A Time-Calibrated Road Map of Brassicaceae Species Radiation and Evolutionary History.
The Brassicaceae include several major crop plants and numerous important model species in comparative evolutionary research such as Arabidopsis, Brassica, Boechera, Thellungiella, and Arabis species. As any evolutionary hypothesis needs to be placed in a temporal context, reliably dated major splits within the evolution of Brassicaceae are essential. We present a comprehensive time-calibrated framework with important divergence time estimates based on whole-chloroplast sequence data for 29 Brassicaceae species. Diversification of the Brassicaceae crown group started at the Eocene-to-Oligocene transition. Subsequent major evolutionary splits are dated to ∼20 million years ago, coinciding with the Oligocene-to-Miocene transition, with increasing drought and aridity and transient glaciation events. The age of the Arabidopsis thaliana crown group is 6 million years ago, at the Miocene and Pliocene border. The overall species richness of the family is well explained by high levels of neopolyploidy (43% in total), but this trend is neither directly associated with an increase in genome size nor is there a general lineage-specific constraint. Our results highlight polyploidization as an important source for generating new evolutionary lineages adapted to changing environments. We conclude that species radiation, paralleled by high levels of neopolyploidization, follows genome size decrease, stabilization, and genetic diploidization.


Identifying key questions in the ecology and evolution of cancer.
The application of evolutionary and ecological principles to cancer prevention and treatment, as well as recognizing cancer as a selection force in nature, has gained impetus over the last 50 years. Following the initial theoretical approaches that combined knowledge from interdisciplinary fields, it became clear that using the eco-evolutionary framework is of key importance to understand cancer. We are now at a pivotal point where accumulating evidence starts to steer the future directions of the discipline and allows us to underpin the key challenges that remain to be addressed. Here, we aim to assess current advancements in the field and to suggest future directions for research. First, we summarize cancer research areas that, so far, have assimilated ecological and evolutionary principles into their approaches and illustrate their key importance. Then, we assembled 33 experts and identified 84 key questions, organized around nine major themes, to pave the foundations for research to come. We highlight the urgent need for broadening the portfolio of research directions to stimulate novel approaches at the interface of oncology and ecological and evolutionary sciences. We conclude that progressive and efficient cross-disciplinary collaborations that draw on the expertise of the fields of ecology, evolution and cancer are essential in order to efficiently address current and future questions about cancer.


Evaluation of four methods used to measure plasma insulin-like growth factor 1 concentrations in healthy cats and cats with diabetes mellitus or other diseases.
To evaluate 4 methods used to measure plasma insulin-like growth factor (IGF) 1 concentrations in healthy cats and cats with diabetes mellitus or other diseases. 39 healthy cats, 7 cats with diabetes mellitus, and 33 cats with other diseases. 4 assays preceded by different sample preparation methods were evaluated, including acid chromatography followed by radioimmunoassay (AC-RIA), acid-ethanol extraction followed by immunoradiometry assay (AEE-IRMA), acidification followed by immunochemiluminescence assay (A-ICMA), and IGF-2 excess followed by RIA (IE-RIA). Validation of the methods included determination of precision, accuracy, and recovery. The concentration of IGF-1 was measured with all methods, and results were compared among cat groups. The intra-assay coefficient of variation was < 10% for AC-RIA, A-ICMA, and AEE-IRMA and 14% to 22% for IE-RIA. The linearity of dilution was close to 1 for each method. Recovery rates ranged from 69% to 119%. Five healthy cats had IGF-1 concentrations > 1,000 ng/mL with the AEE-IRMA, but < 1,000 ng/mL with the other methods. Compared with healthy cats, hyperthyroid cats had significantly higher concentrations of IGF-1 with the A-ICMA method, but lower concentrations with the IE-RIA method. Cats with lymphoma had lower IGF-1 concentrations than did healthy cats regardless of the method used. Differences in the methodologies of assays for IGF-1 may explain, at least in part, the conflicting results previously reported in diabetic cats. Disorders such as hyperthyroidism and lymphoma affected IGF-1 concentrations, making interpretation of results more difficult if these conditions are present in cats with diabetes mellitus.


A simple and accessible synthetic lectin for glucose recognition and sensing.
Binding carbohydrates from water is a difficult task, even for the natural carbohydrate-binding proteins known as lectins. The design of synthetic lectin mimics is correspondingly challenging, especially if good selectivities are required. In previous work we showed that success is possible, but only for complex polycyclic architectures that require lengthy and low-yielding syntheses; for example, one glucose-selective system was made in 21 steps and only 0.1% overall yield. Here we report the discovery of a simple monocyclic host that matches the earlier designs, but is far more accessible as it is prepared in just five steps and 23% overall yield. The new synthetic lectin binds glucose with excellent selectivity versus other common monosaccharides (for example, ~50:1 versus galactose) and sufficient affinity for glucose sensing at the concentrations found in blood. It also features a built-in signalling system in the form of strong and guest-dependent fluorescence emission. The effectiveness and simplicity of this molecule suggests the potential for development into a new methodology for practical glucose monitoring.


The mass-independent fractionation of oxygen: a novel isotope effect and its possible cosmochemical implications.
Experimental evidence is presented which demonstrates a chemically produced, mass-independent isotopic fractionation of oxygen. The effect is thought to result from self-shielding by the major isotopic species (16)O(2), but other possible mechanisms such as molecular symmetry cannot be ruled out. In a three-isotope plot, the experimentally produced fractionation line is essentially equal in slope to the observed carbonaceous chondrite mixing line. The implications for the early history of the solar system are discussed.


Linking CHHiP prostate cancer RCT with GP records: A study proposal to investigate the effect of co-morbidities and medications on long-term symptoms and radiotherapy-related toxicity.
Patients receiving cancer treatment often have one or more co-morbid conditions that are treated pharmacologically. Co-morbidities are recorded in clinical trials usually only at baseline. However, co-morbidities evolve and new ones emerge during cancer treatment. The interaction between multi-morbidity and cancer recovery is significant but poorly understood. To investigate the effect of co-morbidities (e.g. cardiovascular and diabetes) and medications (e.g. statins, antihypertensives, metformin) on radiotherapy-related toxicity and long-term symptoms in order to identify potential risk factors. The possible protective effect of medications such as statins or antihypertensives in reducing radiotherapy-related toxicity will also be explored. Two datasets will be linked. (1) CHHiP (Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer) randomised control trial. CHHiP contains pelvic symptoms and radiation-related toxicity reported by patients and clinicians. (2) GP (General Practice) data from RCGP RSC (Royal College of General Practitioners Research and Surveillance Centre). The GP records of CHHiP patients will be extracted, including cardiovascular co-morbidities, diabetes and prescription medications. Statistical analysis of the combined dataset will be performed in order to investigate the effect. Linking two sources of healthcare data is an exciting area of big healthcare data research. With limited data in clinical trials (not all clinical trials collect information on co-morbidities or medications) and limited lengths of follow-up, linking different sources of information is increasingly needed to investigate long-term outcomes. With increasing pressures to collect detailed information in clinical trials (e.g. co-morbidities, medications), linkage to routinely collected data offers the potential to support efficient conduct of clinical trials.


Oral cryotherapy reduces mucositis and improves nutrition - a randomised controlled trial.
To investigate if oral cryotherapy during myeloablative therapy may influence frequency and severity of mucositis, nutritional status and infection rate after bone marrow transplantation. Patients treated with intensive myeloablative treatment before bone marrow transplantation are all at risk to develop mucositis. Oral mucositis causes severe pain and oral dysfunction, which can contribute to local and systemic infections and bleeding; it may even interrupt cancer therapy. Oral mucositis also decreases the oral food intake, which increases the risk for malnutrition and infection. Reduced food intake, loss of fat and muscles, alterations in energy and substrate metabolism leads to malnutrition. A randomised controlled trial with a random assignment to experimental or control group. A stratified randomisation was used with regard to the type of transplantation. Mucositis was measured on WHO mucositis scale. Number of days of total parenteral nutrition, infection rate, weight, albumin levels and days at hospital was compared. There were significantly fewer patients in the experimental group with mucositis grade 3-4 than in the control group and significantly lower number of days in the hospital (allogeneic patients). Less total parenteral nutrition was needed in the experimental group in both settings, and the S-albumin level was significantly better preserved. No significant difference could be found with regard to infection rate. Oral cryotherapy reduced mucositis, number of hospital days, the need for total parenteral nutrition and resulted in a better nutritional status. Nurses caring for patients treated with myeloablative therapy should place high priority to prevent oral mucositis and hereby reduce its side effects.


The human metabolic reconstruction Recon 1 directs hypotheses of novel human metabolic functions.
Metabolic network reconstructions formalize our knowledge of metabolism. Gaps in these networks pinpoint regions of metabolism where biological components and functions are "missing." At the same time, a major challenge in the post genomic era involves characterisation of missing biological components to complete genome annotation. We used the human metabolic network reconstruction RECON 1 and established constraint-based modelling tools to uncover novel functions associated with human metabolism. Flux variability analysis identified 175 gaps in RECON 1 in the form of blocked reactions. These gaps were unevenly distributed within metabolic pathways but primarily found in the cytosol and often caused by compounds whose metabolic fate, rather than production, is unknown. Using a published algorithm, we computed gap-filling solutions comprised of non-organism specific metabolic reactions capable of bridging the identified gaps. These candidate solutions were found to be dependent upon the reaction environment of the blocked reaction. Importantly, we showed that automatically generated solutions could produce biologically realistic hypotheses of novel human metabolic reactions such as of the fate of iduronic acid following glycan degradation and of N-acetylglutamate in amino acid metabolism. The results demonstrate how metabolic models can be utilised to direct hypotheses of novel metabolic functions in human metabolism; a process that we find is heavily reliant upon manual curation and biochemical insight. The effectiveness of a systems approach for novel biochemical pathway discovery in mammals is demonstrated and steps required to tailor future gap filling algorithms to mammalian metabolic networks are proposed.


Structural and Functional Features of the P2X4 Receptor: An Immunological Perspective.
Extracellular nucleotides are important mediators of activation, triggering various responses through plasma membrane P2 and P1 receptors. P2 receptors are further subdivided into ionotropic P2X receptors and G protein-coupled P2Y receptors. P2X4 is an ATP-gated cation channel broadly expressed in most tissues of the body. Within the P2X family, P2X4 has a unique subcellular distribution, being preferentially localized in lysosomes. In these organelles, high ATP concentrations do not trigger P2X4 because of the low pH. However, when the pH increases to 7.4, P2X4 can be stimulated by intra-lysosomal ATP, which is in its active, tetra-anionic form. Elucidation of P2X4, P2X3 and P2X7 structures has shed some light on the functional differences between these purinergic receptors. The potential interaction between P2X4 and P2X7 has been extensively studied. Despite intensive effort, it has not been possible yet to determine whether P2X4 and P2X7 interact as heterotrimers or homotrimers at the plasma membrane. However, several publications have shown that functional interactions between P2X4 and P2X7 do occur. Importantly, these studies indicate that P2X4 potentiates P2X7-dependent activation of inflammasomes, leading to increased release of IL-1β and IL-18. The role of P2X4 in various diseases could be beneficial or deleterious even though the pathophysiological mechanisms involved are still poorly defined. However, in diseases whose physiopathology involves activation of the NLRP3 inflammasome, P2X4 was found to exacerbate severity of disease. The recent production of monoclonal antibodies specific for the human and mouse P2X4, some of which are endowed with agonist or antagonist properties, raises the possibility that they could be used therapeutically. Analysis of single nucleotide polymorphisms of the human P2RX4 gene has uncovered the association of P2RX4 gene variants with susceptibility to several human diseases.


Metabolism of antithrombin III in cirrhosis and carcinoma of the liver.
1. The metabolism of human antithrombin III (ATIII) was studied by using 125I-labelled tracer. 2. The plasma half-life (t0.5) was 2.71 +/- 0.26 days in normal subjects and was similar in patients with cirrhosis or primary carcinoma of liver. 3. Patients with cirrhosis had low ATIII levels, decreased intravascular mass, total body mass and decreased absolute catabolic rate, suggesting decreased synthesis. The positive correlation of ATIII level with fractional catabolic rate (K10) indicated that the decreased catabolic might exert a positive inhibition on ATIII production. 4. These abnormalities were more exaggerated in patients with macronodular cirrhosis associated with hepatitis surface antigen or in those with ascites. 5. In cirrhotic patients with ascites an additional extravascular pool of ATIII was present which did not turn over at the same rate as the intravascular pool. 6. Patients with primary carcinoma of liver had moderately low ATIII, but normal intravascular mass and total body mass because of the increased plasma volume and normal absolute catabolic rate. 7. The negative correlation of ATIII levels with K10 suggested that the low levels could be due to increased catabolism or consumption. 8. One patient with disseminated malignancy and active superficial thrombophlebitis had normal ATIII metabolism.


Tumor risk in disorders of sex development (DSD).
Disorders of sex development (DSD), previously referred to as intersex disorders, comprise a variety of anomalies defined by congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. Besides issues such as gender assignment, clinical and diagnostic evaluation, surgical and psychosocial management, and sex steroid replacement, the significantly increased risk for developing specific types of malignancies is both clinically and biologically relevant. This relates to germ-cell tumors specifically in DSD patients with hypovirilization or gonadal dysgenesis. The presence of a well-defined part of the Y chromosome (known as the GBY region) is a prerequisite for malignant transformation, for which the testis-specific protein on the Y chromosome (TSPY) is a likely candidate gene. The precursor lesions of these cancers are carcinoma in situ (CIS)/intratubular germ-cell neoplasia unclassified (ITGCNU) in testicular tissue and gonadoblastoma in those without obvious testicular differentiation. Most recently, undifferentiated gonadal tissue (UGT) has been identified as the likely precursor for gonadoblastoma. The availability of markers for the different developmental stages of germ cells allows detailed investigation of the characteristics of normal and (pre)malignant germ cells. Although informative in a diagnostic setting for adult male patients, these markers - such as OCT3/4 - cannot easily distinguish (pre)malignant germ cells from germ cells showing delayed maturation. This latter phenomenon is frequently found in gonads of DSD patients, and may be related to the risk of malignant transformation. Thus, the mere application of these markers might result in over-diagnosis and unnecessary gonadectomy. It is proposed that morphological and histological evaluation of gonadal tissue, in combination with OCT3/4 and TSPY double immunohistochemistry and clinical parameters, is most informative in estimating the risk for germ-cell tumor development in the individual patient, and might in future be used to develop a decision tree for optimal management of patients with DSD.


Vision and touch are automatically integrated for the perception of sequences of events.
The purpose of the present experiment was to investigate the integration of sequences of visual and tactile events. Subjects were presented with sequences of visual flashes and tactile taps simultaneously and instructed to count either the flashes (Session 1) or the taps (Session 2). The number of flashes could differ from the number of taps by +/-1. For both sessions, the perceived number of events was significantly influenced by the number of events presented in the task-irrelevant modality. Touch had a stronger influence on vision than vision on touch. Interestingly, touch was the more reliable of the two modalities-less variable estimates when presented alone. For both sessions, the perceptual estimates were less variable when stimuli were presented in both modalities than when the task-relevant modality was presented alone. These results indicate that even when one signal is explicitly task irrelevant, sensory information tends to be automatically integrated across modalities. They also suggest that the relative weight of each sensory channel in the integration process depends on its relative reliability. The results are described using a Bayesian probabilistic model for multimodal integration that accounts for the coupling between the sensory estimates.


Evaluation of various hemostatic knot configurations performed by veterinary students.
OBJECTIVE To determine the most effective hemostatic knot configuration performed by veterinary students following a brief training session with an experienced surgeon and a subsequent deliberate self-training period. DESIGN Experiment. SAMPLE 24 fourth-year veterinary students with no previous surgical knot-tying experience. PROCEDURES In a 1-hour training session, an experienced surgeon showed veterinary students how to perform 5 hemostatic knot configurations (giant, slip, strangle, surgeon's, and transfixing), which they then practiced at home on a hemostasis simulator for 2 weeks. Thereafter, students performed each knot 4 times (twice each with monofilament and multifilament suture) on a hemostasis simulator. An experienced surgeon evaluated the correct execution of knots and measured their effectiveness by use of a manometer to measure vessel pressure distal to the ligature. Each student completed a questionnaire regarding their perceived learning and execution difficulty and sealing security for each knot. Responses were compared among knots and suture materials. RESULTS Overall, students considered the surgeon's knot the easiest to learn and the strangle knot the most difficult. The slipknot was also considered the easiest knot to perform, and the giant knot was considered the most difficult. The strangle knot was deemed the most effective in reducing vessel pressure distal to the ligature. CONCLUSIONS AND CLINICAL RELEVANCE The strangle knot was the most effective hemostatic knot in inexperienced hands, although veterinary students considered it more difficult to learn than other, perhaps more commonly taught, knots. Therefore, teaching of the strangle knot should be encouraged in veterinary schools.


Depression and ADHD-Related Risk for Substance Use in Adolescence and Early Adulthood: Concurrent and Prospective Associations in the MTA.
Childhood attention-deficit/hyperactivity disorder (ADHD) is prospectively linked to substance use and disorder. Depression emerging in adolescence is an understudied risk factor that may explain some of this risk. In the present study, we considered mediating and moderating roles of adolescent depression in explaining this association by using longitudinal data from the prospective 16-year follow-up of the Multimodal Treatment Study of ADHD (MTA). Participants were 547 children diagnosed with DSM-IV ADHD Combined Type, and 258 age- and sex-matched comparison children. In adolescence, depressive symptoms did not exacerbate effects of childhood ADHD on any substance use. For both groups, time-varying and average depressive symptoms were associated with more frequent use of all substances. Prospectively, we found no evidence of depression mediation to adult substance use. However, adolescent depression moderated the association between childhood ADHD and adult marijuana use. Although adults without ADHD histories used marijuana more frequently if they had elevated depressive symptoms in adolescence, marijuana use by adults with ADHD histories was independent of their adolescent depression. In adulthood, depression diagnoses and ADHD persistence continued to operate as independent, additive correlates of substance use risk. Our findings suggest a circumscribed role for depression in substance use risk that adds to, but does not alter or explain, ADHD-related risk.


Effect of Residual Lignin Type and Amount on Bleaching of Kraft Pulp by Trametes versicolor.
The white rot fungus Trametes (Coriolus) versicolor can delignify and brighten unbleached hardwood kraft pulp within a few days, but softwood kraft pulps require longer treatment. To determine the contributions of higher residual lignin contents (kappa numbers) and structural differences in lignins to the recalcitrance of softwood kraft pulps to biobleaching, we tested softwood and hardwood pulps cooked to the same kappa numbers, 26 and 12. A low-lignin-content (overcooked) softwood pulp resisted delignification by T. versicolor, but a high-lignin-content (lightly cooked) hardwood pulp was delignified at the same rate as a normal softwood pulp. Thus, the longer time taken by T. versicolor to brighten softwood kraft pulp than hardwood pulp results from the higher residual lignin content of the softwood pulp; possible differences in the structures of the residual lignins are important only when the lignin becomes highly condensed. Under the conditions used in this study, when an improved fungal inoculum was used, six different softwood pulps were all substantially brightened by T. versicolor. Softwood pulps whose lignin contents were decreased by extended modified continuous cooking or oxygen delignification to kappa numbers as low as 15 were delignified by T. versicolor at the same rate as normal softwood pulp. More intensive O(2) delignification, like overcooking, decreased the susceptibility of the residual lignin in the pulps to degradation by T. versicolor.


GC-MS lipidomic profiling of the echinoderm Marthasterias glacialis and screening for activity against human cancer and non-cancer cell lines.
Marine organisms have been increasingly regarded as an excellent source of bioactive molecules for human health. As part of an on-going study to elucidate the chemical composition and biological activity of Marthastherias glacialis, we report here the lipidomic profile of this organism and screening for anticancer activity. Two classes of biologically active metabolites were identified and quantified by a GC-MS optimized method for screening several classes of metabolites in a single run. Free fatty acids and sterols were found, including ergosterol, β-sitosterol and cholesterol derivatives, some of which are reported in this species for the first time. Distinct assays were performed to screen extract's effect on viability, membrane integrity and density of three human cancer cell lines: human oestrogen receptor-positive (ER(+)) breast cancer (MCF-7), human neuroblastoma (SH-SY5Y) and human colon cancer (Caco-2). Differential activity towards the three cancer cell lines was found, SH-SY5Y cell line being the most susceptible. No activity was found for Caco-2 cell line. Non-cancer cell lines (human dermal fibroblasts and human foreskin fibroblasts) were also tested and revealed to be less susceptible. This work establishes M. glacialis as a potential source of bioactive molecules for further studies.


Rise of the machines--recommendations for ecologists when using next generation sequencing for microsatellite development.
Next generation sequencing is revolutionizing molecular ecology by simplifying the development of molecular genetic markers, including microsatellites. Here, we summarize the results of the large-scale development of microsatellites for 54 nonmodel species using next generation sequencing and show that there are clear differences amongst plants, invertebrates and vertebrates for the number and proportion of motif types recovered that are able to be utilized as markers. We highlight that the heterogeneity within each group is very large. Despite this variation, we provide an indication of what number of sequences and consequent proportion of a 454 run are required for the development of 40 designable, unique microsatellite loci for a typical molecular ecological study. Finally, to address the challenges of choosing loci from the vast array of microsatellite loci typically available from partial genome runs (average for this study, 2341 loci), we provide a microsatellite development flowchart as a procedural guide for application once the results of a partial genome run are obtained.


High-dose daptomycin therapy for left-sided infective endocarditis: a prospective study from the international collaboration on endocarditis.
The use of daptomycin in Gram-positive left-sided infective endocarditis (IE) has significantly increased. The purpose of this study was to assess the influence of high-dose daptomycin on the outcome of left-sided IE due to Gram-positive pathogens. This was a prospective cohort study based on 1,112 cases from the International Collaboration on Endocarditis (ICE)-Plus database and the ICE-Daptomycin Substudy database from 2008 to 2010. Among patients with left-sided IE due to Staphylococcus aureus, coagulase-negative staphylococci, and Enterococcus faecalis, we compared those treated with daptomycin (cohort A) to those treated with standard-of-care (SOC) antibiotics (cohort B). The primary outcome was in-hospital mortality. Time to clearance of bacteremia, 6-month mortality, and adverse events (AEs) ascribable to daptomycin were also assessed. There were 29 and 149 patients included in cohort A and cohort B, respectively. Baseline comorbidities did not differ between the two cohorts, except for a significantly higher prevalence of diabetes and previous episodes of IE among patients treated with daptomycin. The median daptomycin dose was 9.2 mg/kg of body weight/day. Two-thirds of the patients treated with daptomycin had failed a previous antibiotic regimen. In-hospital and 6-month mortalities were similar in the two cohorts. In cohort A, median time to clearance of methicillin-resistant S. aureus (MRSA) bacteremia was 1.0 day, irrespective of daptomycin dose, representing a significantly faster bacteremia clearance compared to SOC (1.0 versus 5.0 days; P < 0.01). Regimens with higher daptomycin doses were not associated with increased incidence of AEs. In conclusion, higher-dose daptomycin may be an effective and safe alternative to SOC in the treatment of left-sided IE due to common Gram-positive pathogens.


The relationship between the common mutations of the alpha gene cluster and its evolutionary history.
The alpha globin gene cluster is far from static. It shows remarkable diversity within and among populations, both in gene number and the pattern of polymorphisms involving the HVRs. The deletions which have given rise to alpha o thalassemia appear to have resulted from rare genetic events and the affected chromosomes have been distributed among localized populations by selection. On the other hand, the deletions which have given rise to at least one of the alpha+ thalassemias seem to have occurred on multiple occasions in different populations. The genesis of this condition, the commonest single gene disorder, may reflect the concerted evolution of the alpha globin genes, and the alpha+ thalassemias may have arisen as a by-product of this evolutionary process. The existence of such a polymorphic gene family and the fact that its mutations are the commonest single gene disorders in man, provide us with a remarkable, natural model for studying population genetics at the molecular level. Further analysis of this cluster, and of the beta globin genes, may provide valuable information about the timing of racial diversions, population movements, and the molecular events which have helped to maintain such high gene frequencies for some of the mutations of these loci.


Bioaccessible (poly)phenol metabolites from raspberry protect neural cells from oxidative stress and attenuate microglia activation.
Neuroinflammation is an integral part of the neurodegeneration process inherent to several aging dysfunctions. Within the central nervous system, microglia are the effective immune cells, responsible for neuroinflammatory responses. In this study, raspberries were subjected to in vitro digestion simulation to obtain the components that result from the gastrointestinal (GI) conditions, which would be bioaccessible and available for blood uptake. Both the original raspberry extract and the gastrointestinal bioaccessible (GIB) fraction protected neuronal and microglia cells against H2O2-induced oxidative stress and lipopolysaccharide (LPS)-induced inflammation, at low concentrations. Furthermore, this neuroprotective capacity was independent of intracellular ROS scavenging mechanisms. We show for the first time that raspberry metabolites present in the GIB fraction significantly inhibited microglial pro-inflammatory activation by LPS, through the inhibition of Iba1 expression, TNF-α release and NO production. Altogether, this study reveals that raspberry polyphenols may present a dietary route to the retardation or amelioration of neurodegenerative-related dysfunctions.


Imaging performance of annular apertures.
Images formed by aberration free optical systems with annular apertures are investigated in the whole range of central obstruction ratios. Annular apertures form images with central and surrounding ring groups, and the number of rings in each group is given by the outer diameter of the annular aperture divided by the width of the annulus. The theoretical energy fraction of 0.838 in the Airy disk of the unobstructed aperture increases to 0.903 in the central ring groups. Furthermore it is shown that the energy fractions for the central and surrounding ring groups are constant for all obstruction ratios and in each fractional energy level. The central image spot in the central ring group contains only a small energy fraction and therefore the central ring group as a whole is the effective image element.


The biochemistry of CYFRA 21-1 and other cytokeratin-tests.
Soluble forms of keratins in human sera seem to be useful analytes for the monitoring of cancer patients. CYFRA 21-1 is a new test measuring keratin 19 in human blood. The test was developed as sandwich ELISA based on two monoclonal antibodies, both reacting with keratin 19. The epitopes recognised by the antibodies are located on the rod region of the molecule. In sera from malignant patients CYFRA 21-1 detects immunoreactive compounds which appear to be larger than keratin 19 itself, indicating the presence of oligomers in these sera. In a comparison study the reactivity of other keratin tests (TPA, TPS, TPAcyk) with the keratins 8, 18 and 19 were measured both in solution and on immunoblots. The reactivity pattern was found to be different what may explain the different diagnostic properties of the individual tests.


Opposing Mcl-1, the GALIG proapoptotic gene is upregulated as neutrophils die and underexpressed in Acute Myeloid Leukemia cells.
GALIG gene expression induces apoptosis in cultured cells through a pathway still under investigation. It is highly expressed in leukocytes but weakly detectable in bone marrow, suggesting a role in the myeloid lineage homeostasis. We show here that GALIG-induced cell death is counteracted by the overexpression of MCL-1, a pro-survival member of the Bcl2 family. Moreover, during spontaneous neutrophil apoptosis, a substantial increase in GALIG gene expression is observed: GALIG still opposes MCL-1. Finally, in bone marrow and peripheral blood cells from patients with Acute Myeloid Leukemia type 2, the level of GALIG transcripts is massively down-regulated when compared to their normal counterparts, while MCL-1 is expressed to the same extent. These data suggest that GALIG could be a key player in the cell death pathway involved in leukocytes homeostasis and myeloid malignancies.


The interaction of colloidal particles with weak homeotropic anchoring energy in homogeneous nematic liquid crystal cells.
We have investigated interactions of colloidal particles with weak homeotropic anchoring energy in homogeneous nematic liquid crystal cells. Particle-wall and inter-particle interactions were observed experimentally and analyzed using typical dipole-dipole and quadrupole-quadrupole interactions, including substrate effects as the image charges. Both experimental results matched well with the calculated results for the effective particle radius reflecting the weak anchoring. The effective radius is reduced by the amount of extrapolation length than the actual particle radius. The effective radii of polyethylene micro-particles were reduced to a coefficient ζ (0.78 ≥ ζ ≥ 0.52) times the actual radius with anchoring coefficients in the range of 3.8 × 10(-6) to 1.4 × 10(-6) J m(-2). The anchoring energy of the particles is, therefore, a key component for explaining liquid crystal colloidal systems.


The nature of the metal-metal bond in bimetallic surfaces.
The formation of a surface metal-metal bond can produce large perturbations in the electronic, chemical, and catalytic properties of a metal. Recent studies indicate that charge transfer is an important component in surface metal-metal bonds that involve dissimilar elements. The larger the charge transfer, the stronger the cohesive energy of the bimetallic bond. On a surface, the formation of a heteronuclear metal-metal bond induces a flow of electron density toward the element with the larger fraction of empty states in its valence band. This behavior is completely contrary to that observed in bulk alloys, indicating that the nature of a heteronuclear metal-metal bond depends strongly on the structural geometry of the bimetallic system.


CD28-negative cytolytic effector T cells frequently express NK receptors and are present at variable proportions in circulating lymphocytes from healthy donors and melanoma patients.
In humans, NK receptors are expressed by natural killer cells and some T cells, the latter of which are preferentially alphabetaTCR+ CD8+ cytolytic T lymphocytes (CTL). In this study we analyzed the expression of nine NK receptors (p58.1, p58.2, p70, p140, ILT2, NKRP1A, ZIN176, CD94 and CD94/NKG2A) in PBL from both healthy donors and melanoma patients. The percentages of NK receptor-positive T cells (NKT cells) varied strongly, and this variation was more important between individual patients than between individual healthy donors. In all the individuals, the NKT cells were preferentially CD28-, and a significant correlation was found between the percentage of CD28- T cells and the percentage of NK receptor+ T cells. Based on these data and the known activated phenotype of CD28- T cells, we propose that the CD28- CD8+ T cell pool represents or contains the currently active CTL population, and that the frequent expression of NK receptors reflects regulatory mechanisms modulating the extent of CTL effector function. Preliminary results indicate that some tumor antigen-specific T cells may indeed be CD28- and express NK receptors in vivo.


How to solve the cost crisis in health care.
U.S. health care costs currently exceed 17% of GDP and continue to rise. One fundamental reason that providers are unable to reverse the trend is that they don't understand what it costs to deliver patient care or how those costs compare with outcomes. To put it bluntly, few health care providers measure the actual costs for treating a given patient with a given medical condition over a full cycle of care, or compare the costs they incur with the outcomes they achieve. What isn't measured cannot be managed or improved, and this is all too true in health care, where poor costing systems mean that effective and efficient providers go unrewarded, and inefficient ones have little incentive to improve. But all this can be remedied by exploring the concept of value in health care and carefully measuring costs. This article describes a new way to analyze costs that uses patients and their conditions--not organizational units or narrow diagnostic treatment groups--as the fundamental unit of analysis for measuring costs and outcomes. The new approach, called time-driven activity-cased costing, is currently being implemented in pilots at the Head and Neck Center at MD Anderson, the Cleft Lip and Palate Program at Children's Hospital in Boston, and units performing knee replacements at Schön Klinik in Germany and Brigham & Women's Hospital in Boston. As providers and payors better understand costs, they will be positioned to achieve a true "bending of the cost curve" from within the system, not in response to top-down mandates. Accurate costing also unlocks a whole cascade of opportunities, such as process improvement, better organization of care, and new reimbursement approaches that will accelerate the pace of innovation and value creation.


Nonlinear scaling analysis of glucose metabolism in normal and cancer cells.
Cancer progression is commonly accompanied by an altered glucose metabolism. In general, spatially resolved imaging of glucose metabolism and its subtle alterations might provide valuable diagnostic information in vivo. A classical example is positron emission tomography that exploits this feature in obtaining preferential accumulation of fluorescent analog of glucose in tumors, thereby achieving an imaging contrast. We report a novel scaling analysis of glucose metabolism in mammary epithelial (NMuMG) cells by detrended fluctuation analysis of Cerulean (cyan fluorescent protein variant) fluorescence. Fluorescence fluctuations of Cerulean are reasoned to be indicative of dynamic pH changes associated with glucose metabolism. Normal parental cells and the spontaneously transformed (cancerous) NMuMG cells displayed robust scaling exponent that reflects nonrandom fluctuations in Cerulean fluorescence. Acute dependence of cancer cells on glycolysis as compared with normal cells is exploited to yield a statistically significant difference in scaling exponent, thereby providing discrimination between normal and cancer cells in vitro. By careful design of experiments in vivo, the proposed scaling approach might even have diagnostic potential for early detection of cancer lesions in small animal models.


Peginterferon and ribavirin for treatment of recurrent hepatitis C disease in HCV-HIV coinfected liver transplant recipients.
Achievement of a sustained virologic response (SVR) with antiviral therapy significantly improves graft survival in hepatitis C virus (HCV) monoinfected liver transplant (LT) patients. Risks and benefits of HCV therapy in HCV-human immunodeficiency virus (HIV) coinfected LT recipients are not well established. Among 89 HCV-HIV LT recipients in the HIVTR cohort, 39 (23% Black, 79% genotype 1, 83% fibrosis stage ≤ 1) were treated with peginterferon-a2a or a2b plus ribavirin for a median 363 days (14-1373). On intent-to-treat basis, 22% (95% CI: 10-39) and 14% (95% CI: 5-30) achieved an end-of-treatment response (EOTR) and SVR, respectively. By per-protocol analysis (completed 48 weeks of therapy ± dose reductions), 42% and 26% had EOTR and SVR, respectively. Severe adverse events occurred in 85%, with 26% hospitalized with infections and 13% developing acute rejection. Early discontinuations and dose reductions occurred in 38% and 82%, respectively, despite use of growth factors in 85%. Eighteen of 39 treated patients (46%) subsequently died/had graft loss, with 10 (26%) attributed to recurrent HCV. In conclusion, SVR rates are low and tolerability is poor in HCV-HIV coinfected transplant recipients treated with peginterferon and ribavirin. These results highlight the critical need for better tolerated and more efficacious HCV therapies for HCV-HIV coinfected transplant recipients.


STAT1, STAT6 and adenosine 3',5'-cyclic monophosphate (cAMP) signaling drive SOCS3 expression in inactive ulcerative colitis.
Ulcerative colitis (UC) is a chronic disease associated with long periods of quiescent disease followed by fulminant exacerbation. Imminent relapse in UC is associated with high mucosal expression of suppressor of cytokine signaling 3 (SOCS3); hence, knowledge of the mechanisms driving mucosal SOCS3 expression may provide important clues as to rational therapy. Thus, here we aim to characterize the molecular forces driving SOCS3 expression in the mucosal compartment, focusing on druggable pathways. The colon epithelial cell line Caco-2 was stimulated with interferon (IFN)-γ, interleukin (IL)-4 or prostaglandin E(2) (PGE(2)) to allow correlations between SOCS3 expression with signal transducer and activator of transcription 1 (STAT1), STAT6 and adenosine 3',5'-cyclic monophosphate (cAMP) signaling, respectively. The physiological relevance of the findings obtained was assessed by immunohistochemical staining for the activated forms of STAT1, STAT6, protein kinase A (PKA)-Cγ and cAMP response element-binding protein (CREB) in biopsies from inactive UC patients and controls. Stimulation with IFN-γ, IL-4 or PGE(2) induced activation of STAT1, STAT6 and cAMP, respectively, in colonic cells, without any signs of concomitant STAT3 activation. Forced activation of all these signaling pathways was sufficient for SOCS3 expression. Biopsies from patients with inactive UC showed significant increase of phosphorylated STAT1 (p-STAT1) (p < 0.0001), p-STAT6 (p = 0.0001), p-PKA-Cγ (p = 0.0003) and p-CREB (p = 0.0025) expression compared with controls. STAT3-independent SOCS3 induction in inactive UC involves multiple proinflammatory signaling pathways and contradicts the usefulness of pathway-specific antiinflammatory drugs for preventing relapse. Our findings suggest that broad-spectrum antiinflammatory drugs are essential to counteract increases in SOCS3 expression and exacerbation of disease. Our results highlight the multifactorial nature of the factors that cause exacerbation in UC.


Nanotechnology in dentistry today.
A review was done of nanotechnology as it applies to dentistry today. Information was gathered from literature search, research data and material inserts in products.Nanotechnology deals with the physical, chemical and biological properties of structures and their components at nanoscale dimensions. One of the biggest contributionS to restorative and aesthetic dentistry has been nanocomposites. These composites are characterized by filler-particle sizes ≤ 100 nm and offer aesthetic and strength advantages over the current microfilled and hybrid resin-based composites. Nanoparticles for coating implant surfaces and the nanopatterning of dental implants is leading to better osseointegration and improved physiologic functions of implants, while nanophase hydroxyapatite has improved its adaptation into bone graft sites. Nano-biochips are now making oral cancer screening and diagnosis of diseases by saliva easier and more affordable.


Should Hands Be Restricted When Measuring Able-Bodied Participants to Evaluate Machine Learning Controlled Prosthetic Hands?
When evaluating methods for machine-learning controlled prosthetic hands, able-bodied participants are often recruited, for practical reasons, instead of participants with upper limb absence (ULA). However, able-bodied participants have been shown to often perform myoelectric control tasks better than participants with ULA. It has been suggested that this performance difference can be reduced by restricting the wrist and hand movements of able-bodied participants. However, the effect of such restrictions on the consistency and separability of the electromyogram's (EMG) features remains unknown. The present work investigates whether the EMG separability and consistency between unaffected and affected arms differ and whether they change after restricting the unaffected limb in persons with ULA. Both arms of participants with unilateral ULA were compared in two conditions: with the unaffected hand and wrist restricted or not. Furthermore, it was tested if the effect of arm and restriction is influenced by arm posture (arm down, arm in front, or arm up). Fourteen participants (two women, age = 53.4±4.05) with acquired transradial limb loss were recruited. We found that the unaffected limb generated more separated EMG than the affected limb. Furthermore, restricting the unaffected hand and wrist lowered the separability of the EMG when the arm was held down. Limb restriction is a viable method to make the EMG of able-bodied participants more similar to that of participants with ULA. Future research that evaluates methods for machine learning controlled hands in able-bodied participants should restrict the participants' hand and wrist.


Immunization with LytB protein of Streptococcus pneumoniae activates complement-mediated phagocytosis and induces protection against pneumonia and sepsis.
The cell wall glucosaminidase LytB of Streptococcus pneumoniae is a surface exposed protein involved in daughter cell separation, biofilm formation and contributes to different aspects of the pathogenesis process. In this study we have characterized the antibody responses after immunization of mice with LytB in the presence of alhydrogel as an adjuvant. Enzyme-linked immunosorbent assays measuring different subclasses of immunoglobulin G, demonstrated that the antibody responses to LytB were predominantly IgG1 and IgG2b, followed by IgG3 and IgG2a subclasses. Complement-mediated immunity against two different pneumococcal serotypes was investigated using sera from immunized mice. Immunization with LytB increased the recognition of S. pneumoniae by complement components C1q and C3b demonstrating that anti-LytB antibodies trigger activation of the classical pathway. Phagocytosis assays showed that serum containing antibodies to LytB stimulates neutrophil-mediated phagocytosis against S. pneumoniae. Animal models of infection including invasive pneumonia and sepsis were performed with two different clinical isolates. Vaccination with LytB increased bacterial clearance and induced protection demonstrating that LytB might be a good candidate to be considered in a future protein-based vaccine against S. pneumoniae.


Political economy analysis of subnational health management in Kenya, Malawi and Uganda.
The need to bolster primary health care (PHC) to achieve the Sustainable Development Goal (SDG) targets for health is well recognized. In Eastern and Southern Africa, where governments have progressively decentralized health decision-making, health management is critical to PHC performance. While investments in health management capacity are important, so is improving the environment in which managers operate. Governance arrangements, management systems and power dynamics of actors can have a significant influence on health managers' ability to improve PHC access and quality. We conducted a problem-driven political economy analysis (PEA) in Kenya, Malawi and Uganda to explore local decision-making environments and how they affect management and governance practices for health. This PEA used document review and key informant interviews (N = 112) with government actors, development partners and civil societies in three districts or counties in each country (N = 9). We found that while decentralization should improve PHC by supporting better decisions in line with local priorities from community input, it has been accompanied by thick bureaucracy, path-dependent and underfunded budgets that result in trade-offs and unfulfilled plans, management support systems that are less aligned to local priorities, weak accountability between local government and development partners, uneven community engagement and insufficient public administration capacity to negotiate these challenges. Emergent findings suggest that coronavirus disease 2019 (COVID-19) not only resulted in greater pressures on health teams and budgets but also improved relations with central government related to better communication and flexible funding, offering some lessons. Without addressing the disconnection between the vision for decentralization and the reality of health managers mired in unhelpful processes and politics, delivering on PHC and universal health coverage goals and the SDG agenda will remain out of reach.


Comparison of the health-promoting lifestyles of nursing and non-nursing students in Istanbul, Turkey.
Undertaking a health-related course at university can facilitate an awareness of health-promoting lifestyles. We carried out a descriptive and cross-sectional study with 1616 university students in Istanbul, Turkey. Students from the nursing schools were compared to those from the schools of social sciences using a Turkish version of the Health-promoting Lifestyle Profile (HPLP) II after a validation study. The nursing students had more positive health-promoting lifestyles than those of the non-nursing students. Furthermore, fourth-year nursing students had higher scores in most of the subscales of the HPLP II than did the students from the lower years; conversely, the fourth-year non-nursing students had lower scores. The sociodemographic variables, self-perceived health status, relations with family and friends, and self-perceived academic performance were associated with the HPLP. The implications are discussed for the curricula and on-campus facilities that focus on health promotion activities.


Exogenous hCG activity, but not endogenous LH activity, is positively associated with live birth rates in anovulatory infertility.
To evaluate, retrospectively, the roles of endogenous and exogenous luteinising hormone (LH) activity on live birth rate in ovulation induction cycles. Associations between LH activity at baseline, end of stimulation and live birth rate were analysed in relation to patient characteristics, baseline and end of stimulation variables in WHO group II anovulatory women (n = 155) stimulated with recombinant follicle-stimulating hormone (rFSH) or highly purified human menopausal gonadotrophin (HP-hMG). HP-hMG provides FSH and exogenous LH activity mainly in the form of human chorionic gonadotrophin (hCG). Serum LH concentrations at baseline or end of stimulation were not predictive of live birth rate in the rFSH group (n = 79) or HP-hMG group (n = 76). Serum hCG concentration at end of stimulation was a significant positive predictor in HP-hMG-treated women. Other variables were not independently predictive of live birth in either of the groups, except for a negative association between serum FSH concentrations at the start of stimulation and live birth in the rFSH-treated group. Endogenous LH concentrations are not predictive of live birth in anovulatory WHO group II patients undergoing ovulation induction with rFSH or HP-hMG. On the other hand, exogenous hCG activity during HP-hMG stimulation is positively associated with treatment outcome.


The reef-building coral Siderastrea siderea exhibits parabolic responses to ocean acidification and warming.
Anthropogenic increases in atmospheric CO2 over this century are predicted to cause global average surface ocean pH to decline by 0.1-0.3 pH units and sea surface temperature to increase by 1-4°C. We conducted controlled laboratory experiments to investigate the impacts of CO2-induced ocean acidification (pCO2 = 324, 477, 604, 2553 µatm) and warming (25, 28, 32°C) on the calcification rate of the zooxanthellate scleractinian coral Siderastrea siderea, a widespread, abundant and keystone reef-builder in the Caribbean Sea. We show that both acidification and warming cause a parabolic response in the calcification rate within this coral species. Moderate increases in pCO2 and warming, relative to near-present-day values, enhanced coral calcification, with calcification rates declining under the highest pCO2 and thermal conditions. Equivalent responses to acidification and warming were exhibited by colonies across reef zones and the parabolic nature of the corals' response to these stressors was evident across all three of the experiment's 30-day observational intervals. Furthermore, the warming projected by the Intergovernmental Panel on Climate Change for the end of the twenty-first century caused a fivefold decrease in the rate of coral calcification, while the acidification projected for the same interval had no statistically significant impact on the calcification rate-suggesting that ocean warming poses a more immediate threat than acidification for this important coral species.


Contact allergic gastritis: an underdiagnosed entity?
Only a few cases of contact allergic gastritis in patients with nickel allergy have been reported. We report a case of probable contact-allergic gastritis in a 46-year-old woman. Clinical examination revealed lichenoid mucosal lesions of the gums adjacent to bridges and crowns that had been implanted several weeks back. Since implantation, the patient had suffered from gastrointestinal complaints (including stomach pain). Gastroscopy showed eosinophilic gastritis. Patch testing done under the diagnosis of contact allergic stomatitis showed positive reactions to: gold sodium thiosulphate; manganese (II) chloride; nickel (II) sulphate; palladium chloride; vanadium (III) chloride and zirconium (IV) chloride. The crowns and bridge contained gold, palladium and zirconium chloride, hence they were replaced by titan-based dentition. Shortly after replacing the artificial dentition, all gastrointestinal symptoms resolved spontaneously without further treatment. Delayed-type allergy against the components of artificial dentition seemed to be the cause of gastritis.


Moving time: the influence of action on duration perception.
Perceiving the sensory consequences of action accurately is essential for appropriate interaction with our physical and social environments. Prediction mechanisms are considered necessary for fine-tuned sensory control of action, yet paradoxically may distort perception. Here, we examine this paradox by addressing how movement influences the perceived duration of sensory outcomes congruent with action. Experiment 1 required participants to make judgments about the duration of vibrations applied to a moving or stationary finger. In Experiments 2 and 3, participants judged observed finger movements that were congruent or incongruent with their own actions. In all experiments, target events were perceived to be longer when congruent with movement. Interestingly, this temporal dilation did not differ as a function of stimulus perspective (1st or 3rd person) or spatial location. We propose that this bias may reflect the operation of an adaptive mechanism for sensorimotor selection and control that preactivates anticipated outcomes of action. The bias itself may have surprising implications for both action control and perception of others: we may be in contact with grasped objects for less time than we realize, and others' reactions to us may be briefer than we believe.


Adaptation of genetically monomorphic bacteria: evolution of copper resistance through multiple horizontal gene transfers of complex and versatile mobile genetic elements.
Copper-based antimicrobial compounds are widely used to control plant bacterial pathogens. Pathogens have adapted in response to this selective pressure. Xanthomonas citri pv. citri, a major citrus pathogen causing Asiatic citrus canker, was first reported to carry plasmid-encoded copper resistance in Argentina. This phenotype was conferred by the copLAB gene system. The emergence of resistant strains has since been reported in Réunion and Martinique. Using microsatellite-based genotyping and copLAB PCR, we demonstrated that the genetic structure of the copper-resistant strains from these three regions was made up of two distant clusters and varied for the detection of copLAB amplicons. In order to investigate this pattern more closely, we sequenced six copper-resistant X. citri pv. citri strains from Argentina, Martinique and Réunion, together with reference copper-resistant Xanthomonas and Stenotrophomonas strains using long-read sequencing technology. Genes involved in copper resistance were found to be strain dependent with the novel identification in X. citri pv. citri of copABCD and a cus heavy metal efflux resistance-nodulation-division system. The genes providing the adaptive trait were part of a mobile genetic element similar to Tn3-like transposons and included in a conjugative plasmid. This indicates the system's great versatility. The mining of all available bacterial genomes suggested that, within the bacterial community, the spread of copper resistance associated with mobile elements and their plasmid environments was primarily restricted to the Xanthomonadaceae family.


Relation of visceral adiposity to circulating natriuretic peptides in ambulatory individuals.
Natriuretic peptides have important roles in the regulation of vasomotor tone, salt homeostasis, and ventricular remodeling. Lower natriuretic peptide levels observed in obese individuals may underlie the greater cardiovascular risk associated with obesity. Thus the aim of this study was to determine whether lower natriuretic peptide levels in obesity are attributable to differences in regional fat distribution. We investigated the relation of plasma N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) to regional adiposity in 1,873 community-based individuals (46% women, mean age 45 years). Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were measured by multidetector computed tomography. In gender-specific multivariable analyses adjusting for age and blood pressure, log NT-pro-BNP was inversely associated with VAT in men (beta -0.11 per standard deviation increment, p <0.001) and women (beta -0.19, p <0.001). Log NT-pro-BNP was inversely associated with SAT in women only (beta -0.14, p <0.001). In models containing VAT and SAT, only VAT was significantly associated with log NT-pro-BNP (men, beta -0.137, p <0.001; women, beta -0.184, p <0.001). VAT remained associated with log NT-pro-BNP even after adjustment for body mass index and waist circumference (beta -0.119, p <0.001) and in analyses restricted to nonobese patients (beta -0.165, p <0.001). Adjustment for insulin resistance attenuated the associations of NT-pro-BNP with VAT and SAT. In conclusion, this study demonstrates that circulating NT-pro-BNP is related to variations in regional and particularly visceral adiposity. These findings suggest that excess visceral adiposity and concomitant hyperinsulinemia may contribute to the natriuretic peptide "deficiency" observed in obesity.


Ligand chain length conveys thermochromism.
Thermochromic properties of a series of non-ionic copper compounds have been reported. Herein, we demonstrate that Cu(II) ion with straight-chain primary amine (A) and alpha-linolenic (fatty acid, AL) co-jointly exhibit thermochromic properties. In the current case, we determined that thermochromism becomes ligand chain length-dependent and at least one of the ligands (A or AL) must be long chain. Thermochromism is attributed to a balanced competition between the fatty acids and amines for the copper(II) centre. The structure-property relationship of the non-ionic copper compounds Cu(AL)2(A)2 has been substantiated by various physical measurements along with detailed theoretical studies based on time-dependent density functional theory. It is presumed from our results that the compound would be a useful material for temperature-sensor applications.


Characterization of the Clostridium thermocellum AdhE, NfnAB, ferredoxin and Pfor proteins for their ability to support high titer ethanol production in Thermoanaerobacterium saccharolyticum.
The thermophilic anaerobes Thermoanaerobacterium saccharolyticum and Clostridium thermocellum are good candidates for lignocellulosic ethanol production. T. saccharolyticum has been successfully engineered to produce ethanol at high titer (70 g/L). The maximum ethanol titer of engineered strains of C. thermocellum is only 25 g/L. We hypothesize that one or more of the enzymes in the ethanol production pathway in C. thermocellum is not adequate for ethanol production at high titer. In this study, we focused on the enzymes responsible for the part of the ethanol production pathway from pyruvate to ethanol. In T. saccharolyticum, we replaced all of the genes encoding proteins in this pathway with their homologs from C. thermocellum and examined what combination of gene replacements restricted ethanol titer. We found that a pathway consisting of Ct_nfnAB, Ct_fd, Ct_adhE and Ts_pforA was sufficient to support ethanol titer greater than 50 g/L, however replacement of Ts_pforA by Ct_pfor1 dramatically decreased the maximum ethanol titer to 14 g/L. We then demonstrated that the reason for reduced ethanol production is that the Ct_pfor1 is inhibited by accumulation of ethanol and NADH, while Ts_pforA is not.


Intracellular delivery of antibodies by chimeric Sesbania mosaic virus (SeMV) virus like particles.
The therapeutic potential of antibodies has not been fully exploited as they fail to cross cell membrane. In this article, we have tested the possibility of using plant virus based nanoparticles for intracellular delivery of antibodies. For this purpose, Sesbania mosaic virus coat protein (CP) was genetically engineered with the B domain of Staphylococcus aureus protein A (SpA) at the βH-βI loop, to generate SeMV loop B (SLB), which self-assembled to virus like particles (VLPs) with 43 times higher affinity towards antibodies. CP and SLB could internalize into various types of mammalian cells and SLB could efficiently deliver three different monoclonal antibodies-D6F10 (targeting abrin), anti-α-tubulin (targeting intracellular tubulin) and Herclon (against HER2 receptor) inside the cells. Such a mode of delivery was much more effective than antibodies alone treatment. These results highlight the potential of SLB as a universal nanocarrier for intracellular delivery of antibodies.


Optimal placement of accelerometers for the detection of everyday activities.
This article describes an investigation to determine the optimal placement of accelerometers for the purpose of detecting a range of everyday activities. The paper investigates the effect of combining data from accelerometers placed at various bodily locations on the accuracy of activity detection. Eight healthy males participated within the study. Data were collected from six wireless tri-axial accelerometers placed at the chest, wrist, lower back, hip, thigh and foot. Activities included walking, running on a motorized treadmill, sitting, lying, standing and walking up and down stairs. The Support Vector Machine provided the most accurate detection of activities of all the machine learning algorithms investigated. Although data from all locations provided similar levels of accuracy, the hip was the best single location to record data for activity detection using a Support Vector Machine, providing small but significantly better accuracy than the other investigated locations. Increasing the number of sensing locations from one to two or more statistically increased the accuracy of classification. There was no significant difference in accuracy when using two or more sensors. It was noted, however, that the difference in activity detection using single or multiple accelerometers may be more pronounced when trying to detect finer grain activities. Future work shall therefore investigate the effects of accelerometer placement on a larger range of these activities.


Predictors of Outcome following Stroke due to Isolated M2 Occlusions.
Factors influencing outcome after cerebral artery occlusion are not completely understood. Although it is well accepted that the site of arterial occlusion critically influences outcome, the majority of studies investigating this issue has focused on proximal large artery occlusion. To gain a better understanding of factors influencing outcome after distal large artery occlusion, we sought to assess predictors of outcome following isolated M2 middle cerebral artery occlusion infarcts. We retrospectively analyzed patients with isolated acute M2 occlusion admitted to a single academic center from January 2010 to August 2012. Baseline clinical, laboratory imaging, and outcome data were assessed from a prospectively collected database. Factors associated with a modified Rankin Scale (mRS) score ≤2 in univariable analyses (p < 0.05) were entered into multivariable logistic regression analysis. The Admission National Institutes of Health Stroke Scale (aNIHSS) score, age, and infarct volume were also entered as dichotomized variables. Receiver operating characteristic curves were plotted to determine the optimal aNIHSS score, infarct volume, and age cut points predicting an mRS score ≤2. Optimal thresholds were determined by maximizing the Youden index. Respective multivariable logistic regression analyses were used to identify independent predictors of a good 90-day outcome (mRS score ≤2; primary analysis) as well as 90-day mortality (secondary outcome). 90 patients with isolated M2 occlusion were included in the final analyses. Of these, 69% had a good 90-day outcome which was associated with age <80 years (p = 0.007), aNIHSS <10 (p = 0.002), and infarct volume ≤26 ml (p < 0.001). Notably, 20% of patients (64% of those with a poor outcome) had died by 90 days. Secondary analysis for 90-day mortality was performed. This analysis indicated that infarct volume >28 ml (OR 11.874, 95% CI 2.630-53.604, p = 0.001), age >80 years (OR 4.953, 95% CI 1.087-22.563, p = 0.039), need for intubation (OR 7.788, 95% CI 1.072-56.604), and history of congestive heart failure (OR 5.819, 95% CI 1.140-29.695) were independent predictors of 90-day mortality (20% of all included patients). While the majority of patients with isolated M2 occlusion stroke has a good 90-day outcome, a substantial proportion of subjects dies by 90 days, as identified by a unique subset of predictors. The knowledge gained from our study may lead to an improvement in the prognostic accuracy, clinical management, and resource utilization in this patient population.


Mental health training for health workers in Africa: a systematic review.
Commitment to building mental health treatment capacity in Africa is increasing but little agreement exists on strategies to train health workers on mental health or evaluation of training efforts. We systematically reviewed published literature on interventions to train health-care workers in Africa on mental health. 37 studies met our inclusion criteria. Training outcomes focused on changes in knowledge and attitude, with few studies evaluating skill and practice and only two studies measuring clinical outcomes. Quality of study methodology was generally not high, with scarce follow-up data and use of control cohorts. Existing studies provide examples of many training and evaluation strategies, but evidence to draw conclusions about the efficacy of different training techniques is inadequate. Key knowledge gaps include development and testing of innovative educational strategies; development of standardised, competency-based learning objectives and outcome measures; and training that facilitates implementation of integrated mental health systems. African institutions need to be empowered to do research in these areas to encourage the development of best practices for the continent.


Drosophila Evolution over Space and Time (DEST): A New Population Genomics Resource.
Drosophila melanogaster is a leading model in population genetics and genomics, and a growing number of whole-genome data sets from natural populations of this species have been published over the last years. A major challenge is the integration of disparate data sets, often generated using different sequencing technologies and bioinformatic pipelines, which hampers our ability to address questions about the evolution of this species. Here we address these issues by developing a bioinformatics pipeline that maps pooled sequencing (Pool-Seq) reads from D. melanogaster to a hologenome consisting of fly and symbiont genomes and estimates allele frequencies using either a heuristic (PoolSNP) or a probabilistic variant caller (SNAPE-pooled). We use this pipeline to generate the largest data repository of genomic data available for D. melanogaster to date, encompassing 271 previously published and unpublished population samples from over 100 locations in >20 countries on four continents. Several of these locations have been sampled at different seasons across multiple years. This data set, which we call Drosophila Evolution over Space and Time (DEST), is coupled with sampling and environmental metadata. A web-based genome browser and web portal provide easy access to the SNP data set. We further provide guidelines on how to use Pool-Seq data for model-based demographic inference. Our aim is to provide this scalable platform as a community resource which can be easily extended via future efforts for an even more extensive cosmopolitan data set. Our resource will enable population geneticists to analyze spatiotemporal genetic patterns and evolutionary dynamics of D. melanogaster populations in unprecedented detail.


The Impact of the Long-term Care Homes Act and Public Reporting on Physical Restraint and Potentially Inappropriate Antipsychotic Use in Ontario's Long-term Care Homes.
We report on the impact of two system-level policy interventions (the Long-Term Care Homes Act [LTCHA] and Public Reporting) on publicly reported physical restraint use and non-publicly reported potentially inappropriate use of antipsychotics in Ontario, Canada. We used interrupted time series analysis to model changes in the risk-adjusted use of restraints and antipsychotics before and after implementation of the interventions. Separate analyses were completed for early ([a] volunteered 2010/2011) and late ([b] volunteered March 2012; [c] mandated September 2012) adopting groups of Public Reporting. Outcomes were measured using Resident Assessment Instrument Minimum Data Set (RAI-MDS) data from January 1, 2008 to December 31, 2014. For early adopters, enactment of the LTCHA in 2010 was not associated with changes in physical restraint use, while Public Reporting was associated with an increase in the rate (slope) of decline in physical restraint use. By contrast, for the late-adopters of Public Reporting, the LTCHA was associated with significant decreases in physical restraint use over time, but there was no significant increase in the rate of decline associated with Public Reporting. As the LTCHA was enacted, potentially inappropriate use of antipsychotics underwent a rapid short-term increase in the early volunteer group, but, over the longer term, their use decreased for all three groups of homes. Public Reporting had the largest impact on voluntary early adopters while legislation and regulations had a more substantive positive effect upon homes that delayed public reporting.


Application of diazene-directed fragment assembly to the total synthesis and stereochemical assignment of (+)-desmethyl-meso-chimonanthine and related heterodimeric alkaloids.
We describe the first application of our methodology for heterodimerization via diazene fragmentation towards the total synthesis of (-)-calycanthidine, meso-chimonanthine, and (+)-desmethyl-meso-chimonanthine. Our syntheses of these alkaloids feature an improved route to C3a-aminocyclotryptamines, an enhanced method for sulfamide synthesis and oxidation, in addition to a late-stage diversification leading to the first enantioselective total synthesis of (+)-desmethyl-meso-chimonanthine and its unambiguous stereochemical assignment. This versatile strategy for directed assembly of heterodimeric cyclotryptamine alkaloids has broad implications for the controlled synthesis of higher order derivatives with related substructures.


Proteomics analysis of the matrisome from MC38 experimental mouse liver metastases.
Dissemination of primary tumors to distant anatomical sites has a substantial negative impact on patient prognosis. The liver is a common site for metastases from colorectal cancer, and patients with hepatic metastases have generally much shorter survival, raising a need to develop and implement novel strategies for targeting metastatic disease. The extracellular matrix (ECM) is a meshwork of highly crosslinked, insoluble high-molecular-mass proteins maintaining tissue integrity and establishing cell-cell interactions. Emerging evidence identifies the importance of the ECM in cancer cell migration, invasion, intravasation, and metastasis. Here, we isolated the ECM from MC38 mouse liver metastases using our optimized method of mild detergent solubilization followed by biochemical enrichment. The matrices were subjected to label-free quantitative mass spectrometry analysis, revealing proteins highly abundant in the metastatic matrisome. The resulting list of proteins upregulated in the ECM significantly predicted survival in patients with colorectal cancer but not other cancers with strong involvement of the ECM component. One of the proteins upregulated in liver metastatic ECM, annexin A1, was not previously studied in the context of cancer-associated matrisome. Here, we show that annexin A1 was markedly upregulated in colon cancer cell lines compared with cancer cells of other origin and also over-represented in human primary colorectal lesions, as well as hepatic metastases, compared with their adjacent healthy tissue counterparts. In conclusion, our study provides a comprehensive ECM characterization of MC38 experimental liver metastases and proposes annexin A1 as a putative target for this disease.NEW & NOTEWORTHY Here, the authors provide an extensive proteomics characterization of murine colorectal cancer liver metastasis matrisome (the ensemble of all extracellular matrix molecules). The findings presented in this study may enable identification of therapeutic targets or biomarkers of hepatic metastases.


The Rhizobium etli metZ gene is essential for methionine biosynthesis and nodulation of Phaseolus vulgaris.
A mutant strain (CTNUX23) of Rhizobium etli carrying Tn5 unable to grow with sulfate as the sole sulfur source was isolated and characterized. Sequence analysis showed that Tn5 is inserted into a metZ (O-succinylhomoserine sulfhydrylase)-homologous gene. The CTNUX23 mutant strain had a growth dependency for methionine, although cystathionine or homocysteine, but not homoserine or O-succinylhomoserine, allowed growth of the mutant. RNase protection assays showed that the metZ-like gene had a basal level of expression in methionine- or cysteine-grown cells, which was induced when sulfate or thiosulfate was used. The metZ gene was cloned from the parent wild-type strain, CE3, and the resulting plasmid pAR204 relieved, after transformation, the methionine auxotrophy of both strains CTNUX23 of R. etli and PAO503(metZ) of Pseudomonas aeruginosa. Unlike strain CE3 or CTNUX23 (pAR204), strain CTNUX23 showed undetectable levels of O-succinylhomoserine sulfhydrylase activity. Strain CTNUX23 was unable to produce flavonoid-inducible lipo-chitin oligosaccharides (Nod factors) or to induce nodules or nodulelike structures on the roots of Phaseolus vulgaris, unless methionine was added to the growth medium. These data and our previous results support the notion that cysteine or glutathione, but not methionine, is supplied by the root cells to bacteria growing inside the plant.


Population prevalence, incidence, and predictors of atrial fibrillation in the Renfrew/Paisley study.
Though atrial fibrillation (AF) is an important cause of cardiovascular morbidity, there are few large epidemiological studies of its prevalence, incidence, and risk factors. The epidemiological features of AF are described in one of the largest population cohorts ever studied. The prevalence and incidence of AF were studied in the Renfrew/Paisley population cohort of 15 406 men and women aged 45-64 years living in the west of Scotland. This cohort was initially screened between 1972 and 1976 and again between 1977 and 1979. Incident hospitalisations with AF in the 20 year period following initial screening were also studied. The population prevalence of AF in this cohort was 6.5 cases/1000 examinations. Prevalence was higher in men and older subjects. In those who were rescreened, the four year incidence of AF was 0.54 cases/1000 person years. Radiological cardiomegaly was the most powerful predictor of new AF (adjusted odds ratio 14.0). During 20 year follow up, 3.5% of this cohort was discharged from hospital with a diagnosis of AF; the rate of incident hospitalisation for AF was 1.9 cases/1000 person years. Radiological cardiomegaly (adjusted odds ratio 1.46) and systolic blood pressure (adjusted odds ratio 2.1 for >/= 169 mm Hg) were independent predictors of this outcome. Data from one of the largest epidemiological studies ever undertaken confirm that AF has a large population prevalence and incidence, even in middle aged people. More important, it was shown that the long term incidence of hospitalisation related to AF is high and that two simple clinical measurements are highly predictive of incident AF. These findings have important implications for the prevention of AF.


Phenotypic and functional characterization of human T cell clones.
The capacity of human peripheral blood-derived T cell clones to carry out a variety of functions was examined. T cell clones were generated by stimulating individual peripheral blood T cells with PHA by a procedure that yielded a growing clone from a mean of greater than 92% of the cultured cells. A total of 65 T cell clones (44 CD4+ and 21 CD8+) generated from two individual donors were examined for their functional capabilities. All T cell clones examined secreted IL-2, IFN-gamma, and lymphotoxin/tumor necrosis factor like activity when stimulated with immobilized mAb to the CD3 complex (64.1). When 54 additional T cell clones from a third donor were analyzed, all were found to produce IL-2. Upon activation with immobilized 64.1, all CD4+ clones and 91% of the CD8+ clones induced the generation of Ig-secreting cells from purified B cells. The CD8+ clones that did not serve as Th cells alone were able to augment the capacity of fresh CD4+ cells to generate Ig-secreting cells. Each of these clones was also found to effect MHC-unrestricted cytotoxicity upon activation with immobilized 64.1. The CD8+ clones were somewhat more effective killers than CD4+ clones, although there was considerable overlap. A total of 18 clones was analyzed for TCR beta-chain gene rearrangement. Of the clones exhibiting rearrangements of the beta-chain gene, 94% were found to have a single rearrangement pattern. Finally, the detailed phenotype of 15 (11 CD4+ and 4 CD8+) of these clones was examined. Variable numbers of cells of each of the clones expressed Ag identified by mAb 4B4 (CD29), Leu 8, Leu 15 (CD11b), and NKH1. Moreover, cells of 6 of 11 CD4+ clones and 4 of 4 CD8+ clones also expressed CD45R in addition to CD29; expression of CD45R and CD29 varied with the activation status of the clone. The current data demonstrate that nearly all of the T cell clones were able to accomplish each of the functions examined regardless of the surface phenotype. Inasmuch as the clones were generated using a technique that expanded more than 92% of the circulating T cells, the data imply that the progeny of the vast majority of T cells may have the inherent capacity to exert a wide array of functional activities.


25-hydroxycholecalciferol: direct effect on calcium transport.
The perfused small intestine from a vitamin D deficient rat exhibits about one-half the calcium transport of the intestine from a rat given vitamin D. These levels of calcium transport can be maintained for at least 4 hours. Addition of 2.5 micrograms of 25-hydroxycholecalciferol added to the vitamin D deficient intestine via the arterial blood perfusate induces a rise in calcium transport to +D levels within 2 hours. In contrast, 250 micrograms of vitamin D(3) given in the same manner has no effect on the calcium transport level overa 4-hour period. These data provide strong evidence that 25-hydroxycholecalci ferol represents the metabolically active form of vitamin D(3).


Longitudinal imaging in biological tissues with a single laser shot correlation system.
We demonstrate the potential of a new optical imaging system to directly obtain a longitudinal slice of a biological sample. The system, based on a single-shot optical correlator, operates a time-to-space conversion and an optical time-gating by sum-frequency generation in a nonlinear crystal. Owing to the high speed acquisition of the technique, internal structures of in-vivo tissues can be imaged at video rate.With this apparatus, we recorded longitudinal images of ex vivo mouse ear and in vivo human skin with a depth resolution of approximately 15 microm.


Isolation of a mycoplasma-specific binding peptide from an unbiased phage-displayed peptide library.
An important goal in medicine is the development of methods for cell-specific targeting of therapeutic molecules to pathogens or pathogen-infected cells. However, little progress has been made in cell-specific targeting of bacterially infected cells. Using a phage display approach, we have isolated a 20-mer peptide that binds to Mycoplasma arginini infected pancreatic beta-cells in tissue culture. This peptide binds to M. arginini infected beta-cells 200 times better than a control phage and is specific for the infected cells. Furthermore, transferring the M. arginini contamination to another cell line renders the newly infected cell line susceptible to peptide binding. Immunolocalization experiments suggest that the peptide is binding to M. arginini adhered to the cell surface. The free synthetic peptide retains its binding in the absence of the phage vehicle and tetramerization of the peptide increases its affinity for the infected cells. Efforts have been made to use this peptide to eliminate Mycoplasma from infected cell lines using ferromagnetic beads coated with the selected peptide. A ten-fold reduction of infection was accomplished with one fractionation via this approach. Our results suggest that this peptide, isolated from an unbiased selection, may be of utility for the detection and reduction of Mycoplasma infection in cultured cells. Furthermore, a general implication of our findings is that phage display methods may be useful for identifying peptides that target a broad array of other biological pathogens in a specific fashion.


Complete genome sequence of Lactobacillus plantarum LZ227, a potential probiotic strain producing B-group vitamins.
B-group vitamins play an important role in human metabolism, whose deficiencies are associated with a variety of disorders and diseases. Certain microorganisms such as Lactic acid bacteria (LAB) have been shown to have capacities for B-group vitamin production and thus could potentially replace chemically synthesized vitamins for food fortification. A potential probiotic strain named Lactobacillus plantarum LZ227, which was isolated from raw cow milk in this study, exhibits the ability to produce B-group vitamins. Complete genome sequencing of LZ227 was performed to gain insights into the genetic elements involved in B-group vitamin production. The genome of LZ227 contains a circular 3,131,750-bp chromosome, three circular plasmids and two predicted linear plasmids. LZ227 also contains gene clusters for biosynthesis of both riboflavin and folate. This genome sequence provides a basis for further elucidation of its molecular genetics and probiotic functions, and will facilitate its applications as starter cultures in food industry.


Interleukin 6 polymorphism corresponds to the number of severely stenosed coronary arteries.
IL6 gene promoter polymorphisms may influence the outcome of cardiovascular diseases. The aim of our study was to find out whether the -174G>C polymorphism, as well as the IL6 secretory profile, may be linked to the number of severely (> or = 75%) occluded coronary arteries in patients with advanced coronary heart disease (CHD). Three hundred and twenty patients awaiting elective coronary artery bypass grafting were enrolled into the study. Blood was taken the day before surgery. The PCR-RFLP method was used for IL6 gene polymorphism analysis. Spontaneous IL6 release was measured by bioassay in supernatants of whole blood cell cultures (WBCC) incubated for 24 h and 48 h. We found that significantly more patients with triple vessel disease were found within the -174GG group as compared to the -174GC and CC genotype carriers. The highest IL6 serum levels were found in the -174GG and the lowest in the -174CC genotype patients. Spontaneous in vitro IL6 secretion appeared to be significantly higher at all time points in the -174GG as compared to the CC and GC genotype carriers. The serum concentration of IL6 and the spontaneous IL6 secretion were directly related to the number of obstructed coronary vessels. Our results emphasize the role of IL6 as an important, non-classical risk factor predicting the number of severely affected coronary vessels.


The neural dynamics of somatosensory processing and adaptation across childhood: a high-density electrical mapping study.
Young children are often hyperreactive to somatosensory inputs hardly noticed by adults, as exemplified by irritation to seams or labels in clothing. The neurodevelopmental mechanisms underlying changes in sensory reactivity are not well understood. Based on the idea that neurodevelopmental changes in somatosensory processing and/or changes in sensory adaptation might underlie developmental differences in somatosensory reactivity, high-density electroencephalography was used to examine how the nervous system responds and adapts to repeated vibrotactile stimulation over childhood. Participants aged 6-18 yr old were presented with 50-ms vibrotactile stimuli to the right wrist over the median nerve at 5 blocked interstimulus intervals (ranging from ∼7 to ∼1 stimulus per second). Somatosensory evoked potentials (SEPs) revealed three major phases of activation within the first 200 ms, with scalp topographies suggestive of neural generators in contralateral somatosensory cortex. Although overall SEPs were highly similar for younger, middle, and older age groups (6.1-9.8, 10.0-12.9, and 13.0-17.8 yr old), there were significant age-related amplitude differences in initial and later phases of the SEP. In contrast, robust adaptation effects for fast vs. slow presentation rates were observed that did not differ as a function of age. A greater amplitude response in the later portion of the SEP was observed for the youngest group and may be related to developmental changes in responsivity to somatosensory stimuli. These data suggest the protracted development of the somatosensory system over childhood, whereas adaptation, as assayed in this study, is largely in place by ∼7 yr of age.


Ribosome profiling reveals dynamic translational landscape in maize seedlings under drought stress.
Plants can respond to environmental changes with various mechanisms occurred at transcriptional and translational levels. Thus far, there have been relatively extensive understandings of stress responses of plants on transcriptional level, while little information is known about that on translational level. To uncover the landscape of translation in plants in response to drought stress, we performed the recently developed ribosome profiling assay with maize seedlings growing under normal and drought conditions. Comparative analysis of the ribosome profiling data and the RNA-seq data showed that the fold changes of gene expression at transcriptional level were moderately correlated with that of translational level globally (R(2) = 0.69). However, less than half of the responsive genes were shared by transcription and translation under drought condition, suggesting that drought stress can introduce transcriptional and translational responses independently. We found that the translational efficiencies of 931 genes were changed significantly in response to drought stress. Further analysis revealed that the translational efficiencies of genes were highly influenced by their sequence features including GC content, length of coding sequences and normalized minimal free energy. In addition, we detected potential translation of 3063 upstream open reading frames (uORFs) on 2558 genes and these uORFs may affect the translational efficiency of downstream main open reading frames (ORFs). Our study indicates that plant can respond to drought stress with highly dynamic translational mechanism, that acting synergistically with that of transcription.


Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides.
Increasing evidence suggests that cortical astrocytic function is disrupted in mood disorders and suicide. The fine neuroanatomy of astrocytes, however, remains to be investigated in these psychiatric conditions. In this study, we performed a detailed morphometric analysis of 3D-reconstructed gray and white matter astrocytes in Golgi-impregnated anterior cingulate cortex (ACC) samples from depressed suicides and matched controls. Postmortem ACC samples (BA24) from 10 well-characterized depressed suicides and 10 matched sudden-death controls were obtained from the Quebec Suicide Brain Bank. Golgi-impregnated protoplasmic astrocytes (gray matter, layer VI) and fibrous astrocytes (adjacent white matter) were reconstructed, and their morphometric features were analyzed using the Neurolucida software. For each cell, the soma size as well as the number, length, and branching of processes were determined. The densities of thorny protrusions found along the processes of both astrocytic subtypes were also determined. Protoplasmic astrocytes showed no significant difference between groups for any of the quantified parameters. However, fibrous astrocytes had significantly larger cell bodies, as well as longer, more ramified processes in depressed suicides, with values for these parameters being about twice as high as those measured in controls. These results provide the first evidence of altered cortical astrocytic morphology in mood disorders. The presence of hypertrophic astrocytes in BA24 white matter is consistent with reports suggesting white matter alterations in depression, and provides further support to the neuroinflammatory theory of depression.


Early induction of hypothermia for evacuated intracranial hematomas: a post hoc analysis of two clinical trials.
The authors hypothesized that cooling before evacuation of traumatic intracranial hematomas protects the brain from reperfusion injury and, if so, further hypothesized that hypothermia induction before or soon after craniotomy should be associated with improved outcomes. The National Acute Brain Injury Study: Hypothermia I (NABIS:H I) was a randomized multicenter clinical trial of 392 patients with severe brain injury treated using normothermia or hypothermia for 48 hours with patients reaching 33°C at 8.4 ± 3 hours after injury. The National Acute Brain Injury Study: Hypothermia II (NABIS:H II) was a randomized, multicenter clinical trial of 97 patients with severe brain injury treated with normothermia or hypothermia for 48 hours with patients reaching 35°C within 2.6 ± 1.2 hours and 33°C within 4.4 ± 1.5 hours of injury. Entry and exclusion criteria, management, and outcome measures in the 2 trials were similar. In NABIS:H II among the patients with evacuated intracranial hematomas, outcome was poor (severe disability, vegetative state, or death) in 5 of 15 patients in the hypothermia group and in 9 of 13 patients in the normothermia group (relative risk 0.44, 95% CI 0.22-0.88; p = 0.02). All patients randomized to hypothermia reached 35°C within 1.5 hours after surgery start and 33°C within 5.55 hours. Applying these criteria to NABIS:H I, 31 of 54 hypothermia-treated patients reached a temperature of 35°C or lower within 1.5 hours after surgery start time, and the remaining 23 patients reached 35°C at later time points. Outcome was poor in 14 (45%) of 31 patients reaching 35°C within 1.5 hours of surgery, in 14 (61%) of 23 patients reaching 35°C more than 1.5 hours of surgery, and in 35 (60%) of 58 patients in the normothermia group (relative risk 0.74, 95%, CI 0.49-1.13; p = 0.16). A meta-analysis of 46 patients with hematomas in both trials who reached 35°C within 1.5 hours of surgery start showed a significantly reduced rate of poor outcomes (41%) compared with 94 patients treated with hypothermia who did not reach 35°C within that time and patients treated at normothermia (62%, p = 0.009). Induction of hypothermia to 35°C before or soon after craniotomy with maintenance at 33°C for 48 hours thereafter may improve outcome of patients with hematomas and severe traumatic brain injury. Clinical trial registration no.: NCT00178711.


Shortage of full-time faculty in dermatology.
A persistent shortage of full-time faculty exists in dermatology. Despite the addition of 124 new full-time faculty since 1971 through 1972, 136 training programs in 1974 through 1975 were actively seeking 88 new full-time faculty and believed they needed 243. With a net gain of 30 new faculty a year, it will take 2.93 years to add 88 new faculty that are being actively sought and 5.16 years to add 155 more that are urgently needed. During this eight years, demand for new faculty will increase, so that figures of need may remain essentially unchanged in 1982 through 1983 and between 1971 through 1972 and 1974 through 1975. Expertise that was most needed was in immunology, electron microscopy, histopathology, microbiology, and biochemistry; many accept faculty in any area or with no special training. Measures should be taken to attract and retain more dermatologists in full-time academic positions.