Delivery by caesarean section and childhood cancer: a nationwide follow-up study in three countries.
To investigate the association between delivery by caesarean section and risk of childhood cancer. A population-based, follow-up study using register data from three countries. Denmark, Sweden and Finland. Children born in Denmark (1973-2007), Sweden (1973-2006) and Finland (randomly selected sample of 90%, 1987-2007; n = 7,029,843). Exposure was delivery by caesarean section and the outcome was childhood cancer diagnosis. Follow-up started from birth and ended at the first of the following dates: cancer diagnosis, death, emigration, day before 15th birthday or end of follow-up. Cox regression was used to obtain hazard ratios. Childhood cancer diagnosis. A total of 882,907 (12.6%) children were delivered by caesarean section. Of these, 30.3% were elective (n = 267,603), 35.9% unplanned (n = 316,536) and 33.8% had no information on planning (n = 298,768). Altogether, 11,181 children received a cancer diagnosis. No evidence of an increased risk of childhood cancer was found for children born by caesarean section (hazard ratio, 1.05; 95% confidence interval, 0.99, 1.11). No association was found for any major type of childhood cancer, or when split by the type of caesarean section (elective/unplanned). The evidence does not suggest that caesarean section is a risk factor for the overall risk of childhood cancer and possibly not for subtypes of childhood cancer either.


Sequence-dependent solution structure and motions of 13 TATA/TBP (TATA-box binding protein) complexes.
The TATA element is a well-known example of a DNA promoter sequence recognized by the TATA box binding protein (TBP) through its intrinsic motion and deformability. Although TBP recognizes the TATA element octamer unusually (through the minor groove, which lacks the distinctive features of the major groove), single base-pair replacements alter transcriptional activity. Recent crystallographic experiments have suggested that TATA/TBP complexes differing by a single base pair retain substantial structural similarity despite their functional differences in activating transcription. To investigate the subtle role of sequence-dependent motion within the TATA element and certain aspects of its effect on assembly of the transcriptional complex, we examine 5-ns dynamics trajectories of 13 variant TATA/TBP complexes differing from each other by a single base pair. They include the wild-type (WT) adenovirus 2 major late promoter (AdMLP) TATA element, TATAAAAG (the octamer specifies positions -31 to -24 with respect to the transcription initiation site), and the variants A31 (i.e., AATAAAAG), T30, A29, C29, G28, T28, T27, G26, T26, C25, T25, and T24. Our simulated TATA/TBP complexes develop sequence-dependent structure and motion trends that may lead to favorable orientations for high-activity variants (with respect to binding TFIIA, TFIIB, and other transcription factors), while conversely, accelerate dissociation of low-activity TATA/TBP complexes. The motions that promote favorable geometries for preinitiation complexes include small rotations between TBP's N- and C-terminal domains, sense strand DNA backbone "slithering," and rotations in TBP's H2 and H2' helices. Low-activity variants tend to translate the H1 and H1' helices and withdraw the intercalating phenylalanines. These cumulative DNA and protein motions lead to a spatial spread of complex orientations up to 4 A; this is associated with an overall bend of the variant TATA/TBP complexes that spans 93 degrees to 110 degrees (107 degrees for the crystal reference). Taken together, our analyses imply larger differences when these local structural and bending changes are extended to longer DNA (upstream and downstream) and suggest that specific local TATA/TBP motions (e.g., shifts in TBP helices and TATA bases and backbone) play a role in modulating the formation and maintenance of the transcription initiation complex.


Mycobacterial infection in farmed turbot Scophthalmus maximus.
Mycobacteriosis (piscine tuberculosis) has been reported to affect a wide range of freshwater and marine fish species; however, this is the first report describing mycobacterial infections in turbot Scophthalmus maximus. High numbers of granulomas were initially observed in the organs of moribund farmed turbot. Bacteriological analysis of organs with granulomas led to the isolation of Mycobacterium marinum. Further analysis, to determine the prevalence of the infection in the farm and to identify its source, showed the occurrence of a dual infection by M. marinum and M. chelonae. The presence of Nocardia sp. in some of the fish infected with mycobacteria was also detected. The presence of granulomas in internal organs of apparently healthy fish indicated a high prevalence of the disease, a conclusion that was supported by isolating mycobacteria from all fish with or without granulomas. The infection was probably responsible for the mortality observed (approximately 2% mo(-1)), as most of the recently dead fish presented high numbers of granulomas and isolation of mycobacteria was possible from all of the fish. The isolation of M. marinum from the inlet water suggested this as the most plausible source for the infection occurring in the farm.


Miscarriage risk for IVF pregnancies in poor responders to ovarian hyperstimulation.
The increasing miscarriage rate with advancing female age is attributed to a decline in oocyte quality. A poor response to ovarian hyperstimulation is often an expression of a decrease in oocyte quantity. Although oocyte quality and quantity both decrease as a result of ovarian ageing, it is unclear whether these two processes are related to each other. To investigate the relationship between oocyte quantity and quality, we compared miscarriage rates between IVF treated women with a poor and normal response, respectively. Data were studied from a retrospective nationwide cohort of Dutch women undergoing IVF treatment from 1983 to 1995. Women achieving an ongoing pregnancy after their first complete IVF cycle (n=1468) were compared with those experiencing miscarriage (n=357) with respect to their ovarian response. Logistic regression analysis showed a statistically significant association between poor response (fewer than four retrieved oocytes) and miscarriage (P=0.001). Due to interaction, this association became stronger with increasing female age. Among women < 36 years, miscarriage rates between poor and normal responders did not differ, whereas among women 36 years poor responders had a statistically significant increased miscarriage rate compared with normal responders (P=0.001). These results support the hypothesis of a relationship between quantitative ovarian reserve and oocyte quality.


Human milk glycobiome and its impact on the infant gastrointestinal microbiota.
Human milk contains an unexpected abundance and diversity of complex oligosaccharides apparently indigestible by the developing infant and instead targeted to its cognate gastrointestinal microbiota. Recent advances in mass spectrometry-based tools have provided a view of the oligosaccharide structures produced in milk across stages of lactation and among human mothers. One postulated function for these oligosaccharides is to enrich a specific "healthy" microbiota containing bifidobacteria, a genus commonly observed in the feces of breast-fed infants. Isolated culture studies indeed show selective growth of infant-borne bifidobacteria on milk oligosaccharides or core components therein. Parallel glycoprofiling documented that numerous Bifidobacterium longum subsp. infantis strains preferentially consume small mass oligosaccharides that are abundant early in the lactation cycle. Genome sequencing of numerous B. longum subsp. infantis strains shows a bias toward genes required to use mammalian-derived carbohydrates by comparison with adult-borne bifidobacteria. This intriguing strategy of mammalian lactation to selectively nourish genetically compatible bacteria in infants with a complex array of free oligosaccharides serves as a model of how to influence the human supraorganismal system, which includes the gastrointestinal microbiota.


Biodistribution of monoclonal antibodies: scale-up from mouse to human using a physiologically based pharmacokinetic model.
The efficacy of a novel diagnostic or therapeutic agent depends on its selective localization in a target tissue. Biodistribution studies are expensive and difficult to carry out in humans, but such data can be obtained easily in rodents. We have developed a physiologically based pharmacokinetic model for scaling up data from mice to humans, the first such model for genetically engineered macromolecules that bind to their targets in vivo, such as mAbs. The mathematical model uses physiological parameters including organ volumes, blood flow rates, and vascular permeabilities; the compartments (organs) are connected anatomically. This allows the use of scale-up techniques to predict antibody distribution in humans. The model was tested with data obtained in human patients for the biodistribution of a mAb against carcinoembryonic antigen. The model was further tested for a two-step protocol: bifunctional antibodies and radiolabeled hapten, which compared favorably with data in both mice and humans. The model was useful for optimization of treatment parameters, such as dose and time interval of injections, binding affinities, and choice of molecular carrier. This framework may be applicable to other genetically engineered molecules (e.g., growth factors, antisense oligonucleotides, and gene-carrying vectors).


The structure and function of HFE.
The iron overload disease hereditary haemochromatosis (HH) occurs in about 1 in 300 Caucasians; the protein mutated in this disorder is termed HFE.(1) HFE is homologous to major histocompatibility complex (MHC) class I proteins, but unlike MHC class I molecules, HFE does not present peptides to T cells.(2) The transferrin receptor (TfR) is a ligand for HFE, and the crystal structure of the HFE-TfR complex has been determined.(3) The many interesting features of this structure illustrate the diverse roles of the MHC fold in nature and clarify how HFE affects TfR function. Whether the interaction between HFE and TfR explains the pathogenesis of HH is not so clear.


Infectious haematopoietic necrosis epidemic (2001 to 2003) in farmed Atlantic salmon Salmo salar in British Columbia.
I investigated a recent infectious haematopoietic necrosis disease (IHN) epidemic in farmed Atlantic salmon Salmo salar in British Columbia (BC), Canada. All companies with infected farms (n = 36) participated in the study. Over 12 million Atlantic salmon on infected farms died or were culled during the epidemic with cumulative mortality on the farms averaging 58%. The first reported case of IHN occurred in August 2001 and the last outbreak in June 2003. Outbreaks on the farms lasted between 20 and 22 wk. Genetic sequencing by other researchers, revealed that 2 different IHN isolates contributed to this epidemic, one linked to all cases in 4 areas, the other associated with all cases in a fifth area. Spatial and temporal patterns of the farm outbreaks were examined to determine possible methods of spread between the farms. Evidence presented herein appears to show that farming practices themselves contributed significantly to the spread between farms both within and between areas. Natural waterborne transmission may have played a role in the spread of the virus between farms located in close proximity to each other. The data collected from this epidemic are compared with reports which examined the first reported epidemic in Atlantic salmon in BC (1992 to 1996). Evidence is presented for the hypothesis that wild fish species may have been the source of introduction of the virus into the farmed Atlantic salmon population.


Patient aggression in psychiatric services: the experience of a sample of nurses at two psychiatric facilities in Nigeria.
Aggression is a common feature in psychiatric in-patient units in Africa. The attitudes of psychiatric nurses and their perceptions of the frequency of in-patient aggression have not been explored in the Nigerian context. Using a crosssectional study design, two self-report questionnaires (the Attitudes toward Aggression Scale (ATAS) and the Perception of the Prevalence of Aggression Scale (POPAS)) were administered to nursing staff (n=73) at two psychiatric facilities in Benin City, Nigeria. Overall, nurses viewed aggression as offensive, destructive and intrusive. They were less likely to view it as a means of communication or serving protective functions. Verbal aggression was the commonest type of aggression experienced while sexual intimidation and suicide attempts were least common. Male nurses were more likely to experience physical violence and aggressive 'splitting' behaviours, while nurses with over a decade of professional experience were more likely to experience verbal and humiliating aggressive behaviours. In contrast to previous studies, fewer nurses required days off work due to aggressive behaviour. Aggression is commonly experienced by nurses in in-patient units in Nigeria. Their views were predominantly negative. Training programmes are required to change staff attitudes as well as research on the cultural factors mediating these attitude dispositions.


Understanding Real-Time Fluorescence Signals from Bacteria and Wound Tissues Observed with the MolecuLight i:XTM.
The persistent presence of pathogenic bacteria is one of the main obstacles to wound healing. Detection of wound bacteria relies on sampling methods, which delay confirmation by several days. However, a novel handheld fluorescence imaging device has recently enabled real-time detection of bacteria in wounds based on their intrinsic fluorescence characteristics, which differ from those of background tissues. This device illuminates the wound with violet (405 nm) light, causing tissues and bacteria to produce endogenous, characteristic fluorescence signals that are filtered and displayed on the device screen in real-time. The resulting images allow for rapid assessment and documentation of the presence, location, and extent of fluorescent bacteria at moderate-to-heavy loads. This information has been shown to assist in wound assessment and guide patient-specific treatment plans. However, proper image interpretation is essential to assessing this information. To properly identify regions of bacterial fluorescence, users must understand: (1) Fluorescence signals from tissues (e.g., wound tissues, tendon, bone) and fluids (e.g., blood, pus); (2) fluorescence signals from bacteria (red or cyan); (3) the rationale for varying hues of both tissue and bacterial fluorescence; (4) image artifacts that can occur; and (5) some potentially confounding signals from non-biological materials (e.g., fluorescent cleansing solutions). Therefore, this tutorial provides clinicians with a rationale for identifying common wound fluorescence characteristics. Clinical examples are intended to help clinicians with image interpretation-with a focus on image artifacts and potential confounders of image interpretation-and suggestions of how to overcome such challenges when imaging wounds in clinical practice.


LIME, a novel transmembrane adaptor protein, associates with p56lck and mediates T cell activation.
In this study, we identify and characterize a novel transmembrane adaptor protein, designated Lck-interacting membrane protein (LIME), as a binding partner of the Lck Src homology (SH)2 domain. LIME possesses a short extracellular domain, a transmembrane domain, and a cytoplasmic tail containing five tyrosine-based motifs. The protein is primarily expressed in hematopoietic cells and lung. Interestingly, LIME expression is up-regulated by TCR stimulation and sustained up to 24 h, suggesting that LIME acts throughout the early to late stages of T cell activation. LIME is localized to membrane rafts and distributed within the T cell-APC contact site. Upon TCR stimulation of Jurkat T cells, LIME associates with Lck as a tyrosine-phosphorylated protein. Experiments using Jurkat T cells expressing CD8-LIME chimera reveal that the protein associates with phosphatidylinositol 3-kinase, Grb2, Gads, and SHP2, and activates ERK1/2 and JNK but not p38. Moreover, overexpression of LIME in Jurkat T cells induces transcriptional activation of the IL-2 promoter. Our data collectively show that LIME is a raft-associated transmembrane adaptor protein linking TCR stimuli to downstream signaling pathways via associations with Lck.


Nodal signaling regulates specification of ascidian peripheral neurons through control of the BMP signal.
The neural crest and neurogenic placodes are thought to be a vertebrate innovation that gives rise to much of the peripheral nervous system (PNS). Despite their importance for understanding chordate evolution and vertebrate origins, little is known about the evolutionary origin of these structures. Here, we investigated the mechanisms underlying the development of ascidian trunk epidermal sensory neurons (ESNs), which are thought to function as mechanosensory neurons in the rostral-dorsal trunk epidermis. We found that trunk ESNs are derived from the anterior and lateral neural plate border, as is the case in the vertebrate PNS. Pharmacological experiments indicated that intermediate levels of bone morphogenetic protein (BMP) signal induce formation of ESNs from anterior ectodermal cells. Gene knockdown experiments demonstrated that HrBMPa (60A-subclass BMP) and HrBMPb (dpp-subclass BMP) act to induce trunk ESNs at the tailbud stage and that anterior trunk ESN specification requires Chordin-mediated antagonism of the BMP signal, but posterior trunk ESN specification does not. We also found that Nodal functions as a neural plate border inducer in ascidians. Nodal signaling regulates expression of HrBMPs and HrChordin in the lateral neural plate, and consequently specifies trunk ESNs. Collectively, these findings show that BMP signaling that is regulated spatiotemporally by Nodal signaling is required for trunk ESN specification, which clearly differs from the BMP gradient model proposed for vertebrate neural induction.


The power peripherally inserted central catheter is superior to a central venous catheter in management of patients with esophageal variceal bleeding undergoing devascularization.
Peripherally-inserted central catheters (PICC) have a greater retention time and less complications compared to central venous catheters (CVC). The study was conducted from From January of 2014 to December 2015 at Beijing DiTan Hospital, Beijing, China, and comprised 70 patients undergoing devascularisation. Of the total, 36(51.4%) patients underwent placement of PICC (Group A), while 34(48.6%) underwent had CVC (Group B). Venous catheterisation was successful in all patients. The median duration of venous catheterization in Group A was greater than that in Group B (p=0.002). Catheter-associated complications did not differ between the groups (p=0.46). The level of blood platelet (PLT) count, Prothrombin activity (PTA) and white blood cell (WBC) count before venous catheterisation were independent risk factors for bleeding at the puncture site and catheter-related infections. A Power PICC may be a better choice than a CVC in patients undergoing devascularisation requiring catheterisation. For patients with a lower PLT count, a decreased PTA, or a decreased WBC, venous catheterisation should be performed with caution.


"Inflammatory Bowel Disease-Not Just the Bowel's Bane": Peripheral Arterial and Venous Thrombosis in a Patient With Crohn Disease.
Inflammatory bowel disease (IBD) is a chronic multisystem inflammatory condition with associated endothelial dysfunction and dysregulated coagulation. Although deep venous thrombosis (DVT) in IBD has been well described, arterial thrombosis and thromboembolism are less commonly appreciated. A 63-year-old male with a known history of Crohn disease presented with acute-onset right arm pain. His past vascular history was significant for left lower extremity DVT with an existing inferior vena cava filter and acute ischemia of the right lower extremity requiring a below-knee amputation a year ago. Imaging revealed acute brachial, ulnar, and radial artery thrombosis. Patient underwent an open right brachial, radial, and ulnar thrombectomy to restore vascular flow. He required multiple exploration and thrombectomy for reocclusion of the vessels in the early postoperative period. He later developed a rapidly deteriorating clinical status, flank ecchymosis and swelling concerning for soft tissue ischemia, and compartment syndrome heralding an eventual hemodynamic collapse. On exploration, he was found to have chronic fibrosis of his left femoral vein and femoral artery occlusion. Clinically, the patient deteriorated rapidly, which resulted in his demise. The inflammatory reaction in IBD leads to arterial stiffening and hypercoagulability, which should theoretically increase the risk for vascular disease. Although the link between IBD and DVT is well established, arterial thrombosis and thromboembolism remain widely debated, with some implications for therapeutic intervention. The link between vascular thrombosis and IBD must be examined further, as the treatment and prevention of vascular complications in IBD depends on our understanding of this relationship.


The optimal time of B-type natriuretic peptide sampling associated with post-myocardial infarction remodelling after primary percutaneous coronary intervention.
To find the optimal time to evaluate plasma B-type natriuretic peptide (BNP), which is related to post-myocardial infarction remodelling (PMIR), we measured serial plasma BNP levels according to time protocols after primary percutaneous coronary intervention (PCI). It has been established that plasma BNP levels can predict the development of PMIR in patients with ST-elevation myocardial infarction (STEMI). However, the time of plasma BNP sampling associated with PMIR is still controversial. We analysed 42 patients who were diagnosed as PMIR on six-month follow-up echocardiography among 131 patients with STEMI. We then compared clinical variables including plasma BNP between the remodelling group and the non-remodelling group. The plasma BNP level was obtained on hospital admission (acute phase), at two to five days (early phase), three to four weeks (late phase) and at the six-month follow up (long term). Early-phase and long-term BNP levels were higher in the remodelling group. The serial plasma BNP levels, according to study protocols, showed a biphasic pattern of elevation. In multiple logistic regression analyses, early-phase BNP [odds ratio (OR): 1.013, p < 0.01] and acute-phase BNP levels (OR: 1.007, p = 0.02) were independent predictors of PMIR. However, early-phase BNP level was statistically a more powerful predictor of PMIR during follow up. Consecutive BNP levels after primary PCI showed a biphasic peak elevation during follow up. Early-phase plasma BNP level was an independent predictor of PMIR in patients with STEMI.


Face proprioception does not modulate access to visual awareness of emotional faces in a continuous flash suppression paradigm.
An important question in neuroscience is which multisensory information, presented outside of awareness, can influence the nature and speed of conscious access to our percepts. Recently, proprioceptive feedback of the hand was reported to lead to faster awareness of congruent hand images in a breaking continuous flash suppression (b-CFS) paradigm. Moreover, a vast literature suggests that spontaneous facial mimicry can improve emotion recognition, even without awareness of the stimulus face. However, integration of visual and proprioceptive information about the face to date has not been tested with CFS. The modulation of visual awareness of emotional faces by facial proprioception was investigated across three separate experiments. Face proprioception was induced with voluntary facial expressions or with spontaneous facial mimicry. Frequentist statistical analyses were complemented with Bayesian statistics. No evidence of multisensory integration was found, suggesting that proprioception does not modulate access to visual awareness of emotional faces in a CFS paradigm.


How social learning amplifies moral outrage expression in online social networks.
Moral outrage shapes fundamental aspects of social life and is now widespread in online social networks. Here, we show how social learning processes amplify online moral outrage expressions over time. In two preregistered observational studies on Twitter (7331 users and 12.7 million total tweets) and two preregistered behavioral experiments (N = 240), we find that positive social feedback for outrage expressions increases the likelihood of future outrage expressions, consistent with principles of reinforcement learning. In addition, users conform their outrage expressions to the expressive norms of their social networks, suggesting norm learning also guides online outrage expressions. Norm learning overshadows reinforcement learning when normative information is readily observable: in ideologically extreme networks, where outrage expression is more common, users are less sensitive to social feedback when deciding whether to express outrage. Our findings highlight how platform design interacts with human learning mechanisms to affect moral discourse in digital public spaces.


Regulators and mechanisms of anoikis in triple-negative breast cancer (TNBC): A review.
Metastasis leads to poor prognosis and reduced disease-free survival in breast cancer patients, particularly in those with triple-negative breast cancer (TNBC) which is resistant to common treatments. Anoikis is a type of apoptosis commenced by the detachment of cells from the native extracellular matrix and prohibits the attachment of detached cells to other body organs. Resistance to anoikis is a critical culprit in the development and progression of tumours. It is therefore important to understand the anoikis-related molecular pathways in order to design effective therapies for TNBC. Several compounds have been shown to possess the potential to regulate anoikis in breast cancer cells such as DSF, AEB071, nanoencapsulated doxorubicin, berberine, salinomycin, PEM POL5551, AL10, 5-azacytidine, synthesized flavonoid derivative GL-V9, Tubeimoside V (TBMS-V) and HPW-RX40. We reviewed the molecular basis of anoikis regulation, its potential role as an important target to inhibit metastasis in TNBC, and potential anoikis modulators that could serve as drug candidates.


The clinical spectrum of limb girdle muscular dystrophy. A survey in The Netherlands.
A cross-sectional study was performed in the Netherlands to define the clinical characteristics of the various subtypes within the broad and heterogeneous entity of limb girdle muscular dystrophy (LGMD). An attempt was made to include all known cases of LGMD in the Netherlands. Out of the reported 200 patients, 105 who fulfilled strictly defined criteria were included. Forty-nine patients, mostly suffering from dystrophinopathies and facioscapulohumeral muscular dystrophy, appeared to be misdiagnosed. Thirty-four cases were sporadic, 42 patients came from autosomal recessive and 29 from autosomal dominant families. The estimated prevalence of LGMD in the Netherlands was at least 8.1 x 10(-6). The clinical features of the autosomal recessive and sporadic cases were indistinguishable from those of the autosomal dominant patients, although calf hypertrophy was seen more frequently, and the course of the disease was more severe in autosomal recessive and sporadic cases. The pectoralis, iliopsoas and gluteal muscles, hip adductors and hamstrings were the most affected muscles. Distal muscle involvement occurred late in the course of the disease. Facial weakness was a rare phenomenon. The severity of the clinical picture was correlated with a deteriorating lung function. All autosomal dominantly inherited cases showed a mild course, although in two families life-expectancy was reduced because of concomitant cardiac involvement.


Neurocognitive, Autonomic, and Mood Effects of Adderall: A Pilot Study of Healthy College Students.
Prescription stimulant medications are considered a safe and long-term effective treatment for Attention Deficit Hyperactivity Disorder (ADHD). Studies support that stimulants enhance attention, memory, self-regulation and executive function in individuals with ADHD. Recent research, however, has found that many college students without ADHD report misusing prescription stimulants, primarily to enhance their cognitive abilities. This practice raises the question whether stimulants actually enhance cognitive functioning in college students without ADHD. We investigated the effects of mixed-salts amphetamine (i.e., Adderall, 30 mg) on cognitive, autonomic and emotional functioning in a pilot sample of healthy college students without ADHD (n = 13), using a double-blind, placebo-controlled, within-subjects design. The present study was the first to explore cognitive effects in conjunction with mood, autonomic effects, and self-perceptions of cognitive enhancement. Results revealed that Adderall had minimal, but mixed, effects on cognitive processes relevant to neurocognitive enhancement (small effects), and substantial effects on autonomic responses, subjective drug experiences, and positive states of activated emotion (large effects). Overall, the present findings indicate dissociation between the effects of Adderall on activation and neurocognition, and more importantly, contrary to common belief, Adderall had little impact on neurocognitive performance in healthy college students. Given the pilot design of the study and small sample size these findings should be interpreted cautiously. The results have implications for future studies and the education of healthy college students and adults who commonly use Adderall to enhance neurocognition.


Secondary ion MS imaging to relatively quantify cholesterol in the membranes of individual cells from differentially treated populations.
Time-of-flight secondary ion mass spectrometry (TOF-SIMS) is a well-established bioanalytical method for directly imaging the chemical distribution across single cells. Here we report a protocol for the use of SIMS imaging to comparatively quantify the relative difference in cholesterol level between the plasma membranes of two cells. It should be possible to apply this procedure to the study of other selected lipids. This development enables direct comparison of the chemical effects of different drug treatments and incubation conditions in the plasma membrane at the single-cell level. Relative, quantitative TOF-SIMS imaging has been used here to compare macrophage cells treated to contain elevated levels of cholesterol with respect to control cells. In situ fluorescence microscopy with two different membrane dyes was used to discriminate morphologically similar but differentially treated cells prior to SIMS analysis. SIMS images of fluorescently identified cells reveal that the two populations of cells have distinct outer leaflet membrane compositions with the membranes of the cholesterol-treated macrophages containing more than twice the amount of cholesterol of control macrophages. Relative quantification with SIMS to compare the chemical composition of single cells can provide valuable information about normal biological functions, causative agents of diseases, and possible therapies for diseases.


Feasibility of a randomized controlled trial of functional strength training for people between six months and five years after stroke: FeSTivaLS trial.
Functional Strength Training (FST) could enhance recovery late after stroke. The aim of this study was to evaluate the feasibility of a subsequent fully powered, randomized controlled trial. The study was designed as a randomized, observer-blind trial. Both interventions were provided for up to one hour a day, four days a week, for six weeks. Evaluation points were before randomization (baseline), after six weeks intervention (outcome), and six weeks thereafter (follow-up). The study took place in participants' own homes. Participants (n = 52) were a mean of 24.4 months after stroke with a mean age of 68.3 years with 67.3% male. All had difficulty using their paretic upper (UL) and lower limb (LL). Participants were allocated to FST-UL or FST-LL by an independent randomization service. The outcome measures were recruitment rate, attrition rate, practicality of recruitment strategies, occurrence of adverse reactions, acceptability of FST, and estimation of sample size for a subsequent trial. Primary clinical efficacy outcomes were the Action Research Arm Test (ARAT) and the Functional Ambulation Categories (FAC). Analysis was conducted using descriptive statistics and thematic analysis of participants' views of FST. A power calculation used estimates of clinical efficacy variance to estimate sample size for a subsequent trial. The screening process identified 1,127 stroke survivors of whom 52 (4.6%) were recruited. The recruitment rate was higher for referral from community therapists than for systematic identification of people discharged from an acute stroke unit. The attrition rate was 15.5% at the outcome and follow-up time-points. None of the participants experienced an adverse reaction. The participants who remained in the study at outcome had received 68% of the total possible amount of therapy. Participants reported that their experience of FST provided a sense of purpose and involvement and increased their confidence in performing activities. The power calculation provides estimation that 150 participants in each group will be required for a subsequent clinical trial. This study found that a subsequent clinical trial was feasible with modifications to the recruitment strategy to be used. Controlled-trials.com ISCTN71632550, 30 January 2009.


Bone regeneration in rat calvarial defects implanted with fibrous scaffolds composed of a mixture of silicate and borate bioactive glasses.
Previous studies have evaluated the capacity of porous scaffolds composed of a single bioactive glass to regenerate bone. In the present study, scaffolds composed of a mixture of two different bioactive glasses (silicate 13-93 and borate 13-93B3) were created and evaluated for their response to osteogenic MLO-A5 cells in vitro and their capacity to regenerate bone in rat calvarial defects in vivo. The scaffolds, which have similar microstructures (porosity=58-67%) and contain 0, 25, 50 and 100 wt.% 13-93B3 glass, were fabricated by thermally bonding randomly oriented short fibers. The silicate 13-93 scaffolds showed a better capacity to support cell proliferation and alkaline phosphatase activity than the scaffolds containing borate 13-93B3 fibers. The amount of new bone formed in the defects implanted with the 13-93 scaffolds at 12 weeks was 31%, compared to values of 25, 17 and 20%, respectively, for the scaffolds containing 25, 50 and 100% 13-93B3 glass. The amount of new bone formed in the 13-93 scaffolds was significantly higher than in the scaffolds containing 50 and 100% 13-93B3 glass. While the 13-93 fibers were only partially converted to hydroxyapatite at 12 weeks, the 13-93B3 fibers were fully converted and formed a tubular morphology. Scaffolds composed of an optimized mixture of silicate and borate bioactive glasses could provide the requisite architecture to guide bone regeneration combined with a controllable degradation rate that could be beneficial for bone and tissue healing.


Estrogen use and early onset Alzheimer's disease: a population-based study.
Estrogen use may be protective for Alzheimer's disease with late onset. However, the effects on early onset Alzheimer's disease are unclear. This issue was studied in a population based setting. For each female patient, a female control was matched on age (within 5 years) and place of residence. Information on estrogen use and other risk factors were, for cases (n=109) and controls (n=119), collected from the next of kin by structured interview. The strength of the association between estrogen use and early onset Alzheimer's disease was studied using conditional logistic regression with adjustment for age and education level. There was an inverse association between estrogen use and early onset Alzheimer's disease (adjusted odds ratio 0.34; 95% confidence interval 0.12-0.94). The study therefore suggests that estrogen use is beneficial to Alzheimer's disease with early onset.


Long noncoding RNAs in cardiac development and ageing.
A large part of the mammalian genome is transcribed into noncoding RNAs. Long noncoding RNAs (lncRNAs) have emerged as critical epigenetic regulators of gene expression. Distinct molecular mechanisms allow lncRNAs either to activate or to repress gene expression, thereby participating in the regulation of cellular and tissue function. LncRNAs, therefore, have important roles in healthy and diseased hearts, and might be targets for therapeutic intervention. In this Review, we summarize the current knowledge of the roles of lncRNAs in cardiac development and ageing. After describing the definition and classification of lncRNAs, we present an overview of the mechanisms by which lncRNAs regulate gene expression. We discuss the multiple roles of lncRNAs in the heart, and focus on the regulation of embryonic stem cell differentiation, cardiac cell fate and development, and cardiac ageing. We emphasize the importance of chromatin remodelling in this regulation. Finally, we discuss the therapeutic and biomarker potential of lncRNAs.


Variability in 24 hour excretion of cyanuric acid: implications for water exposure assessment.
Cyanuric acid (CYA) excretion in urine has been used to estimate the volume of water ingested during swimming and other recreational activities in outdoor pools containing this chemical. These estimates of water ingestion are based on the assumption of 100% excretion within 24 hours, but the supporting evidence for this is scant. While adapting this methodology to investigate other water ingestion scenarios, we observed a high degree of variability in cyanuric acid excretion among experimental subjects, with over 25% of individuals excreting less than 80% of an ingested dose. Use of cyanuric acid to measure inadvertent water ingestion may be a valuable tool to generate data for health risk assessment of non-potable water sources, but our observations indicate that this technique carries an inherent degree of underestimation that should be taken into account when calculating water exposure.


Ovarian steroids regulate gene expression related to DNA repair and neurodegenerative diseases in serotonin neurons of macaques.
Depression often accompanies the perimenopausal transition and it often precedes overt symptomology in common neurodegenerative diseases (NDDs, such as Alzheimer's, Parkinson's, Huntington, amyotrophic lateral sclerosis). Serotonin dysfunction is frequently found in the different etiologies of depression. We have shown that ovariectomized (Ovx) monkeys treated with estradiol (E) for 28 days supplemented with placebo or progesterone (P) on days 14-28 had reduced DNA fragmentation in serotonin neurons of the dorsal raphe nucleus, and long-term Ovx monkeys had fewer serotonin neurons than intact controls. We questioned the effect of E alone or E+P (estradiol supplemented with progesterone) on gene expression related to DNA repair, protein folding (chaperones), the ubiquitin-proteosome, axon transport and NDD-specific genes in serotonin neurons. Ovx macaques were treated with placebo, E or E+P (n=3 per group) for 1 month. Serotonin neurons were laser captured and subjected to microarray analysis and quantitative real-time PCR (qRT-PCR). Increases were confirmed with qRT-PCR in five genes that code for proteins involved in repair of strand breaks and nucleotide excision. NBN1, PCNA (proliferating nuclear antigen), GADD45A (DNA damage-inducible), RAD23A (DNA damage recognition) and GTF2H5 (gene transcription factor 2H5) significantly increased with E or E+P treatment (all analysis of variance (ANOVA), P<0.01). Chaperone genes HSP70 (heat-shock protein 70), HSP60 and HSP27 significantly increased with E or E+P treatment (all ANOVA, P<0.05). HSP90 showed a similar trend. Ubiquinase coding genes UBEA5, UBE2D3 and UBE3A (Parkin) increased with E or E+P (all ANOVA, P<0.003). Transport-related genes coding kinesin, dynein and dynactin increased with E or E+P treatment (all ANOVA, P<0.03). SCNA (α-synuclein) and ADAM10 (α-secretase) increased (both ANOVA, P<0.02) but PSEN1 (presenilin1) decreased (ANOVA, P<0.02) with treatment. APP decreased 10-fold with E or E+P administration. Newman-Keuls post hoc comparisons indicated variation in the response to E alone versus E+P across the different genes. In summary, E or E+P increased gene expression for DNA repair mechanisms in serotonin neurons, thereby rendering them less vulnerable to stress-induced DNA fragmentation. In addition, E or E+P regulated four genes encoding proteins that are often misfolded or malfunctioning in neuronal populations subserving overt NDD symptomology. The expression and regulation of these genes in serotonergic neurons invites speculation that they may mediate an underlying disease process in NDDs, which in turn may be ameliorated or delayed with timely hormone therapy in women.


Near final height in pubertal growth hormone (GH)-deficient patients treated with GH alone or in combination with luteinizing hormone-releasing hormone analog: results of a prospective, randomized trial.
To study the effects of delaying puberty in GH-deficient (GHD) children, we studied 21 GHD (9 boys, 14 girls), treatment-naive, pubertal patients in a prospective, randomized trial. Their chronological age was 14.3 +/- 1.6 yr, and their bone age was 11.3 +/- 1.1 yr (mean +/- SD) at the beginning of the study. Four patients who developed hypogonadotropic hypogonadism were subsequently excluded from the study. Patients were randomly assigned to receive GH + LH-releasing hormone analog (LHRH-A) (n = 7), or GH alone (n = 10). GH and LHRH-A treatment started simultaneously in each patient. GH (Nutropin) was administered at a dose of 0.1 U/kg x day sc, until patients reached a bone age (BA) of 14 yr in girls and 16 yr in boys, and LHRH-A (Lupron depot) was administered at a dose of 300 microg/ kg every 28 days in during 3 yr. We defined GH deficiency as patients with a growth velocity less than 4 cm/yr, BA delay more than 1 yr in relationship to chronological age, GH response to two stimulation tests less than 7 microg/L, associated with low serum insulin-like growth factor I and insulin-like growth factor binding protein 3 levels. Statistical analysis was performed by ANOVA or Kruskall Wallis when variances were not homogeneous. We observed a significant decrease in the rate of BA maturation in the group treated with GH+LHRH-A (1.5 +/- 0.2 yr) compared with the group treated with GH alone (4.2 +/-0.5 yr) during the 3 years of LHRH-A therapy (P < 0.05). This delay in BA maturation produced a significant gain in final height in the group treated with GH+LHRH-A, which reached - 1.3 +/- 0.5 SD score compared with -2.7 +/- 0.3 SD score (P < 0.05) in the group treated with GH alone. These results indicate that delaying puberty with LHRH-A in GHD children during treatment with GH increases final height.


Delayed degradation in soil of foliar herbicides glyphosate and sulcotrione previously absorbed by plants: consequences on herbicide fate and risk assessment.
Following application, pesticides can be intercepted and absorbed by weeds and/or crops. Plants containing pesticides residues may then reach the soil during the crop cycle or after harvest. However, the fate in soil of pesticides residues in plants is unknown. Two commonly used foliar herbicides, glyphosate and sulcotrione, (14)C-labeled, were applied on leaves of oilseed rape and/or maize, translocation was studied, and then soil incubations of aerial parts of plants containing herbicides residues were performed. Soil treated directly with herbicides was used as control. The effects of adjuvants on herbicide plant-absorption and subsequent soil-degradation were also investigated comparing herbicides application as active ingredients and as commercial formulations. The fate in soil of herbicides residues in plants was different from that of control, and different for glyphosate and sulcotrione. Mineralization in soil of glyphosate in crops decreased compared to control, and amounts of (14)C-extractable residues, mainly composed by the metabolite aminomethylphosphonic acid (AMPA), and non-extractable residues (NER) increased. In contrast, mineralization in soil of sulcotrione in maize increased compared to control, with a decrease in the (14)C-extractable residues and an increase in NER. The fate of both herbicides was influenced by the type of plant organ in which herbicide was incorporated, because of differences in herbicides bioavailability and organs biodegradability, but not by adjuvants. Absorption of both herbicides in plant delays their subsequent soil-degradation, and particularly, glyphosate persistence in soil could increase from two to six times. The modifications of herbicide degradation in soil due to interception by plants should be considered for environmental risks assessment.


The antibody response in Lyme disease.
We determined the antibody response against the Ixodes dammini spirochete in Lyme disease patients by indirect immunofluorescence and an enzyme-linked immunosorbent assay (ELISA). The specific IgM response became maximal three to six weeks after disease onset, and then declined, although titers sometimes remained elevated during later disease. Specific IgM levels correlated directly with total serum IgM. The specific IgG response, often delayed initially, was nearly always present during neuritis and arthritis, and frequently remained elevated after months of remission. Although results obtained by indirect immunofluorescence and the ELISA were similar, the ELISA was more sensitive and specific. Cross-reactive antibodies from patients with other spirochetal infections were blocked by absorption of sera with Borrelia hermsii, but titers of Lyme disease sera were also decreased. To further characterize the specificity of the humoral immune response against the I. dammini spirochete, 35S-methionine-labeled spirochetal antigens were identified by immunoprecipitation with sera from Lyme arthritis patients. These polypeptides had molecular weights of 62, 60, 47, 37, 22, 18, and 15 kDa, and were not recognized by control sera. We conclude that the ELISA, without absorption, is the best method to assay the humoral immune response in Lyme disease, and we have identified methionine-containing spirochetal polypeptides that may be important in Lyme arthritis.


Direct evidence that the reaction intermediate of metallo-beta-lactamase L1 is metal bound.
In an effort to probe the structure of the reaction intermediate of metallo-beta-lactamase L1 when reacted with nitrocefin and other beta-lactams, time-dependent absorption and rapid-freeze-quench (RFQ) EPR spectra were obtained using the Co(II)-substituted form of the enzyme. When using nitrocefin as the substrate, time-dependent absorption spectra demonstrate that Co(II)-substituted L1 utilizes a reaction mechanism, similar to that of the native Zn(II) enzyme, in which a short-lived intermediate forms. RFQ-EPR spectra of this intermediate demonstrate that the binding of substrate results in a change in the electronic properties of one or both of the Co(II)'s in the enzyme that is consistent with a change in the coordination sphere of this metal ion. This observation provides evidence that the reaction intermediate is a metal-bound species. RFQ-EPR studies also demonstrate that other beta-lactams, such as cephalothin, meropenem, and penicillin G, proceed through an electronically similar complex and that the role of metal is similar in all cases. EPR spectroscopy has also identified distinct product-bound species of L1, indicating that reversible product binding must be considered in all future kinetic mechanisms. Consideration of the time-dependent optical and EPR studies in light of available crystallographic information indicates the intimate involvement of the metal ion in the Zn(2)-binding site of L1 in the hydrolytic reaction.


Drivers of cost after surgical and medical therapy for chronic ulcerative colitis: a nested case-cohort study in Olmsted County, Minnesota.
We previously reported the costs associated with surgery for chronic ulcerative colitis in the Olmsted County population and found that direct medical costs after surgery were significantly reduced compared with before surgery. However, in that study, costs associated with chronic medical therapy for ulcerative colitis were not assessed in nonsurgical patients. To gain insight into the drivers of costs of treatment for chronic ulcerative colitis, we assessed direct costs after surgical and medical therapy in 120 patients in the Rochester Epidemiology Project database. A cohort of 60 patients who recovered from surgery for ulcerative colitis from 1988 to 2006 were 1:1 matched by age, sex, and referent year to medically managed patients. Direct health care costs were estimated from an institutional database, and observed cost differences over a 2-year period were calculated. Statistical significance was assessed by paired t tests and bootstrapping; mean costs are adjusted 2009 constant dollars. Two-year direct health care costs in the surgical and medical cohorts were $10,328 vs $6,586 (p = 0.19). In the surgical cohort, Brooke ileostomy patients were observed to have higher costs than patients with ileal pouches ([INCREMENT]$8187, p = 0.04), and after ileal pouch, pouchitis was associated with increased costs ([INCREMENT]$12,763, p < 0.01). In the medical cohort, disease extent ([INCREMENT]$6059, p = 0.04) but not disease severity was associated with increased costs. This study was limited by the relatively small population size and by its performance in a county with a tertiary referral center. Before the introduction of biologic therapies for ulcerative colitis, patients were observed to have similar health care costs after surgical and medical therapy. In medically treated patients, disease extent was associated with increased costs, whereas in surgically treated patients, permanent ileostomy and pouchitis were observed to be associated with increased costs.


Neural site of the redundant target effect electrophysiological evidence.
The present study represents an attempt to find an electrophysiological correlate of the redundant targets effect, or RTE (i.e., the speeding up of reaction time, or RT, for redundant vs. single targets). Subjects made a speeded response either to one small checkerboard presented to the left or right of fixation or to a pair of identical checkerboards presented simultaneously to both hemifields. Both single and double targets could appear either in the upper or lower visual hemifield. The task required detection but not discrimination of the stimuli. During task performance, we recorded the event-related potentials (ERPs) elicited by the checkerboard targets. As in previous studies, we found that manual RTs to bilateral stimuli were faster than those to unilateral stimuli. This effect was more marked for lower- than for upper-field stimuli and could not be ascribed to probability summation. In addition, we found that the P1 and N1 components of the visual ERP had a shorter latency for bilateral than for summed unilateral stimuli presented to the two hemifields. In parallel with the behavioral findings, the latency values for the above components showed a larger RTE for lower-field stimuli. These findings indicate that the RTE occurs at the level of early visual processing, probably in the extrastriate visual cortex, rather than at late decisional or pre-motor stages.


A search for radical intermediates in the photocycle of LOV domains.
LOV domains are the light sensitive parts of phototropins and many other light-activated enzymes that regulate the response to blue light in plants and algae as well as some fungi and bacteria. Unlike all other biological photoreceptors known so far, the photocycle of LOV domains involves the excited triplet state of the chromophore. This chromophore is flavin mononucleotide (FMN) which forms a covalent adduct with a cysteine residue in the signaling state. Since the formation of this adduct from the triplet state involves breaking and forming of two bonds as well as a change from the triplet to the singlet spin state, various intermediates have been proposed, e.g. a protonated triplet state (3)FMNH(+), the radical anion (2)FMN˙(-), or the neutral semiquinone radical (2)FMNH˙. We performed an extensive search for these intermediates by two-dimensional transient absorption (2D-TA) with a streak camera. However, no transient with a rate constant between the decay of fluorescence and the decay of the triplet state could be detected. Analysis of the decay associated difference spectra results in quantum yields for the formation of the adduct from the triplet of ΦA(LOV1) ≈ 0.75 and ΦA(LOV2) ≈ 0.80. This is lower than the values ΦA(LOV1) ≈ 0.95 and ΦA(LOV2) ≈ 0.99 calculated from the rate constants, giving indirect evidence of an intermediate that reacts either to form the adduct or to decay back to the ground state. Since there is no measurable delay between the decay of the triplet and the formation of the adduct, we conclude that this intermediate reacts much faster than it is formed. The LOV1-C57S mutant shows a weak and slowly decaying (τ > 100 μs) transient whose decay associated spectrum has bands at 375 and 500 nm, with a shoulder at 400 nm. This transient is insensitive to the pH change in the range 6.5-10.0 but increases on addition of β-mercaptoethanol as the reducing agent. We assign this intermediate to the radical anion which is protected from protonation by the protein. We propose that the adduct is formed via the same intermediate by combination of the radical ion pair.


Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.
Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.


Intravascular versus surface cooling speed and stability after cardiopulmonary resuscitation.
Mild therapeutic hypothermia (MTH) is used to limit neurological injury and improve survival after cardiac arrest (CA) and cardiopulmonary resuscitation, but the optimal mode of cooling is controversial. We therefore compared the effectiveness of MTH using invasive intravascular or non-invasive surface cooling with temperature feedback control. This retrospective study in post-CA patients studied the effects of intravascular cooling (CoolGard, Zoll, n=97), applied on the intensive care unit (ICU) in one university hospital compared with those of surface cooling (Medi-Therm, Gaymar, n=76) applied in another university hospital. Time to reach target temperature and cooling speeds did not differ between groups. During the maintenance phase, mean core temperature was 33.1°C (range 32.7-33.7°C) versus 32.5°C (range 31.7-33.4°C) at targets of 33.0 and 32.5°C in intravascularly versus surface cooled patients, respectively. The variation coefficient for temperature during maintenance was higher in the surface than the intravascular cooling group (mean 0.85% vs 0.35%, p<0.0001). ICU survival was 60% and 50% in the intravascularly and surface cooled groups, respectively (NS). Lower age (OR 0.95; 95% CI 0.93 to 0.98; p<0.0001), ventricular fibrillation/ventricular tachycardia as presenting rhythm (OR 7.6; 95% CI 1.8 to 8.9; p<0.0001) and lower mean temperature during the maintenance phase (OR 0.52; 95% CI 0.25 to 1.08; p=0.081) might be independent determinants of ICU survival, while cooling technique and temperature variability did not contribute. In post-CA patients, intravascular cooling systems result in equal cooling speed, but less variation in temperature during the maintenance phase, as surface cooling. This may not affect the outcome.


pH, ionic strength and dissolved organic matter alter aggregation of fullerene C60 nanoparticles suspensions in wastewater.
The rapid increase in the production and use of fullerene C(60) nanoparticles raise concerns about environmental risks and human health. Wastewater treatment plants are key barriers to their discharge into the environment. The aggregation behavior of aqueous suspensions of C(60) nanoparticles (nC(60)) could affect their transport, bioavailability, and removal during wastewater treatment. We tested the aggregation of nC(60) in wastewater at different values of pH, ionic strength, and dissolved organic matter (DOM). The nC(60) remained relatively stable in filtered wastewater under environmentally relevant conditions up to 24 h. But at pH 3 or at high ionic strength (>100 mM NaCl), the aggregate size increased greatly, reaching micrometer scale after only 1 h. However, the aggregation behavior varied among wastewater samples even at values of similar zeta potential, compared with that in filtered secondary effluent and aeration tank liquor, that in filtered primary effluent was obviously inhibited. This inhibition could be attributed to the steric stabilization due to the adsorption of DOM on nC(60) aggregate in addition to electrostatic stabilization. The aggregation results also suggest that membrane filtration could be improved by adjustments to pH.


Advances in bone augmentation to enable dental implant placement: Consensus Report of the Sixth European Workshop on Periodontology.
Bone augmentation procedures to enable dental implant placement are frequently performed in practice. In this session the European Workshop on Periodontology discussed the evidence in support of the procedures and examined both adverse events and implant performance in the augmented bone. While the available evidence improved both in quantity and quality since previous workshops the conclusions that could be drawn were limited by elements of design and/or reporting that are amenable to improvement. With regards to lateral bone augmentation, a sizable body of evidence supports its use to enable dental implant placement. The group recognized the potential for vertical ridge augmentation procedures to allow implant placement in clinical practice but questioned the applicability of these data to a wider array of operators and clinical settings. With regards to sinus floor augmentation, perforation of the sinus membrane, graft infection and graft loss resulting in inability of implant placement were the major reported adverse events. In cases with <6 mm of residual bone height, 17% of subjects experienced implant loss in the first 3 years following lateral window augmentation. After trans-alveolar sinus floor augmentation 11% of subjects experienced implant loss over 3 years. Significant research activity (both pre-clinical and clinical) was identified in the area of growth factors-induced bone augmentation. Initial clinical trials support the potential of BMP-2. Clinically, the consensus highlighted that bone augmentation procedures can fail and that implants placed in these areas do not necessarily enjoy the high long-term survival rates of dental implants placed in pristine sites. The consensus emphasized the research need to answer questions on: (i) long-term performance of dental implants placed in augmented bone; (ii) the clinical performance of dental implants placed in augmented or pristine sites; and (iii) the clinical benefits of bone augmentation with respect to alternative treatments.


The evolution of a distance education initiative into a major telehealth project.
After a five-year collaboration in distance learning, the University of Texas Medical Branch in Galveston School of Nursing and the Lamar University Department of Nursing in Beaumont, Texas, opened discussions during the mid-1990s about working together to establish a cutting-edge telehealth clinic. Other participants in this dialogue were the UTMB Division of Pediatric Special Services (DPSS) and the East Texas Area Health Education Center (ETAHEC). DPSS hoped to provide telehealth services for children who had to commute routinely to receive comprehensive health care. ETAHEC, which specializes in building community-academic partnerships to improve the health of populations in its service region, had already worked with members of the team, providing support for the distance education collaboration between UTMB and LU. Several meetings between representatives from the two universities and ETAHEC resulted in the decision by LU to establish an infrastructure for distance learning that could also support telehealth activities. UTMB, which offered family nurse practitioner education at LU through the earlier distance learning initiative, had extensive experience in both distance education and telehealth. It provided the expertise to ensure that the two types of technology could be provided on the LU campus. Eventually, a third university came on board, and the program expanded to provide services in six public schools. A single telehealth clinic, in operation for two years with over 112 client visits, has grown into a major telehealth initiative linking an academic health science center, universities, and school districts in Texas.


The geometric increase in meta-analyses from China in the genomic era.
Meta-analyses are increasingly popular. It is unknown whether this popularity is driven by specific countries and specific meta-analyses types. PubMed was used to identify meta-analyses since 1995 (last update 9/1/2012) and catalogue their types and country of origin. We focused more on meta-analyses from China (the current top producer of meta-analyses) versus the USA (top producer until recently). The annual number of meta-analyses from China increased 40-fold between 2003 and 2011 versus 2.4-fold for the USA. The growth of Chinese meta-analyses was driven by genetics (110-fold increase in 2011 versus 2003). The HuGE Navigator identified 612 meta-analyses of genetic association studies published in 2012 from China versus only 109 from the USA. We compared in-depth 50 genetic association meta-analyses from China versus 50 from USA in 2012. Meta-analyses from China almost always used only literature-based data (92%), and focused on one or two genes (94%) and variants (78%) identified with candidate gene approaches (88%), while many USA meta-analyses used genome-wide approaches and raw data. Both groups usually concluded favorably for the presence of genetic associations (80% versus 74%), but nominal significance (P<0.05) typically sufficed in the China group. Meta-analyses from China typically neglected genome-wide data, and often included candidate gene studies published in Chinese-language journals. Overall, there is an impressive rise of meta-analyses from China, particularly on genetic associations. Since most claimed candidate gene associations are likely false-positives, there is an urgent global need to incorporate genome-wide data and state-of-the art statistical inferences to avoid a flood of false-positive genetic meta-analyses.


Preoperative regional chemotherapy and rapid-fraction irradiation for sarcomas of the soft tissue and bone.
Conventional treatment for high grade and large sarcomas uses a radical surgical approach, including amputation, in many patients. We evaluated a limb-sparing treatment approach using preoperative regional Adriamycin chemotherapy and rapid-fraction radiation therapy. Thirty patients with soft tissue or skeletal sarcoma were treated in a prospective, nonrandomized clinical trial to evaluate local disease control and limb salvage in these patients who would otherwise require amputation or face a high risk of local recurrence with surgical excision. Almost all patients had large tumors with grade III histologic findings. All patients had a three day intra-arterial regional chemotherapy infusion with Adriamycin (100 milligrams total dose), followed within ten days by rapid-fraction irradiation (3,000 rads over a two week period) prior to surgical excision of the tumor. The size and location of the sarcoma permitted only a marginal resection in one-half of the patients, while the remainder could be excised in a three dimensional en bloc manner. Almost all patients received post-operative systemic Adriamycin chemotherapy (450 milligrams per square meter given intravenously over a six month period). Two of six patients with significant wound complications later required amputation. Only one patient (3 per cent) has had a local recurrence of sarcoma develop after a mean follow-up of 22 months (range nine to 42 months), and 90 per cent of the patients have a useful extremity. The three year survival rate was 68 per cent for soft tissue sarcomas, compared with an expected survival rate of 38 per cent for published historical control studies. The patient with osteogenic sarcoma has a projected 83 per cent survival rate at 18 months after treatment. This multimodality approach is an effective treatment for local disease control in patients with high risk sarcoma. It permits limb salvage in most patients without compromising the survival rates.


Fluticasone furoate nasal spray consistently and significantly improves both the nasal and ocular symptoms of seasonal allergic rhinitis: a review of the clinical data.
Allergic rhinitis (AR) is a highly prevalent disorder, which often manifests as both nasal (congestion, sneezing, itching and rhinorrhoea) and ocular (redness, watery eyes, itching and burning) symptoms. Until recently, efficacy against the ocular symptoms of AR has been inconsistent for any single intranasal corticosteroid (INS). Fluticasone furoate is an enhanced-affinity glucocorticoid with potent anti-inflammatory activity. To assess better the efficacy of an INS in the treatment of both the nasal and ocular symptoms of seasonal AR (SAR). Data from all four trials of fluticasone furoate nasal spray (FFNS) in the treatment of SAR are reviewed and critically considered. FFNS consistently and significantly improved the nasal and ocular symptoms of SAR in patients sensitised to several different seasonal allergens (grass, ragweed and mountain cedar pollen) in all trials. An integrated analysis of the results also confirmed improvements in both nasal and ocular symptom scores in previously under-represented adolescent patients treated with FFNS. FFNS is the first INS to show consistent nasal and ocular efficacy across all SAR trials.


Wolbachia-Based Dengue Virus Inhibition Is Not Tissue-Specific in Aedes aegypti.
Dengue fever, caused by the dengue virus (DENV), is now the most common arbovirus transmitted disease globally. One novel approach to control DENV is to use the endosymbiotic bacterium, Wolbachia pipientis, to limit DENV replication inside the primary mosquito vector, Aedes aegypti. Wolbachia that is naturally present in a range of insects reduces the capacity for viruses, bacteria, parasites and fungi to replicate inside insects. Wolbachia's mode of action is not well understood but may involve components of immune activation or competition with pathogens for limited host resources. The strength of Wolbachia-based anti DENV effects appear to correlate with bacterial density in the whole insect and in cell culture. Here we aimed to determine whether particular tissues, especially those with high Wolbachia densities or immune activity, play a greater role in mediating the anti DENV effect. Ae. aegypti mosquito lines with and without Wolbachia (Wildtype) were orally fed DENV 3 and their viral loads subsequently measured over two time points post infection in the midgut, head, salivary glands, Malpighian tubules, fat body and carcass. We did not find correlations between Wolbachia densities and DENV loads in any tissue, nor with DENV loads in salivary glands, the endpoint of infection. This is in contrast with strong positive correlations between DENV loads in a range of tissues and salivary gland loads for Wildtype mosquitoes. Lastly, there was no evidence of a heightened role for tissues with known immune function including the fat body and the Malpighian tubules in Wolbachia's limitation of DENV. We conclude that the efficacy of DENV blocking in Wolbachia infected mosquitoes is not reliant on any particular tissue. This work therefore suggests that the mechanism of Wolbachia-based antiviral effects is either systemic or acts locally via processes that are fundamental to diverse cell types. We further conclude that the relationship between DENV blocking and Wolbachia density is not linear in mosquito tissues.


Microparticle subpopulations are potential markers of disease progression and vascular dysfunction across a spectrum of connective tissue disease.
Microparticles (MPs) are membrane-bound vesicles derived from vascular and intravascular cells such as endothelial cells (EMPs) and platelets (PMPs). We investigated EMP and PMP numbers across a spectrum of autoimmune rheumatic diseases (AIRDs) with the aim of comparing the levels of, and relationship between, EMPs and PMPs. Patients with Systemic Lupus Erythematosus (SLE) (n = 24), Systemic Sclerosis (SSc) (n = 24), Primary Raynauds Phenomenon (RP) (n = 17) and "other CTD" (n = 15) (Primary Sjogrens Syndrome, UCTD or MCTD) as well as 15 healthy controls were recruited. EMPs and PMPs were quantified using flow cytometry. Associations between MP levels and objective functional vascular assessments were evaluated. SLE patients had significantly higher EMPs compared with healthy controls and SSc patients. Higher PMP levels were noted in SSc and primary RP when compared to healthy controls and 'other CTD' patients. A modest correlation was noted between EMP and PMP levels in healthy controls (Spearman r = 0.6, p = 0.017). This relationship appeared stronger in SLE (r = 0.72, p < 0.0001) and other CTD patients (r = 0.75, p < 0.0001). The association between EMPs and PMPs was notably less strong in SSc (r = 0.45, p = 0.014) and RP (r = 0.37, p = 0.15). A significantly lower EMP/PMP ratio was detected in SSc/RP patients in comparison to both healthy controls and SLE/other CTD patients. Higher EMP and PMP levels were associated with higher digital perfusion following cold challenge in SSc. In contrast, higher PMP (but not EMP) levels were associated with lower digital perfusion at both baseline and following cold challenge in primary RP. Higher PMP levels were associated with greater endothelial-independent dilation in patients with SLE. MP populations differ across the spectrum of AIRDS, possibly reflecting differences in vascular cell injury and activation. MP levels are associated with functional assessments of vascular function and might have a role as novel vascular biomarkers in AIRDs. Levels of circulating endothelial and platelet microparticles differ between SSc/primary RP compared with SLE and other CTDs (UCTD, MCTD and Primary Sjogrens). MP release may occur within different vascular sites across these disease groups (macrovascular and microvascular). The association between circulating MP levels and objective assessment of macro- and microvascular dysfunction within these disease areas suggests that MPs might have a useful role as novel circulating biomarkers of vascular disease within the CTDs.


Bipotential precursors of B cells and macrophages in murine fetal liver.
LYMPHOCYTES (B and T cells) derive continuously from the same multipotential stem cells that produce myeloid cells, including erythrocytes, granulocytes and macrophages. Tri- and bipotential myeloid intermediates between the multipotential stem cells and later unipotential cells have been identified using clonal methods in culture. Although similar methods have detected committed pre-B cells in mouse fetal liver, earlier progenitors with additional non-B lineage options have not been demonstrated in normal tissues. We report the characterization and purification of fetal liver cells that generate clones containing both macrophages and B cells, identified biochemically and morphologically. The common origin of the two cell types was shown by culture of single precursor cells. Their dual potential and unrearranged immunoglobulin loci place the precursors before exclusive B-lineage commitment in the haematopoietic hierarchy. The availability of such cells in purified form will allow direct study of lineage choice in cells having both lymphoid and non-lymphoid options.


Refining the Identity and Role of Kv4 Channels in Mouse Substantia Nigra Dopaminergic Neurons.
Substantia nigra pars compacta (SNc) dopaminergic (DA) neurons display a peculiar electrical phenotype characterized in vitro by a spontaneous tonic regular activity (pacemaking activity), a broad action potential (AP) and a biphasic postinhibitory response. The transient A-type current (IA) is known to play a crucial role in this electrical phenotype, and so far, this current was considered to be carried exclusively by Kv4.3 potassium channels. Using Kv4.3-/- transgenic mice, we demonstrate that the constitutive loss of this channel is associated with increased exploratory behavior and impaired motor learning at the behavioral level. Consistently, it is also associated with a lack of compensatory changes in other ion currents at the cellular level. Using antigen retrieval (AR) immunohistochemistry, we then demonstrate that Kv4.2 potassium channels are also expressed in SNc DA neurons, although their contribution to IA appears significant only in a minority of neurons (∼5-10%). Using correlative analysis on recorded electrophysiological parameters and multicompartment modeling, we then demonstrate that, rather than its conductance level, IA gating kinetics (inactivation time constant) appear as the main biophysical property defining postinhibitory rebound delay and pacemaking frequency. Moreover, we show that the hyperpolarization-activated current (IH) has an opposing and complementary influence on the same firing features.


Risk factors for colistin-resistant Enterobacteriaceae in a low-endemicity setting for carbapenem resistance - a matched case-control study.
BackgroundEmergence of colistin resistance has been related to increased use in clinical settings, following global spread of carbapenem-resistant Gram-negative bacteria. Use of colistin in animal production may constitute a further source of spread of resistant strains to humans. We sought to determine risk factors for human colonisation or infection with colistin-resistant Escherichia coli and Klebsiella pneumoniae in a setting where colistin is mainly used for animal production. Methods: This retrospective matched case-control study was performed during a 5-year period at two university-affiliated hospitals in Basel, Switzerland. Conditional univariable logistic regression was used to calculate odds ratios (OR) for colistin resistance. All variables found to be significant in univariable analyses were included in the conditional multivariable regression model using stepwise forward and backward selection. Results: Forty-two cases (33 with colistin-resistant E. coli, 9 with colistin-resistant K. pneumoniae) and 126 matched controls were identified. Baseline characteristics, comorbidities, prior exposure to antibiotics and healthcare settings did not differ between cases and controls, except for prior exposure to carbapenems, hospitalisation and stay abroad during the prior 3 months. In multivariable analyses, only prior exposure to carbapenems remained associated with colistin resistance (OR: 5.00; 95% confidence interval (95% CI): 1.19-20.92; p = 0.028). Conclusion: In a low-endemicity setting for carbapenem resistance, prior exposure to carbapenems was the only risk factor for colonisation or infection with colistin-resistant E. coli or K. pneumoniae. Prior exposure to colistin was not significantly associated with detection of colistin resistance, which mainly occurred in the absence of concurrent carbapenem resistance.


Leveraging Big Data Towards Functionally-Based, Catchment Scale Restoration Prioritization.
The persistence of freshwater degradation has necessitated the growth of an expansive stream and wetland restoration industry, yet restoration prioritization at broad spatial extents is still limited and ad-hoc restoration prevails. The River Basin Restoration Prioritization tool has been developed to incorporate vetted, distributed data models into a catchment scale restoration prioritization framework. Catchment baseline condition and potential improvement with restoration activity is calculated for all National Hydrography Dataset stream reaches and catchments in North Carolina and compared to other catchments within the river subbasin to assess where restoration efforts may best be focused. Hydrologic, water quality, and aquatic habitat quality conditions are assessed with peak flood flow, nitrogen and phosphorus loading, and aquatic species distribution models. The modular nature of the tool leaves ample opportunity for future incorporation of novel and improved datasets to better represent the holistic health of a watershed, and the nature of the datasets used herein allow this framework to be applied at much broader scales than North Carolina.


Determining the role of inflammation in the selection of JAK2 mutant cells in myeloproliferative neoplasms.
Myeloproliferative neoplasm (MPN) is a hematologic malignancy characterized by the clonal outgrowth of hematopoietic cells with a somatically acquired mutation most commonly in JAK2 (JAK2V617F). This mutation endows upon myeloid progenitors cytokine independent growth and consequently leads to excessive production of myeloid lineage cells. It has been previously suggested that inflammation may play a role in the clonal evolution of JAK2V617F mutants. In particular, it is possible that one or more cellular kinetic parameters of hematopoietic stem cells (HSCs) are affected by inflammation, such as division or death rates of cells, and the probability of HSC differentiation. This suggests a mechanism that can steer the outcome of the cellular competition in favor of the mutants, initiating the disease. In this paper we create a number of mathematical evolutionary models, from very abstract to more concrete, that describe cellular competition in the context of inflammation. It is possible to build a model axiomatically, where only very general assumptions are imposed on the modeling components and no arbitrary (and generally unknown) functional forms are used, and still generate a set of testable predictions. In particular, we show that, if HSC death is negligible, the evolutionary advantage of mutant cells can only be conferred by an increase in differentiation probability of HSCs in the presence of inflammation, and if death plays a significant role in the dynamics, an additional mechanism may be an increase of HSC's division-to-death ratio in the presence of inflammation. Further, we show that in the presence of inflammation, the wild type cell population is predicted to shrink under inflammation (even in the absence of mutants). Finally, it turns out that if only the differentiation probability is affected by the inflammation, then the resulting steady state population of wild type cells will contain a relatively smaller percentage of HSCs under inflammation. If the division-to-death rate is also affected, then the percentage of HSCs under inflammation can either decrease or increase, depending on other parameters.


Specific elements of the glyoxylate pathway play a significant role in the functional transition of the soybean cotyledon during seedling development.
The soybean (Glycine max) cotyledon is a specialized tissue whose main function is to serve as a nutrient reserve that supplies the needs of the young plant throughout seedling development. During this process the cotyledons experience a functional transition to a mainly photosynthetic tissue. To identify at the genetic level the specific active elements that participate in the natural transition of the cotyledon from storage to photosynthetic activity, we studied the transcript abundance profile at different time points using a new soybean oligonucleotide chip containing 19,200 probes (70-mer long). After normalization and statistical analysis we determined that 3,594 genes presented a statistically significant altered expression in relation to the imbibed seed in at least one of the time points defined for the study. Detailed analysis of this data identified individual, specific elements of the glyoxylate pathway that play a fundamental role during the functional transition of the cotyledon from nutrient storage to photosynthesis. The dynamics between glyoxysomes and peroxisomes is evident during these series of events. We also identified several other genes whose products could participate co-ordinately throughout the functional transition and the associated mechanisms of control and regulation and we described multiple unknown genetic elements that by association have the potential to make a major contribution to this biological process. We demonstrate that the global transcript profile of the soybean cotyledon during seedling development is extremely active, highly regulated and dynamic. We defined the expression profiles of individual gene family members, enzymatic isoforms and protein subunits and classified them accordingly to their involvement in different functional activities relevant to seedling development and the cotyledonary functional transition in soybean, especially the ones associated with the glyoxylate cycle. Our data suggests that in the soybean cotyledon a very complex and synchronized system of control and regulation of several metabolic pathways is essential to carry out the necessary functions during this developmental process.


Complete Genome Sequence of GD1696, a Low-Virulence Strain of Human-Associated ST398 Methicillin-Susceptible Staphylococcus aureus.
The emerging livestock-associated Staphylococcus aureus multilocus sequence type 398 (ST398) appears to have augmented virulence in humans. However, it is unclear if all ST398 strains are equally virulent. Here, we present the chromosomal sequence of a low-virulence ST398 methicillin-susceptible S. aureus (MSSA) strain, GD1696, to investigate ST398 sublineage virulence.


Managing with Learning Disability and Diabetes: OK-Diabetes - a case-finding study and feasibility randomised controlled trial.
Obesity and type 2 diabetes are common in adults with a learning disability. It is not known if the principles of self-management can be applied in this population. To develop and evaluate a case-finding method and undertake an observational study of adults with a learning disability and type 2 diabetes, to develop a standardised supported self-management (SSM) intervention and measure of adherence and to undertake a feasibility randomised controlled trial (RCT) of SSM versus treatment as usual (TAU). Observational study and an individually randomised feasibility RCT. Three cities in West Yorkshire, UK. In the observational study: adults aged > 18 years with a mild or moderate learning disability, who have type 2 diabetes that is not being treated with insulin and who are living in the community. Participants had mental capacity to consent to research and to the intervention. In the RCT participants had glycated haemoglobin (HbA1c) levels of > 6.5% (48 mmol/mol), a body mass index (BMI) of > 25 kg/m2 or self-reported physical activity below national guideline levels. Standardised SSM. TAU supported by an easy-read booklet. (1) The number of eligible participants identified and sources of referral; (2) current living and support arrangements; (3) current health state, including level of HbA1c, BMI and waist circumference, blood pressure and lipids; (4) mood, preferences for change; (5) recruitment and retention in RCT; (6) implementation and adherence to the intervention; (7) completeness of data collection and values for candidate primary outcomes; and (8) qualitative data on participant experience of the research process and intervention. In the observational study we identified 147 eligible consenting participants. The mean age was 54.4 years. In total, 130 out of 147 (88%) named a key supporter, with 113 supporters (77%) being involved in diabetes management. The mean HbA1c level was 54.5 mmol/mol [standard deviation (SD) 14.8 mmol/mol; 7.1%, SD 1.4%]. The BMI of 65% of participants was > 30 kg/m2 and of 21% was > 40 kg/m2. Many participants reported low mood, dissatisfaction with lifestyle and diabetes management and an interest in change. Non-response rates were high (45/147, 31%) for medical data requested from the primary care team. In the RCT, 82 participants were randomised. The mean baseline HbA1c level was 56 mmol/mol (SD 16.5 mmol/mol; 7.3%, SD 1.5%) and the mean BMI was 34 kg/m2 (SD 7.6 kg/m2). All SSM sessions were completed by 35 out of 41 participants. The adherence measure was obtained in 37 out of 41 participants. The follow-up HbA1c level and BMI was obtained for 75 out of 82 (91%) and 77 out of 82 (94%) participants, respectively. Most participants reported a positive experience of the intervention. A low response rate and difficulty understanding the EuroQol-5 Dimensions were challenges in obtaining data for an economic analysis. We recruited from only 60% of eligible general practices, and 90% of participants were on a general practice learning disability register, which meant that we did not recruit many participants from the wider population with milder learning disability. A definitive RCT is feasible and would need to recruit 194 participants per arm. The main barrier is the resource-intensive nature of recruitment. Future research is needed into the effectiveness of obesity treatments in this population, particularly estimating the longer-term outcomes that are important for health benefit. Research is also needed into improving ways of assessing quality of life in adults with a learning disability. Current Controlled Trials ISRCTN41897033. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 26. See the NIHR Journals Library website for further project information.


[Cytologic diagnosis of sarcoma].
Soft tissue swelling represents a common clinical sign of a variety of neoplastic and non-neoplastic lesions. Sarcoma is rarely a cause. Fine needle biopsy as a minimally invasive, economic and accurate method is well suited for the diagnosis of inflammatory/infectious processes as well as of recurrent and metastatic disease. Cytologic diagnosis of primary soft tissue tumors is also feasible. It requires close collaboration with other medical disciplines and incorporation of clinical, radiological and morphologic findings. Clinical data such as age, gender, size and topography are important parameters. The differentiation of cells and properties of the extracellular matrix supplies clues for the differential diagnosis and forms the starting point for immunohistochemical or molecular analysis (FISH, RT-PCR). This analysis may be performed on cytological smears, paraffin embedded material of the cell blocks or on frozen material.


Purkinje cell number decreases in the adult female rat cerebellum following exposure to 900 MHz electromagnetic field.
The biological effects of electromagnetic field (EMF) exposure from mobile phones have growing concern among scientists since there are some reports showing increased risk for human health, especially in the use of mobile phones for a long duration. In the presented study, the effects on the number of Purkinje cells in the cerebellum of 16-week (16 weeks) old female rats were investigated following exposure to 900 MHz EMF. Three groups of rats, a control group (CG), sham exposed group (SG) and an electromagnetic field exposed group (EMFG) were used in this study. While EMFG group rats were exposed to 900 MHz EMF (1h/day for 28 days) in an exposure tube, SG was placed in the exposure tube but not exposed to EMF (1h/day for 28 days). The specific energy absorption rate (SAR) varied between 0.016 (whole body) and 2 W/kg (locally in the head). The CG was not placed into the exposure tube nor was it exposed to EMF during the study period. At the end of the experiment, all of the female rats were sacrificed and the number of Purkinje cells was estimated using a stereological counting technique. Histopathological evaluations were also done on sections of the cerebellum. Results showed that the total number of Purkinje cells in the cerebellum of the EMFG was significantly lower than those of CG (p<0.004) and SG (p<0.002). In addition, there was no significant difference at the 0.05 level between the rats' body and brain weights in the EMFG and CG or SG. Therefore, it is suggested that long duration exposure to 900 MHz EMF leads to decreases of Purkinje cell numbers in the female rat cerebellum.


Dietary and behavioral interventions protect against age related activation of caspase cascades in the canine brain.
Lifestyle interventions such as diet, exercise, and cognitive training represent a quietly emerging revolution in the modern approach to counteracting age-related declines in brain health. Previous studies in our laboratory have shown that long-term dietary supplementation with antioxidants and mitochondrial cofactors (AOX) or behavioral enrichment with social, cognitive, and exercise components (ENR), can effectively improve cognitive performance and reduce brain pathology of aged canines, including oxidative damage and Aβ accumulation. In this study, we build on and extend our previous findings by investigating if the interventions reduce caspase activation and ceramide accumulation in the aged frontal cortex, since caspase activation and ceramide accumulation are common convergence points for oxidative damage and Aβ, among other factors associated with the aged and AD brain. Aged beagles were placed into one of four treatment groups: CON--control environment/control diet, AOX--control environment/antioxidant diet, ENR--enriched environment/control diet, AOX/ENR--enriched environment/antioxidant diet for 2.8 years. Following behavioral testing, brains were removed and frontal cortices were analyzed to monitor levels of active caspase 3, active caspase 9 and their respective cleavage products such as tau and semaphorin7a, and ceramides. Our results show that levels of activated caspase-3 were reduced by ENR and AOX interventions with the largest reduction occurring with combined AOX/ENR group. Further, reductions in caspase-3 correlated with reduced errors in a reversal learning task, which depends on frontal cortex function. In addition, animals treated with an AOX arm showed reduced numbers of cells expressing active caspase 9 or its cleavage product semaphorin 7A, while ENR (but not AOX) reduced ceramide levels. Overall, these data demonstrate that lifestyle interventions curtail activation of pro-degenerative pathways to improve cellular health and are the first to show that lifestyle interventions can regulate caspase pathways in a higher animal model of aging.


Exploring consensus across sectors for measuring the social determinants of health.
The importance of social determinants of health (SDOH) -such as affordable housing, stable employment, consistent transportation, healthy food access, and quality schools-is well-established as a key component of chronic disease prevention and health promotion. Increasingly, practitioners within and beyond public health are collaborating to implement such strategies, part of which involves measuring their impacts over time. This study assesses the current state of SDOH measurement across sectors by systematically identifying how many and what kinds of tools exist and whether there is consensus around SDOH categories and indicators selected. This study revealed that while numerous SDOH measurement resources exist, relatively few are tools for measuring the SDOH. Although the SDOH categories being measured could be readily summarized across tools, there was wide variation in the particular SDOH categories included in each tool. Finally, remarkably little consensus exists for the specific indicators used to measure SDOH categories. While complete consensus across tools may not be possible, learning how different sectors measure SDOH and more systematically aligning SDOH categories and indicators being measured will enable greater collaboration and deepen the impacts of place-based interventions to improve community health and well-being.


Time-resolved fluorescence line-narrowing of Eu3+ in biocompatible eutectic glass-ceramics.
The spectroscopic properties of Eu(3+) in biocompatible glass and glass-ceramic eutectic rods of composition 0.8CaSiO(3)-0.2Ca(3)(PO(4))(2) doped with 0.5 wt% of Eu(2)O(3) are investigated to explore their potential applications as optical probes. The samples were obtained by the laser floating zone technique. Depending on the growth rate, they exhibit three (two crystalline and one amorphous) or two (one crystalline and one amorphous) phases. The crystalline phases correspond to Ca(2)SiO(4) and apatite-like structures. At high growth rates the system presents an amorphous arrangement which gives a glass phase. The results of time-resolved fluorescence line narrowing spectroscopy obtained under excitation within the inhomogeneous broadened (7)F(0)→(5)D(0) absorption band allow to isolate the emission from Eu(3+) ions in the crystalline and amorphous environments and to accurately correlate the spectroscopic properties with the microstructure of these eutectics.


Assessing the effects of weather conditions on physical activity participation using objective measures.
Habitual physical activity is an important determinant of health, yet many people are considered to be inactive. Identification of the obstacles to greater participation is necessary for the development of strategies to overcome those obstacles. The weather has been identified as a perceived barrier to participation in physical activity, but exactly which adverse weather conditions are most important, and the extent to which they contribute to decreases in physical activity have rarely been quantified in populations. In the past decade, a small number of studies have used publicly available databases to examine the quantitative effects of weather (e.g., temperature, precipitation, wind) on physical activity in children, adolescents and adults. This review examines our historical, qualitative versus emerging, quantitative understanding of how specific weather conditions affect a population's activity.


Development of biodegradable crosslinked urethane-doped polyester elastomers.
Traditional crosslinked polyester elastomers are inherently weak, and the strategy of increasing crosslink density to improve their mechanical properties makes them brittle materials. Biodegradable polyurethanes, although strong and elastic, do not fare well in dynamic environments due to the onset of permanent deformation. The design and development of a soft, strong and completely elastic (100% recovery from deformation) material for tissue engineering still remains a challenge. Herein, we report the synthesis and evaluation of a new class of biodegradable elastomers, crosslinked urethane-doped polyesters (CUPEs), which is able to satisfy the need for soft, strong, and elastic biomaterials. Tensile strength of CUPE was as high as 41.07+/-6.85 MPa with corresponding elongation at break of 222.66+/-27.84%. The initial modulus ranged from 4.14+/-1.71 MPa to 38.35+/-4.5 MPa. Mechanical properties and degradation rates of CUPE could be controlled by varying the choice of diol used for synthesis, the polymerization conditions, as well as the concentration of urethane bonds in the polymer. The polymers demonstrated good in vitro and in vivo biocompatibilities. Preliminary hemocompatibility evaluation indicated that CUPE adhered and activated lesser number of platelets compared to PLLA. Good mechanical properties and easy processability make these materials well suited for soft tissue engineering applications. The introduction of CUPEs provides new avenues to meet the versatile requirements of tissue engineering and other biomedical applications.