parsortix PR1-enriched cells when as few as 5 SKBR3 cells were spiked into blood. Finally, the HTG EdgeSeq nuclease protection assay was able to profile mRNA expression of over 2,560 cancer-related genes from Parsortix PR1 enriched cells, showing enrichment in cancer signaling pathways and ERBB2, KRT19, and KRT7. Overall, the Parsortix PR1 platform may be amenable to transition into routine clinical workflows.


Recurrent oligodendroglioma with changed 1p/19q status.
We report a case of oligodendroglioma that had consistent histopathological features as well as a distinct change in 1p/19q status in the second recurrence, after temozolomide chemotherapy and radiotherapy. The first tumor recurrence had oligodendroglial morphology, IDH1 R132H and TERT promoter mutations, and 1p/19q codeletion detected by fluorescent in situ hybridization (FISH). Copy number analysis, assessed by next-generation sequencing, confirmed 1p/19q codeletion, and disclosed loss of heterozygosity (LOH) of chromosomes 4 and 9 and chromosome 11 gain. The second recurrence featured not only oligodendroglial morphology but also the appearance of admixed multinucleated giant cells or neoplastic cells having oval nuclei and mitoses and showing microvascular proliferation; it maintained IDH1 R132H and TERT promoter mutations, acquired TP53 mutation, and showed 19q LOH, but disomic 1p, detected by FISH. Copy number analysis depicted LOH of chromosomes 3p, 13, and 19q, 1p partial deletion (1p chr1p34.2-p11), and gain of chromosomes 2p25.3-p24.1, 8q12.2-q24.3, and 11q13.3-q25. B-allele frequency analysis of polymorphic sites disclosed copy-neutral LOH at 1p36.33-p34.2, supporting the initial deletion of 1p, followed by reduplication of 1p36.33-p34.2 alone. These findings suggest that the two tumor recurrences might have originated from an initial neoplastic clone, featuring 1p/19q codeletion and IDH1 and TERT promoter mutations, and have independently acquired other copy number alterations. The reduplication of chromosome 1p might be the result of temozolomide treatment, and gave rise to false negative 1p deletion detected by FISH. The possibility of 1p copy-neutral LOH should be considered in recurrent oligodendrogliomas with altered 1p/19q status detected by FISH.


Early Diagnosis of Respiratory Abnormalities in Asbestos-Exposed Workers by the Forced Oscillation Technique.
The current reference test for the detection of respiratory abnormalities in asbestos-exposed workers is spirometry. However, spirometry has several shortcomings that greatly affect the efficacy of current asbestos control programs. The forced oscillation technique (FOT) represents the current state-of-the-art technique in the assessment of lung function. This method provides a detailed analysis of respiratory resistance and reactance at different oscillatory frequencies during tidal breathing. Here, we evaluate the FOT as an alternative method to standard spirometry for the early detection and quantification of respiratory abnormalities in asbestos-exposed workers. Seventy-two subjects were analyzed. The control group was composed of 33 subjects with a normal spirometric exam who had no history of smoking or pulmonary disease. Thirty-nine subjects exposed to asbestos were also studied, including 32 volunteers in radiological category 0/0 and 7 volunteers with radiological categories of 0/1 or 1/1. FOT data were interpreted using classical parameters as well as integer (InOr) and fractional-order (FrOr) modeling. The diagnostic accuracy was evaluated by investigating the area under the receiver operating characteristic curve (AUC). Exposed workers presented increased obstruction (resistance p<0.001) and a reduced compliance (p<0.001), with a predominance of obstructive changes. The FOT parameter changes were correlated with the standard pulmonary function analysis methods (R = -0.52, p<0.001). Early respiratory abnormalities were identified with a high diagnostic accuracy (AUC = 0.987) using parameters obtained from the FrOr modeling. This accuracy was significantly better than those obtained with classical (p<0.001) and InOr (p<0.001) model parameters. The FOT improved our knowledge about the biomechanical abnormalities in workers exposed to asbestos. Additionally, a high diagnostic accuracy in the diagnosis of early respiratory abnormalities in asbestos-exposed workers was obtained. This makes the FOT particularly useful as a screening tool in the context of asbestos control and elimination. Moreover, it can facilitate epidemiological research and the longitudinal follow-up of asbestos exposure and asbestos-related diseases.


Targeted protein functionalization using His-tags.
With the impressive growth in gene sequence data that has become available, recombinant proteins represent an increasingly vast source of molecular components, with unique functional and structural properties, for use in biotechnological applications and devices. To facilitate the use, manipulation, and integration of such molecules into devices, a controllable method for their chemical modification was developed. In this approach, a trifunctional labeling reagent first recognizes and binds a His-tag on the target protein's surface. After binding, a photoreactive group on the trifunctional molecule is triggered to create a covalent linkage between the reagent and the target protein. The third moiety on the labeling reagent can be varied to bring unique chemical functionality to the target protein. This approach provides: (1) specificity in that only His-tagged targets are modified, (2) regio-specific control in that the target is modified proximal to the His-tag, the position of which can be varied, and (3) stoichiometric control in that the number modifications is limited by the binding capacity of the His-tag. Two such labeling reagents were designed, synthesized, and used to modify both N- and C-terminally His-tagged versions of the enzyme murine dihydrofolate reductase (mDHFR). The first reagent biotinylated the enzyme,while the second served to attach an oligonucleotide to yield a protein-DNA conjugate. In all cases, modification in this manner brings new functionality to the protein while leaving the enzymatic activity intact. The protein-DNA conjugate was used to specifically immobilize the active enzyme through DNA hybridization onto polystyrene microspheres, a step toward creating a functional protein microarray.


Understanding what students bring to the classroom: moderators of the effects of diversity courses on student attitudes.
We investigated the impact of required diversity courses on students' understanding of racial inequality and their social development with regard to racial outgroups, with a specific focus on the effects of student race and empathy as moderators of diversity course effectiveness. First-semester students (N = 173), enrolled in either diversity courses or introduction to psychology, completed surveys at the beginning and end of the semester. Diversity courses increased understanding of White privilege, acknowledgment of blatant racism, and intersectional consciousness overall, but had a greater impact on intersectional consciousness for White students compared with students of color. White students taking diversity courses experienced a reduction in Protestant work ethic ideology that was absent for White students in psychology courses and for all students of color. Notably, empathy moderated the effect of diversity courses on both outgroup comfort and willingness to act to promote diversity.


An official American Thoracic Society workshop report: assessment and palliative management of dyspnea crisis.
In 2009, the American Thoracic Society (ATS) funded an assembly project, Palliative Management of Dyspnea Crisis, to focus on identification, management, and optimal resource utilization for effective palliation of acute episodes of dyspnea. We conducted a comprehensive search of the medical literature and evaluated available evidence from systematic evidence-based reviews (SEBRs) using a modified AMSTAR approach and then summarized the palliative management knowledge base for participants to use in discourse at a 2009 ATS workshop. We used an informal consensus process to develop a working definition of this novel entity and established an Ad Hoc Committee on Palliative Management of Dyspnea Crisis to further develop an official ATS document on the topic. The Ad Hoc Committee members defined dyspnea crisis as "sustained and severe resting breathing discomfort that occurs in patients with advanced, often life-limiting illness and overwhelms the patient and caregivers' ability to achieve symptom relief." Dyspnea crisis can occur suddenly and is characteristically without a reversible etiology. The workshop participants focused on dyspnea crisis management for patients in whom the goals of care are focused on palliation and for whom endotracheal intubation and mechanical ventilation are not consistent with articulated preferences. However, approaches to dyspnea crisis may also be appropriate for patients electing life-sustaining treatment. The Ad Hoc Committee developed a Workshop Report concerning assessment of dyspnea crisis; ethical and professional considerations; efficient utilization, communication, and care coordination; clinical management of dyspnea crisis; development of patient education and provider aid products; and enhancing implementation with audit and quality improvement.


Effects of electrostimulation and plyometric training program combination on jump height in teenage athletes.
The purpose of this study was to examine the effects of eight-week (2 days/week) training periods of plyometric exercises (PT) and neuromuscular electrostimulation (EMS) on jump height in young athletes. Squat jump (SJ), counter movement jump (CMJ) and drop jump (DJ) were performed to assess the effects of the training protocols 98 athletes (100 & 200m and 100m & 110m hurdles) voluntarily took part in this study, 51 males (52%) and 47 females (48%), 17.91 ± 1.42 years old, and 5.16 ± 2.56 years of training experience. The participants were randomly assigned to four different groups according to the frequency and the timing of the stimulation. Analysis of covariance was used to analyze the effects of every training program on jump height. Our findings suggest that compared to control (Plyometrics (PT) only), the combination of 150Hz EMS + PT simultaneously combined in an 8 week (2days/week) training program, we could observe significant jump height improvements in the different types of strength: explosive, explosive-elastic, and explosive-elastic-reactive. The combination of PT after ≤ 85 Hz EMS did not show any jump height significant increase in sprinters. In conclusion, an eight week training program (with just two days per week) of EMS combined with plyometric exercises has proven useful for the improvement of every kind of vertical jump ability required for sprint and hurdles disciplines in teenage athletes.


Disseminated Scedosporium apiospermum infection in a cystic fibrosis patient after double-lung transplantation.
Scedosporium apiospermum is a saprophytic ubiquitous filamentous fungus. It can cause a wide spectrum of diseases, from localized to invasive infections. S apiospermum has been described as one of the major fungal agents of chronic colonization of airways in cystic fibrosis (CF) patients. Invasive infections due to S apiospermum are only rarely reported in CF after lung transplantation. A 26-year-old woman with CF and chronic bronchial colonization by S apiospermum developed bilateral chorioretinitis and subcutaneous nodules 4 weeks after double-lung transplantation (LTx). Isolates of S apiospermum from sputum samples before and after LTx and from vitreal fluid were typed by random amplification of polymorphic DNA (RAPD). The patient was treated with voriconazole (VRC). The patient improved with VRC given orally for 6 months. Two days after VRC discontinuation, she developed sub-acute meningitis (isolation of S apiospermum from the cerebrospinal fluid). She was again given VRC, but died 23 days later from uncontrolled fungal infection. Molecular typing of clinical isolates of S apiospermum performed by RAPD demonstrated that all isolates belonged to the same genotype. S apiospermum is a frequent, but late colonizing fungal agent in CF patients. In the case of LTx, these patients can develop invasive infection due to the colonizing strain, as confirmed by molecular typing.


Fine-scale variation and genetic determinants of alternative splicing across individuals.
Recently, thanks to the increasing throughput of new technologies, we have begun to explore the full extent of alternative pre-mRNA splicing (AS) in the human transcriptome. This is unveiling a vast layer of complexity in isoform-level expression differences between individuals. We used previously published splicing sensitive microarray data from lymphoblastoid cell lines to conduct an in-depth analysis on splicing efficiency of known and predicted exons. By combining publicly available AS annotation with a novel algorithm designed to search for AS, we show that many real AS events can be detected within the usually unexploited, speculative majority of the array and at significance levels much below standard multiple-testing thresholds, demonstrating that the extent of cis-regulated differential splicing between individuals is potentially far greater than previously reported. Specifically, many genes show subtle but significant genetically controlled differences in splice-site usage. PCR validation shows that 42 out of 58 (72%) candidate gene regions undergo detectable AS, amounting to the largest scale validation of isoform eQTLs to date. Targeted sequencing revealed a likely causative SNP in most validated cases. In all 17 incidences where a SNP affected a splice-site region, in silico splice-site strength modeling correctly predicted the direction of the micro-array and PCR results. In 13 other cases, we identified likely causative SNPs disrupting predicted splicing enhancers. Using Fst and REHH analysis, we uncovered significant evidence that 2 putative causative SNPs have undergone recent positive selection. We verified the effect of five SNPs using in vivo minigene assays. This study shows that splicing differences between individuals, including quantitative differences in isoform ratios, are frequent in human populations and that causative SNPs can be identified using in silico predictions. Several cases affected disease-relevant genes and it is likely some of these differences are involved in phenotypic diversity and susceptibility to complex diseases.


Kinetic theory molecular dynamics and hot dense matter: theoretical foundations.
Electrons are weakly coupled in hot, dense matter that is created in high-energy-density experiments. They are also mildly quantum mechanical and the ions associated with them are classical and may be strongly coupled. In addition, the dynamical evolution of plasmas under these hot, dense matter conditions involve a variety of transport and energy exchange processes. Quantum kinetic theory is an ideal tool for treating the electrons but it is not adequate for treating the ions. Molecular dynamics is perfectly suited to describe the classical, strongly coupled ions but not the electrons. We develop a method that combines a Wigner kinetic treatment of the electrons with classical molecular dynamics for the ions. We refer to this hybrid method as "kinetic theory molecular dynamics," or KTMD. The purpose of this paper is to derive KTMD from first principles and place it on a firm theoretical foundation. The framework that KTMD provides for simulating plasmas in the hot, dense regime is particularly useful since current computational methods are generally limited by their inability to treat the dynamical quantum evolution of the electronic component. Using the N-body von Neumann equation for the electron-proton plasma, three variations of KTMD are obtained. Each variant is determined by the physical state of the plasma (e.g., collisional versus collisionless). The first variant of KTMD yields a closed set of equations consisting of a mean-field quantum kinetic equation for the electron one-particle distribution function coupled to a classical Liouville equation for the protons. The latter equation includes both proton-proton Coulombic interactions and an effective electron-proton interaction that involves the convolution of the electron density with the electron-proton Coulomb potential. The mean-field approach is then extended to incorporate equilibrium electron-proton correlations through the Singwi-Tosi-Land-Sjolander (STLS) ansatz. This is the second variant of KTMD. The STLS contribution produces an effective electron-proton interaction that involves the electron-proton structure factor, thereby extending the usual mean-field theory to correlated but near equilibrium systems. Finally, a third variant of KTMD is derived. It includes dynamical electrons and their correlations coupled to a MD description for the ions. A set of coupled equations for the one-particle electron Wigner function and the electron-electron and electron-proton correlation functions are coupled to a classical Liouville equation for the protons. This latter variation has both time and momentum dependent correlations.


Exploring the effects of roadway characteristics on the frequency and severity of head-on crashes: case studies from Malaysian federal roads.
Head-on crashes are among the most severe collision types and of great concern to road safety authorities. Therefore, it justifies more efforts to reduce both the frequency and severity of this collision type. To this end, it is necessary to first identify factors associating with the crash occurrence. This can be done by developing crash prediction models that relate crash outcomes to a set of contributing factors. This study intends to identify the factors affecting both the frequency and severity of head-on crashes that occurred on 448 segments of five federal roads in Malaysia. Data on road characteristics and crash history were collected on the study segments during a 4-year period between 2007 and 2010. The frequency of head-on crashes were fitted by developing and comparing seven count-data models including Poisson, standard negative binomial (NB), random-effect negative binomial, hurdle Poisson, hurdle negative binomial, zero-inflated Poisson, and zero-inflated negative binomial models. To model crash severity, a random-effect generalized ordered probit model (REGOPM) was used given a head-on crash had occurred. With respect to the crash frequency, the random-effect negative binomial (RENB) model was found to outperform the other models according to goodness of fit measures. Based on the results of the model, the variables horizontal curvature, terrain type, heavy-vehicle traffic, and access points were found to be positively related to the frequency of head-on crashes, while posted speed limit and shoulder width decreased the crash frequency. With regard to the crash severity, the results of REGOPM showed that horizontal curvature, paved shoulder width, terrain type, and side friction were associated with more severe crashes, whereas land use, access points, and presence of median reduced the probability of severe crashes. Based on the results of this study, some potential countermeasures were proposed to minimize the risk of head-on crashes.


A novel method of removing artifacts because of metallic dental restorations in 3-D CT images of jaw bone.
CT images, especially in a three-dimensional (3-D) mode, give valuable information for oral implant surgery. However, image quality is often severely compromised by artifacts originating from metallic dental restorations, and an effective solution for artifacts is being sought. This study attempts to substitute the damaged areas of the jaw bone images with dental cast model images obtained by CT. The position of the dental cast images was registered to that of the jaw bone images using a devised interface that is composed of an occlusal bite made of self-curing acrylic resin and a marker plate made of gypsum. The patient adapted this interface, and CT images of the stomatognathic system were filmed. On the other hand, this interface was placed between the upper and lower cast models and filmed by CT together with the cast models. The position of the marker plate imaged with the dental casts was registered to those adapted by the patient. The error of registration was examined to be 0.25 mm, which was satisfactory for clinical application. The damaged region in the cranial bone images as an obstacle for implant surgery was removed and substituted with the trimmed images of the dental cast. In the method developed here, the images around the metallic compounds severely damaged by artifacts were successfully reconstructed, and the stomatognathic system images became clear, and this is useful for implant surgery.


Expertise as a Response to Limited Multilateralism: The Case of South Korea's Vaccine Procurement Task Force for COVID-19 Vaccines amid Unequal Access via the COVAX Facility.
This study investigates South Korea's trials and errors in procuring COVID-19 vaccines from abroad, amid the limitations of a multilateral scheme for global provision through the COVID-19 Vaccines Global Access (COVAX) program via the World Health Organization (WHO) and the discussions on COVID-19 vaccine patent waivers at the World Trade Organization. Using the framework of "self-help" in the international system and country categorization to explicate country behaviors by state-business relations and expertise to explain South Korea's COVID-19 vaccine procurement process, this study argues that in the absence of a global mechanism that guarantees adequate and timely vaccine provision, countries are left to the sole option of depending on their own capabilities: expertise, budget, and policy planning by consolidating public and private capacities to acquire vaccines for the public. To support the argument, an in-depth case investigation of South Korea's Vaccine Procurement Task Force is presented. The case study focuses on the policy assessment of critical elements in South Korea's vaccine procurement and rollout on facing obstacles to sufficient procurement through COVAX: decision-making impacting the timing and dosage of procurement, diplomatic and business channels to sign bilateral contracts, setup of a smart-factory vaccination hub, and indigenous vaccine development for WHO approval.


Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation.
Recently, the BRAF V600E mutation was reported in all cases of hairy cell leukemia (HCL) but not in other peripheral B-cell neoplasms. We wished to confirm these results and assess BRAF status in well-characterized cases of HCL associated with poor prognosis, including the immunophenotypically defined HCL variant (HCLv) and HCL expressing the IGHV4-34 immunoglobulin rearrangement. Fifty-three classic HCL (HCLc) and 16 HCLv cases were analyzed for BRAF, including 5 HCLc and 8 HCLv expressing IGHV4-34. BRAF was mutated in 42 (79%) HCLc, but wild-type in 11 (21%) HCLc and 16 (100%) HCLv. All 13 IGHV4-34(+) HCLs were wild-type. IGHV gene usage in the 11 HCLc BRAF wild-type cases included 5 IGHV4-34, 5 other, and 1 unknown. Our results suggest that HCLv and IGHV4-34(+) HCLs have a different pathogenesis than HCLc and that a significant minority of other HCLc are also wild-type for BRAF V600.


Effects of dietary fats differing in n-6:n-3 ratio fed to high-yielding dairy cows on fatty acid composition of ovarian compartments, follicular status, and oocyte quality.
The objectives were to determine the incorporation of dietary encapsulated fats differing in n-6:n-3 ratio into milk fat, plasma, and various ovarian compartments and to examine the effects on ovarian follicular status, preovulatory follicle characteristics, and oocyte quality. Twenty-four multiparous Israeli Holstein cows, averaging 114 d in milk, were assigned to 1 of 3 treatment groups: 1) control (n=7), in which cows were fed a lactating cow diet; 2) E-FLAX (n=8), in which cows were fed a lactating cow diet that consisted of 1kg/d of encapsulated fat (3.8% of dry matter) containing 40.8% flaxseed oil, providing 242.2g of C18:3n-3 (low n-6:n-3 ratio); or 3) E-SUN (n=9), in which cows were fed a lactating cow diet that consisted of 1kg/d of encapsulated fat (3.8% of dry matter) containing 40.8% sunflower oil, providing 260.0g of C18:2n-6 (high n-6:n-3 ratio). Ovaries were monitored by ultrasonography for follicular status, and after synchronization, follicles >7mm were aspirated and evaluated. Ovum pickup was performed (19 sessions for the control and E-FLAX groups and 11 for the E-SUN group), and in vitro maturation and oocyte fertilization were conducted. The E-FLAX treatment increased the proportions of C18:3n-3 (5.8 fold), C20:5n-3, and C22:5n-3 (approximately 4-fold) in milk fat as compared with the other 2 treatments. The proportion of C18:3n-3 fatty acid in plasma increased dramatically with the E-FLAX treatment, from 1.43 and 1.49% in the control and E-SUN groups, respectively, to 7.98% in the E-FLAX group. Consequently, the n-6:n-3 ratio in plasma was reduced from approximately 42 in the control and E-SUN groups to 6.74 in the E-FLAX group. Proportions of C18:3n-3 in follicular fluid and granulosa cells were approximately 5-fold higher in the E-FLAX group than in the other 2 groups. The percentage of C18:2n-6 in cumulus-oocyte complexes of cows in the E-SUN group was 54% higher than that in the E-FLAX group and was 2.4-fold higher than that in the control group; the proportion of C18:3n-3 in the E-FLAX group was 4.73% and was not detected in the other groups. The average numbers of 2- to 5-mm follicles on d 5 and 9 of the cycle were higher in the E-FLAX group than in the E-SUN group, whereas the average numbers of follicles > or =10mm on d 5, 9, and 13 were higher in the E-SUN group than in the other 2 groups. The estrous cycles of the cows were synchronized and PGF(2alpha) was injected on d 16 to 17 of the cycle. The interval from PGF(2alpha) injection to behavioral estrus was longer in the E-FLAX group than in the E-SUN group, and the beginning of the luteal phase of the subsequent cycle was delayed. Concentrations of estradiol in follicular fluid of the preovulatory follicles were higher in the E-SUN group than in the E-FLAX group. The number of follicles aspirated by ovum pickup was higher in the E-FLAX group than in the control group, and the cleavage rate in the E-FLAX group was higher than in the control group, but not the E-SUN group. In conclusion, dietary n-3 fatty acids influenced the follicular status and increased the cleavage rate of oocytes as compared with those of control cows. These findings could be related to modifications of the fatty acid composition in plasma and ovarian compartments in response to dietary supplementation.


Single-center experience of catheter ablation for atrial fibrillation using multi-electrode mapping and ablation catheters.
Radiofrequency ablation (RFA) is an established therapy for the treatment of paroxysmal and persistent atrial fibrillation (AF). Many techniques have been reported to achieve RFA. We report a single-center experience of RFA using three multi-electrode catheters. We collected data of the patients who had RFA for AF using custom-designed multi-electrode mapping and ablation catheters between May 2007 and November 2009 at this center. A total of 105 patients aged 56 ± 9.6 years underwent RFA using three multi-electrode catheters. Eighty-seven patients were new and 18 patients had re-do AF ablation using the multi-electrode mapping and ablation catheters. In the new patients, the mean procedure duration was 141 ± 38 minutes and fluoroscopy time was 38 ± 4 minutes. The mean duration of follow-up was 15.8 ± 6.4 months. Symptomatic improvement was achieved in 75 patients (86%), 48 patients (55%) remained in sinus rhythm (SR) after the first procedure, while 7 (8%) had multiple procedures and remained in SR without antiarrhythmic drugs (AAD). Fourteen patients (16%) required AAD following a single procedure and 1 patient (1.1%) after multiple procedures to remain in SR. Seven patients (8%) had reduced burden of symptoms. No improvement occurred in 12 patients (13.7%). In the 18 re-do patients, 15 (83.3%) had symptom improvement. Four patients (22.2%) remained in SR after a single procedure and 4 patients (22.2%) required multiple procedures to remain in SR without AAD. One patient (5.5%) remained in SR on AAD following a single procedure and 1 patient (5.5%) remained in SR on AAD following multiple procedures. Five patients (27%) had reduced burden of symptoms and 3 patients (16.6%) had no improvement. PVI using multi-electrode mapping and ablation catheters is an effective treatment of paroxysmal and persistent AF with a complication rate equivalent to published data.


Bis(phenylsulfone) as a strong electron acceptor of thermally activated delayed fluorescent emitters.
Bis(phenylsulfone) was developed as a strong electron acceptor of thermally activated delayed fluorescent emitters. The connection of two electron withdrawing phenylsulfone moieties through meta-position of phenyl produced the bis(phenylsulfone) acceptor and the strong electron acceptor strength of bis(phenylsulfone) enabled preparation of sky-blue and green thermally activated delayed fluorescent emitters in combination with weak carbazole donors. The bis(phenylsulfone) acceptor and carbazole donor combined organic materials performed as thermally activated delayed fluorescent emitters with a high quantum efficiency of 18.3%.


[Foreign migrants in the labor force. The case of Lombardy].
"The article examines...the integration of immigrant workers into the regular labour force [in Italy]. The analysis concentrates its attention upon Lombardy, one of the regions in which the integration is more relevant. The author compares the situation in Milan, a metropolis where the tertiary sector is highly developed and job opportunities are very diversified, with the one in Brescia where immigrants are mainly employed as factory workers." (SUMMARY IN ENG AND FRE)


Functional representation of tissue phantom ratios for photon fields.
The tissue phantom ratio (TPR) is a common dosimetric quantity used in photon dose calculations. For small photon fields with side lengths less than 4 cm, TPR data hardly exist in literature. In this work, a self-contained functional representation of TPR is proposed, valid for the whole range of clinically relevant depth and field sizes. This is especially useful for small fields shaped by multileaf collimators. TPRs were measured for quadratic fields with side lengths between 0.4 and 18 cm. The measured data were fitted to a physically meaningful function taking electron buildup, buildup of scattered photons, beam attenuation, and beam hardening into account. The achievable accuracy was tested against measurement and data from the literature. A set of parameters for the proposed function was derived for 6 and 10 MV beams. The comparison of the calculated and the measured data generally yielded a difference of less than 1%. For field sizes below 2 cm, a systematic discrepancy between the author's data and those from Cheng et al. [Med. Phys 34, 3149-3157 (2007)] was found. With the proposed model, TPRs can be calculated for the full range of field sizes and depths required by treatment planning system algorithms and monitor unit check programs with very high accuracy. The method is also useful in detecting and reducing errors in measurement.


Life-threatening cold and exercise-induced asthma potentiated by administration of propranolol.
We present two patients with acute respiratory failure secondary to cold and exercise-induced asthma. Neither patient had a prior history of asthma, and both had recently been placed on therapy with propranolol for treatment of hypertension. We discuss the postulated mechanism of bronchospasm in these patients. In addition, we urge aggressive searching for any change in respiratory symptoms in patients receiving propranolol.


[Consenting and declining patients for an intervention group after breast cancer surgery differ in terms of quality of life, coping and immunological functional assays].
Psychosocial intervention during the course of cancer is still being controversially disputed in psychosomatic studies. Immunological and endocrinological parameters can serve as links in observing the influence of the interactive processes involved. The approach to determine whether psychotherapeutic intervention can lead to an improved quality of life on the one hand, and to a change in immune defenses in breast cancer patients as well, employed using the EORTC QLQ-C30 and optimistic self-efficacy (OKE) as well as evaluating lymphocyte subpopulations, lymphocyte proliferation and NK cell activity. Fifty-three breast cancer patients were offered the chance to participate in a psychosocial intervention group. Twenty-three accepted the offer. Randomized sampling of the group participants was determined twice by using the 30 EORTC QLQ-C30 parameters. In addition, immune function was measured before beginning (T1) and after completing the group intervention sessions (T2). This data was compared with that of the declining group. The analysis of the individual EORTC parameters in the pre- and post-comparison showed a decrease in "emotional strain" and an increase in "all-around quality of life" at the T2 test period. NK cell activity was increased at T2 as well in the participating group and was higher than that of the declining group both at T1 and T2 testing times. Participation in the psychosocial intervention group resulted in a marked decrease in the emotional strain and an increase in the quality of life. The increased NK-cell activity with lowered T-cell activation in comparison to the decliners hints at a coherence between coping behaviour and changes of the immunological cell function. The results of this study will be investigated further in a greater sample.


Isolation and separation of physicochemically distinct fimbrial types expressed on a single culture of Escherichia coli O7:K1:H6.
The fimbrial (pili) profile of a single strain of Escherichia coli O7:K1:H6 (WF96) was evaluated. Fimbriae were isolated by sucrose density gradient ultracentrifugation, purified from flagellae by the use of 0.4% sodium dodecyl sulfate (SDS), and separated into distinct fimbrial types. Analysis of the purified WF96 fimbriae by SDS-polyacrylamide gel electrophoresis revealed two polypeptide bands with molecular weights of 16,000 and 21,000. Treatment of the fimbrial mixture with saturated guanidine hydrochloride resulted in the appearance of a third band with a molecular weight of 19,500. The relative susceptibilities of the WF96 fimbrial types to disrupting chemicals (octyl-glucoside, urea, SDS, and guanidine hydrochloride) were assessed by exposure of the fimbrial mixture to each agent, separation of the depolymerized fimbriae from intact fimbriae by gel filtration on Sepharose CL-4B, and identification of the disaggregated fimbrial types by SDS-polyacrylamide gel electrophoresis of column fractions. The physicochemical heterogeneity of the three fimbrial types coexpressed on WF96 was exploited to develop a method for separation of individual fimbriae.


[Fibromyalgia in adults-a mainly psychosomatic entity].
This paper presents the clinical entity of fibromyalgia and is a review of the research data on its pathogenesis and treatment. Current data indicate that bio-genetic factors associated mainly with the mechanisms of pain, combined with serious stressfull experiences, may be responsible for causing the disease. The contribution of neurotransmitters (such as substance P), of hormones (in particular of the hypothalamus-pituitar y axis), of sleep disturbance, of brain circuits linked to the perception of pain is discussed. The treatment of fibromyalgia is complex and involves in particular antidepressant therapy in combination with psychoeducational cognitive and behavioral interventions and rehabilitation programs. In the diagnosis and treatment of the disease, which, without assistance can become torturing, many specialties of health professionals are involved.


Separation of wind's influence on harmful cyanobacterial blooms.
Wind is an important physical factor involved in Harmful Cyanobacterial blooms (CyanoHABs). Its integrated influence was separated to three components: (a) Direct Disturbance Impact (DDI) on cyanbacterial proliferation, (b) Indirect Nutrient Impact (INI) by sediment release and (c) Direct Transportation Impact (DTI) by both gentle wind-induced surface drift and wave-generated Stokes drift. By the combination of field investigation, laboratory experiment and numerical simulation their individual contributions to the severe bloom event in May 2007 in Meiliang Bay, Lake Taihu, was explored. Wind synthetically made 10.5 percent promotion to the bloom on May 28, 2007, but the impact varied with locations. DTI was featured with the strongest contribution of wind's impacts on CyanoHABs, while INI stood at the lowest level and DDI played an intermediate role. From the point of whole Meiliang Bay, the influencing weights of DTI, DDI and INI were approximately 48.55%, 32.30% and 19.15% respectively. DTI exerted the higher promotion in the regions of middle-east (ME), southwest (SW) and southeast (SE), and its actual contribution rate on CyanoHABs ranged from 6.41% to 7.46%. Due to the background nutrient load, INI was characterized by a tiny effect with the contribution rate being 2.18% on average. From the south bay to the north, DDI was detected with a decreasing tendency, with the practical contribution rate generally falling from 4.13% to 2.7%.


The effect of lipopolysaccharide on bovine mammary macrophage function.
The effect of Escherichia coli lipopolysaccharide (LPS) on the expression of major histocompatibility complex (MHC) class II molecules by bovine mammary macrophages was examined. The ability of LPS-treated mammary macrophages to support antigen-specific T-cell proliferation, as a measure of their antigen presentation ability, was also evaluated. For this purpose, control and LPS-treated macrophages were pulsed with heat-killed Staphylococcus aureus and then cultured with S. aureus-sensitized T-cells. Our data show that LPS had no significant effect on the expression of MHC class II molecules on the surface of mammary macrophages. Furthermore, LPS-induced macrophages were no more active in supporting T-cell proliferation on a per cell basis than unstimulated macrophages. The lack of macrophage response to LPS with respect to expression of MHC class II molecules and the antigen presentation ability is another example of the hyporesponsive nature of macrophages isolated from the bovine mammary gland.


Efficacy of Preoperative Oral Antibiotic Prophylaxis for the Prevention of Surgical Site Infections in Patients With Crohn Disease: A Randomized Controlled Trial.
We investigated the efficacy of oral antimicrobial prophylaxis in patients undergoing surgery for Crohn disease. Although oral antibiotic prophylaxis with mechanical bowel preparation has been recommended for colorectal surgery, the use of this approach remains somewhat controversial. Moreover, the efficacy of this approach for inflammatory bowel disease also remains unclear. This study was conducted as a randomized controlled trial at the Hyogo College of Medicine. The study protocols were registered with the University Hospital Medical Information Network Clinical Trials Registry (000013369). In this study, 335 patients with Crohn disease who were scheduled to undergo intestinal resection with an open approach were randomly assigned to either group A or group B. The patients in group A received both preoperative oral antibiotics and intravenous antimicrobial prophylaxis, and intravenous antimicrobial prophylaxis alone was given to the patients in group B. All patients underwent preoperative mechanical bowel preparation with sodium picosulfate hydrate. The primary endpoint of this study was the incidence of surgical site infection (SSI) according to an intention-to-treat analysis. Although the incidences of overall and organ/space SSI were not significantly different, the incidence of incisional SSI was significantly lower in group A (12/163; 7.4%) than in group B (27/162; 16.6%) (P = 0.01). In the multivariate analysis, the absence of oral antibiotic prophylaxis was an independent risk factor for incisional SSI (odds ratio: 3.3; 95% confidence interval: 1.3-8.3; P = 0.01). Combined oral and intravenous antimicrobial prophylaxis in patients with Crohn disease contributed to the prevention of SSI.


Trace MicroRNA Quantification by Means of Plasmon-Enhanced Hybridization Chain Reaction.
Quantifying trace microRNAs (miRNAs) is extremely important in a number of biomedical applications but remains a great challenge. Here we present an enzyme-free amplification strategy called plasmon-enhanced hybridization chain reaction (PE-HCR) for quantifying trace miRNAs with an outstanding linear range from 1 fM to 1 pM (r(2) = 0.991), along with a detection limit of 0.043 fM (1300 molecules in 50 μL of sample). The merits of the PE-HCR assay, including high sensitivity and specificity, quantitative detection, no enzyme involvement, low false positives, and easy-to-operate procedures, have been demonstrated for high-confidence quantification of the contents of miRNAs in even single cancer cells. The PE-HCR assay may open up new avenues for highly sensitive quantification of biomarkers and thus should hold great potentials in clinical diagnosis and prognosis.


My imagination versus your feelings: can personal affective forecasts be improved by knowing other peoples' emotions?
A proposed remedy for biased affective forecasts is to base judgments on the actual feelings of people (surrogates) currently experiencing the event, rather than using imagination which conjures an inaccurate vision of the future. Gilbert et al. (2009) forced people to use surrogate reports by withholding all event information, resulting in better predictions. However, in life surrogate information rarely supplants event information--can people effectively integrate both types of information into their judgments? In five studies, respondents predicted the impact of a health state on their own happiness. Respondents incorporated surrogate information into their judgments both in the presence and absence of event information. However, they inappropriately discounted other people's experiences as a valid predictor of their own--particularly in the presence of event information--and imagined their happiness would be different to surrogates' happiness. Excluding preexisting event knowledge, changing the size of the surrogate sample, or increasing the size of the response scale did not alter the adjustment. Although surrogate information improved affective forecasts, its influence was diminished by the presence of event information.


[Preparation of surface-modified carbon nanotubes/silica composite gel glass].
Owing to their unique structure and properties, carbon nanotubes (CNTs) have become the highlight of research since they were discovered. Part of the research interest lies in introducing them into solid state matrix to make them materialized. However, CNTs tend to aggregate in the matrix, which makes it difficult to make homogeneous composites. In order to solve this problem, we first modified the surface of CNTs by chemically bonding them to 3-aminopropyltrie-thoxysilane (NH2 (CH2)3Si(OC2H5)3, APTES) using three-step reactions, and then connected them to silica network by sol-gel technique. In the present paper, CNTs were first treated with HNO3 to get CNTs-COOH, which were then treated with SOCl2 to be transferred to CNTs-COCl, and finally CNTs-COCl reacted with APTES to get CNTs-APTES. After that, CNTs were introduced into silica net work through the individual hydrolysis of CNTs-APTES, tetrathyloxysilane (Si(OC2H5)4, TEOS) and 3-glycidoxy-propltrimethoxysilane (CH2OCHCH2O(CH2)3Si(OCH3)3, GPTMS) as sol-gel precursors, and the copolymerization of their hydrolysis products. FTIR and SEM were used to characterize the composition and microstructure of the obtained samples. (Owing to the connection of CNTs with silica network, little aggregation of CNTs was observed and high-quality CNTs/SiO2 composite gel glass was obtained. A model of CNTs/SiO2 network was also given.


Induction of sister chromatid exchange in spleen and bone marrow cells of rats exposed by inhalation to different dose rates of ethylene oxide.
We investigated the effects of dose rate on the frequency of sister chromatid exchange (SCE) in bone marrow and spleen cells of rats exposed to ethylene oxide (EtO). Four groups (18/group) of male Fischer 344 rats were exposed to EtO by inhalation. The exposures consisted of 100 ppm for 6 hr/day, 300 ppm for 2 hr/day, 600 ppm for 1 hr/day, and clean air control. All EtO treated rats were given a total exposure dose of 600 ppm.hr daily, 5 days/week for 3, 6, or 9 months. Six rats per group were sacrificed at each time point, and SCEs were measured in cultured spleen and bone marrow cells. A statistically significant increase was found in SCEs in both bone marrow and spleen cells for all treated groups and at each time point when compared to the control, except at the 3-month exposure for the middle and high dose-rate groups in bone marrow cells. In the spleen, the increases in SCEs were similar among the three experimental groups. In bone marrow, the lowest dose rate (100 ppm) resulted in higher SCE frequencies than the medium and high dose-rate group after 3 and 6 month exposures. The overall frequencies of SCEs in the spleen cells were higher than in the bone marrow cells. The increase in SCE frequencies and decrease in the replicative index in spleen cells were also dependent on the duration of exposure. These results indicate that (1) EtO, by inhalation, can cause SCEs both in spleen and bone marrow cells of Fischer 344 rats, (2) spleen cells are more sensitive to EtO than bone marrow cells, and (3) in bone marrow cells the lowest dose-rate (longest) exposure causes more SCEs than the highest dose-rate (shortest) exposures.


Strategies for reducing ovarian dose in volumetric modulated arc therapy (VMAT) for postoperative uterine cervical cancer.
To reduce the ovarian dose with volumetric modulated arc therapy (VMAT), an original VMAT was designed with two types of arcs to restrict angles and fields (R-VMAT). The subjects were 11 patients who underwent ovarian transposition with clips left by a surgeon. Three methods, intensity-modulated radiotherapy (IMRT), standard VMAT (S-VMAT) and R-VMAT, were optimized for assessment of the ovarian dose with the target coverage kept high. The homogeneity and conformity indexes for the planning target volume (PTV) were similar for the three methods. However, the average ± SD of the ovarian mean dose (OMD) was 5.0 ± 1.5, 4.9 ± 1.9 and 3.5 ± 1.4 Gy, and the percentage of ovarian volume exceeding 5 Gy (V5) was 41.5 ± 34.1%, 34.1 ± 38.05% and 8.4 ± 20.5% for IMRT, S-VMAT and R-VMAT, respectively. The OMD and V5 were significantly smaller for R-VMAT than for the other plans (p < 0.01). Correlation values between the OMD and the lateral distance from the ovaries to the PTV surface were 0.86, 0.81 and 0.82 for IMRT, S-VMAT and R-VMAT, respectively. These findings suggest that R-VMAT delivered the lowest dose to the ovaries. To reduce the OMD to less than 3 Gy, ovaries should be transposed laterally 6.1 cm away from the PTV surface when R-VMAT is used. Advances in knowledge: When organs with high susceptibility to radiation, such as ovaries, are near the PTV, R-VMAT is superior to IMRT and S-VMAT.


A polygenic risk score for multiple myeloma risk prediction.
There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 × 10-15 for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 × 10-13 for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population.


Current Status of Hepatitis C Virus-Infected Maintenance Hemodialysis Patients in Japan.
Complete recovery using interferon therapy in Japanese hepatitis C virus (HCV)-infected dialysis patients is difficult to achieve because >70 % of the HCV genotypes observed in Japan are type 1. In 2016, new direct-acting antiviral drugs against HCV genotype 1 were reported to be effective and safe for HCV-infected hemodialysis patients. Although new direct antiviral therapy has become available, no large-scale studies evaluating the status of HCV infection in Japanese hemodialysis patients have been conducted since 2007. Therefore, we conducted a questionnaire survey to determine the current status of HCV infection in patients. Our results indicated that the HCV antibody prevalence was 5.02 %, and HCV RNA prevalence was 72.3 %. Genotype testing revealed that 62.1 % of patients had HCV genotype 1. New direct antiviral therapy may improve the survival of Japanese HCV-infected dialysis patients.


[Effects of continuous lighting on secretion of melatonin and pituitary hormones in women].
Effects of light exposure on the serum concentrations of melatonin, prolactin, LH and FSH were studied in 53 women during their follicular phases. Twenty seven women were exposed to light (500-800 lux at eye level) from 17:30h to 22:00h, and 17 women received the same light intensity from 17:30h to 2:00h, while 9 women stayed in a dark room from 21:00h to 2:00h as control subjects. The light exposure suppressed a nocturnal increase in the serum concentrations of melatonin both at 22:00h and 2:00h. The light exposure and awake condition suppressed the serum prolactin concentrations and increased the serum FSH concentrations at 2:00h, while the influence on the serum LH concentrations was not clear because of LH pulsatility. These results show that the circadian rhythm of melatonin, prolactin and FSH is affected by light exposure and wakefulness, and the effects of light exposure would become more evident if light exposure was continued over a longer period.


Endoscopist specialty is associated with colonoscopy quality.
Some studies have shown that endoscopist specialty is associated with colorectal cancers missed by colonoscopy. We sought to examine the relationship between endoscopist specialty and polypectomy rate, a colonoscopy quality indicator. Polypectomy rate is defined as the proportion of colonoscopies that result in the removal of one or more polyps. A cross-sectional study was conducted of endoscopists and their patients from 7 Montreal and 2 Calgary endoscopy clinics. Eligible patients were aged 50-75 and covered by provincial health insurance. A patient questionnaire assessed family history of colorectal cancer, history of large bowel conditions and symptoms, and previous colonoscopy. The outcome, polypectomy status, was obtained from provincial health administrative databases. For each city, Bayesian hierarchical logistic regression was used to estimate the odds ratio for polypectomy comparing surgeons to gastroenterologists. Model covariates included patient age, sex, family history of colorectal cancer, colonoscopy indication, and previous colonoscopy. In total, 2,113 and 538 colonoscopies were included from Montreal and Calgary, respectively. Colonoscopies were performed by 38 gastroenterologists and 6 surgeons in Montreal, and by 31 gastroenterologists and 5 surgeons in Calgary. The adjusted odds ratios comparing surgeons to gastroenterologists were 0.48 (95% CI: 0.32-0.71) in Montreal and 0.73 (95% CI: 0.43-1.21) in Calgary. An association between endoscopist specialty and polypectomy was observed in both cities after adjusting for patient-level covariates. Results from Montreal suggest that surgeons are half as likely as gastroenterologists to remove polyps, while those from Calgary were associated with a wide, non-significant Bayesian credible interval. However, residual confounding from patient-level variables is possible, and further investigation is required.


An Unusual Cause of Recurrent Urinary Retention in an Adolescent Female.
Herlyn-Werner-Wunderlich syndrome (HWWS) is a rare, combined Mullerian and Mesonephric duct anomaly characterized by the triad of uterus didelphys, obstructed hemivagina and ipsilateral renal agenesis. We present the case of an otherwise healthy 16-year-old female with acute urinary retention secondary to HWWS. The diagnosis was established with abdominal ultrasound and Magnetic Resonance Imaging (MRI). The patient subsequently underwent surgical resection of the vaginal septum resulting in relief of obstruction. Clinical symptoms in patients with HWWS typically present after menarche with progressive hematometra causing pain and compression of localized structures. Even though ultrasound can help in the diagnosis, MRI is the best choice of imaging for the visualization of these anomalies. The diagnosis of HWWS is important to consider in young females of reproductive age presenting with symptoms of obstruction of adjacent structures. Our patient presented with acute urinary retention which is a rare symptom in this entity. A high index of clinical suspicion and awareness of the syndrome are required to make a speedy diagnosis and prevent future complications.


Minor segmental dyssynergy reflects extensive myocardial damage and global left ventricle dysfunction in chronic Chagas disease.
The majority of patients with Chagas disease (ChD) remain for 10 to 30 years or even for life in the indeterminate form (IF) of this disease. They have positive-specific serology tests for ChD, but no symptoms or physical signs, and normal findings for electrocardiograms (ECGs) and heart, esophagus, and colon radiographs. To investigate whether patients in this phase of disease have any impairment of left ventricular (LV) systolic performance, we assessed their contractility index by the slope of the LV end-systolic pressure-dimension (P(es)-D(es)) relation. We studied 35 patients with ChD (14 IF, 11 digestive form [DF], 10 cardiac form [CF]) and 13 healthy subjects. Patients with the CF had only minor cardiac involvement (bundle-branch block, normal LV ejection fraction). All patients had normal baseline global LV systolic function on 2-dimensional echocardiography, but minor segmental wall motion abnormalities were observed in 3 DF, 3 IF, and 2 CF patients. At rest and during intravenous phenylephrine infusion, we measured LV dimensions by echocardiography, and LV end-systolic pressure was estimated by a calibrated carotid pulse tracing. We also measured percent fractional shortening (%DeltaD) and the rate-corrected mean velocity of fiber shortening (Vcf(c)). Mean values (+/- SD) of %DeltaD and Vcf(c) were not significantly different from those exhibited by healthy control subjects in any of the ChD groups at rest (except for CF) or at peak stress using phenylephrine. The P(es)-D(es) slope was similarly and significantly reduced in all ChD patients (IF: 50.7 +/- 25; DF: 52.3 +/- 24; CF: 60.8 +/- 22 mm Hg/cm) compared with normal subjects (89 +/- 17 mm Hg/cm). The P(es)-D(es) slope was even more depressed (39.6 +/- 10 mm Hg/cm) in ChD patients who had minor segmental wall motion abnormalities (SWMAs) on the baseline 2-dimensional echocardiograph in comparison with the slightly reduced values found in patients with CF who had isolated conduction abnormalities on the ECG (71.8 +/- 10 mm Hg/cm). Although %DeltaD and Vcf(c), even at peak afterload, do not differentiate ChD patients from normal controls, the P(es)-D(es) slope is significantly impaired in IF, DF, and CF patients. The remarkably lower P(es)-D(es) slope value documented in ChD patients exhibiting only minor LVWMAs suggests a more extensive myocardial damage in this group of patients, indicating that they should be considered as exhibiting symptoms of the CF version of the disease.


Electrophysiological Evidence for Use of the Animacy Hierarchy, but not Thematic Role Assignment, During Verb Argument Processing.
Animacy is known to play an important role in language processing and production, but debate remains as to how it exerts its effects: 1) through links to syntactic ordering, 2) through inherent differences between animate and inanimate entities in their salience/lexico-semantic accessibility, 3) through links to specific thematic roles. We contrasted these three accounts in two event related potential (ERP) experiments examining the processing of direct object arguments in simple English sentences. In Experiment 1, we found a larger N400 to animate than inanimate direct object arguments assigned the Patient role, ruling out the second account. In Experiment 2 we found no difference in the N400 evoked by animate direct object arguments assigned the Patient role (prototypically inanimate) and those assigned the Experiencer role (prototypically animate), ruling out the third account. We therefore suggest that animacy may impact processing through a direct link to syntactic linear ordering, at least on post-verbal arguments in English. We also examined processing on direct object arguments that violated the animacy-based selection restriction constraints of their preceding verbs. These violations evoked a robust P600, which was not modulated by thematic role assignment or reversibility, suggesting that the so-called semantic P600 is driven by overall propositional impossibility, rather than thematic role reanalysis.


A survey on knowledge and attitudes towards molar-incisor hypomineralization among undergraduate and postgraduate students at the School of Stomatology, Wuhan University.
Molar incisor hypomineralization (MIH) is a developmental dental disease, and its clinical management challenges dentists. This study aimed to investigate the knowledge about MIH and the attitudes towards learning more about MIH among undergraduate and postgraduate students attending the School of Stomatology, Wuhan University. This survey was based on a questionnaire modified based on previous studies. The questionnaire was sent to 540 undergraduate and postgraduate students from the School of Stomatology, Wuhan University. The questions covered their clinical experience, perceptions, clinical management, and preferences for further training. Data were analysed with the Chi-square test. We collected 368 questionnaires (response rate: 68%). Among them, 89% (328/368) were eligible for analysis. Most respondents (80%) had heard of MIH, primarily from classroom teaching. However, only 40% of the students had observed the disease clinically, and a relatively low proportion of students were familiar with the aetiology, prevalence, differential diagnosis, and treatment of MIH. Most respondents were highly enthusiastic and had great expectations about further systematic teaching about MIH. Most students in this study had heard of MIH, but few were familiar with the principles of its differential diagnosis. Systematic teaching about MIH is warranted.


Adaptive regulation of assistance 'as needed' in robot-assisted motor skill learning and neuro-rehabilitation.
We propose a general adaptive procedure to select the appropriate degree of assistance based on a Bayesian mechanism used to estimate psychophysical thresholds. This technique does not need an accurate model of learning and recovery processes. This procedure is validated in the context of a motor skill learning problem (control of a virtual object), in which the controller is used to gradually increase task difficulty as learning proceeds. These automatic adjustments of task difficulty or the degree of assistance can be used to promote not only motor skill learning but also neuromotor recovery.


[Mental health among elderly relocated to a rural resort area].
This study examined mental health and its related factors comparing elderly relocated to a rural resort area to elderly living in a rural old area. Each sample of 400 aged 65 and over were randomly obtained. Valid responses obtained from the resort area and the old area were 193 and 242 respectively. Mental health was measured from two aspects: Geriatric Depression Scale (GDS) and Life Satisfaction Index A (LSIA). We used self-evaluated living environment, social support, social activities, Activities of Daily Living (ADL), economic status, decision to move, and reason for move (push- and pull-factor), as factors which seem to be related to mental health. The findings were as follows: 1) Respondents in the resort area showed lower GDS and higher LSIA than respondents in the old area. 2) Although for the respondents in the resort area assessment that their community was safe, participation in community groups, or involvement in recreational activities occupied a significant higher level in their mental health, these factors had no significant impact on the mental health among the respondents in the old area. 3) A difference in self-evaluated housing condition, ADL, and economic status between both groups had a cause for the area differences in mental health among the elderly. 4) Push-factor had both a direct effect and an indirect effect mediated by decision to move on GDS. Pull-factor had both a direct and an indirect effect on LSIA. Elderly relocated to a rural resort area had better mental health than elderly living in an old area, partly because they had better physical health, better economic status, and better housing condition. Self evaluated living environment and social activities were related to the mental health of the elderly in the resort area stronger than that of the elderly in the old area. Reason for move was related to the mental health of the elderly both directly and indirectly mediated by decision to move.


Coherent Lattice Vibrations in Mono- and Few-Layer WSe2.
We report the observation of coherent lattice vibrations in mono- and few-layer WSe2 in the time domain, which were obtained by performing time-resolved transmission measurements. Upon the excitation of ultrashort pulses with the energy resonant to that of A excitons, coherent oscillations of the A1g optical phonon and longitudinal acoustic phonon at the M point of the Brillouin zone (LA(M)) were impulsively generated in monolayer WSe2. In multilayer WSe2 flakes, the interlayer breathing mode (B1) is found to be sensitive to the number of layers, demonstrating its usefulness in characterizing layered transition metal dichalcogenide materials. On the basis of temperature-dependent measurements, we find that the A1g optical phonon mode decays into two acoustic phonons through the anharmonic decay process.


A study of the biological partitioning behavior of n-alkanes and n-alkanols in causing anesthetic effects.
n-Alkanes and n-alkanols are two groups of common volatile organic compounds (VOCs) having potential anesthetic effects on workers and building occupants. A partition model based on the octanol-air partition coefficient was developed in this investigation to describe the biological partitioning of n-alkanes and n-alkanols in causing general anesthesia. Data on anesthetic potency (minimum alveolar concentration, MAC) for the test groups in rats were found to fit the model. The slight difference between the n-alkanes and n-alkanols in testing the model could be largely eliminated by correcting for the potential partial pressure gradients of the long-chain alkanes across the blood-brain barrier. The corrected MAC data for the two test groups fit well onto one common activity-partition regression line. This suggests that n-alkanes and n-alkanols may share a common biophase or mechanistic pathway for anesthesia. The present findings may provide some useful insight into setting anesthesia-based health standards for VOC mixtures.


Testicular infarction secondary to acute inflammatory disease: demonstration by B-scan ultrasound.
Acute epididymitis can lead to obstruction of the adjacent testicular blood supply, resulting in focal or diffuse infarction of the testis or epididymis in the absence of torsion. Four cases are presented to demonstrate the spectrum of B-scan ultrasound findings, ranging from focal necrosis of the epididymis and ischemic infarction of the testis to diffuse testicular infarction. Epididymal enlargement and skin thickening are consistently seen on ultrasound as well as swelling and decreased echogenicity of the testicle. The authors suggest a protocol for acute scrotal symptoms, incorporating clinical findings and (where appropriate) radionuclide scans.


Sensory function in spinal cord injury patients with and without central pain.
Spinal cord injury (SCI) frequently results in neuropathic pain. However, the pathophysiology underlying this pain is unclear. In this study, we compared clinical examination, quantitative sensory testing (QST) and somatosensory evoked potentials (SEPs) in SCI patients with and without pain below spinal lesion level, with a control group of 20 subjects without injury. All patients had a traumatic SCI with a lesion above T10; 20 patients presented with spontaneous central neuropathic pain below lesion level, and 20 patients had no neuropathic pain or dysaesthesia. Patients with and without pain had a similar reduction of mechanical and thermal detection and pain thresholds, and SEPs. SCI patients with central pain more frequently had sensory hypersensitivity (brush- or cold-evoked pain, dysaesthesia or pinprick hyperalgesia) in dermatomes corresponding to lesion level than SCI patients without pain. There was no difference in intensity of pain evoked by repetitive pinprick at lesion level between patient groups. There was a significant correlation between intensity of brush-evoked dysaesthesia at lesion level and spontaneous pain below lesion level of SCI. These data suggest that lesion of the spinothalamic pathway alone cannot account for central pain in SCI patients, and that neuronal hyperexcitability at injury or higher level may be an important mechanism for pain below injury level.


Malathion-induced oxidative stress, cytotoxicity, and genotoxicity in human liver carcinoma (HepG2) cells.
Malathion is an organophosphate pesticide that is known for its high toxicity to insects and low to moderate potency to humans and other mammals. Its toxicity has been associated with the inhibition of acetylcholinesterase activity, leading to the interference with the transmission of nerve impulse, accumulation of acetylcholine at synaptic junctions, and subsequent induction of adverse health effects including headache, dizziness, nausea, vomiting, bradycardia, and miosis. Oxidative stress (OS) has been reported as a possible mechanism of malathion toxicity in humans. Hence, the aim of this study was to examine the role of OS in malathion-induced cytotoxicity and genotoxicity. To achieve this goal, MTT, lipid peroxidation, and single cell gel electrophoresis (Comet) assays were performed, respectively, to evaluate the levels of cell viability, malondialdehyde (MDA) production, and DNA damage in human liver carcinoma (HepG(2)) cells. Study results indicated that malathion is mitogenic at lower levels of exposure, and cytotoxic at higher levels of exposure. Upon 48 h of exposure, the average percentages of cell viability were 100% +/- 11%, 117% +/- 15%, 86% +/- 15%, 35% +/- 9%, and 27% +/- 7% for 0, 6, 12, 18, and 24 mM, respectively. In the lipid peroxidation assay, the concentrations of MDA produced were 12.55 +/- 0.16, 20.65 +/- 0.27, 31.1 +/- 0.40, 34.75 +/- 0.45, and 15.1 +/- 0.20 muM in 0, 6, 12, 18, and 24 mM malathion, respectively. The Comet assay showed a significant increase in DNA damage at the 24 mM malathion exposure. Taken together, our results indicate that malathion exposure at higher concentrations induces cytotoxic and genotoxic effects in HepG(2) cells, and its toxicity may be mediated through OS as evidenced by a significant production of MDA, an end product of lipid peroxidation.


Stepwise adaptations of citrate synthase to survival at life's extremes. From psychrophile to hyperthermophile.
The crystal structure of citrate synthase from the thermophilic Archaeon Sulfolobus solfataricus (optimum growth temperature = 85 degrees C) has been determined, extending the number of crystal structures of citrate synthase from different organisms to a total of five that span the temperature range over which life exists (from psychrophile to hyperthermophile). Detailed structural analysis has revealed possible molecular mechanisms that determine the different stabilities of the five proteins. The key to these mechanisms is the precise structural location of the additional interactions. As one ascends the temperature ladder, the subunit interface of this dimeric enzyme and loop regions are reinforced by complex electrostatic interactions, and there is a reduced exposure of hydrophobic surface. These observations reveal a progressive pattern of stabilization through multiple additional interactions at solvent exposed, loop and interfacial regions.


The use of phages for the removal of infectious biofilms.
Biofilm formation occurs spontaneously on both inert and living systems and is an important bacterial survival strategy. In humans biofilms are responsible for many pathologies, most of them associated with the use of medical devices. A major problem of biofilms is their inherent tolerance to host defences and antibiotic therapies; there is therefore an urgent need to develop alternative ways to prevent and control biofilm-associated clinical infections. Several in vitro experiments have shown that phages are able to infect biofilm cells and that those phages inducing the production of depolymerases have an advantage since they can penetrate the inner layers of the biofilm by degrading components of the biofilm exopolymeric matrix. In practice clinically relevant biofilms and especially those associated with the use of medical devices can possibly be controlled for example by the topic application or the impregnation of the surface of the device with a phage solution. Another interesting approach has been the use of a phage encoding a phage polysaccharide lyase to treat Pseudomonas aeruginosa biofilms in cystic fibrosis patients by aerosol administration. All these strategies require prior identification of the phage and/or polysaccharide depolymerase capable of infecting the bacterial cells and degrading the polysaccharide within the biofilm, respectively. The biofilm organisms must therefore be isolated and screened against a bank of phages. This procedure is essential and raises important biotechnological challenges: the existence of a bank of phages well characterised (physiologically and genetically) whose efficacy in vivo has been tested and pharmacokinetics studied; the existence of economical and safe production protocols and purification methods (e.g. the presence of endotoxins in a phage preparation may compromise phage therapy). It is however important to consider the fact that the chances of getting a specific phage with a high lytic capability and preferential expressing a relevant exopolymer degrading enzyme is likely to be low. Genetically engineered phages can play an important role in this process. Phages can be genetically manipulated to alter their host range and to induce the production of depolymerases. It is therefore important to reinforce the application of synthetic biology to engineer phages able to efficiently degrade medical biofilms. It is also important to develop efficient methods of phage delivery and to study "in vivo" the phage performance against biofilms. It is still not clear how effective the biofilm can be in protecting the phages against the immune system. Efficient and economic phage production and purification protocols need also to be addressed before one can hope to use phage treatment to prevent or control infectious biofilms.


Central European parasitic flatworms of the Cyclocoelidae Stossich, 1902 (Trematoda: Plagiorchiida): molecular and comparative morphological analysis suggests the reclassification of Cyclocoelum obscurum (Leidy, 1887) into the Harrahium Witenberg, 1926.
Cyclocoelidae Stossich, 1902 are medium-sized to large digenean bird parasites. Although these parasites bear few visible autapomorphic signs, and their diagnostic characters are unstable in response to the pressure applied during preparation, the numerous hitherto suggested re-classifications within the family have not been supported by any molecular analysis. We analyse here cyclocoelids found during the extensive examination of central European birds performed from 1962 to 2016, provide comparative measurements, host spectra, prevalence and intensity, and provide and analyse sequences of four DNA loci of five of the cyclocoelid species. Cyclocoleum Brandes, 1892 appears paraphyletic; thus we suggest the re-classification of Cyclocoleum obscurum (Leidy, 1887) as Harrahium obscurum (Leidy, 1887) Sitko and Heneberg comb. n. Molecular phylogenetics questioned also the validity of Cyclocoelinae Stossich, 1902 and Hyptiasminae Dollfus, 1948, which formed a single clade, whereas Allopyge Johnston, 1913, Prohyptiasmus Witenberg, 1923 and Morishitium Witenberg, 1928 formed another clade. Haematotrephinae Dollfus, 1948 are newly characterized as having a pretesticular or intertesticular ovary that forms a triangle with the testes. Analyses of non-European genera of the Cyclocoelidae and an examination of the position of families within Echinostomata La Rue, 1926 are needed.


Implementation of CYP2D6 genotyping in psychiatry.
Response to pharmacotherapy is subject to large inter-individual variation. Most medicine is metabolised by CYP450 enzymes, including CYP2D6. CYP2D6 activity is determined substantially by the genetic composition. Polymorphisms of CYP2D6 are associated with inadequate response on treatment with psychotropics. The large number of polymorphisms of CYP2D6 raises the question of the way associations between genotype and clinical outcome measurements should be analysed and implemented into a clinical setting. Several methods used for grouping CYP2D6 genotypes are discussed, including the Predicted Phenotype method, the Semi-quantitative Gene Dose system and the Activity Score system. Possible ways to translate genetic information into dose recommendations and to implement genetic information into a clinical setting are discussed. A 100% accurate prediction of metabolic activity is not possible due to the effect of non-genetic factors on metabolic activity. When used for clinical purposes, none of the methods for grouping CYP2D6 genotypes has substantial advantages. The Semi-quantitative Gene Dose or Activity Score system might be preferred for research purposes. Large clinical studies on cost-efficiency will be needed to assure the cost-efficiency of routinely genotyping CYP2D6. Creating more awareness among prescribers of psychotropics about the genetic causes for aberrant drug response, and the possibility of genotyping, is desirable.


Cryopreservation of Winter-dormant Apple Buds IV: Critical Temperature Variation that Can Compromise Survival.
Precise temperature control in several key areas during cryopreservation of dormant, winter apple buds is critical for maximal survival. To consider the effects of pre-harvest temperature, the duration of incubation at -30°C and variation in rewarming rate on survival. Dormant winter buds of Malus x domestica cultivars were harvested with two different acclimation histories and cryopreserved with variation in incubation time at -30°C. Recovery from LN using slow, intermediate and rapid rewarming was investigated as well as preservation after prolonged storage at -4°C. The effects on survival of preharvest temperature regime and an altered -30°C incubation regime are cultivar dependent and an increase in rewarming rate has a strong negative effect on recovery. Post-thaw survival of the winter-dormant buds can be compromised by increased temperature over a period as short as 5 days prior to bud harvest. Varying incubation times at -30°C produce variable, cultivar dependent, survival and moderate increases in rewarming rates can also radically reduce survival.


Social communication disorder outside autism? A diagnostic classification approach to delineating pragmatic language impairment, high functioning autism and specific language impairment.
Developmental disorders of language and communication present considerable diagnostic challenges due to overlapping of symptomatology and uncertain aetiology. We aimed to further elucidate the behavioural and linguistic profile associated with impairments of social communication occurring outside of an autism diagnosis. Six to eleven year olds diagnosed with pragmatic language impairment (PLI), high functioning autism (HFA) or specific language impairment (SLI) were compared on measures of social interaction with peers (PI), restricted and repetitive behaviours/interests (RRBIs) and language ability. Odds ratios (OR) from a multinomial logistic regression were used to determine the importance of each measure to diagnostic grouping. MANOVA was used to investigate differences in subscale scores for the PI measure. Greater degrees of PI difficulties (OR = 1.22, 95% CI = 1.05-1.41), RRBI (OR = 1.23, 95% CI = 1.06-1.42) and expressive language ability (OR = 1.16, 95% CI = 1.03-1.30) discriminated HFA from PLI. PLI was differentiated from SLI by elevated PI difficulties (OR = 0.82, 95% CI = 0.70-0.96) and higher expressive language ability (OR = 0.88, 95% CI = 0.77-0.98), but indistinguishable from SLI using RRBI (OR = 1.01, 95% CI=0.94-1.09). A significant effect of group on PI subscales was observed (θ = 1.38, F(4, 56) = 19.26, p < .01) and PLI and HFA groups shared a similar PI subscale profile. Results provide empirical support for a conceptualisation of PLI as a developmental impairment distinguishable from HFA by absence of RRBIs and by the presence of expressive language difficulties. PI difficulties appear elevated in PLI compared with SLI, but may be less pervasive than in HFA. Findings are discussed with reference to the proposed new category of 'social communication disorder' in DSM-5.


The dark matter of microbiome: the mother-infant pair virome.
The human virome belongs to one of the most complex ecosystems in the world, the microbiome. The virome that inhabits the intestinal niche and its dynamic variation during the first year of life had been the most investigated. Many pathogenic viruses are well known to be potentially transmitted transplacentally or during vaginal delivery to the newborn, but recent studies on healthy term pregnancies found that there was no evidence of a principal viral community. In the maternal-fetal dyad, human milk has been demonstrated to be one of the earliest factors involved in the direct virome transmission. Despite the relationship between humans and viruses traces its roots back to ancient times, the mother-infant pair virome has been poorly investigated and represents currently a "dark matter" of the microbiome.


Genome sequence of the solvent-producing bacterium Clostridium carboxidivorans strain P7T.
Clostridium carboxidivorans strain P7(T) is a strictly anaerobic acetogenic bacterium that produces acetate, ethanol, butanol, and butyrate. The C. carboxidivorans genome contains all the genes for the carbonyl branch of the Wood-Ljungdahl pathway for CO(2) fixation, and it encodes enzymes for conversion of acetyl coenzyme A into butanol and butyrate.


Angiotensin-II type 1 receptor (AT1R) and alpha-1D adrenoceptor form a heterodimer during pregnancy-induced hypertension.
Pregnancy courses with low response to angiotensin II and adrenergic agonists. In preeclampsia, both effects are reverted. It is known that angiotensin II regulates adrenergic system. It is not known, however, the interaction between both systems receptors. Our aim was to study if AT(1)R and alpha1D adrenoceptor heterodimerize in preeclampsia. We used subrenal aorctic coarctation in pregnant rats. Aortic tissues were prepared for confocal imaging and coimmunoprecipitated for alpha1D and AT(1) receptors. We found that AT(1)R and alpha1D adrenoceptor heterodimerize in both, healthy and preeclamptic groups. In healthy pregnant rats, heterodimer is barely detected. In preeclamptic rats however, we found higher heterodimerization. These results suggest that AT(1)R and alpha1D -adrenoceptor may form heterodimers, and may play a role in preeclampsia.


Effect of surface charge of small unilamellar liposomes on uptake and transfer of carboxyfluorescein across the perfused human term placenta.
We aim to investigate the effect of surface charge of small unilamellar liposomes on transfer and uptake of a low molecular weight, hydrophilic and polar molecule carboxyfluorescein in an in vitro model of perfused human term placenta. Carboxyfluorescein-encapsulated neutral liposomes were prepared by using an equimolar concentration of lecithin and cholesterol. Anionic and cationic liposomes were prepared by adding dicetylcholine and stearylamine, respectively. Size distribution, encapsulation efficiency, and stability of liposomes in blood-based medium were determined. The transfer kinetics of free carboxyfluorescein and liposomally encapsulated carboxyfluorescein were studied in a dually perfused isolated lobule of human term placenta. The concentration of carboxyfluorescein was measured fluorometrically. The maternal to fetal transfer and placental uptake of free carboxyfluorescein was 1.6 +/- 0.1% and 4.2 +/- 0.1% of the initial dose, respectively. This constitutes the control data. The placental transfer of carboxyfluorescein was significantly increased by neutral (2.5 +/- 0.1%; p < 0.01) and anionic liposomes (3.1 +/- 0.2%; p < 0.001), whereas cationic liposomes prevented its transfer (0.4 +/- 0.1%; p < 0.001). The placental uptake of neutral (14.9 +/- 2.3%; p < 0.001) and anionic liposomes (21.1 +/- 1.2%; p < 0.001) were significantly higher than the cationic liposomes (2.3 +/- 0.6%) and control group (p < 0.001). The placental uptake of cationic liposomes was comparable with the control data. These results indicate that placental uptake of small unilamellar liposomes depends upon their surface charge, and transfer of carboxyfluorescein is enhanced by anionic and impeded by cationic liposomes.


Creation of drug-specific herpes simplex virus type 1 thymidine kinase mutants for gene therapy.
Herpes simplex virus type 1 (HSV-1) thymidine kinase is currently used as a suicide agent in the gene therapy of cancer. This therapy is based on the preferential phosphorylation of nucleoside analogs by tumor cells expressing HSV-1 thymidine kinase. However, the use of HSV-1 thymidine kinase is limited in part by the toxicity of the nucleoside analogs. We have used random sequence mutagenesis to create new HSV-1 thymidine kinases that, compared with wild-type thymidine kinase, render cells much more sensitive to specific nucleoside analogs. A segment of the HSV-1 thymidine kinase gene at the putative nucleoside binding site was substituted with random nucleotide sequences. Mutant enzymes that demonstrate preferential phosphorylation of the nucleoside analogs, ganciclovir or acyclovir, were selected from more than one million Escherichia coli transformants. Among the 426 active mutants we have isolated, 26 demonstrated enhanced sensitivity to ganciclovir, and 54 were more sensitive to acyclovir. Only 6 mutant enzymes displayed sensitivity to both ganciclovir and acyclovir when expressed in E. coli. Analysis of 3 drug-sensitive enzymes demonstrated that 1 produced stable mammalian cell transfectants that are 43-fold more sensitive to ganciclovir and 20-fold more sensitive to acyclovir.


Thiol-ene Enabled Chemical Synthesis of Truncated S-Lipidated Teixobactin Analogs.
Herein is described the introduction of lipid moieties onto a simplified teixobactin pharmacophore using a modified Cysteine Lipidation on a Peptide or Amino acid (CLipPA) technique, whereby cysteine was substituted for 3-mercaptopropionic acid (3-MPA). A truncated teixobactin analog was prepared with the requisite thiol handle, thus enabling an array of vinyl esters to be conveniently conjugated onto the simplified teixobactin pharmacophore to yield S-lipidated cyclic lipopeptides.


Solid variant of mammary "adenoid cystic carcinoma with basaloid features" merging with "small cell carcinoma".
We describe a rare case of a solid variant of a mammary adenoid cystic carcinoma with basaloid features (sbACC) and its coexistence with a "small cell" carcinoma (SCC), identified and confirmed by histological and immunohistochemical observations: the absence of glandular structures and PAS-positive globules, positivity for neuroendocrine markers (NSE, synaptophysin and chromogranin), and negativity for 34betaE12 and SMA actin were the aspects suggesting the presence of SCC. Furthermore, positivity for CD10 was found both in sbACC and in SCC, supporting the hypothesis that the two components share the same histogenetic myoepithelial origin and represent an example of dedifferentiation along neuroendocrine phenotype lines occurring in a multipotential neoplastic stem line, already committed towards a myoepithelial phenotype. To our knowledge, this is the first reported case of a solid basaloid adenoid cystic carcinoma merging with an SCC carcinoma. Furthermore, it is the first study in which CD10 was used to investigate the histogenesis of the two neoplastic components.


Plasmids in coryneform bacteria of human origin.
A study of plasmids in coryneform bacteria isolated from human sources is reported. Seventy of 269 strains possessed a total of 89 plasmids. These were shown to be of varying sizes and in some cases of varying structures by endonuclease restriction digest. In six of 20 strains antibiotic resistance was cured with loss of the plasmid. The diversity of plasmids is emphasized.


A new genus and species of Sophiini Townsend, 1936 (Diptera: Tachinidae) from Brazil, with an updated key to the genera of the tribe.
Sophiini is a New World tribe of Tachinidae composed, prior to this study, of 19 species in eight genera. Cryptosophia aurulenta gen. and sp. nov. from Amazonas, Brazil, is described and assigned to that tribe. The new genus can be easily distinguished from the other genera in the tribe, mainly by: head with occiput clearly swollen medially; thorax without a proepisternal seta; and meron with pale yellow setae almost indistinguishable from the yellow integument. It is most similar to members of the genera Neosophia Guimarães and Sophiella Guimarães. An updated and illustrated key to the genera of Sophiini is provided, including Cryptosophia gen. nov. Descriptions and illustrations of the female terminalia, spermatheca, and first instar larva are also provided for the new genus and species.