Ca(2+) Channel Re-localization to Plasma-Membrane Microdomains Strengthens Activation of Ca(2+)-Dependent Nuclear Gene Expression.
In polarized cells or cells with complex geometry, clustering of plasma-membrane (PM) ion channels is an effective mechanism for eliciting spatially restricted signals. However, channel clustering is also seen in cells with relatively simple topology, suggesting it fulfills a more fundamental role in cell biology than simply orchestrating compartmentalized responses. Here, we have compared the ability of store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels confined to PM microdomains with a similar number of dispersed CRAC channels to activate transcription factors, which subsequently increase nuclear gene expression. For similar levels of channel activity, we find that channel confinement is considerably more effective in stimulating gene expression. Our results identify a long-range signaling advantage to the tight evolutionary conservation of channel clustering and reveal that CRAC channel aggregation increases the strength, fidelity, and reliability of the general process of excitation-transcription coupling.


Cancer gene therapy: 'delivery, delivery, delivery' .
Gene therapy for cancer treatment represents a promising approach that has shown selectivity and efficacy in experimental systems as well as clinical trials. Some major problems remain to be solved before this strategy becomes routinely adopted in the clinic, one of the main challenges being the improvement of gene delivery. Namely, the development of DNA vectors characterized by maximum efficiency and minimal toxicity will define the success of gene therapy and its chances of being accepted by public and clinicians. A number of issues need to be considered. The "magic" vector should be targeted, protected from degradation and immune attack, and safe for the recipient and the environment. Moreover, it should express the therapeutic gene for as long as required, in an appropriately regulated fashion. Vehicles such as retroviruses, adenoviruses and liposomes have been adopted in clinical studies, with varying results. New therapeutic modalities are also being explored in order to overcome the limitation of poor gene transfer and patient toxicity, including bacteria, adeno-associated and herpes simplex viruses, lentiviruses, cationic polymer-DNA complexes and electroporation. Some of the delivery systems tested in preclinical and clinical models are reviewed in this article, with particular attention to the targeting of the tumor environment.


RNase 1 genes from the family Sciuridae define a novel rodent ribonuclease cluster.
The RNase A ribonucleases are a complex group of functionally diverse secretory proteins with conserved enzymatic activity. We have identified novel RNase 1 genes from four species of squirrel (order Rodentia, family Sciuridae). Squirrel RNase 1 genes encode typical RNase A ribonucleases, each with eight cysteines, a conserved CKXXNTF signature motif, and a canonical His(12)-Lys(41)-His(119) catalytic triad. Two alleles encode Callosciurus prevostii RNase 1, which include a Ser(18)<-->Pro, analogous to the sequence polymorphisms found among the RNase 1 duplications in the genome of Rattus exulans. Interestingly, although the squirrel RNase 1 genes are closely related to one another (77-95% amino acid sequence identity), the cluster as a whole is distinct and divergent from the clusters including RNase 1 genes from other rodent species. We examined the specific sites at which Sciuridae RNase 1s diverge from Muridae/Cricetidae RNase 1s and determined that the divergent sites are located on the external surface, with complete sparing of the catalytic crevice. The full significance of these findings awaits a more complete understanding of biological role of mammalian RNase 1s.


Consumption of Oxidized and Partially Hydrogenated Oils Differentially Induces Trans-Fatty Acids Incorporation in Rats' Heart and Dyslipidemia.
A direct effect of process-induced trans-fatty acids (TFAs) on nonalcoholic fatty liver disease (NAFLD) as a cardiovascular disease (CVD) risk factor has previously been shown. We hypothesized that TFAs directly induced CVD. This article describes an investigation of the association between TFAs, provided by the consumption of oxidized soybean oil and margarine, and plasma lipid profiles, coronary artery lesions, and coronary fatty acids distribution in rats. Male rats were fed a standard chow or high-fat diet containing different TFA levels ranging from <1%, <2%, and >2% of total fat in fresh soybean oil, oxidized soybean oil, and margarine, respectively, for 4 weeks. The results indicated that the high-fat diets differently changed the plasma lipid profiles by significantlt increasing triglycerides, total cholesterol, low-density lipoprotein cholesterol, and the ratio of low-density to high-density lipoprotein cholesterol compared to control rats. Compared to fresh soybean oil, oxidized oil further increased plasma lipid markers. The strongest inflammatory effect was induced by margarine, which contains the highest level of TFAs, or 2% of total fat. Total TFAs in the heart of the margarine-fed group were increased by 4.7 regarding to control and by 2.17 and 2.6 relative to groups receiving oxidized and fresh oil, respectively. Increased TFAs consumption was associated with increased histological aspects of atherosclerotic lesions in a dose-dependent manner. In conclusion, process-induced TFAs cause changes including proatherogenic plasma lipid markers, heart fatty acid profiles, and coronary artery histology depending on the TFA level in the supplemented fat and therefore on the type of technological process used.


NMR and MD investigations of human galectin-1/oligosaccharide complexes.
The specific recognition of carbohydrates by lectins plays a major role in many cellular processes. Galectin-1 belongs to a family of 15 structurally related beta-galactoside binding proteins that are able to control a variety of cellular events, including cell cycle regulation, adhesion, proliferation, and apoptosis. The three-dimensional structure of galectin-1 has been solved by x-ray crystallography in the free form and in complex with various carbohydrate ligands. In this work, we used a combination of two-dimensional NMR titration experiments and molecular-dynamics simulations with explicit solvent to study the mode of interaction between human galectin-1 and five galactose-containing ligands. Isothermal titration calorimetry measurements were performed to determine their affinities for galectin-1. The contribution of the different hexopyranose units in the protein-carbohydrate interaction was given particular consideration. Although the galactose moiety of each oligosaccharide is necessary for binding, it is not sufficient by itself. The nature of both the reducing sugar in the disaccharide and the interglycosidic linkage play essential roles in the binding to human galectin-1.


[The importance of early diagnosis for the survival of HIV positive patients].
In Argentina, HIV diagnosis is reached by voluntary testing or symptom-based case findings. However, because of the high proportion of infected individuals unaware of their serologic status new strategies are required. In this article we show how a mathematic model predicts the impact of expanding HIV testing in Argentina. The model is based on time-dependent Markov matrixes and applies parameters-dependent transition-probabilities obtained from both national and international cohort studies. Outputs include time on clinical stages and therapy regime, CD4-count, viral-load, infection-state and age; mortality rates and proportion of unidentified infection at a population-level. Simulations were performed for current testing strategy and for a theoretical scenario with earlier diagnosis. We show how our prediction suggests that diagnosis before onset of symptoms would increase life expectancy by 10.7 years. Also, we show how a reduction of time to diagnosis to 5 or less years from infection would reduce mortality rates in the first year of HAART from 7.6% to 2.1%, the proportion of unrecognized infection from 43.2% to 23.8% and the proportion of individuals with unaware infection needing treatment from 12% to 0.2%. Based on this prediction we stress the importance of implementing health policies aimed at detecting HIV infection in early stages in Argentina.


Genomic evaluation during permeability of indomethacin and its solid dispersion.
Drug resistance was first identified in cancer cells that express proteins known as multidrug resistance proteins that extrude the therapeutic agents out of the cells resulting in alteration of pharmacokinetics, tissue distribution, and pharmacodynamics of drugs. To this end studies were carried out to investigate the role of pharmacological inhibitors and pharmaceutical excipients with a primary focus on P-glycoprotein (P-gp). The aim of this study was to investigate holistic changes in transporter gene expression during permeability upon formulation of indomethacin as solid dispersion. Initial characterization studies of solid dispersion of indomethacin showed that the drug was dispersed within the carrier in amorphous form. Analysis of permeability data across Caco-2 monolayers revealed that drug absorption increased by 4-fold when reformulated as solid dispersion. The last phase of the work involved investigation of gene expression changes of transporter genes during permeability. The results showed that there were significant differences in the expression of both ATP-binding cassette (ABC) transporter genes as well as solute carrier transporter (SLC) genes suggesting that the inclusion of polyethylene glycol as well as changes in molecular form of drug from crystalline to amorphous have a significant bearing on the expression of transporter network genes resulting in differences in drug permeability.


Prostate cancer in men aged less than 50 years at diagnosis.
Prostate cancer (CaP) in younger men (age ≤50 years) appears to present differently compared with older men. This study describes CaP characteristics and outcomes in Australian young men. The South Australian Prostate Cancer Clinical Outcomes Collaborative database was used to identify men diagnosed with CaP 1998-2012. Men were stratified by age at diagnosis into groups ≤50, 50-70 and ≥70 years. Primary outcomes of cumulative biochemical recurrence (BCR) and cumulative prostate cancer-specific mortality (PCSM) were assessed at 5 and 10 years. In total, 7018 men were included. At time of diagnosis, 182 (2.6 %) were aged ≤50 years. Median follow-up exceeded 4 years. Younger men had a greater proportion of T stage <2 disease, lower median PSA and higher rates of Gleason score <7 (all p < 0.001). They were more likely to experience active surveillance (AS) (4.9, 3.1, 1.5 %) or radical prostatectomy (RP) (70, 55, 8 %) and less likely radiotherapy (13, 24, 29 %) as their principal modality (all p < 0.001). Although only 4.9 % underwent AS, 48 % of men ≤50 years were eligible for AS. Men ≤50 years had both the lowest unadjusted cumulative BCR and PCSM at 10 years. After multivariate analysis, BCR was not significantly different. Sample size limited multivariate analysis of PCSM. In our cohort, men ≤50 years with CaP had less aggressive clinical characteristics, but were more likely to undergo RP. They appear to experience lower unadjusted PCSM, but similar rates of adjusted BCR. Further studies are needed to assess whether AS is appropriately utilised in these men.


Dissipative Optomechanical Preparation of Macroscopic Quantum Superposition States.
The transition from quantum to classical physics remains an intensely debated question even though it has been investigated for more than a century. Further clarifications could be obtained by preparing macroscopic objects in spatial quantum superpositions and proposals for generating such states for nanomechanical devices either in a transient or a probabilistic fashion have been put forward. Here, we introduce a method to deterministically obtain spatial superpositions of arbitrary lifetime via dissipative state preparation. In our approach, we engineer a double-well potential for the motion of the mechanical element and drive it towards the ground state, which shows the desired spatial superposition, via optomechanical sideband cooling. We propose a specific implementation based on a superconducting circuit coupled to the mechanical motion of a lithium-decorated monolayer graphene sheet, introduce a method to verify the mechanical state by coupling it to a superconducting qubit, and discuss its prospects for testing collapse models for the quantum to classical transition.


Reversibility of gelsolin/actin interaction in macrophages. Evidence of Ca2+-dependent and Ca2+-independent pathways.
We have developed an immunoadsorption technique for quantitating EGTA-resistant gelsolin/actin complexes in macrophages extracted with Triton X-100. We report here that the proportion of gelsolin complexed irreversibly to actin is low in freshly harvested macrophages. The amount of the EGTA-resistant complex increases spontaneously during incubation of the cells in suspension at 37 degrees C, or after exposure to the Ca2+ ionophore ionomycin. On the other hand, exposure of suspended cells to the chemotactic oligopeptide, FMLP, or plating of the cells onto tissue culture dishes causes the EGTA-resistant complex to dissociate rapidly. Plating even prevents Ca2+ ionomycin-treated cells with elevated intracellular Ca2+ from inducing this complex. Therefore, our results suggest that macrophages possess a mechanism, not directly involving Ca2+, for dissociating actin/gelsolin EGTA-resistant complexes. This mechanism may be a Ca2+-independent signal for leukocyte activation.


A population-based study of multiple sclerosis in twins.
Results from studies of twin concordance in multiple sclerosis have not conclusively differentiated between environmental and genetic factors that determine susceptibility to the disease. Published studies that have been based on case finding by public appeal have been characterized by difficulties in ascertainment. The data reported here are from a large population-based study of multiple sclerosis in twins, in which ascertainment has been relatively unbiased and the cooperation of patients nearly complete. A total of 5463 patients attending 10 multiple sclerosis clinics across Canada were surveyed. Twenty-seven monozygotic and 43 dizygotic twin pairs were identified, and the diagnosis of multiple sclerosis was verified by examination and laboratory investigation. Seven of 27 monozygotic pairs (25.9 percent) and 1 of 43 dizygotic pairs (2.3 percent) were concordant for multiple sclerosis. The concordance rate for 4582 nontwin siblings of patients at two multiple sclerosis clinics was 1.9 percent, closely paralleling the concordance rate in dizygotic twins. To the extent that the difference in concordance rates between monozygotic and dizygotic twins indicates genetic susceptibility, the results of this study show a major genetic component in susceptibility to multiple sclerosis.


Strange magnetism and the anapole structure of the proton.
The violation of mirror symmetry in the weak force provides a powerful tool to study the internal structure of the proton. Experimental results have been obtained that address the role of strange quarks in generating nuclear magnetism. The measurement reported here provides an unambiguous constraint on strange quark contributions to the proton's magnetic moment through the electron-proton weak interaction. We also report evidence for the existence of a parity-violating electromagnetic effect known as the anapole moment of the proton. The proton's anapole moment is not yet well understood theoretically, but it could have important implications for precision weak interaction studies in atomic systems such as cesium.


Evolution of the felid brain.
Endocranial casts of 15 genera of fossil felids provide a record of felid brain evolution over the past 35 million years. Brains of the earliest felids, known as paleofelids, had coronolateral, suprasylvian and variably developed ectosylvian sulci as their only neocortical sulci. The last paleofelids, which became extinct around 8 million years ago, show little change in external brain morphology except for the addition of a presylvian sulcus. The other group of felids, the neofelids, appears about 25 million years ago, with coronolateral and suprasylvian sulci their main neocortical sulci, plus a discontinuous ectosylvian sulcus and small postlateral, sylvian and presylvian sulci. The posterior cerebellar vermis was straight and unexpanded. Beginnings of expansion of the sigmoid gyri and development of the cruciate sulcus are evident in neofelids 15-20 million years ago, and by 5-9 million years ago neofelids had brains that appear modern in external morphology. Endocasts of four genera of Pleistocene saber-toothed felids are similar in sulcal pattern to those of modern felids, except for Dinobastis, which had a unique expansion of visual cortex. Endocasts of 27 species of modern felids, representing the six commonly recognized genera, are strikingly similar in external morphology, although the brains of a few species, such as cheetahs, lynxes and jagouarundis, display distinguishing features. Modern felid brains average about the same size relative to body weight as do those of viverrids, but are about 25% smaller in relative size than those of canids. Olfactory bulbs are relatively smaller in felids than in canids or viverrids.


Linking surveillance and clinical data for evaluating trends in bloodstream infection rates in neonatal units in England.
To evaluate variation in trends in bloodstream infection (BSI) rates in neonatal units (NNUs) in England according to the data sources and linkage methods used. We used deterministic and probabilistic methods to link clinical records from 112 NNUs in the National Neonatal Research Database (NNRD) to national laboratory infection surveillance data from Public Health England. We calculated the proportion of babies in NNRD (aged <1 year and admitted between 2010-2017) with a BSI caused by clearly pathogenic organisms between two days after admission and two days after discharge. We used Poisson regression to determine trends in the proportion of babies with BSI based on i) deterministic and probabilistic linkage of NNRD and surveillance data (primary measure), ii) deterministic linkage of NNRD-surveillance data, iii) NNRD records alone, and iv) linked NNRD-surveillance data augmented with clinical records of laboratory-confirmed BSI in NNRD. Using deterministic and probabilistic linkage, 5,629 of 349,740 babies admitted to a NNU in NNRD linked with 6,660 BSI episodes accounting for 38% of 17,388 BSI records aged <1 year in surveillance data. The proportion of babies with BSI due to clearly pathogenic organisms during their NNU admission was 1.0% using deterministic plus probabilistic linkage (primary measure), compared to 1.0% using deterministic linkage alone, 0.6% using NNRD records alone, and 1.2% using linkage augmented with clinical records of BSI in NNRD. Equivalent proportions for babies born before 32 weeks of gestation were 5.0%, 4.8%, 2.9% and 5.9%. The proportion of babies who linked to a BSI decreased by 7.5% each year (95% confidence interval [CI]: -14.3%, -0.1%) using deterministic and probabilistic linkage but was stable using clinical records of BSI or deterministic linkage alone. Linkage that combines BSI records from national laboratory surveillance and clinical NNU data sources, and use of probabilistic methods, substantially improved ascertainment of BSI and estimates of BSI trends over time, compared with single data sources.


Surveillance procedures for patients treated for endometrial cancer: a review of the literature.
The aim of this review was to analyze the role of follow-up in patients treated for endometrial cancer and to provide some compelling issues that may contribute to improve daily practice while waiting for evidence-based guidelines. A literature search has been conducted in MEDLINE database using key words "endometrial neoplasms" and "follow up". Endometrial cancer represents the most common gynecologic malignancy after breast cancer. The overall recurrence rate is 13% and correlates with prognostic factors of the primary tumor. The anatomic sites of endometrial cancer relapse are mostly equivalently distributed between local (pelvic) and distant (abdominal and chest). Most endometrial cancer recurrences are symptomatic, even if vaginal vault relapses represent a particular setting of a more frequently asymptomatic disease. Most of endometrial cancer recurrences occur within 3 years since diagnosis of primary tumor. Long-term surveillance programs are mainly addressed to the early detection of recurrence, the rationale of follow-up being that an earlier diagnosis of relapse correlates with lower morbidity and mortality rates. Adjunctive objectives of routine follow-up are identification of treatment complications and detection of possible second tumors associated with endometrial cancer. No rationale (examination sensitivity/sensibility, cost-effectiveness, or patient's survival benefit) is available today for any particular follow-up protocol; follow-up procedures should probably be tailored according to different prognostic factors; only physical examination, including pelvic-rectal examination, showed some utility in detecting recurrence. In this uncertain setting, follow-up interval should be defined with the consideration of the patient's will.


Molecular and functional characteristics of dendritic cells generated from highly purified CD14+ peripheral blood monocytes.
Dendritic cells (DC) are the most potent APCs within the immune system. We show here that highly purified CD14(bright) peripheral blood monocytes supplemented with granulocyte-monocyte (GM)-CSF plus IL-4 develop with high efficacy (>95% of input cells) into DC. They neo-expressed CD1a, CD1b, CD1c, CD80, and CD5; they massively up-regulated CD40 (109-fold) and HLA-DQ and DP (125- and 87-fold); and significantly (>5-fold) up-regulated HLA-DR, CD4, CD11b, CD11c, CD43, CD45, CD45R0, CD54, CD58, and CD59. CD14, CD15s, CD64, and CDw65 molecules were down-regulated to background levels, and no major changes were observed for HLA class I, CD11a, CD32, CD33, CD48, CD50, CD86, CDw92, CD93, or CD97. Monocytes cultured in parallel with GM-CSF plus TNF-alpha were more heterogeneous in expression densities but otherwise similar in their surface molecule repertoire. They clearly differed, however, in their accessory cell capacity. Only GM-CSF plus IL-4-cultured cells were found to be potent stimulators in allogeneic and autologous MLR and they presented tetanus toxoid 100- to 1000-fold more efficiently than other cell populations tested. Furthermore, only cytokine-treated monocytes formed clusters with resting T cells. At variance from all these similarities between in vitro-generated monocyte-derived DC and in vivo-developing DC, the DC populations generated by us contained significant amounts of myeloperoxidase and also expressed lysozyme. At least in this respect they, thus, differ from "classical" DC types.


Pre-exposure prophylaxis (PrEP) in an era of stalled HIV prevention: Can it change the game?
Pre-exposure prophylaxis (PrEP) for HIV prevention has evolved significantly over the years where clinical trials have now demonstrated the efficacy of oral PrEP, and the field is scaling-up implementation. The WHO and UNAIDS have made PrEP implementation a priority for populations at highest risk, and several countries have developed guidelines and national plans accordingly, largely based on evidence generated by demonstration projects. PrEP presents the opportunity to change the face of HIV prevention by offering a new option for protection against HIV and disrupting current HIV prevention systems. Nevertheless, as with all new technologies, both practical and social requirements for implementation must be taken into account if there is to be sustained and widespread adoption, which will also apply to forthcoming prevention technologies. Defining and building success for PrEP within the scope of scale-up requires careful consideration. This review summarises where the PrEP field is today, lessons learned from the past, the philosophy and practicalities of how successful programming may be defined, and provides perspectives of costs and affordability. We argue that a successful PrEP programme is about effective intervention integration and ultimately keeping people HIV negative.


The human proteome project: current state and future direction.
After the successful completion of the Human Genome Project, the Human Proteome Organization has recently officially launched a global Human Proteome Project (HPP), which is designed to map the entire human protein set. Given the lack of protein-level evidence for about 30% of the estimated 20,300 protein-coding genes, a systematic global effort will be necessary to achieve this goal with respect to protein abundance, distribution, subcellular localization, interaction with other biomolecules, and functions at specific time points. As a general experimental strategy, HPP research groups will use the three working pillars for HPP: mass spectrometry, antibody capture, and bioinformatics tools and knowledge bases. The HPP participants will take advantage of the output and cross-analyses from the ongoing Human Proteome Organization initiatives and a chromosome-centric protein mapping strategy, termed C-HPP, with which many national teams are currently engaged. In addition, numerous biologically driven and disease-oriented projects will be stimulated and facilitated by the HPP. Timely planning with proper governance of HPP will deliver a protein parts list, reagents, and tools for protein studies and analyses, and a stronger basis for personalized medicine. The Human Proteome Organization urges each national research funding agency and the scientific community at large to identify their preferred pathways to participate in aspects of this highly promising project in a HPP consortium of funders and investigators.


Massively parallel sequencing of forensic STRs: Considerations of the DNA commission of the International Society for Forensic Genetics (ISFG) on minimal nomenclature requirements.
The DNA Commission of the International Society for Forensic Genetics (ISFG) is reviewing factors that need to be considered ahead of the adoption by the forensic community of short tandem repeat (STR) genotyping by massively parallel sequencing (MPS) technologies. MPS produces sequence data that provide a precise description of the repeat allele structure of a STR marker and variants that may reside in the flanking areas of the repeat region. When a STR contains a complex arrangement of repeat motifs, the level of genetic polymorphism revealed by the sequence data can increase substantially. As repeat structures can be complex and include substitutions, insertions, deletions, variable tandem repeat arrangements of multiple nucleotide motifs, and flanking region SNPs, established capillary electrophoresis (CE) allele descriptions must be supplemented by a new system of STR allele nomenclature, which retains backward compatibility with the CE data that currently populate national DNA databases and that will continue to be produced for the coming years. Thus, there is a pressing need to produce a standardized framework for describing complex sequences that enable comparison with currently used repeat allele nomenclature derived from conventional CE systems. It is important to discern three levels of information in hierarchical order (i) the sequence, (ii) the alignment, and (iii) the nomenclature of STR sequence data. We propose a sequence (text) string format the minimal requirement of data storage that laboratories should follow when adopting MPS of STRs. We further discuss the variant annotation and sequence comparison framework necessary to maintain compatibility among established and future data. This system must be easy to use and interpret by the DNA specialist, based on a universally accessible genome assembly, and in place before the uptake of MPS by the general forensic community starts to generate sequence data on a large scale. While the established nomenclature for CE-based STR analysis will remain unchanged in the future, the nomenclature of sequence-based STR genotypes will need to follow updated rules and be generated by expert systems that translate MPS sequences to match CE conventions in order to guarantee compatibility between the different generations of STR data.


Testing reminder and motivational telephone calls to increase screening mammography: a randomized study.
Prospective randomized trials have demonstrated that motivational telephone calls increase adherence to screening mammography. To better understand the effects of motivational calls and to maximize adherence, we conducted a randomized trial among women aged 50-79 years. We created a stratified random sample of 5062 women due for mammograms within the Group Health Cooperative of Puget Sound, including 4099 women with prior mammography and 963 without it. We recruited and surveyed 3743 (74%) of the women before mailing a recommendation. After 2 months, 1765 (47%) of the 3743 women had not scheduled a mammogram and were randomly assigned to one of three intervention groups: a reminder post-card group (n = 590), a reminder telephone call group (n = 585), and a motivational telephone call addressing barriers group (n = 590). The telephone callers could schedule mammography. We used Cox proportional hazards models to estimate the hazard ratio (HR) and 95% confidence interval (CI) for documented mammography use by 1 year. Women who received reminder calls were more likely to get mammograms (HR = 1.9; 95% CI = 1.6-2.4) than women who were mailed postcards. The motivational and reminder calls (average length, 8.5 and 3.1 minutes, respectively) had equivalent effects (HR = 0.97; 95% CI = 0.8-1.2). After we controlled for the intervention effect, women with prior mammography (n = 1277) were much more likely to get a mammogram (HR = 3.4; 95% CI = 2.7-4.3) than women without prior use (n = 488). Higher income, but not race or more education, was associated with higher adherence. Reminding women to schedule an appointment was as efficacious as addressing barriers. Simple intervention groups should be included as comparison groups in randomized trials so that we better understand more complex intervention effects.


The effects of transcription on the nucleosome structure of four Dictyostelium genes.
Micrococcal nuclease digestion of Dictyostelium discoideum nuclei from various developmental stages was used to investigate transcription-related changes in the chromatin structure of the coding region of four genes. Gene activity was determined by Northern blotting and nuclear run on experiments. During strong transcription of the developmentally regulated cysteine proteinase I gene, a smear superimposed on a nucleosomal ladder was observed, indicating perturbation of nucleosomal structure was occurring. However, two other developmentally regulated genes, discoidin I and pSC253, showed only slight nucleosome disruption during high levels of transcription. The chromatin structure of a fourth gene (pCZ22) was disrupted throughout development, even at those stages where transcription was greatly reduced. We suggest that although nucleosome structure can be transiently perturbed by the passage of the transcription complex in vivo, the degree of perturbation and the speed with which nucleosomes reassemble is also influenced by the DNA sequence.


Ly6G+ inflammatory cells enable the conversion of cancer cells to cancer stem cells in an irradiated glioblastoma model.
Most glioblastomas frequently recur at sites of radiotherapy, but it is unclear if changes in the tumor microenvironment due to radiotherapy influence glioblastoma recurrence. Here, we demonstrate that radiation-induced senescent glioblastoma cells exhibit a senescence-associated secretory phenotype that functions through NFκB signaling to influence changes in the tumor microenvironment, such as recruitment of Ly6G+ inflammatory cells and vessel formation. In particular, Ly6G+ cells promote conversion of glioblastoma cells to glioblastoma stem cells (GSCs) through the NOS2-NO-ID4 regulatory axis. Specific inhibition of NFκB signaling in irradiated glioma cells using the IκBα super repressor prevents changes in the tumor microenvironment and dedifferentiation of glioblastoma cells. Treatment with Ly6G-neutralizing antibodies also reduces the number of GSCs and prolongs survival in tumor-bearing mice after radiotherapy. Clinically, a positive correlation exists between Ly6G+ cells and the NOS2-NO-ID4 regulatory axis in patients diagnosed with recurrent glioblastoma. Together, our results illustrate important roles for Ly6G+ inflammatory cells recruited by radiation-induced SASP in cancer cell dedifferentiation and tumor recurrence.


Response time differences between men and women during hand mental rotation.
This study explored gender differences in correct response rates and response times on a task involving left or right arrow selection and another involving the transformation of mental rotation of the hand. We recruited 15 healthy, right-handed men (age 24.5 ± 6.4) and 15 healthy, right-handed women (age 21.3 ± 4.9). For the tasks, we used pictures of left and right arrows and 32 hand pictures (left and right, palm and back) placed in cons (each at 45° from 0° to 315°). Hand and arrow pictures alternated and were shown at random. Participants decided as quickly as possible whether each picture was left or right. To compare the time taken for the transformation of mental rotation of the hand, we subtracted the average arrow response time from that for the left and right hand pictures for each participant. Correct response rates did not differ significantly between men and women or left and right for either arrow or hand pictures. Regardless of gender, the response time was longer for the left arrow picture than right arrow picture. The response time for the hand picture was longest for both men and women for pictures at rotation angles that were most difficult to align with participants' hands. While there was no difference between men's responses for left and right hand pictures, the responses of women were longer for left than right hand pictures and also than those of men. These findings suggest that both men and women mainly perform the hand mental rotation task with implicit motor imagery. On the other hand, the gender difference in performance might be explained by the difference in balance with other strategies, such as visual imagery, and by cognitive, neurophysiological, and morphological differences.


Performance of Thrombectomy-Capable, Comprehensive, and Primary Stroke Centers in Reperfusion Therapies for Acute Ischemic Stroke: Report from the Get With The Guidelines Stroke Registry: Stroke Outcomes Per Hospital Certification Status.
The thrombectomy-capable stroke center (TSC) is a recently introduced intermediate tier of accreditation for hospitals caring for patients with acute ischemic stroke (AIS). The comparative quality and clinical outcomes of reperfusion therapies at TSCs, primary stroke centers (PSCs), and comprehensive stroke centers (CSCs) has not been well delineated. We conducted a retrospective, observational, cohort study from 2018-2020 that included patients with AIS who received endovascular (EVT) and/or intravenous (IVT) reperfusion therapies at CSC, TSC, or PSC. Participants were recruited from Get With The Guidelines-Stroke registry. Study endpoints included timeliness of IVT and EVT, successful reperfusion, discharge destination, discharge mortality, and functional independence at discharge. Among 84,903 included patients, 48,682 received EVT, of whom 73% were treated at CSCs, 22% at PSCs, and 4% at TSCs. The median annual EVT volume was 76 for CSCs, 55 for TSCs, and 32 for PSCs. Patient differences by center status included higher NIHSS, longer onset-to-arrival time, and higher transfer-in rates for CSC/TSC/PSC, respectively. In adjusted analyses, the likelihood of achieving the goal door-to-needle time was higher in CSCs compared to PSCs (OR 1.39; 95% CI 1.17-1.66) and in TSCs compared to PSCs (OR 1.45; 95% CI 1.08-1.96). Similarly, the odds of achieving the goal door-to-puncture time were higher in CSCs compared to PSCs (OR 1.58; 95% CI 1.13-2.21). CSCs and TSCs also demonstrated better clinical efficacy outcomes compared to PSCs. The odds of discharge to home or rehabilitation were higher in CSCs compared to PSCs (OR 1.18; 95% CI 1.06-1.31), while the odds of in-hospital mortality/discharge to hospice were lower in both CSCs compared to PSCs (OR 0.87; 95% CI 0.81-0.94) and TSCs compared to PSCs (OR 0.86; 95% CI 0.75-0.98). There were no significant differences in any of the quality-of-care metrics and clinical outcomes between TSCs and CSCs. In this study representing national US practice, CSCs and TSCs exceeded PSCs in key quality-of-care reperfusion metrics and outcomes, whereas TSCs and CSCs demonstrated similar performance. Considering that over one-fifth of all EVT procedures during the study period were conducted at PSCs, it may be desirable to explore national initiatives aimed at facilitating the elevation of eligible PSCs to a higher certification status.


Expansion of extrathymic T cells as well as granulocytes in the liver and other organs of granulocyte-colony stimulating factor transgenic mice: why they lost the ability of hybrid resistance.
When we attempted to characterize the immunological state in G-CSF transgenic mice, a large number of not only granulocytes but also lymphoid cells expanded in various immune organs. Such lymphoid cells were present at unusual sites of these organs, e.g., the parenchymal space in the liver. We then determined the phenotype of these lymphoid cells by immunofluorescence tests. It was demonstrated that CD3intIL-2Rbeta+ cells (i.e., extrathymic T cells), including the NK1.1+ subset of CD3int cells (i.e., NKT cells), increased in the liver and all other tested organs. These T cells as well as NK cells mediated NK and NK-like cytotoxicity, especially at youth. However, they were not able to mediate such cytotoxicity in the presence of granulocytes. This result might be associated with deficiency in the hybrid resistance previously ascribed to these mice. In other words, G-CSF transgenic mice had a large number of extrathymic T cells (including NKT cells) and NK cells that mediate hybrid resistance, but their function was suppressed by activated granulocytes. Indeed, these granulocytes showed an elevated level of Ca2+ influx upon stimulation. The present results suggest that, in parallel with overactivation of granulocytes, extrathymic T cells and NK cells are concomitantly activated in number but that their function is suppressed in G-CSF transgenic mice.


MEP1A allele for meprin A metalloprotease is a susceptibility gene for inflammatory bowel disease.
The MEP1A gene, located on human chromosome 6p (mouse chromosome 17) in a susceptibility region for inflammatory bowel disease (IBD), encodes the alpha-subunit of metalloproteinase meprin A, which is expressed in the intestinal epithelium. This study shows a genetic association of MEP1A with IBD in a cohort of ulcerative colitis (UC) patients. There were four single-nucleotide polymorphisms in the coding region (P=0.0012-0.04), and one in the 3'-untranslated region (P=2 x 10(-7)) that displayed associations with UC. Moreover, meprin-alpha mRNA was decreased in inflamed mucosa of IBD patients. Meprin-alpha knockout mice exhibited a more severe intestinal injury and inflammation than their wild-type counterparts following oral administration of dextran sulfate sodium. Collectively, the data implicate MEP1A as a UC susceptibility gene and indicate that decreased meprin-alpha expression is associated with intestinal inflammation in IBD patients and in a mouse experimental model of IBD.


Cerebral Sinus Thrombosis.
Although cerebral venous thrombosis/cerebral sinus thrombosis (CVT/CST) remains a relatively uncommon cause of stroke and other neurologic complications, the widespread availability of noninvasive brain imaging has led to an increase in its diagnosis. Through a review and description of its epidemiology, clinical features and treatment, to heighten awareness of CVT/CST. Via a systematic review of the more recently published medical literature relevant to the topic and focusing in particular on primary sources, we compiled data related to the incidence of CVT/CST and its diagnosis, treatment and prognosis. Thrombosis of a cerebral vein or sinus may occur in individuals of any age and may be caused by a myriad of prothrombotic conditions, both primary and acquired. The clinical presentation of CVT/CST is widely variable, but headache is present in the great majority of cases, and the predominant symptom in many. The headache associated with CVT/CST may be acute, severe, and even "thunderclap" in character, or it may be chronic, pervasive, and of lower intensity. Given its eclectic epidemiology, its potential to produce a highly unfavorable clinical outcome, and evidence suggesting that specific treatment improves outcome, CVT/CST is a disorder whose salient features should be familiar to virtually all clinicians.


Paraneoplastic bleeding disorder due to isolated hypofibrinogenemia: a case report.
An 80 years old male patient was admitted in our hospital with massive haematomas in the left forearm, chest and abdominal wall accompanied by intense back pain symptoms. Laboratory evaluation showed anemia, mild thrombocytopenia and elevated lactate dehydrogenase and alkaline phosphatase levels and normal concentrations of all the other biochemical parameters. Study of the coagulation status demonstrated prolonged thrombin time (TT), low fibrinogen levels--0.98 g/l while plasminogen, antithrombin III (AT III) and protein C levels were found to be within normal range. Computed tomography scans of the head, chest and abdomen showed an enlarged infiltrative prostate, osteolytic bone lesions in vertebras L5-S1 and a large haematoma of the abdominal wall as the only pathologic findings. Very high levels of the prostate specific antigen indicated the possible existence of a prostate carcinoma with metastases to the vertebral column that resulted in elevated alkaline phosphate and lactate dehydrogenase levels. There were no signs of liver involvement and impaired hepatic synthetic function. Based on the results of the laboratory tests we concluded that the cause of the bleeding disorder in our patient was an acquired hypofibrinogenemia, which is a very rare paraneoplastic phenomenon. The patient was treated with daily transfusions of cryoprecipitate with no long-term improvement. Then the specific anti-tumor therapy (ciproteron acetate) was initiated, and two weeks later, fibrinogen concentration and TT returned to normal values.


Reactivity with DNA bases and mutagenicity toward Salmonella typhimurium of methylchrysene diol epoxide enantiomers.
The reactions with DNA and mutagenic activities toward Salmonella typhimurium TA 100 of the R,S,S,R and S,R,R,S enantiomers of anti-1,2,-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (anti-5-MeC-1,2-diol-3,4-epoxide), anti-5-MeC-7,8-diol-9,10-epoxide, and anti-6-MeC-1,2-diol-3,4-epoxide were compared because among these compounds only the R,S,S,R enantiomer of anti-5-MeC-1,2-diol-3,4-epoxide is highly tumorigenic. The major products formed in the reaction of each racemic diol epoxide with DNA were two pairs of deoxyguanosine (dGuo) and deoxyadenosine (dAdo) adducts; one product in each pair was formed from the R,S,S,R enantiomer and the other from the S,R,R,S enantiomer of each racemic diol epoxide. Formation of products from R,S,S,R enantiomers exceeded formation of those from S,R,R,S enantiomers in each case. Among the R,S,S,R enantiomers, 5-MeC-1,2-diol-3,4-epoxide, which has a methyl group in the same bay region as the epoxide ring, was most reactive toward DNA, and in particular toward dGuo. The dGuo/dAdo adduct ratios were greater for the products formed from the R,S,S,R enantiomer compared to the S,R,R,S enantiomer of each diol epoxide. The dGuo/dAdo adduct ratios were also greater for the enantiomers of anti-5-MeC-1,2-diol-3,4-epoxide than for the enantiomers of either anti-5-MeC-7,8-diol-9,10-epoxide or anti-6-MeC-1,2-diol-3,4-epoxide. In S. typhimurium TA 100, the R,S,S,R enantiomer of anti-5-MeC-1,2-diol-3,4-epoxide was the most mutagenic compound (6700 revertants/nmol), followed by the R,S,S,R enantiomer of anti-5-MeC-7,8-diol-9,10-epoxide (1500 revertants/nmol). The other diol epoxide enantiomers were weakly active or inactive at the doses tested. The results of this study demonstrate that both the absolute configuration of a diol epoxide and the position of the methyl group have major effects on its reactivity with DNA. The greatest reactivity is seen in an R,S,S,R enantiomer with the methyl group and epoxide ring in the same bay region, e.g., the highly tumorigenic and mutagenic 5-MeC-1R,2S-diol-3S,4R-epoxide. Comparison of the dGuo/dAdo adduct ratios of the various diol epoxides with their tumorigenic and mutagenic activities suggests that dGuo adducts are important in the expression of biological activity of methylchrysene diol epoxides.


Discrete, continuous, and stochastic models of protein sorting in the Golgi apparatus.
The Golgi apparatus plays a central role in processing and sorting proteins and lipids in eukaryotic cells. Golgi compartments constantly exchange material with each other and with other cellular components, allowing them to maintain and reform distinct identities despite dramatic changes in structure and size during cell division, development, and osmotic stress. We have developed three minimal models of membrane and protein exchange in the Golgi-a discrete, stochastic model, a continuous ordinary differential equation model, and a continuous stochastic differential equation model-each based on two fundamental mechanisms: vesicle-coat-mediated selective concentration of cargoes and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins during vesicle formation and SNARE-mediated selective fusion of vesicles. By exploring where the models differ, we hope to discover whether the discrete, stochastic nature of vesicle-mediated transport is likely to have appreciable functional consequences for the Golgi. All three models show similar ability to restore and maintain distinct identities over broad parameter ranges. They diverge, however, in conditions corresponding to collapse and reassembly of the Golgi. The results suggest that a continuum model provides a good description of Golgi maintenance but that considering the discrete nature of vesicle-based traffic is important to understanding assembly and disassembly of the Golgi. Experimental analysis validates a prediction of the models that altering guanine nucleotide exchange factor expression levels will modulate Golgi size.


Occurrence of Potato Powdery Scab Caused by Spongospora subterranea f. sp. subterranea in Costa Rica.
Powdery scab of potatoes, caused by Spongospora subterranea (Wallr.) Lagerheim f. sp. subterranea Tomlinson, is important worldwide due to its effect on tuber quality and transmission of Potato mop-top virus. Although powdery scab-like lesions have been observed on potato in Costa Rica (1), the presence of the pathogen has not been confirmed. During a survey in 2001, powdery scab-on was observed from a field and a greenhouse in the high elevation zone of the main potato-producing area of Costa Rica. Commercial potatoes with scab-like lesions were also obtained at a farmers' market. Scraping the lesions, and observing spore balls or cystosori with a honey-comb-like structure under light microscopy confirmed the identity of S. subterranea. The identity of the pathogen was also confirmed by enzyme-linked immunosorbent assay using monoclonal antibodies specific for S. subterranea (BioReba Ag, Reinach, Switzerland). Pathogenicity of S. subterranea was confirmed by a bioassay on tomato plants grown in nutrient solution culture (2). Tomato cv. Supermarmande plants were grown from seed in pots filled with quartz and watered with nutrient solution. Three weeks after planting, the roots were trimmed to 60 mm, and the plants were transferred to the nutrient solution for additional growth. After growing for 1 week in the nutrient solution, tomato seedlings were inoculated by replacing the nutrient solution with nutrient solution containing cystosori (20 mg/liter, wt/vol) that were scraped from the scab lesions. Zoosporangia of S. subterranea were observed in root hairs and epidermal cells of the seedlings 2 weeks after inoculation. To our knowledge, this is the first report that confirms the presence of S. subterranea on potato in Costa Rica. References: (1) R. Amador. Invest. Agri. Costa Rica. 1(1):16, 1987. (2) U. Merz. Bull. OEPP 19:585, 1989.


Appropriateness of percutaneous revascularization of coronary chronic total occlusions: an overview.
Coronary chronic total occlusions (CTOs) are commonly encountered in patients undergoing coronary angiography. Several observational studies have demonstrated that successful CTO revascularization is associated with better cardiovascular outcomes and enhanced quality of life (QOL). However, in the absence of randomized trials, its prognostic benefit for patients remains debated. Over the past decade, the interest of the interventional community in CTO percutaneous coronary intervention (PCI) has exponentially grown due to important developments in dedicated equipment and techniques, resulting in high success and low complication rates. Both European and American guidelines have assigned a class IIa (level of evidence B) recommendation for CTO PCI. In the current review, we focus on the impact of CTO revascularization on clinical outcomes and QOL and on appropriate patient selection, and we provide a critical assessment of the current guidelines and recommendations on CTO PCI.


Fish consumption and the 30-year risk of fatal myocardial infarction.
Epidemiologic data on the possible benefit of eating fish to reduce the risk of coronary heart disease have been inconsistent. We used data from the Chicago Western Electric Study to examine the relation between base-line fish consumption and the 30-year risk of death from coronary heart disease. The study participants were 1822 men who were 40 to 55 years old and free of cardiovascular disease at base line. Fish consumption, as determined from a detailed dietary history, was stratified (0, 1 to 17, 18 to 34, and > or = 35 g per day). Mortality from coronary heart disease, ascertained from death certificates, was classified as death from myocardial infarction (sudden or nonsudden) or death from other coronary causes. During 47,153 person-years of follow-up, there were 430 deaths from coronary heart disease; 293 were due to myocardial infarctions (196 were sudden, 94 were nonsudden, and 3 were not classifiable). Cox proportional-hazards regression showed that for men who consumed 35 g or more of fish daily as compared with those who consumed none, the relative risks of death from coronary heart disease and from sudden or nonsudden myocardial infarction were 0.62 (95 percent confidence interval, 0.40 to 0.94) and 0.56 (95 percent confidence interval, 0.33 to 0.93), respectively, with a graded relation between the relative risks and the strata of fish consumption (P for trend = 0.04 and 0.02, respectively). These findings were accounted for by the relation of fish consumption to nonsudden death from myocardial infarction (relative risk, 0.33; 95 percent confidence interval, 0.12 to 0.91; P for trend= 0.007). These data show an inverse association between fish consumption and death from coronary heart disease, especially nonsudden death from myocardial infarction.


A Climatic Record from Searles Lake, California.
Data concerning past climatic conditions in arid California have been presented. Palynological and geological evidence points to the existence of past cooler moister climates and to climatic fluctuations. These have been tentatively correlated with late Pleistocene events in glaciated North America. The existence of a rather extensive woodland community at times of more favorable moisture conditions seems to be indicated.


Impact of atrial fibrillation and heart failure, independent of each other and in combination, on mortality in community-dwelling older adults.
Atrial fibrillation (AF) and heart failure (HF), common in older adults, are associated with poor outcomes. However, little is known about their impact, independent of each other. We studied 5,673 community-dwelling adults aged ≥ 65 years in the Cardiovascular Health Study. Baseline prevalent AF and HF were centrally adjudicated, and 116 patients had AF only, 219 had HF only, 39 had both, and 5,263 had neither. The Cox proportional hazards model was used to estimate age-gender-race-adjusted hazard ratio (aHR) and 95% confidence intervals (CIs) for all-cause, cardiovascular (CV), and non-CV mortalities. Participants had a mean age of 73 years (± 6 years), 58% were women, and 15% African-American. During 13 years of follow-up, all-cause mortality occurred in 43%, 66%, 74%, and 85% of those with neither, AF only, HF only, and both, respectively. Compared with neither, aHR (95% CIs) for all-cause mortality associated with AF only, HF only, and both was 1.36 (1.08 to 1.72), 2.31 (1.97 to 2.71), and 3.04 (2.15 to 4.29), respectively. Similar associations were observed with CV mortality, but HF only also had greater non-CV mortality (aHR 1.72, 95% CI 1.35 to 2.18). Compared with AF alone, aHR (95% CIs) associated with HF alone for all-cause, CV, and non-CV mortalities was 1.69 (1.29 to 2.23), 1.73 (1.20 to 2.51), and 1.64 (1.09 to 2.46), respectively. Compared with HF alone, those with both conditions had greater CV but not all-cause mortality. In conclusion, community-dwelling older adults with AF have greater mortality than those without but lesser than those with HF, and both conditions were associated with greater CV and all-cause mortalities, whereas only those with HF had greater non-CV mortality.


The ISUP system of staging, grading and classification of renal cell neoplasia.
There have been significant changes in the staging, classification and grading of renal cell neoplasia in recent times. Major changes have occurred in our understanding of extra-renal extension by renal cell cancer and how gross specimens must be handled to optimally display extra-renal spread. Since the 1981 World Health Organization (WHO) classification of renal tumors, in which only a handful of different entities were reported, many new morphological types have been described in the literature, resulting in 50 different entities reported in the 2004 WHO classification. Since 2004, further new entities have been recognized and reported necessitating an update of the renal tumor classification. There have also been numerous grading systems for renal cell carcinoma with Fuhrman grading, the most widely used system. In recent times, the prognostic value and the applicability of the Fuhrman grading system in practice has been shown to be, at best, suboptimal. To address these issues and to recommend reporting guidelines, the International Society of Urological Pathology (ISUP) undertook a review of adult renal neoplasia through an international consensus conference in Vancouver in 2012. The conduct of the conference was based upon evidence from the literature and the current practice amongst recognized experts in the field. Working groups selected to deal with key topics evaluated current data and identified points of controversy. A pre-meeting survey of the ISUP membership was followed by the consensus conference at which a formal ballot was taken on each key issue. A 65% majority vote was taken as consensus. This review summarizes the outcome and recommendations of this conference with regards to staging, classification and grading of renal cell neoplasia.


Capsule staining as an adjunct to cataract surgery: a report from the American Academy of Ophthalmology.
This document evaluates currently available data in the published literature to answer the question of whether the use of dye such as indocyanine green or trypan blue to stain the lens capsule to improve visualization is safe and effective as an adjunct to cataract surgery. Literature searches conducted in March 2003 and May 2004 retrieved 139 citations. The panel members reviewed the abstracts and selected 47 of possible clinical relevance for review. An additional 14 articles were identified for evaluation. Of the 61 articles reviewed, the panel members selected 36 for the panel methodologist to review and rate according to the strength of the evidence. A level I rating was assigned to properly conducted, well-designed, randomized clinical trials; a level II rating was assigned to well-designed cohort and case-control studies; and a level III rating was assigned to case series and case reports. There is level III evidence that indocyanine green, trypan blue, and fluorescein are each effective in staining the lens capsule and that indocyanine green and trypan blue provide better ease of use and visualization of the capsule than fluoroscein. There is level II evidence that staining the capsule is helpful in completing capsulorrhexis and that it is helpful for pediatric patients under age 5 years and in cases of white cataract. The overall surgical advantage of a completed continuous curvilinear capsulorrhexis using dye has not been demonstrated, but this may be related to the outcome measures chosen rather than a failure to confer advantage. There are substantial data indicating that trypan blue 0.1% is not toxic to the cornea. There are limited data suggesting that indocyanine green 0.125% to 0.5% is not toxic to anterior segment structures. There are data confirming that dye is safe and effective as an adjunct for capsule visualization in cataract surgery. It is reasonable to use dye when inadequate capsule visualization may compromise the outcome in cataract surgery. More studies are needed to confirm a lack of toxicity of indocyanine green and trypan blue, particularly in the event of posterior segment or longer duration exposure.


Spontaneous choices for insect-pollinated flower shapes by wild non-eusocial halictid bees.
The majority of angiosperms require animal pollination for reproduction, and insects are the dominant group of animal pollinators. Bees are considered one of the most important and abundant insect pollinators. Research into bee behaviour and foraging decisions has typically centred on managed eusocial bee species, including Apis mellifera and Bombus terrestris. Non-eusocial bees are understudied with respect to foraging strategies and decision making, such as flower preferences. Understanding whether there are fundamental foraging strategies and preferences that are features of insect groups can provide key insights into the evolution of flower-pollinator co-evolution. In the current study, Lasioglossum (Chilalictus) lanarium and Lasioglossum (Parasphecodes) sp., two native Australian generalist halictid bees, were tested for flower shape preferences between native insect-pollinated and bird-pollinated flowers. Each bee was presented with achromatic images of either insect-pollinated or bird-pollinated flowers in a circular arena. Both native bee species demonstrated a significant preference for images of insect-pollinated flowers. These preferences are similar to those found in A. mellifera, suggesting that flower shape preference may be a deep-rooted evolutionary occurrence within bees. With growing interest in the sensory capabilities of non-eusocial bees as alternative pollinators, the current study also provides a valuable framework for further behavioural testing of such species.


Locations of 18S and 28S ribosomal genes on the chromosomes of the Indian muntjac.
The locations of genes coding for 18S and 28S ribosomal RNA have been mapped on metaphase chromosomes of the Indian muntjac M. muntjak by in situ hybridization with (3H)rRNA from the toad X. laevis. The results show that, in the muntjac, rDNA clusters are associated with the prominent secondary constrictions on the X and the Y1 chromos. In addition a cluster of rDNA is found near the tip of one arm on the longest pair of autosomes. The autosomal cluster of rDNAs usually does not express as a secondary constriction at metaphase.


Heterotopic ossification in high-energy wartime extremity injuries: prevalence and risk factors.
Heterotopic ossification in the extremities remains a common complication in the setting of high-energy wartime trauma, particularly in blast-injured amputees and in those in whom the definitive amputation was performed within the zone of injury. The purposes of this cohort study were to report the experience of one major military medical center with high-energy wartime extremity wounds, to define the prevalence of heterotopic ossification in these patients, and to explore the relationship between heterotopic ossification and other potential independent predictors. We retrospectively reviewed the records and radiographs of all combat-wounded patients admitted to this institution between March 1, 2003, and December 31, 2006. Patients with a minimum of two months of radiographic follow-up who underwent at least one orthopaedic procedure on an extremity constituted our study group; those who underwent at least one orthopaedic procedure but had not had heterotopic ossification develop constituted the control group. Variables recorded for each study subject included age and sex, location and mechanism of injury, method(s) of fracture fixation, number of débridement procedures, duration of negative pressure therapy, location of heterotopic ossification, presence and severity of traumatic brain injury, and Injury Severity Scores. During the study period, 1213 war-wounded patients were admitted. Of those patients, 243 (157 in the heterotopic ossification group and eighty-six controls) met the inclusion criteria. The observed rate of heterotopic ossification was 64.6%. A significant relationship was detected between heterotopic ossification and the presence (p = 0.006) and severity (p = 0.003) of a traumatic brain injury. Risk factors for the development of heterotopic ossification were found to be an age of less than thirty years (p = 0.007, odds ratio = 3.0), an amputation (p = 0.048, odds ratio = 2.9), multiple extremity injuries (p = 0.002, odds ratio = 3.9), and an Injury Severity Score of >or=16 (p = 0.02, odds ratio = 2.2). The prevalence of heterotopic ossification in war-wounded patients is higher than that in civilian trauma. Although trends associated with local wound conditions were identified, the risk factors for the development of heterotopic ossification found in this study suggest that systemic causes predominate.


Functional genomic methods to study estrogen receptor activity.
Estrogen Receptor (ER) is a nuclear receptor that mediates the actions of estrogen and tamoxifen. ER is expressed in a major fraction of human breast cancers. Recently, genomic maps for estrogen- and tamoxifen-ER have been published. Interestingly, estrogen and tamoxifen induce similar genomic interactions and both ligands have been shown to use co-operating factors. The interactions of these co-operating factors within ER regions have impact both on ER-DNA interactions and gene expression regulated by estrogen and tamoxifen. Moreover, the study of chromatin changes induced by these factors has also provided significant insight into our understanding of ER transcriptional regulation. This methods review describes some functional genomic methods to study the influence of both ER ligands and ER co-operating factors. The analysis of protein-DNA interactions and chromatin changes can be explored by using classical and novel methods such as Chromatin Immunoprecipitation (ChIP) or Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE). This review also explores the properties of each of these methods and the advantages of combining them with high throughput sequencing.


Spinach and tomato consumption increases lymphocyte DNA resistance to oxidative stress but this is not related to cell carotenoid concentrations.
The increased consumption of fruit and vegetables has been linked to protection against different chronic diseases, but the dietary constituents responsible for this association have not been clearly identified. We evaluated the effect of spinach and spinach+tomato puree consumption on cell DNA resistance to an oxidative stress. To this aim, in a dietary controlled intervention study, 9 healthy female volunteers consumed a basal diet low in carotenoids (< 600 microg/day) enriched with daily portions (150 g) of spinach (providing about 9 mg lutein, 0.6 mg zeaxanthin, 4 mg beta-carotene) for 3 weeks (from day 0 to day 21) followed by a 2 week wash-out period (basal diet) and finally another 3 weeks (from day 35 to day 56) of diet enriched with daily portions of spinach (150 g) + tomato puree (25 g, providing about 7 mg lycopene, 0.3 mg beta-carotene). At the beginning and the end of each period of vegetable intake, blood samples were collected for lymphocyte separation. Carotenoid concentrations of lymphocytes were determined by HPLC and DNA damage was evaluated by the comet assay following an ex vivo treatment with H(2)O(2). During the first period of spinach consumption, lymphocyte lutein concentration did not increase significantly (from 1.6 to 2.2 micromol/10(12) cells) while lycopene and beta-carotene concentrations decreased significantly (from 1.0 to 0.1 micromol/10(12) cells, P < 0.001, and from 2.2 to 1.2 micromol/10(12) cells, P < 0.05, respectively). Lutein and lycopene concentrations increased after spinach+tomato puree consumption (from 1.2 to 3.5 micromol/10(12) cells, P < 0.01, and from 0.1 to 0.7 micromol/10(12) cells, P < 0.05, respectively). The increase may be attributed to the addition of tomato puree to spinach; however, the different concentrations of carotenoids in lymphocytes registered at the beginning of the two intervention periods may have affected the results. DNA resistance to H(2)O(2) insult increased significantly after both the enriched diets (P < 0.01); however, no "additive effect" was seen after spinach + tomato puree consumption. In the spinach + tomato intervention period an inverse correlation was observed between lymphocyte lycopene concentration and DNA damage, but this seems not able to explain the protection observed. The consumption of carotenoid-rich foods even for a short period of time gives protection against oxidative stress. The results obtained seem to suggest that this protective role is not specifically related to carotenoids. However they may contribute together with other substances present in vegetables to lymphocyte resistance to oxidative damage.


Antibacterial activity of a dual peptide targeting the Escherichia coli sliding clamp and the ribosome.
The bacterial processivity factor, or sliding clamp (SC), is a target of choice for new antibacterial drugs development. We have previously developed peptides that target Escherichia coli SC and block its interaction with DNA polymerases in vitro. Here, one such SC binding peptide was fused to a Proline-rich AntiMicrobial Peptide (PrAMP) to allow its internalization into E. coli cells. Co-immunoprecipitation assays with a N-terminally modified bifunctional peptide that still enters the bacteria but fails to interact with the bacterial ribosome, the major target of PrAMPs, demonstrate that it actually interacts with the bacterial SC. Moreover, when compared to SC non-binding controls, this peptide induces a ten-fold higher antibacterial activity against E. coli, showing that the observed antimicrobial activity is linked to SC binding. Finally, an unmodified bifunctional compound significantly increases the survival of Drosophila melanogaster flies challenged by an E. coli infection. Our study demonstrates the potential of PrAMPs to transport antibiotics into the bacterial cytoplasm and validates the development of drugs targeting the bacterial processivity factor of Gram-negative bacteria as a promising new class of antibiotics.


Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary artery disease. European COMAC Group.
A high plasma homocysteine concentration is a risk factor for atherosclerosis, and circulating concentrations of homocysteine are related to levels of folate and vitamin B6. This study was performed to explore the interrelationships between homocysteine, B vitamins, and vascular diseases and to evaluate the role of these vitamins as risk factors for atherosclerosis. In a multicenter case-control study in Europe, 750 patients with documented vascular disease and 800 control subjects frequency-matched for age and sex were compared. Plasma levels of total homocysteine (before and after methionine loading) were determined, as were those of red cell folate, vitamin B12, and vitamin B6. In a conditional logistic regression model, homocysteine concentrations greater than the 80th percentile for control subjects either fasting (12.1 micromol/L) or after a methionine load (38.0 micromol/L) were associated with an elevated risk of vascular disease independent of all traditional risk factors. In addition, concentrations of red cell folate below the lowest 10th percentile (<513 nmol/L) and concentrations of vitamin B6 below the lowest 20th percentile (<23.3 nmol/L) for control subjects were also associated with increased risk. This risk was independent of conventional risk factors and for folate was explained in part by increased homocysteine levels. In contrast, the relationship between vitamin B6 and atherosclerosis was independent of homocysteine levels both before and after methionine loading. Lower levels of folate and vitamin B6 confer an increased risk of atherosclerosis. Clinical trials are now required to evaluate the effect of treatment with these vitamins in the primary and secondary prevention of vascular diseases.


Cytochrome P4503A does not mediate the interaction between methadone and ritonavir-lopinavir.
Plasma concentrations of orally administered methadone are reduced by the human immunodeficiency virus protease inhibitor combination ritonavir and lopinavir, but the mechanism is unknown. Methadone metabolism, clearance, and drug interactions have been attributed to CYP3A4, but this remains controversial. This investigation assessed the effects of acute (2 days) and steady-state (2 weeks) ritonavir-lopinavir on intravenous and oral methadone metabolism and clearance, hepatic and intestinal CYP3A4/5 activity (using the probe substrate intravenous and oral alfentanil), and intestinal transporter activity (using oral fexofenadine) in healthy volunteers. Plasma and urine concentrations of methadone and metabolite enantiomers, and other analytes, were determined by mass spectrometry. Acute and chronic ritonavir-lopinavir reduced plasma methadone enantiomer concentrations in half, with an average 2.6- and 1.5-fold induction of systemic and apparent oral methadone clearances. Induction was attributable to stereoselectively increased hepatic methadone N-demethylation, hepatic extraction, and hepatic clearance, and there was a strong correlation between methadone N-demethylation and clearance. Methadone renal clearance was unchanged. Alfentanil's systemic clearance and hepatic extraction, apparent oral clearance, and intestinal extraction were reduced to 25%, 16%, and 35% of control, indicating strong inhibition of hepatic and intestinal CYP3A activities. Ritonavir-lopinavir (acute > chronic) increased fexofenadine exposure, suggesting intestinal P-glycoprotein inhibition. No correlation was found between methadone clearance and CYP3A activity. Acute and steady-state ritonavir-lopinavir stereoselectively induced methadone N-demethylation and clearance, despite significant inhibition of hepatic and intestinal CYP3A activity. Ritonavir-lopinavir inhibited intestinal transporters activity but had no effect on methadone bioavailability. These results do not support a significant role for CYP3A or ritonavir-lopinavir-inhibitable intestinal transporters in single-dose methadone disposition.


Protease-activated receptor 2 mediates mucus secretion in the airway submucosal gland.
Protease-activated receptor 2 (PAR2), a G protein-coupled receptor expressed in airway epithelia and smooth muscle, plays an important role in airway inflammation. In this study, we demonstrated that activation of PAR2 induces mucus secretion from the human airway gland and examined the underlying mechanism using the porcine and murine airway glands. The mucosa with underlying submucosal glands were dissected from the cartilage of tissues, pinned with the mucosal side up at the gas/bath solution interface of a physiological chamber, and covered with oil so that secretions from individual glands could be visualized as spherical bubbles in the oil. Secretion rates were determined by optical monitoring of the bubble diameter. The Ca(2+)-sensitive dye Fura2-AM was used to determine intracellular Ca(2+) concentration ([Ca(2+)](i)) by means of spectrofluorometry. Stimulation of human tracheal mucosa with PAR2-activating peptide (PAR2-AP) elevated intracellular Ca(2+) and induced glandular secretion equal to approximately 30% of the carbachol response in the human airway. Porcine gland tissue was more sensitive to PAR2-AP, and this response was dependent on Ca(2+) and anion secretion. When the mouse trachea were exposed to PAR2-AP, large amounts of secretion were observed in both wild type and ΔF508 cystic fibrosis transmembrane conductance regulator mutant mice but there is no secretion from PAR-2 knock out mice. In conclusion, PAR2-AP is an agonist for mucus secretion from the airway gland that is Ca(2+)-dependent and cystic fibrosis transmembrane conductance regulator-independent.


Mechanisms underlying transition from acute glomerular injury to late glomerular sclerosis in a rat model of nephrotic syndrome.
Functional and morphologic measurements were performed in Munich-Wistar rats after a single central venous injection of puromycin aminonucleoside (PA) or saline vehicle (sham). During phase I, PA rats exhibited overt nephrotic syndrome and impaired glomerular filtration, primarily due to a reduction in the glomerular capillary ultrafiltration coefficient. The morphologic counterpart of the latter consisted of effacement of glomerular epithelial cell foot processes and decrease in the number of filtration slit diaphragms. Administration of the angiotensin I converting enzyme inhibitor (CEI) enalapril to PA rats did not ameliorate glomerular dysfunction. During phase II, PA rats exhibited spontaneous resolution of proteinuria, impaired function, and morphologic abnormalities. However, PA rats now demonstrated marked glomerular capillary hypertension and continued, albeit lesser, reductions in the ultrafiltration coefficient. Concurrent CEI administration modestly lowered systemic arterial pressure, and normalized the glomerular capillary hydraulic pressure and ultrafiltration coefficient. Additional rats were studied during phase III, 70 wk after injection. In PA rats, prior glomerular hypertension was associated with development of recurrent proteinuria and extensive glomerular sclerosis, whereas concurrent CEI administration limited these parameters to values comparable to those in sham rats. Glomerular hypertension thus may explain the development of glomerular sclerosis and renal failure long after an episode of acute glomerular injury.


The effects of calcium on water balance of the brown trout Salmo trutta.
Water space, tritiated water flux, drinking and urine flow rates of the brown trout were decreased by increasing the environmental calcium concentration. Diffusional and osmotic permeabilities were identical in fresh water. This suggests that water flow across the gill occurs entirely by diffusion. Previous suggestions of a discrepancy between the two permeabilities in freshwater teleosts could have been due to an overestimation of urine flow rate upon which the determination of osmotic permeability coefficient is based. The wide-ranging effects of calcium on hydro-mineral regulation suggests that the ion interacts with the gills.


Estimating the burden of early onset dementia; systematic review of disease prevalence.
Dementia is more common in older age but a number of people develop symptoms at a younger age and are said to have early onset dementia (EOD). Those with EOD face different challenges to those with onset later in life. It has been difficult to quantify this disease burden. This is a systematic review of papers reporting on the prevalence of EOD. A search of Medline and Embase was performed. This was followed by a hand search of the references of these papers. Eleven suitable studies were included. All of the data was from more economically developed countries. The studies were heterogeneous in their design hindering direct comparison. The majority of the papers looked at all types of dementia although many gave a breakdown of the prevalence of different subgroups. A variety of diagnostic criteria was employed. Figures of 38 to 260 per 100,000 are quoted by papers looking at various different types of dementia together with an onset of between 30 and 64 or up to 420 per 100,000 for those aged 55-64. Prevalence rises as age approaches 65. Epidemiological data for prevalence rates for EOD are sparse. EOD remains a rare condition with low case numbers. Assimilation and comparison of results from existing studies is difficult due to methodological heterogeneity. Cross-national standardization of methodology should be a priority for future research in this area.


SLMP53-2 Restores Wild-Type-Like Function to Mutant p53 through Hsp70: Promising Activity in Hepatocellular Carcinoma.
Half of human cancers harbor TP53 mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation of mutant p53 (mutp53) through restoration of wild-type-like function constitutes a valuable anticancer therapeutic strategy. In order to search for mutp53 reactivators, a small library of tryptophanol-derived oxazoloisoindolinones was synthesized and the potential of these compounds as mutp53 reactivators and anticancer agents was investigated in human tumor cells and xenograft mouse models. By analysis of their anti-proliferative effect on a panel of p53-null NCI-H1299 tumor cells ectopically expressing highly prevalent mutp53, the compound SLMP53-2 was selected based on its potential reactivation of multiple structural mutp53. In mutp53-Y220C-expressing hepatocellular carcinoma (HCC) cells, SLMP53-2-induced growth inhibition was mediated by cell cycle arrest, apoptosis, and endoplasmic reticulum stress response. In these cells, SLMP53-2 restored wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the heat shock protein 70 (Hsp70), leading to the reestablishment of p53 transcriptional activity. Additionally, SLMP53-2 displayed synergistic effect with sorafenib, the only approved therapy for advanced HCC. Notably, it exhibited potent antitumor activity in human HCC xenograft mouse models with a favorable toxicological profile. Collectively, SLMP53-2 is a new mutp53-targeting agent with promising antitumor activity, particularly against HCC.


Dissecting regulatory networks in host-pathogen interaction using chIP-on-chip technology.
Understanding host-microbe interactions has been greatly enhanced by our broadening knowledge of the regulatory mechanisms at the heart of pathogenesis. The "transcriptomics" approach of measuring global gene expression has identified genes involved in bacterial pathogenesis. More recently, chromatin immunoprecipitation (ChIP) and hybridization to microarrays (chIP-on-chip) has emerged as a complementary tool that permits protein-DNA interactions to be studied in vivo. Thus, chIP-on-chip can be used to map the binding sites of transcription factors, thereby teasing apart gene regulatory networks. In this Review, we discuss the ChIP-on-chip technique and focus on its application to the study of host-pathogen interactions.


Gentamicin versus ceftriaxone for the treatment of gonorrhoea (G-TOG trial): study protocol for a randomised trial.
Gonorrhoea is a common sexually transmitted infection which causes genital pain and discomfort; in women it can also lead to pelvic inflammatory disease and infertility, and in men to epididymo-orchitis. Current treatment is with ceftriaxone, but there is increasing evidence of antimicrobial resistance which is reducing its effectiveness against gonorrhoea. A small, but increasing, number of patients have already been found to have highly resistant strains of gonorrhoea which has been associated with clinical failure. This trial aims to determine whether gentamicin is not clinically worse than ceftriaxone in the treatment of gonorrhoea. This is a blinded, two-arm, multicentre, noninferiority randomised trial. Patients are eligible if they are aged 16-70 years with a diagnosis of genital, pharyngeal and/or rectal gonorrhoea. Exclusion criteria are: known concurrent sexually transmitted infection(s) (excluding chlamydia); bacterial vaginosis and/or Trichomonas vaginalis infection; contraindications or an allergy to gentamicin, ceftriaxone, azithromycin or lidocaine; pregnancy or breastfeeding; complicated gonorrhoeal infection; weight under 40 kg; use of ceftriaxone, gentamicin or azithromycin within the preceding 28 days. Randomisation is to receive a single intramuscular injection of either gentamicin or ceftriaxone, all participants receive 1 g oral azithromycin as standard treatment. The estimated sample size is 720 participants (noninferiority limit 5%). The primary outcome is clearance of Neisseria gonorrhoeae at all infected sites by a negative Nucleic Acid Amplification Test, 2 weeks post treatment. Secondary outcomes include clinical resolution of symptoms, frequency of adverse events, tolerability of therapy, relationship between clinical effectiveness and antibiotic minimum inhibitory concentration for N. gonorrhoeae, and cost-effectiveness. The options for future treatment of gonorrhoea are limited. Results from this randomised trial will demonstrate whether gentamicin is not clinically worse than ceftriaxone for the treatment of gonorrhoea. This will inform clinical practice and policy for the treatment of gonorrhoea when current therapy with cephalosporins is no longer effective, or is contraindicated. International Standard Randomised Controlled Trial Number - ISRCTN51783227 , Registered on 18 September 2014. Current protocol version 2.0 17 June 2015.


Isolated pulmonary valve endocarditis in a patient with aplastic anaemia.
A 42-year-old female patient of aplastic anaemia on maintenance blood transfusion presented with a 3-week history of fever, cough, dyspnoea and pedal oedema. Upon examination she was found to have severe pallor, temperature of 101°F, tachycardia, bilateral pitting pedal oedema, raised jugular venous pressure, ejection systolic murmur (grade 2/6) in pulmonary area and petechiae over extensor aspect of both lower limbs. Blood investigations revealed low haemoglobin, thrombocytopaenia and mild increase in serum creatine. Chest x-ray was normal. Initial 2D trans thoracic echocardiography performed after hospital admission was normal. Antibiotics were started empirically to treat a possible underlying infection. Subsequently, three sets of blood cultures grew Enterococcus faecalis. Upon searching for the source, repeat echocardiograph done showed 2×0.5 cm vegetation on both pulmonary leaflets with severe pulmonary regurgitation, all other valves were free of vegetations. She was treated with intravenous antibiotics for the endocarditis and improved.


The Hidden Roles That Management Partners Play In Accountable Care Organizations.
Accountable care organizations (ACOs) are often discussed and promoted as driven by physicians, hospitals, and other health care providers. However, because of the flexible nature of ACO contracts, management organizations may also become partners in ACOs. We used data from 2013-15 on 276 ACOs from the National Survey of Accountable Care Organizations to understand the prevalence of nonprovider management partners' involvement in ACOs, the services these partners provide, and the structure of ACOs that have such partners. We found that 37 percent of ACOs reported having a management partner, and two-thirds of these ACOs reported that the partner shared in the financial risks or rewards. Among ACOs with partners, 94 percent had data services provided by the partner, 87 percent received administrative services, 68 percent received educational services, and 66 percent received care coordination services. Half received all four of these services from their partner. ACOs with partners were more heavily primary care than other ACOs. ACOs with and without partners had similar performance on costs and quality in Medicare ACO programs. Our findings suggest that management partners play a central role in many ACOs, perhaps supplying smaller and physician-run ACOs with services or expertise perceived as necessary for ACO success.


The DNA and RNA specificity of eilatin Ru(II) complexes as compared to eilatin and ethidium bromide.
Eilatin-containing ruthenium complexes bind to a broad range of different nucleic acids including: calf thymus (CT) DNA, tRNA(Phe), polymeric RNAs and DNAs, and viral RNAs including the HIV-1 RRE and TAR. The nucleic acid specificity of Lambda- and Delta-[Ru(bpy)2eilatin]2+ have been compared to that of the 'free' eilatin ligand, and to the classic intercalating agent ethidium bromide. Interestingly, all four compounds appear to bind to nucleic acids by intercalation, but the trends in nucleic acid binding specificity are highly diverse. Unlike ethidium bromide, both eilatin and the eilatin-containing coordination complexes bind to certain single-stranded RNAs with high affinity (K(d) < or = 1 microM). Eilatin itself is selective for electron-poor polymeric purines, while the eilatin-coordination complexes exhibit preference for the polypyrimidine r(U). These results show how the binding specificity of an intercalating ligand can change upon its incorporation into an octahedral metal complex.


Long-term effect of a tidal, hydroelectric propeller turbine on the populations of three anadromous fish species.
Tidal hydroelectric power has been proposed as one potential solution for sustainable energy sources. The first tidal turbine in North America began continuous operation in the Annapolis River estuary (44 °45'N; 65° 29'W) in June, 1985. The machine is an axial-flow, hydraulic-lift propeller turbine, a type known to cause fish mortality. Anadromous populations of American shad Alosa sapidissima, striped bass Morone saxatilis and Atlantic sturgeon Acipenser oxyrinchus utilize the Annapolis River for spawning and other life history phases. After power generation commenced obvious turbine mortalities of these fishes began appearing downstream of the turbine. Assessments of the A. sapidissima adult spawning runs during 1981-1982 (pre-operation) and 1989-1996 (operational) indicated significant changes in population characteristics after power generation began. Adult length, mass, age and per cent repeat spawners declined and total instantaneous mortality (Z) increased from 0.30 to 0.55. The pre-turbine spawning runs had older fish with numerous adult cohorts whereas by 12 years after operation began runs consisted of younger fish with fewer adult cohorts. During 1972-1987 numerous studies indicated the Annapolis River had an important angling fishery for M. saxatilis, but detailed annual records kept by a fishing contest during 1983-1987 and an elite angler family during the period 1976-2008 demonstrated a rapid decline in the number of fish >4.0 kg after turbine operation began. Pre-turbine catch by the angling family of fish >4.0 kg accounted for 84.1% of total catch, but declined significantly to 39.6% of total catch from 1986-1999, and to none from 2000-2008. The existence of an A. oxyrinchus stock in the Annapolis River was unknown before turbine operation, but during 1985-2017, 21 mortalities were recovered by chance seaward of the turbine. Mechanical strike and cavitation mortalities consisted of juveniles, mature males and gravid and spent females of ages 10 to 53 years found during June to October, the period when this anadromous species returns to its natal river to spawn. The results of the long-term studies at Annapolis indicate managers should realize substantial risks exist for the fish resources of the world's oceans from deployment of instream propeller turbines.


High-Accuracy Mass, Spin, and Recoil Predictions of Generic Black-Hole Merger Remnants.
We present accurate fits for the remnant properties of generically precessing binary black holes, trained on large banks of numerical-relativity simulations. We use Gaussian process regression to interpolate the remnant mass, spin, and recoil velocity in the seven-dimensional parameter space of precessing black-hole binaries with mass ratios q≤2, and spin magnitudes χ_{1}, χ_{2}≤0.8. For precessing systems, our errors in estimating the remnant mass, spin magnitude, and kick magnitude are lower than those of existing fitting formulae by at least an order of magnitude (improvement is also reported in the extrapolated region at high mass ratios and spins). In addition, we also model the remnant spin and kick directions. Being trained directly on precessing simulations, our fits are free from ambiguities regarding the initial frequency at which precessing quantities are defined. We also construct a model for remnant properties of aligned-spin systems with mass ratios q≤8, and spin magnitudes χ_{1}, χ_{2}≤0.8. As a byproduct, we also provide error estimates for all fitted quantities, which can be consistently incorporated into current and future gravitational-wave parameter-estimation analyses. Our model(s) are made publicly available through a fast and easy-to-use Python module called surfinBH.


Interdisciplinary care of hip fractures.: Orthogeriatric models, alternative models, interdisciplinary teamwork.
Hip fractures are common among older people, and the prognosis is serious in terms of mobility, independence in daily life activities, and cognition, with 42% of patients never achieving the same function as before the fracture. Norway has the highest incidence of hip fractures, and the important tasks are to improve patient care and prevent new fractures. The aim was to develop Norwegian Guidelines for Interdisciplinary Care for Hip Fractures, which included models of care, organization, and clinical issues. These guidelines were based on review of the literature, including existing guidelines such as the NICE guidelines, as well as clinical experience of the members of the group, where consensus was reached after discussions. The guidelines focus on interdisciplinary patient management through a clinical pathway from admission to discharge. Here, we will present a shortened and internationally adapted version of these guidelines, which has newly been released.


Evaluation of docetaxel in previously untreated extensive-stage small cell lung cancer: a Southwest Oncology Group phase II trial.
This phase II multi-institutional trial of the Southwest Oncology Group was designed to evaluate the efficacy and toxicity of docetaxel in chemotherapy-naive patients with extensive-stage small cell lung cancer. Forty-seven patients with extensive-stage small cell lung cancer were entered onto the study. Treatment consisted of docetaxel, 100 mg/m2, as a 1-hour intravenous infusion repeated every 21 days, with protocol-specified dose reductions for toxicity. Forty-three patients were eligible. A total of 158 cycles of docetaxel were administered (median, three cycles; range, one to nine). Ten patients (23%) (95% confidence interval, 12% to 39%) achieved partial responses. The median progression-free and overall survivals were 3 and 9 months, respectively. Therapy was generally well tolerated. Grade 4 neutropenia occurred in 58% of patients. Febrile neutropenia developed in five patients (12%), and infection was documented in 14% of patients. There was one treatment-related death caused by pneumonia in a patient who had developed bilateral pneumothoraces. Other toxicities (grade 3/4) included malaise, fatigue, and lethargy (21%); nausea (19%); stomatitis (14%); edema (9%); and sensory neuropathy (9%). Docetaxel, at a dose of 100 mg/m2, is an active agent in the treatment of small cell lung cancer. Reversible neutropenia is the most common toxicity associated with this treatment. The overall survival (9 months) with this agent is comparable to that reported with other new chemotherapeutic agents in small cell lung cancer and warrants additional evaluation of docetaxel in combination therapy.


Operationalizing diagnostic criteria for Alzheimer's disease and other age-related cognitive impairment-Part 2.
This article focuses on the effects of operational differences in case ascertainment on estimates of prevalence and incidence of cognitive impairment and/or dementia of the Alzheimer type. Experience and insights are discussed by investigators from the Framingham Heart Study, the East Boston Senior Health Project, the Chicago Health and Aging Project, the Mayo Clinic Study of Aging, the Baltimore Longitudinal Study of Aging, and the Aging, Demographics, and Memory Study. There is a general consensus that the single most important factor determining prevalence estimates of Alzheimer's disease (AD) is the severity of cognitive impairment used as a threshold to define cases. Studies that require a level of cognitive impairment in which persons are unable to provide self-care will have much lower estimates than the studies aimed at identifying persons in the earliest stages of AD. There are limited autopsy data from the aforementioned epidemiological studies to address accuracy in the diagnosis of etiological subtype, namely the specification of AD alone or in combination with other types of pathology. However, other community-based cohort studies show that many persons with mild cognitive impairment and also some persons without dementia or mild cognitive impairment meet pathological criteria for AD, thereby suggesting that the number of persons who would benefit from an effective secondary prevention intervention is probably higher than the published prevalence estimates. Improved accuracy in the clinical diagnosis of AD is anticipated with the addition of molecular and structural biomarkers in the next generation of epidemiological studies.


A novel observation: melatonin's interaction with malondiadehyde.
A purpose of this study is to determine whether melatonin, a novel antioxidant, can interact with malondialdehyde in an in vitro condition. The reaction kinetics and thermodynamics of this reaction have been performed and a new product has been identified using liquid chromatography onlining with mass spectrometry. A new product generated with an interaction of melatonin and malondialdehyde has been identified to be a three-ring structure with a molecular weight 286, which has the specific wavelength absorption with the maximum at 345 nm. The reaction was completed within a few minutes and the product was proportional to the concentrations of the reactants. Based on its molecular weight and the deduced structure of the new product, we speculate that this reaction occurs between one melatonin molecule and one malondialdehyde and to form a 3 ring conjugated adduct. This is the first report to show that melatonin directly interacts with malondialdehyde to form a new product. The findings suggest that melatonin may detoxify unsaturated carbonyls and protect against cellular damage induced by oxidative stress.


Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy.
Programmed cell death pathways have been implicated in the mechanism by which neurons die following brief and prolonged seizures, but the significance of proapoptotic Bcl-2 family proteins in the process remains poorly defined. Expression of the death agonist Bcl-2-interacting mediator of cell death (Bim) is under the control of the forkhead in rhabdomyosarcoma (FKHR) transcription factors. This prompted us to examine the response of this pathway to experimental seizures and in hippocampi from patients with intractable temporal lobe epilepsy. A short period of status epilepticus in rats that damaged the hippocampus activated FKHR/FKHRL-1 and induced a significant increase in expression of Bim. Blocking of FKHR/FKHRL-1 dephosphorylation after seizures improved hippocampal neuronal survival in vivo, and Bim antisense oligonucleotides were neuroprotective against seizures in vitro. Inhibition of Akt increased the FKHR/Bim response and DNA fragmentation within the normally resistant cortex. Analysis of hippocampi from patients with intractable epilepsy revealed that Bim levels were significantly lower than in controls and FKHR was inhibited; we were able to reproduce these results experimentally in rats by evoking multiple brief, noninjurious electroshock seizures. We conclude that Bim expression may be a critical determinant of whether seizures damage the brain, and that its control may be neuroprotective in status epilepticus and epilepsy.