Liver cirrhosis: an unfavorable factor for nonoperative management of blunt splenic injury.
Nonoperative management (NOM) of blunt splenic injury (BSI) is currently a well-accepted treatment modality for hemodynamically stable patients. More than 60% of BSI patients can be successfully treated without operation. Old age, high-grade injury, contrast blush, and multiple associated injuries were reported to have a higher failure rate but not to be exclusive of NOM. The purpose of this study was to review the treatment courses and results of a special group of BSI patients with coexistent liver cirrhosis. Factors leading to poor results were analyzed and treatment strategy was proposed accordingly. During a 5-year period, 487 patients with BSI were treated following a standard protocol. Twelve of them had underlying liver cirrhosis. The medical records, radiographic findings, laboratory data, and operative variables were retrospectively reviewed. Eighty-nine (18%) patients had immediate celiotomy for splenic hemorrhage with unstable hemodynamic status, 59 (12%) had non-spleen-related or nontherapeutic laparotomy, and 339 (70%) patients received NOM initially. Failure of NOM was found in 74 patients (22%). Twelve patients with initial NOM had coexistent liver cirrhosis. The amount of blood transfusion within 72 hours after admission for these 12 patients ranged from 4 to 26 units. Patients with coexistent liver cirrhosis and BSI had a significantly higher NOM failure rate (92% vs. 19%). In NOM failure patients, those with liver cirrhosis had lower Injury Severity Scores, lower splenic injury severity grades, more blood transfusions, and a higher mortality rate. Risk factors for mortality in these patients included a higher Injury Severity Score, a severely elevated prothrombin time (PT), a larger transfusion requirement, and a lower serum albumin level. Liver cirrhosis with subsequent development of portal hypertension, splenomegaly, and coagulopathy makes spontaneous hemostasis of the injured spleen difficult. NOM for BSI patients with coexistent liver cirrhosis carries a high failure and mortality rate. NOM may be successful in only a small group of patients with low-grade single-organ injury and with a normal or mildly elevated PT. Aggressive correction of coagulopathy should be performed in these patients. High-grade splenic injury, multiple associated injuries, and an elevated PT are indicators for early surgery. The mortality rate is high in patients with a severely prolonged PT irrespective of treatment modalities.


Two fixed-dose artemisinin combinations for drug-resistant falciparum and vivax malaria in Papua, Indonesia: an open-label randomised comparison.
The burden of Plasmodium vivax infections has been underappreciated, especially in southeast Asia where chloroquine resistant strains have emerged. Our aim was to compare the safety and efficacy of dihydroartemisinin-piperaquine with that of artemether-lumefantrine in patients with uncomplicated malaria caused by multidrug-resistant P falciparum and P vivax. 774 patients in southern Papua, Indonesia, with slide-confirmed malaria were randomly assigned to receive either artemether-lumefantrine or dihydroartemisinin-piperaquine and followed up for at least 42 days. The primary endpoint was the overall cumulative risk of parasitological failure at day 42 with a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, trial number 00157833. Of the 754 evaluable patients enrolled, 466 had infections with P falciparum, 175 with P vivax, and 113 with a mixture of both species. The overall risk of failure at day 42 was 43% (95% CI 38-48) for artemether-lumefantrine and 19% (14-23) for dihydroartemisinin-piperaquine (hazard ratio=3.0, 95% CI 2.2-4.1, p<0.0001). After correcting for reinfections, the risk of recrudescence of P falciparum was 4.4% (2.6-6.2) with no difference between regimens. Recurrence of vivax occurred in 38% (33-44) of patients given artemether-lumefantrine compared with 10% (6.9-14.0) given dihydroartemisinin-piperaquine (p<0.0001). At the end of the study, patients receiving dihydroartemisinin-piperaquine were 2.0 times (1.2-3.6) less likely to be anaemic and 6.6 times (2.8-16) less likely to carry vivax gametocytes than were those given artemether-lumefantrine. Both dihydroartemisinin-piperaquine and artemether-lumefantrine were safe and effective for the treatment of multidrug-resistant uncomplicated malaria. However, dihydroartemisinin-piperaquine provided greater post-treatment prophylaxis than did artemether-lumefantrine, reducing P falciparum reinfections and P vivax recurrences, the clinical public-health importance of which should not be ignored.


Evidence that endoplasmic reticulum (ER)-associated degradation of cystic fibrosis transmembrane conductance regulator is linked to retrograde translocation from the ER membrane.
The ubiquitin-proteasome pathway has been implicated in the degradation of newly synthesized, misfolded and unassembled proteins in the endoplasmic reticulum (ER). Using a cell-free reticulocyte lysate system we have examined the relationship between biosynthesis and ER-associated degradation of the cystic fibrosis transmembrane conductance regulator (CFTR), a polytopic protein with 12 predicted transmembrane segments. Our results provide direct evidence that full-length, glycosylated and membrane-integrated CFTR is a substrate for degradation and that degradation involves polyubiquitination and cytosolic proteolytic activity. CFTR ubiquitination was both temperature- and ATP-dependent. Degradation was significantly inhibited by EDTA, apyrase, and the proteasome inhibitors hemin and MG132. Degradation was inhibited to a lesser extent by clasto-lactacystin beta-lactone, ALLN, and Nalpha-tosyl-L-phenylalanine chloromethyl ketone and was relatively unaffected by lactacystin and N-tosyl lysyl chloromethyl ketone. In the presence of hemin, polyubiquitinated CFTR remained tightly associated with ER microsomes. However, membrane-bound ubiquitinated CFTR could be subsequently degraded into trichloroacetic acid-soluble fragments upon incubation in hemin-free, ATP-containing lysate. Thus ER-associated degradation of CFTR occurs via a membrane-bound, rather than cytosolic, intermediate and likely involves recruitment of degradation machinery to the ER membrane. Our data suggest a model in which the degradation of polytopic proteins such as CFTR is coupled to retrograde translocation and removal of the polypeptide from the lipid bilayer.


Effective forces in square well and square shoulder fluids.
We derive an analytical expression for the effective force between a pair of macrospheres immersed in a sea of microspheres, in the case where the interaction between the two unlike species is assumed to be a square well or a square shoulder of given range and depth (or height). This formula extends a similar one developed in the case of hard core interactions only. Qualitative features of such effective force and the resulting phase diagrams are then analyzed in the limit of no interaction between the small particles. Approximate force profiles are then obtained by means of integral equation theories (PY and HNC) combined with the superposition approximation and compared with exact ones from direct Monte Carlo simulations.


Signatures of the preagricultural peopling processes in sub-Saharan Africa as revealed by the phylogeography of early Y chromosome lineages.
The study of Y chromosome variation has helped reconstruct demographic events associated with the spread of languages, agriculture, and pastoralism in sub-Saharan Africa, but little attention has been given to the early history of the continent. In order to overcome this lack of knowledge, we carried out a phylogeographic analysis of haplogroups A and B in a broad data set of sub-Saharan populations. These two lineages are particularly suitable for this objective because they are the two most deeply rooted branches of the Y chromosome genealogy. Their distribution is almost exclusively restricted to sub-Saharan Africa where their frequency peaks at 65% in groups of foragers. The combined high-resolution single nucleotide polymorphism analysis with short tandem repeats variation of their subclades reveals strong geographic and population structure for both haplogroups. This has allowed us to identify specific lineages related to regional preagricultural dynamics in different areas of sub-Saharan Africa. In addition, we observed signatures of relatively recent contact, both among Pygmies and between them and Khoisan speaker groups from southern Africa, thus contributing to the understanding of the complex evolutionary relationships among African hunter-gatherers. Finally, by revising the phylogeography of the very early human Y chromosome lineages, we have obtained support for the role of southern Africa as a sink, rather than a source, of the first migrations of modern humans from eastern and central parts of the continent. These results open new perspectives on the early history of Homo sapiens in Africa, with particular attention to areas of the continent where human fossil remains and archaeological data are scant.


Enterotomy risk in abdominal wall repair: a prospective study.
To establish the incidence and predictive factors of enterotomy made during adhesiolysis in abdominal wall repair and to assess the impact of enterotomies and long-lasting adhesiolysis on postoperative morbidity such as sepsis, wound infection, abdominal complications and pneumonia, and socioeconomic costs. Adhesions frequently complicate surgical repair of abdominal wall hernia. Enterotomies made during adhesiolysis specifically have a large impact on morbidity of patients, especially surgical site infections. Little is known on the incidence and burden of enterotomies and long-lasting adhesiolysis in abdominal wall repair. Between June 2008 and June 2010 demographics, disease characteristics and perioperative data of all patients undergoing elective abdominal wall repair were included in a prospective cohort study that was focused on adhesiolysis-related problems. A trained researcher observed all surgeries and collected data on adhesion location, tenacity, adhesiolysis time, and inadvertent organ damage such as enterotomies. Primary outcome was the incidence of enterotomy, and predictive factors for enterotomy were assessed through univariate and multivariate analyses. In addition, we evaluated the impact of adhesiolysis and enterotomy on morbidity. A cohort of 133 abdominal wall repairs was analyzed. Adhesiolysis was required in 124 (93.2%), with a mean adhesiolysis time of 35.7 ± 29.8 minutes. Thirty-three enterotomies were made in 17 patients (12.8%). Two patients had a delayed diagnosed bowel perforation. Adhesiolysis time, hernia size greater than 10 cm, and fistula were significant predictive factors in univariate analysis. In multivariate analysis, only adhesiolysis time was a significant and independent predictive factor for enterotomy (P = 0.004). Trends toward an increased risk were seen for patients with mesh in situ and hernia size greater than 10 cm. Patients with enterotomy had significantly more urgent reoperations (P = 0.029), and they more often required parenteral feeding (P = 0.037). Moreover, patients with extensive adhesiolysis (adhesiolysis time, >30 minutes) more often suffered from wound infection (9/63 vs 2/70; P = 0.025), abdominal complications (5/63 vs 0/70; P = 0.022), and sepsis (4/63 vs 0/70; P = 0.048). One in 8 patients undergoing abdominal wall repair suffer inadvertent enterotomy following adhesiolysis. Adhesiolysis time predicts enterotomy. Morbidity in patients with extensive adhesiolysis and adhesiolysis complicated by enterotomy is high, inducing longer hospital stay and increased health care utilization.


A single intravenous injection of oncolytic picornavirus SVV-001 eliminates medulloblastomas in primary tumor-based orthotopic xenograft mouse models.
Difficulties of drug delivery across the blood-brain barrier (BBB) and failure to eliminate cancer stem cells (CSCs) are believed to be the major causes of tumor recurrences in children with medulloblastoma (MB). Seneca Valley virus-001 (SVV-001) is a naturally occurring oncolytic picornavirus that can be systemically administered. Here, we report its antitumor activities against MB cells in a panel of 10 primary tumor-based orthotopic xenograft mouse models. We found that SVV-001 killed the primary cultured xenograft cells, infected and replicated in tumor cells expressing CSC surface marker CD133, and eliminated tumor cells capable of forming neurospheres in vitro in 5 of the 10 xenograft models. We confirmed that SVV-001 could pass through BBB in vivo. A single i.v. injection of SVV-001 in 2 anaplastic MB models led to widespread infection of the preformed intracerebellar (ICb) xenografts, resulting in significant increase in survival (2.2-5.9-fold) in both models and complete elimination of ICb xenografts in 8 of the 10 long-term survivors. Mechanistically, we showed that the intracellular replication of SVV-001 is mediated through a subverted autophagy that is different from the bona fide autophagic process induced by rapamycin. Our data suggest that SVV-001 is well suited for MB treatment. This work expands the current views in the oncolytic therapy field regarding the utility of oncolytic viruses in simultaneous targeting of stem and nonstem tumor cells.


Impaired migration and delayed differentiation of pancreatic islet cells in mice lacking EGF-receptors.
Pancreatic acini and islets are believed to differentiate from common ductal precursors through a process requiring various growth factors. Epidermal growth factor receptor (EGF-R) is expressed throughout the developing pancreas. We have analyzed here the pancreatic phenotype of EGF-R deficient (-/-) mice, which generally die from epithelial immaturity within the first postnatal week. The pancreata appeared macroscopically normal. The most striking feature of the EGF-R (-/-) islets was that instead of forming circular clusters, the islet cells were mainly located in streak-like structures directly associated with pancreatic ducts. Based on BrdU-labelling, proliferation of the neonatal EGF-R (-/-) beta-cells was significantly reduced (2.6+/-0.4 versus 5.8+/-0.9%, P<0.01) and the difference persisted even at 7-11 days of age. Analysis of embryonic pancreata revealed impaired branching morphogenesis and delayed islet cell differentiation in the EGF-R (-/-) mice. Islet development was analyzed further in organ cultures of E12.5 pancreata. The proportion of insulin-positive cells was significantly lower in the EGF-R (-/-) explants (27+/-6 versus 48+/-8%, P<0.01), indicating delayed differentiation of the beta cells. Branching of the epithelium into ducts was also impaired. Matrix metalloproteinase (MMP-2 and MMP-9) activity was reduced 20% in EGF-R (-/-) late-gestation pancreata, as measured by gelatinase assays. Furthermore, the levels of secreted plasminogen activator inhibitor-1 (PAI-1) were markedly higher, while no apparent differences were seen in the levels of active uPA and tPa between EGF-R (-/-) and wild-type pancreata. Our findings suggest that the perturbation of EGF-R-mediated signalling can lead to a generalized proliferation defect of the pancreatic epithelia associated with a delay in beta cell development and disturbed migration of the developing islet cells as they differentiate from their precursors. Upregulated PAI-1 production and decreased gelatinolytic activity correlated to this migration defect. An intact EGF-R pathway appears to be a prerequisite for normal pancreatic development.


Neuronal network plasticity and recovery from depression.
The brain processes sensory information in neuronal networks that are shaped by experience, particularly during early life, to optimally represent the internal and external milieu. Recent surprising findings have revealed that antidepressant drugs reactivate a window of juvenile-like plasticity in the adult cortex. When antidepressant-induced plasticity was combined with appropriate rehabilitation, it brought about a functional recovery of abnormally wired neuronal networks. These observations suggest that antidepressants act permissively to facilitate environmental influence on neuronal network reorganization and so provide a plausible neurobiological explanation for the enhanced effect of combining antidepressant treatment with psychotherapy. The results emphasize that pharmacological and psychological treatments of mood disorders are closely entwined: the effect of antidepressant-induced plasticity is facilitated by rehabilitation, such as psychotherapy, that guides the plastic networks, and psychotherapy benefits from the enhanced plasticity provided by the drug treatment. Optimized combinations of pharmacological and psychological treatments might help make best use of existing antidepressant drugs and reduce the number of treatment-resistant patients. The network hypothesis of antidepressant action presented here proposes that recovery from depression and related mood disorders is a gradual process that develops slowly and is facilitated by structured guidance and rehabilitation.


5,10,15,20-Tetra-kis(4-acetyl-oxyphen-yl)porphyrin including an unknown solvate.
Mol-ecules of the title compound, C52H38N4O8, are located on an inversion center so that the asymmetric cell contains one half of the mol-ecule. The macrocycle exhibits a ruffled conformation with a maximum deviation of 0.16 Å for the 24 macrocycle atoms: the dihedral angle between adjacent five-membered rings is 5.13 (19)°. The benzene rings are rotated by 70.25 (19)° with respect to their adjacent protonated five-membered rings, and by 65.56 (19)° with respect to the unprotonated rings. The porphyrin conformation is supported by bifurcated N-H⋯(N,N) hydrogen bonds. The structure contained poorly resolved solvent mol-ecules in voids of volume 217 Å(3) per unit cell. The latter were treated using the SQUEEZE routine in PLATON [Spek (2009 ▶). Acta Cryst. D65, 148-155]. As the solvent could not be identified exactly, it was not included in the calculation of the overall formula weight, density and absorption coefficient.


Is Decoupling GDP Growth from Environmental Impact Possible?
The argument that human society can decouple economic growth-defined as growth in Gross Domestic Product (GDP)-from growth in environmental impacts is appealing. If such decoupling is possible, it means that GDP growth is a sustainable societal goal. Here we show that the decoupling concept can be interpreted using an easily understood model of economic growth and environmental impact. The simple model is compared to historical data and modelled projections to demonstrate that growth in GDP ultimately cannot be decoupled from growth in material and energy use. It is therefore misleading to develop growth-oriented policy around the expectation that decoupling is possible. We also note that GDP is increasingly seen as a poor proxy for societal wellbeing. GDP growth is therefore a questionable societal goal. Society can sustainably improve wellbeing, including the wellbeing of its natural assets, but only by discarding GDP growth as the goal in favor of more comprehensive measures of societal wellbeing.


Sex differences in hypertension prevalence and control: Analysis of the 2010-2014 Korea National Health and Nutrition Examination Survey.
Although not fully understood, sex may affect both the prevalence and control rate of hypertension. The present study was designed to investigate factors associated with hypertension prevalence and control among Korean adults. We analyzed 27,887 individuals (12,089 males and 15,798 females) aged 30 years or older who participated in the fifth (2010-2012) and sixth (2013-2014) Korea National Health and Nutrition Examination Survey. Multiple logistic regression models were applied to delineate factors associated with the prevalence and control of hypertension separately for men and women. Overall, the prevalence of hypertension was higher in men (34.6%) than in women (30.8%). However, after the age of 60 years, hypertension was more prevalent in females than in males. Regardless of sex, the older the participants were, the more likely they were to have hypertension. Factors positively associated with hypertension prevalence were old age, low education, and high BMI in women (p<0.001) and increasing age, low income, alcohol intake, and high BMI in men (p<0.001). The overall control rate of hypertension was higher in women (51.3%) than in men (44.8%). However, after the age of 60 years, hypertension control rates were higher in men than in women. Factors decreasing hypertension control were white-collared women and young age, alcohol consumption in men. Sex differences in hypertension prevalence and control were discovered among Korean adults. After the age of 60, females were more likely to have hypertension and less likely to maintain hypertension control than males of the same age range. Accordingly, sex-specific approaches are recommended for effective blood pressure management.


The Relationship Between People's Environmental Considerations and Pro-environmental Behavior in Lithuania.
Given the need for global action on climate change, it is crucial to comprehend which factors motivate people in different countries to act more pro-environmentally. Lithuania is a post-socialist country that has recently increased commitment to foster pro-environmental behavior of individuals, by implementing interventions that target mainly the personal costs and benefits of relevant behaviors. Yet, research suggests that people's general environmental considerations, namely biospheric values and environmental self-identity, can drive people' pro-environmental behavior and may be important targets for interventions. These studies, however, have been mostly conducted in Western Europe and the United States, with limited evidence of relationship between people's biospheric values, environmental self-identity and pro-environmental behaviors across different countries and cultures. We performed a correlational study with a convenience sample in Lithuania (n = 334). Consistent with previous studies and the theory, our study revealed that people's general environmental considerations were positively related with recycling and environmental activism, but not with fuel-efficient driving and the use of sustainable transportation in Lithuania. We conclude that general environmental considerations are related to pro-environmental behaviors beyond Western Europe and the United States. Yet, future studies need to examine the boundary conditions of this relationship and test whether interventions targeting environmental consideration can be effective to promote pro-environmental behavior.


Description of quantum coherence in thermodynamic processes requires constraints beyond free energy.
Recent studies have developed fundamental limitations on nanoscale thermodynamics, in terms of a set of independent free energy relations. Here we show that free energy relations cannot properly describe quantum coherence in thermodynamic processes. By casting time-asymmetry as a quantifiable, fundamental resource of a quantum state, we arrive at an additional, independent set of thermodynamic constraints that naturally extend the existing ones. These asymmetry relations reveal that the traditional Szilárd engine argument does not extend automatically to quantum coherences, but instead only relational coherences in a multipartite scenario can contribute to thermodynamic work. We find that coherence transformations are always irreversible. Our results also reveal additional structural parallels between thermodynamics and the theory of entanglement.


A targeted e-learning program for surgical trainees to enhance patient safety in preventing surgical infection.
Surgical site infection accounts for 20% of all health care-associated infections (HCAIs); however, a program incorporating the education of surgeons has yet to be established across the specialty. An audit of surgical practice in infection prevention was carried out in Beaumont Hospital from July to November 2009. An educational Web site was developed targeting deficiencies highlighted in the audit. Interactive clinical cases were constructed using PHP coding, an HTML-embedded language, and then linked to a MySQL relational database. PowerPoint tutorials were produced as online Flash audiovisual movies. An online repository of streaming videos demonstrating best practice was made available, and weekly podcasts were made available on the iTunes© store for free download. Usage of the e-learning program was assessed quantitatively over 6 weeks in May and June 2010 using the commercial company Hitslink. During the 5-month audit, deficiencies in practice were highlighted, including the timing of surgical prophylaxis (33% noncompliance) and intravascular catheter care in surgical patients (38% noncompliance regarding necessity). Over the 6-week assessment of the educational material, the SurgInfection.com Web pages were accessed more than 8000 times; 77.9% of the visitors were from Ireland. The most commonly accessed modality was the repository with interactive clinical cases, accounting for 3463 (43%) of the Web site visits. The average user spent 57 minutes per visit, with 30% of them visiting the Web site multiple times. Interactive virtual cases mirroring real-life clinical scenarios are likely to be successful as an e-learning modality. User-friendly interfaces and 24-hour accessibility will increases uptake by surgical trainees.


A comparison of acute treatment regimens for migraine in the emergency department.
Migraine headache is a common pediatric complaint among emergency department (ED) patients. There are limited trials on abortive therapies in the ED. The objective of this study was to apply a comparative effectiveness approach to investigate acute medication regimens for the prevention of ED revisits. Retrospective study using administrative data (Pediatric Health Information System) from 35 pediatric EDs (2009-2012). Children aged 7 to 18 years with a principal diagnosis of migraine headache were studied. The primary outcome was a revisit to the ED within 3 days for discharged patients. The primary analysis compared the treatment regimens and individual medications on the risk for revisit. The study identified 32,124 children with migraine; 27,317 (85%) were discharged, and 5.5% had a return ED visit within 3 days. At the index visit, the most common medications included nonopioid analgesics (66%), dopamine antagonists (50%), diphenhydramine (33%), and ondansetron (21%). Triptans and opiate medications were administered infrequently (3% each). Children receiving metoclopramide had a 31% increased odds for an ED revisit within 3 days compared with prochlorperazine. Diphenhydramine with dopamine antagonists was associated with 27% increased odds of an ED revisit compared with dopamine antagonists alone. Children receiving ondansetron had similar revisit rates to those receiving dopamine antagonists. The majority of children with migraines are successfully discharged from the ED and only 1 in 18 required a revisit within 3 days. Prochlorperazine appears to be superior to metoclopramide in preventing a revisit, and diphenhydramine use is associated with increased rates of return.


Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man.
In order to investigate the pharmacokinetic properties of psilocybin (PY), the main psychoactive compound of Psilocybe mushrooms, high performance liquid chromatographic procedures with column-switching coupled with electrochemical detection (HPLC-ECD) for reliable quantitative determination of the PY metabolites psilocin (PI) and 4-hydroxyindole-3-acetic acid (4HIAA) in human plasma were established. Sample work-up includes protection of the highly unstable phenolic analytes with ascorbic acid, freeze-drying and in-vitro microdialysis. The data of two controlled clinical studies with healthy volunteers are presented. The subjects (N = 6 for both studies) received single oral PY doses of 0.224 +/- 0.02 mg/kg b.wt. (10-20 mg) and intravenous doses of 1 mg PY, respectively. Peak plasma levels of PI after oral administration of PY were measured after 105 +/- 37 min showing an average concentration of 8.2 +/- 2.8 ng PI/ml plasma. 4HIAA peak concentrations of 150 +/- 61 ng/ml plasma were found 113 +/- 41 min after ingestion of PY. After intravenous administration, a mean PI maximum plasma concentration of 12.9 +/- 5.6 ng/ml plasma was found 1.9 +/- 1.0 min after injection. The maximum plasma levels appearing within a very short period indicate a rapid dephosphorylation of PY also when administered systemically. 4HIAA was not detected after 1 mg of intravenous PY. Estimates for the absolute bioavailability of PI after oral administration of PY were 52.7 +/- 20% (N = 3).


Does acupuncture have a role in the treatment of threatened miscarriage? Findings from a feasibility randomised trial and semi-structured participant interviews.
Threatened miscarriage is a common complication of early pregnancy increasing the risk of miscarriage or premature labour. Currently there is limited evidence to recommend any biomedical pharmacological or self-care management, resulting in a 'watchful waiting' approach. The objective of this study was to examine the feasibility of offering acupuncture as a therapeutic treatment for women presenting with threatened miscarriage. A mixed methods study involving a randomised controlled trial and semi structured interviews. A pragmatic acupuncture protocol including medical self-care advice was compared to an active control receiving touch intervention and medical self-care advice. Descriptive statistics were used to examine the demographic and baseline characteristics. Endpoints were analysed between groups using a mean t-test and chi-square tests with P < 0.05 considered statistically significant. Dichotomous data was expressed as Risk Ratio with 95 % confidence intervals. Eleven participants were purposively interviewed about their experiences on exiting the trial with interviews analysed using thematic analysis. Forty women were successfully randomised. For women receiving acupuncture there was a statically significant reduction with threatened miscarriage symptoms including bleeding, cramping and back pain compared with the control (p = 0.04). Thematic analysis revealed women were dissatisfied with the medical support and advice received. An overarching theme emerged from the data of 'finding something you can do.' This encompassed the themes: 'they said there was nothing they could do,' 'feeling the benefits' and 'managing while marking time.' Acupuncture was a feasible intervention and reduced threatened miscarriage symptoms when compared to a touch intervention. Further research is required to further explore acupuncture use for this common complication and whether it can reduce the incidence of miscarriage. Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12610000850077 . Date of registration 12/10/2010. Retrospectively registered, with first participant enrolled 11/10/2012.


The Glycolytic Enzyme PFKFB3 Is Involved in Estrogen-Mediated Angiogenesis via GPER1.
The endogenous estrogen 17β-estradiol (E2) is a key factor in promoting endothelial healing and angiogenesis. Recently, proangiogenic signals including vascular endothelial growth factor and others have been shown to converge in endothelial cell metabolism. Because inhibition of the glycolytic enzyme activator phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) reduces pathologic angiogenesis and estrogen receptor (ER) signaling stimulates glucose uptake and glycolysis by inducing PFKFB3 in breast cancer, we hypothesized that E2 triggers angiogenesis in endothelial cells via rapid ER signaling that requires PFKFB3 as a downstream effector. We report that treatment with the selective G protein-coupled estrogen receptor (GPER1) agonist G-1 (10-10 to 10-7 M) mimicked the chemotactic and proangiogenic effect of E2 as measured in a number of short-term angiogenesis assays in human umbilical vein endothelial cells (HUVECs); in addition, E2 treatment upregulated PFKFB3 expression in a time- and concentration-dependent manner. Such an effect peaked at 3 hours and was also induced by G-1 and abolished by pretreatment with the GPER1 antagonist G-15 or GPER1 siRNA, consistent with engagement of membrane ER. Experiments with the PFKFB3 inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one showed that PFKFB3 activity was required for estrogen-mediated HUVEC migration via GPER1. In conclusion, E2-induced angiogenesis was mediated at least in part by the membrane GPER1 and required upregulation of the glycolytic activator PFKFB3 in HUVECs. These findings unravel a previously unrecognized mechanism of estrogen-dependent endocrine-metabolic crosstalk in HUVECs and may have implications in angiogenesis occurring in ischemic or hypoxic tissues.


Ultraviolet light propagation under low visibility atmospheric conditions and its application to aircraft landing aid.
Light scattering in the atmosphere by particles and molecules gives rise to an aureole surrounding the source image that tends to reduce the contrast of the source with respect to the background. However, UV scattering phase functions of the haze droplets present a very important forward peak. The spreading of a detected signal in the UV is not as important as in the case of a clear atmosphere where Rayleigh scattering predominates. This physical property has to be taken into account to evaluate the potential of UV radiation as an aircraft landing aid under low visibility conditions. Different results characterizing UV runway lights, simulations of UV radiation propagation in the atmosphere, and the use of a simple detection algorithm applied to one particular sensor are presented.


Implementation of a four-year multimedia computer curriculum in cardiology at six medical schools.
The pressures of a changing health care system are making inroads on the commitment and effort that both basic science and clinical faculty can give to medical education. A tool that has the potential to compensate for decreased faculty time and thereby to improve medical education is multimedia computer instruction that is applicable at all levels of medical education, developed according to instructional design principles, and supported by evidence of effectiveness. The authors describe the experiences of six medical schools in implementing a comprehensive computer-based four-year curriculum in bedside cardiology developed by a consortium of university cardiologists and educational professionals. The curriculum consisted of ten interactive, patient-centered, case-based modules focused on the history, physical examination, laboratory data, diagnosis, and treatment. While an optimal implementation plan was recommended, each institution determined its own strategy. Major goals of the project, which took place from July 1996 to June 1997, were to identify and solve problems of implementation and to assess learners' and instructors' acceptance of the system and their views of its value. A total of 1,586 students used individual modules of the curriculum 6,131 times. Over 80% of students rated all aspects of the system highly, especially its clarity and educational value compared with traditional lectures. The authors discuss the aspects of the curriculum that worked, problems that occurred (such as difficulties in scheduling use of the modules in the third year), barriers to change and ways to overcome them (such as the type of team needed to win acceptance for and oversee implementation of this type of curriculum), and the need in succeeding years to formally assess the educational effectiveness of this and similar kinds of computer-based curricula.


Bilateral Deafness as a Complication of the Vaccination-A Case Report.
The vaccination has much profit for an infectious disease. On the other hand, there is little frequency, side effects may appear. It includes severe complication. We reported the case that resulted in bilateral acute profound hearing loss after mumps alone and measles and rubella (MR) vaccination. The case was a 5 years old girl. She inoculated mumps alone and MR vaccine. After 18days later, both sides profound hearing loss occurred in her. The hearing loss was not improved by the intravenous feeding of the steroid. Three months later, cochlea implantation was carried out to her right ear. She got hearing again. As for the hearing loss, mumps vaccine was considered as a cause from a latency period until the onset. The bilateral profound hearing loss that was a very rare complication was occurred by vaccination. The care of the hearing is important, but the mental care of an affected child and the parent is important, too.


The parallelism motifs of genomic data analysis.
Genomic datasets are growing dramatically as the cost of sequencing continues to decline and small sequencing devices become available. Enormous community databases store and share these data with the research community, but some of these genomic data analysis problems require large-scale computational platforms to meet both the memory and computational requirements. These applications differ from scientific simulations that dominate the workload on high-end parallel systems today and place different requirements on programming support, software libraries and parallel architectural design. For example, they involve irregular communication patterns such as asynchronous updates to shared data structures. We consider several problems in high-performance genomics analysis, including alignment, profiling, clustering and assembly for both single genomes and metagenomes. We identify some of the common computational patterns or 'motifs' that help inform parallelization strategies and compare our motifs to some of the established lists, arguing that at least two key patterns, sorting and hashing, are missing. This article is part of a discussion meeting issue 'Numerical algorithms for high-performance computational science'.


Firearm Legislation and Fatal Police Shootings in the United States.
To examine whether stricter firearm legislation is associated with rates of fatal police shootings. We used a cross-sectional, state-level design to evaluate the effect of state-level firearm legislation on rates of fatal police shootings from January 1, 2015, through October 31, 2016. We measured state-level variation in firearm laws with legislative scorecards from the Brady Center, and for fatal police shootings we used The Counted, an online database maintained by The Guardian. State-level firearm legislation was significantly associated with lower rates of fatal police shootings (incidence rate ratio = 0.961; 95% confidence interval = 0.939, 0.984). When we controlled for sociodemographic factors, states in the top quartile of legislative strength had a 51% lower incidence rate than did states in the lowest quartile. Laws aimed at strengthening background checks, promoting safe storage, and reducing gun trafficking were associated with fewer fatal police shootings. Legislative restrictions on firearms are associated with reductions in fatal police shootings. Public Health Implications. Although further research is necessary to determine causality and potential mechanisms, firearm legislation is a potential policy solution for reducing fatal police shootings in the United States.


Direct measurement of onset and offset phonation threshold pressure in normal subjects.
Phonation threshold pressures were directly measured in five normal subjects in a variety of voicing conditions. The effects of fundamental frequency, intensity, closure speed of the vocal folds, and laryngeal airway resistance on phonation threshold pressures were determined. Subglottic air pressures were measured using percutaneous puncture of the cricothyroid membrane. Both onset and offset of phonation were studied to see if a hysteresis effect produced lower offset pressures than onset pressures. Univariate analysis showed that phonation threshold pressure was influenced most strongly by fundamental frequency and intensity. Multiple linear regression showed that these two variables, as well as laryngeal airway resistance, most strongly predicted phonation threshold pressure. Two of the five subjects demonstrated a significant hysteresis effect, but one subject actually had higher offset pressures than onset pressures.


The pupil: a window on social automatic processing in autism spectrum disorder children.
Faces are crucial social stimuli, eliciting automatic processing associated with increased physiological arousal in observers. The level of arousal can be indexed by pupil diameter (the 'Event-Related Pupil Dilation', ERPD). However, many parameters could influence the arousal evoked by a face and its social saliency (e.g. virtual vs. real, neutral vs. emotional, static vs. dynamic). A few studies have shown an atypical ERPD in autism spectrum disorder (ASD) patients using several kinds of faces but no study has focused on identifying which parameter of the stimulus is the most interfering with face processing in ASD. In order to disentangle the influence of these parameters, we propose an original paradigm including stimuli along an ecological social saliency gradient: from static objects to virtual faces to dynamic emotional faces. This strategy was applied to 186 children (78 ASD and 108 typically developing (TD) children) in two pupillometric studies (22 ASD and 47 TD children in the study 1 and 56 ASD and 61 TD children in the study 2). Strikingly, the ERPD in ASD children is insensitive to any of the parameters tested: the ERPD was similar for objects, static faces or dynamic faces. On the opposite, the ERPD in TD children is sensitive to all the parameters tested: the humanoid, biological, dynamic and emotional quality of the stimuli. Moreover, ERPD had a good discriminative power between ASD and TD children: ASD had a larger ERPD than TD in response to virtual faces, while TD had a larger ERPD than ASD for dynamic faces. This novel approach evidences an abnormal physiological adjustment to socially relevant stimuli in ASD.


The hSkn-1a POU transcription factor enhances epidermal stratification by promoting keratinocyte proliferation.
Skn-1a is a POU transcription factor that is primarily expressed in the epidermis and is known to modulate the expression of several genes associated with keratinocyte differentiation. However, the formation of a stratified epidermis requires a carefully controlled balance between keratinocyte proliferation and differentiation, and a role for Skn-1a in this process has not been previously demonstrated. Here, our results show, surprisingly, that human Skn-1a contributes to epidermal stratification by primarily promoting keratinocyte proliferation and secondarily by enhancing the subsequent keratinocyte differentiation. In organotypic raft cultures of both primary human keratinocytes and immortalized HaCaT keratinocytes, human Skn-1a expression is associated with increased keratinocyte proliferation and re-epithelialization of the dermal substrates, resulting in increased numbers of keratinocytes available for the differentiation process. In these same raft cultures, human Skn-1a expression enhances the phenotypic changes of keratinocyte differentiation and the upregulated expression of keratinocyte differentiation genes. Conversely, expression of a dominant negative human Skn-1a transcription factor lacking the C-terminal transactivation domain blocks keratinocytes from proliferating and stratifying. Keratinocyte stratification is dependent on a precise balance between keratinocyte proliferation and differentiation, and our results suggest that human Skn-1a has an important role in maintaining epidermal homeostasis by promoting keratinocyte proliferation.


Information-maximization clustering based on squared-loss mutual information.
Information-maximization clustering learns a probabilistic classifier in an unsupervised manner so that mutual information between feature vectors and cluster assignments is maximized. A notable advantage of this approach is that it involves only continuous optimization of model parameters, which is substantially simpler than discrete optimization of cluster assignments. However, existing methods still involve nonconvex optimization problems, and therefore finding a good local optimal solution is not straightforward in practice. In this letter, we propose an alternative information-maximization clustering method based on a squared-loss variant of mutual information. This novel approach gives a clustering solution analytically in a computationally efficient way via kernel eigenvalue decomposition. Furthermore, we provide a practical model selection procedure that allows us to objectively optimize tuning parameters included in the kernel function. Through experiments, we demonstrate the usefulness of the proposed approach.


SU-E-T-215: A Technique for Treating Patients outside the Mosaiq R&V System for TrueBeam Users (or 4DTC).
When the record and verify (R&V) system (Mosaiq, Elekta Medical Systems) is unavailable to send information to the treatment console of the linear accelerator (Varian Clinac, Varian Medical Systems), treatment is manually delivered by entering parameters into the treatment console and loading backed up MLC files. The new linear accelerator, the TrueBeam (Varian Medical Systems) lacks the ability to manually deliver treatment by entering machine parameters into the treatment console. The TrueBeam can only deliver treatments using the R&V system or loading DICOM RT plan files directly in File Mode. Every time a prescription site is sent from the R&V system to the accelerator, a DICOM RT plan file is created by the R&V system. A script was created that reads the headers of these files, copies them to the treatment console and renames them in an identifiable form. At the end of each treatment day, the script is executed transferring only the DICOM RT plan files created that treatment day. A contingency report is then generated from the R&V system, which contains machine parameters for all fields for all patients under treatment. When the R&V system is unavailable the RT plan files are opened in file mode, and the machine parameters are verified using the contingency report before delivery. This system was tested on a cohort of patients. Each patient's plan was opened in file mode and the machine parameters were verified against the patient's planned treatment in the R&V system. All files opened in file mode were identical to the information stored in the R&V system. This was tested both on the TrueBeam and accelerators having the 4DTC. Our technique was validated and is an alternative method for delivering treatment when the R&V system is unavailable.


Dynamics of angiogenesis during murine retinal development: a coupled in vivo and in silico study.
The manner in which the superficial retinal vascular plexus (RVP) develops in neonatal wild-type mice is relatively well documented and poses an interesting challenge to the mathematical modelling community. Prior to birth, astrocyte sprouting and proliferation begin around the edge of the optic nerve head, and subsequent astrocyte migration in response to a chemotactic gradient of platelet-derived growth factor (PDGF)-A results in the formation of a dense scaffold on the surface of the inner retina. Astrocytes express a variety of chemotactic and haptotactic proteins that subsequently induce endothelial cell sprouting and modulate growth of the RVP. An experimentally informed, two-dimensional hybrid partial differential equation-discrete model is derived to track the outward migration of individual astrocyte and endothelial tip cells in response to the appropriate biochemical cues. Blood perfusion is included throughout the development of the plexus, and the evolving retinal trees are allowed to adapt and remodel by means of several biological stimuli. The resulting wild-type in silico RVP structures are compared with corresponding experimental whole mounts taken at various stages of development, and agreement between the respective vascular morphologies is found to be excellent. Subsequent numerical predictions help elucidate some of the key biological processes underlying retinal development and demonstrate the potential of the virtual retina for the investigation of various vascular-related diseases of the eye.


Host membrane glycosphingolipids and lipid microdomains facilitate Histoplasma capsulatum internalisation by macrophages.
Recognition and internalisation of intracellular pathogens by host cells is a multifactorial process, involving both stable and transient interactions. The plasticity of the host cell plasma membrane is fundamental in this infectious process. Here, the participation of macrophage lipid microdomains during adhesion and internalisation of the fungal pathogen Histoplasma capsulatum (Hc) was investigated. An increase in membrane lateral organisation, which is a characteristic of lipid microdomains, was observed during the first steps of Hc-macrophage interaction. Cholesterol enrichment in macrophage membranes around Hc contact regions and reduced levels of Hc-macrophage association after cholesterol removal also suggested the participation of lipid microdomains during Hc-macrophage interaction. Using optical tweezers to study cell-to-cell interactions, we showed that cholesterol depletion increased the time required for Hc adhesion. Additionally, fungal internalisation was significantly reduced under these conditions. Moreover, macrophages treated with the ceramide-glucosyltransferase inhibitor (P4r) and macrophages with altered ganglioside synthesis (from B4galnt1-/- mice) showed a deficient ability to interact with Hc. Coincubation of oligo-GM1 and treatment with Cholera toxin Subunit B, which recognises the ganglioside GM1, also reduced Hc association. Although purified GM1 did not alter Hc binding, treatment with P4 significantly increased the time required for Hc binding to macrophages. The content of CD18 was displaced from lipid microdomains in B4galnt1-/- macrophages. In addition, macrophages with reduced CD18 expression (CD18low ) were associated with Hc at levels similar to wild-type cells. Finally, CD11b and CD18 colocalised with GM1 during Hc-macrophage interaction. Our results indicate that lipid rafts and particularly complex gangliosides that reside in lipid rafts stabilise Hc-macrophage adhesion and mediate efficient internalisation during histoplasmosis.


Computational study of the free energy landscape of the miniprotein CLN025 in explicit and implicit solvent.
The prediction capabilities of atomistic simulations of peptides are hampered by different difficulties, including the reliability of force fields, the treatment of the solvent or the adequate sampling of the conformational space. In this work, we have studied the conformational profile of the 10 residue miniprotein CLN025 known to exhibit a β-hairpin in its native state to understand the limitations of implicit methods to describe solvent effects and how these may be compensated by using different force fields. For this purpose, we carried out a thorough sampling of the conformational space of CLN025 in explicit solvent using the replica exchange molecular dynamics method as a sampling technique and compared the results with simulations of the system modeled using the analytical linearized Poisson-Boltzmann (ALPB) method with three different AMBER force fields: parm94, parm96, and parm99SB. The results show the peptide to exhibit a funnel-like free energy landscape with two minima in explicit solvent. In contrast, the higher minimum nearly disappears from the energy surface when the system is studied with an implicit representation of the solvent. Moreover, the different force fields used in combination with the ALPB method do not describe the system in the same manner. The results of this work suggest that the balance between intra- and intermolecular interactions is the cause of the differences between implicit and explicit solvent simulations in this system, stressing the role of the environment to define properly the conformational profile of a peptide in solution.


Trade-offs of predation and foraging explain sexual segregation in African buffalo.
1. Many studies have investigated why males and females segregate spatially in sexually dimorphic species. These studies have focused primarily on temperate zone ungulates in areas lacking intact predator communities, and few have directly assessed predation rates in different social environments. 2. Data on the movement, social affiliation, mortality and foraging of radio-collared African buffalo (Syncerus caffer) were collected from 2001-06 in the Kruger National Park, South Africa. 3. The vast majority of mortality events were due to lion (Panthera leo) predation, and the mortality hazard associated with being an adult male buffalo in a male-only 'bachelor' group was almost four times higher than for adult females in mixed herds. The mortality rates of adult males and females within mixed herds were not statistically different. Mortality sites of male and female buffalo were in areas of low visibility similar to those used by bachelor groups, while mixed herds tended to use more open habitats. 4. Males in bachelor groups ate similar or higher quality food (as indexed by percentage faecal nitrogen), and moved almost a third less distance per day compared with mixed herds. As a result, males in bachelor groups gained more body condition than did males in breeding herds. 5. Recent comparative analyses suggest the activity-budget hypothesis as a common underlying cause of social segregation. However, our intensive study, in an area with an intact predator community showed that male and female buffalo segregated by habitat and supported the predation-risk hypothesis. Male African buffalo appear to trade increased predation risk for additional energy gains in bachelor groups, which presumably leads to increased reproductive success.


Comparison of rehabilitation outcomes in day hospital and home settings for people with acquired brain injury - a systematic review.
To conduct a systematic literature review that identifies and summarises the findings of studies that have compared the outcomes of outpatient, brain injury rehabilitation programmes conducted in real-life home settings and day hospital clinic settings. A systematic search, using specific inclusion and exclusion criteria, of English language electronic databases, as well as manual search of reference lists of identified articles. Each study was evaluated and rated using 11 methodological criteria. The findings are summarised. Database searches, using key terms, initially yielded 4484 articles. Of these articles, 17 articles were included in the review and rated according to methodological quality. The majority of studies indicated that the outcomes of rehabilitation programmes conducted in home settings are at least equivalent to rehabilitation conducted in day hospital and outpatient settings for people with acquired brain injury. Most identified studies (15/17) were with groups of people with a diagnosis of stroke, primarily over the age of 65 years. Assessments of impairment or activity limitation were primarily used to reflect outcomes and no studies used participation or goal-based outcome measures. The available studies indicate that outcomes of outpatient rehabilitation programmes delivered at home, of short-term duration (mostly 3 months) for people with stroke recently discharged from hospital, are at least equivalent to day hospital-based outpatient rehabilitation programme outcomes. However, there have been no controlled studies designed to investigate the influence of therapy context (home and clinic settings) on outcomes for people receiving outpatient neurological rehabilitation. Furthermore, investigations of the efficacy of community-based rehabilitation with younger people with brain injuries, caused by mechanisms other than stroke, are required.


ETS-domain transcription factor Elk-1 mediates neuronal survival: SMN as a potential target.
Elk-1 belongs to the ternary complex factors (TCFs) subfamily of the ETS domain proteins, and plays a critical role in the expression of immediate-early genes (IEGs) upon mitogen stimulation and activation of the mitogen-activated protein kinase (MAPK) cascade. The association of TCFs with serum response elements (SREs) on IEG promoters has been widely studied and a role for Elk-1 in promoting cell cycle entry has been determined. However, the presence of the ETS domain transcription factor Elk-1 in axons and dendrites of post-mitotic adult brain neurons has implications for an alternative function for Elk-1 in neurons other than controlling proliferation. In this study, possible alternative roles for Elk-1 in neurons were investigated, and it was demonstrated that blocking TCF-mediated transactivation in neuronal cells leads to apoptosis through a caspase-dependent mechanism. Indeed RNAi-mediated depletion of endogenous Elk-1 results in increased caspase activity. Conversely, overexpression of either Elk-1 or Elk-VP16 fusion proteins was shown to rescue PC12 cells from chemically-induced apoptosis, and that higher levels of endogenous Elk-1 correlated with longer survival of DRGs in culture. It was shown that Elk-1 regulated the Mcl-1 gene expression required for survival, and that RNAi-mediated degradation of endogenous Elk-1 resulted in elimination of the mcl-1 message. We have further identified the survival-of-motor neuron-1 (SMN1) gene as a novel target of Elk-1, and show that the ets motifs in the SMN1 promoter are involved in this regulation.


Isoindoline scaffold-based dual inhibitors of HDAC6 and HSP90 suppressing the growth of lung cancer in vitro and in vivo.
This study reports the synthesis of a series of 2-aroylisoindoline hydroxamic acids employing N-benzyl, long alkyl chain and acrylamide units as diverse linkers. In-vitro studies led to the identification of N-benzyl linker-bearing compound (10) and long chain linker-containing compound (17) as dual selective HDAC6/HSP90 inhibitors. Compound 17 displays potent inhibition of HDAC6 isoform (IC50 = 4.3 nM) and HSP90a inhibition (IC50 = 46.8 nM) along with substantial cell growth inhibitory effects with GI50 = 0.76 μM (lung A549) and GI50 = 0.52 μM (lung EGFR resistant H1975). Compound 10 displays potent antiproliferative activity against lung A549 (GI50 = 0.37 μM) and lung H1975 cell lines (GI50 = 0.13 μM) mediated through selective HDAC6 inhibition (IC50 = 33.3 nM) and HSP90 inhibition (IC50 = 66 nM). In addition, compound 17 also modulated the expression of signatory biomarkers associated with HDAC6 and HSP90 inhibition. In the in vivo efficacy evaluation in human H1975 xenografts, 17 induced slightly remarkable suppression of tumor growth both in monotherapy as well as the combination therapy with afatinib (20 mg/kg). Moreover, compound 17 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner suggesting that dual inhibition of HDAC6 and HSP90 can modulate immunosuppressive ability of tumor area.


Robotic-assisted laparoscopic prostatectomy.
Prostate cancer remains a significant health problem worldwide and is the second highest cause of cancer-related death in men. While there is uncertainty over which men will benefit from radical treatment, considerable efforts are being made to reduce treatment related side-effects and in optimising outcomes. This article reviews the development and introduction of robotic-assisted laparoscopic radical prostatectomy (RALP), the results to date, and the possible future directions of RALP.


Polaribacter vadi sp. nov., isolated from a marine gastropod.
A Gram-reaction-negative, non-motile, yellow-pigmented, NaCl-requiring bacterial strain, designated LPB0003T, was isolated from a marine gastropod, the granulated dogwhelk (Thais luteostoma). The complete genome sequence of strain LPB0003T (GenBank accession number CP017477), sized 3.81 Mb, had 3296 protein-coding genes. 16S rRNA gene sequence analysis indicated that strain LPB0003T belongs to the genus Polaribacter within the family Flavobacteriaceae with sequence similarities of 95.3-97.8 % to other species of the genus Polaribacter. The average nucleotide identities with closely related species were not higher than 80 %. The isoprenoid quinone (MK-6) and DNA G+C content (29.6 mol%) of strain LPB0003T fell within the expected ranges for the genus Polaribacter. The major polar lipids of the isolate were phosphatidylethanolamine, two unidentified aminolipids, an unidentified phospholipid, an unidentified glycolipid, and two unidentified lipids. The predominant cellular fatty acids were iso-C15 : 0, iso-C15 : 0 3-OH, C16 : 1ω7c and/or C16 : 1ω6c (summed feature 3), and C15 : 1ω6c. Based on phylogenetic, genomic and phenotypic data presented in this study, strain LPB0003T should be classified as a novel species of the genus Polaribacter, for which the name Polaribacter vadi sp. nov. is proposed. The type strain is LPB0003T (=KACC 18704T=JCM 31217T).


A prospective, quantitative study of mental health act assessments in England following the 2007 amendments to the 1983 act: did the changes fulfill their promise?
In 2008, the Mental Health Act (MHA) 2007 amendments to the MHA 1983 were implemented in England and Wales. The amendments were intended to remove perceived obstacles to the detention of high risk patients with personality disorders (PDs), sexual deviance and learning disabilities (LDs). The AMEND study aimed to test the hypothesis that the implementation of these changes would lead to an increase in numbers or proportions of patients with these conditions who would be assessed and detained under the MHA 2007. A prospective, quantitative study of MHA assessments undertaken between July-October 2008-11 at three English sites. Data were collected from local forms used for MHA assessment documentation and patient electronic databases. The total number of assessments in each four month period of data collection varied: 1034 in 2008, 1042 in 2009, 1242 in 2010 and 1010 in 2011 (n = 4415). Of the assessments 65.6% resulted in detention in 2008, 71.3% in 2009, 64.7% in 2010 and 63.5% in 2011. There was no significant change in the odds ratio of detention when comparing the 2008 assessments against the combined 2009, 2010 and 2011 data (OR = 1.025, Fisher's exact Χ 2 p = 0.735). Only patients with LD and 'any other disorder or disability of the mind' were significantly more likely to be assessed under the MHA post implementation (Χ2 = 5.485, P = 0.018; Χ2 = 24.962, P > 0.001 respectively). There was no significant change post implementation in terms of the diagnostic category of detained patients. In the first three years post implementation, the 2007 Act did not facilitate the compulsory care of patients with PDs, sexual deviance and LDs.


Free/dissociable insulin-like growth factor (IGF)-I, not total IGF-I, correlates with growth response during growth hormone treatment in children born small for gestational age.
IGF-I plays an important role in pre- and postnatal growth. Its serum levels are regulated by metabolic and genetic factors. Mean total IGF-I in short, small for gestational age (SGA) children is reduced, but within the normal range. Free/dissociable IGF-I is the bioactive form of IGF-I. The aim of the study was to investigate changes in free IGF-I during GH treatment in short SGA children and to evaluate whether free IGF-I levels contribute to predicting first-year growth response and/or adult height. DESIGN, SETTING, AND INTERVENTION: We conducted a randomized, double-blind GH dose-response study with a GH dose of either 1 mg/m(2).d (group A) or 2 mg/m(2).d (group B). Free IGF-I, total IGF-I, and IGF binding protein (IGFBP)-3 were determined at baseline, after 1 and 5 yr, at stop, and 6 months after GH discontinuation. We studied 73 (46 male) short SGA children (36 group A) with a baseline mean age of 7.7 (2.2) yr and a mean GH duration of 8.2 (2.1) yr. Untreated SGA children had a mean free IGF-I sd score (SDS) of -0.2 (1.2), not related to total IGF-I. During GH therapy, free IGF-I significantly increased to 1.6 (0.7) SDS, as did total IGF-I and IGFBP-3 [2.0 (0.8) and 1.3 (0.9), respectively]. Multiple regression analysis showed that baseline free IGF-I and IGFBP-3 were negatively correlated with adult height SDS, whereas baseline bone age delay, target height SDS, baseline height SDS, and GH dose were positively correlated. Free IGF-I was also negatively correlated with first-year growth response. Circulating baseline free IGF-I and IGFBP-3 were better predictors for adult height in GH-treated SGA children than total IGF-I, or total IGF-I to IGFBP-3 ratio. This suggests a possible role for free IGF-I measurement in predicting the effect of GH therapy in short SGA children.


Myospryn is a novel binding partner for dysbindin in muscle.
Dysbindin is a coiled-coil-containing protein that was initially identified in a screen for dystrobrevin-interacting proteins. Recently, dysbindin has been shown to be involved in the biogenesis of lysosome-related organelles and is also a major schizophrenia susceptibility factor. Although dysbindin has been implicated in a number of different cellular processes, little is known about its function. To determine the function of dysbindin in muscle, we performed a yeast two-hybrid screen to identify potential interacting proteins. Here we show that dysbindin binds to a novel 413-kDa protein, myospryn, which is expressed in cardiac and skeletal muscle. The transcript encoding myospryn encompasses genethonin-3, a transcript that is down-regulated in muscle from Duchenne muscular dystrophy patients and stretch-responsive protein 553, which is up-regulated in experimental muscle hypertrophy. The C terminus of myospryn contains BBC, FN3, and SPRY domains in a configuration reminiscent of the tripartite motif protein family, as well as the dysbindin-binding site and a region mediating self-association. Dysbindin and myospryn co-immunoprecipitate from muscle extracts and are extensively co-localized. These data demonstrate for the first time that there are tissue-specific ligands for dysbindin that may play important roles in the different disease states involving this protein.


Scaling body size fluctuations.
The size of an organism matters for its metabolic, growth, mortality, and other vital rates. Scale-free community size spectra (i.e., size distributions regardless of species) are routinely observed in natural ecosystems and are the product of intra- and interspecies regulation of the relative abundance of organisms of different sizes. Intra- and interspecies distributions of body sizes are thus major determinants of ecosystems' structure and function. We show experimentally that single-species mass distributions of unicellular eukaryotes covering different phyla exhibit both characteristic sizes and universal features over more than four orders of magnitude in mass. Remarkably, we find that the mean size of a species is sufficient to characterize its size distribution fully and that the latter has a universal form across all species. We show that an analytical physiological model accounts for the observed universality, which can be synthesized in a log-normal form for the intraspecies size distributions. We also propose how ecological and physiological processes should interact to produce scale-invariant community size spectra and discuss the implications of our results on allometric scaling laws involving body mass.


Cavity-enhanced optical parametric chirped-pulse amplification.
A novel method for the generation of high-energy ultrashort optical pulses is described and studied theoretically and numerically. Through the combination of parametric amplification and enhancement cavities, this method opens a route to generate few-cycle pulses at unprecedented average power levels through the use of a low-energy, high average-power pump source and energy storage in the enhancement cavity. Dispersion in the enhancement cavity ceases to be a concern with the use of long pump pulses. Limitations set by the Kerr nonlinearity of the amplifier crystal are analyzed, and ways to overcome them using self-defocusing nonlinearities are discussed.


Green/Roasted Coffee May Reduce Cardiovascular Risk in Hypercholesterolemic Subjects by Decreasing Body Weight, Abdominal Adiposity and Blood Pressure.
In previous studies, after regularly consuming a green/roasted coffee blend, body weight, body fat%, glucose, plasminogen activator inhibitor-1 (PAI-1), resistin, leptin, ghrelin, diastolic (DBP) and systolic blood pressure (SBP) significantly changed in healthy and hypercholesterolemic subjects. However, glucagon, total-cholesterol (T-C), triglycerides (TG), LDL-cholesterol (LDL-C) and Homeostasis Model Assessment index to estimate insulin resistance (HOMA-IR) only changed in the hypercholesterolemics. This work looks into the antiobesity effects of coffee blend and into the relationship of antiobesity with the aforementioned cardiometabolic modifications in hypercholesterolemics. (1) Methods: Tricipital and subscapular skinfolds, hip, thigh, arm and waist circumference (WC) were measured in normocholesterolemic and hypercholesterolemics. To understand the relationship between cardiometabolic and antiobesity results in hypercholesterolemics, factor analysis was carried out using baseline values of the variables that changed. (2) Results: WC, WC/hip and WC/height showed significant coffee×group interaction, and in hypercholesterolemics tended to decrease. After factor analysis, three factors emerged, accounting for 29.46, 13.13 and 11.79% of variance. Only factor 1 (main loadings: WC, DBP and SBP, body weight, WC/hip and WC/height ratios, TG and ghrelin, inversely) decreased after coffee intake. (3) Conclusion: Regularly consuming green/roasted coffee may help to control body weight, and in hypercholesterolemics, may reduce cardiovascular risk by reducing abdominal adiposity and blood pressure.


Mycobacterium microti tuberculosis in its maintenance host, the field vole (Microtus agrestis): characterization of the disease and possible routes of transmission.
The field vole (Microtus agrestis) is a known maintenance host of Mycobacterium microti. Previous studies have shown that infected animals develop tuberculosis. However, the disease is also known in cats and is sporadically reported from humans and other mammalian species. We examined trapped field voles from an endemic area, using a range of diagnostic approaches. These confirmed that a combination of gross and histological examination with culture is most appropriate to identify the true prevalence of the disease, which was shown to be more than 13% at times when older animals that have previously been shown to be more likely to develop the disease dominate the population. The thorough pathological examination of diseased animals showed that voles generally develop systemic disease with most frequent involvement of spleen and liver, followed by skin, lymph nodes, and lungs. The morphology of the lesions was consistent with active disease, and their distribution suggested skin wounds or oral and/or aerogenic infection as the main portal of entry. The demonstration of mycobacteria in open skin lesions, airways, and salivary glands indicated bacterial shedding from the skin and with sputum and saliva. This suggests not only the environment but also direct contact and devouring as likely sources of infection.


Microsatellite instability at AAAG repeat sequences in respiratory tract cancers.
We surveyed the occurrence of novel alleles at microsatellite sequences in non-small cell lung cancers (NSCLC) using 61 tetranucleotide repeat markers. The presence of at least one new allele, consistent with microsatellite instability (MSI), was observed in 26 of 61 (43%) markers involving 30 of 47 (64%) NSCLC. Twelve of the 26 markers detected new alleles in 2 or more tumors and 11 of these 12 markers contained an AAAG repeat sequence. Using this panel of 12 markers, MSI was detected in 24 of 47 (51%) NSCLC and 10 of 18 (56%) head and neck cancers but was only observed in 8 of 38 (21%) bladder cancers and 3 of 25 (12%) kidney cancers. Our results suggested that about 50% of respiratory tract cancers exhibited microsatellite instability predominantly at AAAG sequences. This distinct type of instability was termed EMAST for elevated microsatellite alterations at selected tetranucleotide repeats. The identification of markers with EMAST should have potential application for the molecular detection of respiratory tract cancers.


RetroPath2.0: A retrosynthesis workflow for metabolic engineers.
Synthetic biology applied to industrial biotechnology is transforming the way we produce chemicals. However, despite advances in the scale and scope of metabolic engineering, the research and development process still remains costly. In order to expand the chemical repertoire for the production of next generation compounds, a major engineering biology effort is required in the development of novel design tools that target chemical diversity through rapid and predictable protocols. Addressing that goal involves retrosynthesis approaches that explore the chemical biosynthetic space. However, the complexity associated with the large combinatorial retrosynthesis design space has often been recognized as the main challenge hindering the approach. Here, we provide RetroPath2.0, an automated open source workflow for retrosynthesis based on generalized reaction rules that perform the retrosynthesis search from chassis to target through an efficient and well-controlled protocol. Its easiness of use and the versatility of its applications make this tool a valuable addition to the biological engineer bench desk. We show through several examples the application of the workflow to biotechnological relevant problems, including the identification of alternative biosynthetic routes through enzyme promiscuity or the development of biosensors. We demonstrate in that way the ability of the workflow to streamline retrosynthesis pathway design and its major role in reshaping the design, build, test and learn pipeline by driving the process toward the objective of optimizing bioproduction. The RetroPath2.0 workflow is built using tools developed by the bioinformatics and cheminformatics community, because it is open source we anticipate community contributions will likely expand further the features of the workflow.


Heschl's gyrification pattern is related to speech-listening hemispheric lateralization: FMRI investigation in 281 healthy volunteers.
This study investigates the structure-function relationships between the anatomy of Heschl's gyri (HG) and speech hemispheric lateralization in 281 healthy volunteers (135 left-handers). Hemispheric lateralization indices (HFLIs) were calculated with Wilke's method from the activations obtained via functional magnetic resonance imaging while listening to lists of words (LIST). The mean HFLI during LIST was rightward asymmetrical, and left-handers displayed a trend toward decreased rightward asymmetry. The correlations between LIST BOLD contrast maps and individual HFLIs demonstrated that among the cortical areas showing significant asymmetry during LIST, only phonological regions explained HFLI variability. Significant positive correlations were present among the left HG, supramarginal gyri, and the anterior insula. Significant negative correlations occurred in the mid-part of the right superior temporal sulcus. Left HG had the largest functional activity during LIST and explained 10% of the HFLI variance. There was a strong anatomo-functional link in the HG: duplication was associated with a decrease in both the surface area of the anterior HG and HG functional activity. Participants with a single left HG exhibited leftward anatomical and functional asymmetry of HG, but participants with a left duplication lost either anatomical and/or functional leftward asymmetries. Finally, manual preference was related to HG anatomy, but not to HG functional asymmetries measured during LIST. The anatomical characteristics of left-handers (lower occurrence of right HG duplication and a smaller surface area of the right first HG) thus appeared to be unrelated to variations in speech lateralization with handedness.


HairMax LaserComb laser phototherapy device in the treatment of male androgenetic alopecia: A randomized, double-blind, sham device-controlled, multicentre trial.
The use of low levels of visible or near infrared light for reducing pain, inflammation and oedema, promoting healing of wounds, deeper tissue and nerves, and preventing tissue damage has been known for almost 40 years since the invention of lasers. The HairMax LaserComb is a hand-held Class 3R lower level laser therapy device that contains a single laser module that emulates 9 beams at a wavelength of 655 nm (+/-5%). The device uses a technique of parting the user's hair by combs that are attached to the device. This improves delivery of distributed laser light to the scalp. The combs are designed so that each of the teeth on the combs aligns with a laser beam. By aligning the teeth with the laser beams, the hair can be parted and the laser energy delivered to the scalp of the user without obstruction by the individual hairs on the scalp. The primary aim of the study was to assess the safety and effectiveness of the HairMax LaserComb laser phototherapy device in the promotion of hair growth and in the cessation of hair loss in males diagnosed with androgenetic alopecia (AGA). This double-blind, sham device-controlled, multicentre, 26-week trial randomized male patients with Norwood-Hamilton classes IIa-V AGA to treatment with the HairMax LaserComb or the sham device (2 : 1). The sham device used in the study was identical to the active device except that the laser light was replaced by a non-active incandescent light source. Of the 110 patients who completed the study, subjects in the HairMax LaserComb treatment group exhibited a significantly greater increase in mean terminal hair density than subjects in the sham device group (p < 0.0001). Consistent with this evidence for primary effectiveness, significant improvements in overall hair regrowth were demonstrated in terms of patients' subjective assessment (p < 0.015) at 26 weeks over baseline. The HairMax LaserComb was well tolerated with no serious adverse events reported and no statistical difference in adverse effects between the study groups. The results of this study suggest that the HairMax LaserComb is an effective, well tolerated and safe laser phototherapy device for the treatment of AGA in males.


Restricted mean survival time over 15 years for patients starting renal replacement therapy.
The restricted mean survival time (RMST) estimates life expectancy up to a given time horizon and can thus express the impact of a disease. The aim of this study was to estimate the 15-year RMST of a hypothetical cohort of incident patients starting renal replacement therapy (RRT), according to their age, gender and diabetes status, and to compare it with the expected RMST of the general population. Using data from 67 258 adult patients in the French Renal Epidemiology and Information Network (REIN) registry, we estimated the RMST of a hypothetical patient cohort (and its subgroups) for the first 15 years after starting RRT (cRMST) and used the general population mortality tables to estimate the expected RMST (pRMST). Results were expressed in three different ways: the cRMST, which calculates the years of life gained under the hypothesis of 100% death without RRT treatment, the difference between the pRMST and the cRMST (the years lost), and a ratio expressing the percentage reduction of the expected RMST: (pRMST - cRMST)/pRMST. Over their first 15 years of RRT, the RMST of end-stage renal disease (ESRD) patients decreased with age, ranging from 14.3 years in patients without diabetes aged 18 years at ESRD to 1.8 years for those aged 90 years, and from 12.7 to 1.6 years, respectively, for those with diabetes; expected RMST varied from 15.0 to 4.1 years between 18 and 90 years. The number of years lost in all subgroups followed a bell curve that was highest for patients aged 70 years. After the age of 55 years in patients with and 70 years in patients without diabetes, the reduction of the expected RMST was >50%. While neither a clinician nor a survival curve can predict with absolute certainty how long a patient will live, providing estimates on years gained or lost, or percentage reduction of expected RMST, may improve the accuracy of the prognostic estimates that influence clinical decisions and information given to patients.


Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects.
Anecdotal information and case reports suggest that intravenously administered vitamin C is used by Complementary and Alternate Medicine (CAM) practitioners. The scale of such use in the U.S. and associated side effects are unknown. We surveyed attendees at annual CAM Conferences in 2006 and 2008, and determined sales of intravenous vitamin C by major U.S. manufacturers/distributors. We also queried practitioners for side effects, compiled published cases, and analyzed FDA's Adverse Events Database. Of 199 survey respondents (out of 550), 172 practitioners administered IV vitamin C to 11,233 patients in 2006 and 8876 patients in 2008. Average dose was 28 grams every 4 days, with 22 total treatments per patient. Estimated yearly doses used (as 25 g/50 ml vials) were 318,539 in 2006 and 354,647 in 2008. Manufacturers' yearly sales were 750,000 and 855,000 vials, respectively. Common reasons for treatment included infection, cancer, and fatigue. Of 9,328 patients for whom data is available, 101 had side effects, mostly minor, including lethargy/fatigue in 59 patients, change in mental status in 21 patients and vein irritation/phlebitis in 6 patients. Publications documented serious adverse events, including 2 deaths in patients known to be at risk for IV vitamin C. Due to confounding causes, the FDA Adverse Events Database was uninformative. Total numbers of patients treated in the US with high dose vitamin C cannot be accurately estimated from this study. High dose IV vitamin C is in unexpectedly wide use by CAM practitioners. Other than the known complications of IV vitamin C in those with renal impairment or glucose 6 phosphate dehydrogenase deficiency, high dose intravenous vitamin C appears to be remarkably safe. Physicians should inquire about IV vitamin C use in patients with cancer, chronic, untreatable, or intractable conditions and be observant of unexpected harm, drug interactions, or benefit.


The Combination of Radiotherapy and Complement C3a Inhibition Potentiates Natural Killer cell Functions Against Pancreatic Cancer.
Pancreatic cancer is one of the deadliest cancers, against which current immunotherapy strategies are not effective. Herein, we analyzed the immune cell composition of the tumor microenvironment of pancreatic cancer samples in The Cancer Genome Atlas and found that the presence of intratumoral NK cells correlates with survival. Subsequent analysis also indicated that NK cell exclusion from the microenvironment is found in a high percentage of clinical pancreatic cancers and in preclinical models of pancreatic cancer. Mechanistically, NK cell exclusion is regulated in part by complement C3a and its receptor signaling. Inhibition of the C3a receptor enhances NK cell infiltration in syngeneic mouse models of pancreatic cancer resulting in tumor growth delay. However, tumor growth inhibition mediated by NK cells is not sufficient alone for complete tumor regression, but is potentiated when combined with radiation therapy. Our findings indicate that although C3a inhibition is a promising approach to enhance NK cell-based immunotherapy against pancreatic cancer, its combination with radiation therapy hold greater therapeutic benefit.


Glycosylation of immunoglobulin g: role of genetic and epigenetic influences.
To determine the extent to which genetic and epigenetic factors contribute to variations in glycosylation of immunoglobulin G (IgG) in humans. 76 N-glycan traits in circulating IgG were analyzed by UPLC in 220 monozygotic and 310 dizygotic twin pairs from TwinsUK. A classical twin study design was used to derive the additive genetic, common and unique environmental components defining the variance in these traits. Epigenome-wide association analysis was performed using the Illumina 27k chip. 51 of the 76 glycan traits studied have an additive genetic component (heritability, h (2) ) ≥ 0.5. In contrast, 12 glycan traits had a low genetic contribution (h(2)<0.35). We then tested for association between methylation levels and glycan levels (P<2 x10(-6)). Among glycan traits with low heritability probe cg08392591 maps to a CpG island 5' from the ANKRD11 gene, a p53 activator on chromosome 16. Probe cg26991199 maps to the SRSF10 gene involved in regulation of RNA splicing and particularly in regulation of splicing of mRNA precursors upon heat shock. Among those with high heritability we found cg13782134 (mapping to the NRN1L gene) and cg16029957 mapping near the QPCT gene to be array-wide significant. The proportion of array-wide epigenetic associations was significantly larger (P<0.005) among glycans with low heritability (42%) than in those with high heritability (6.2%). Glycome analyses might provide a useful integration of genetic and non-genetic factors to further our understanding of the role of glycosylation in both normal physiology and disease.


Evaluation of a modified clinical prediction rule for use with spinal manipulative therapy in patients with chronic low back pain: a randomized clinical trial.
Spinal Manipulative Therapy (SMT) and Active Exercise Therapy (AET) have both demonstrated efficacy in the treatment of Chronic Lower Back Pain (CLBP). A Clinical Prediction Rule (CPR) for responsiveness to SMT has been validated in a heterogeneous lower back pain population; however there is a need to evaluate this CPR specifically for patients with CLBP, which is a significant source of disability. We conducted a randomized controlled trial (RCT) in Veteran Affairs and civilian outpatient clinics evaluating a modification of the original CPR (mCPR) in CLBP, eliminating acute low back pain and altering the specific types of SMT to improve generalizability. We enrolled and followed 181 patients with CLBP from 2007 to 2010. Patients were randomized by status on the mCPR to undergo either SMT or AET twice a week for four weeks. Providers and statisticians were blinded as to mCPR status. We collected outcome measures at 5, 12 and 24-weeks post baseline. We tested our study hypotheses by a general linear model repeated measures procedure following a univariate analysis of covariance approach. Outcome measures included, Visual Analogue Scale, Bodily pain subscale of SF-36 and the Oswestry Disability Index, Patient Satisfaction and Patient Expectation. Of the 89 AET patients, 69 (78%) completed the study and of the 92 SMT patients, 76 (83%) completed the study. As hypothesized, we found main effects of time where the SMT and AET groups showed significant improvements in pain and disability from baseline. There were no differences in treatment outcomes between groups in response to the treatment, given the lack of significant treatment x time interactions. The mCPR x treatment x time interactions were not significant. The differences in outcomes between treatment groups were the same for positive and negative on the mCPR groups, thus our second hypothesis was not supported. We found no evidence that a modification of the original CPR can be used to discriminate CLBP patients that would benefit more from SMT. Further studies are needed to further clarify the patient characteristics that moderate treatment responsiveness to specific interventions for CLBP. ISRCTN30511490.


ZINC-INDUCED FACILITATOR-LIKE family in plants: lineage-specific expansion in monocotyledons and conserved genomic and expression features among rice (Oryza sativa) paralogs.
Duplications are very common in the evolution of plant genomes, explaining the high number of members in plant gene families. New genes born after duplication can undergo pseudogenization, neofunctionalization or subfunctionalization. Rice is a model for functional genomics research, an important crop for human nutrition and a target for biofortification. Increased zinc and iron content in the rice grain could be achieved by manipulation of metal transporters. Here, we describe the ZINC-INDUCED FACILITATOR-LIKE (ZIFL) gene family in plants, and characterize the genomic structure and expression of rice paralogs, which are highly affected by segmental duplication. Sequences of sixty-eight ZIFL genes, from nine plant species, were comparatively analyzed. Although related to MSF_1 proteins, ZIFL protein sequences consistently grouped separately. Specific ZIFL sequence signatures were identified. Monocots harbor a larger number of ZIFL genes in their genomes than dicots, probably a result of a lineage-specific expansion. The rice ZIFL paralogs were named OsZIFL1 to OsZIFL13 and characterized. The genomic organization of the rice ZIFL genes seems to be highly influenced by segmental and tandem duplications and concerted evolution, as rice genome contains five highly similar ZIFL gene pairs. Most rice ZIFL promoters are enriched for the core sequence of the Fe-deficiency-related box IDE1. Gene expression analyses of different plant organs, growth stages and treatments, both from our qPCR data and from microarray databases, revealed that the duplicated ZIFL gene pairs are mostly co-expressed. Transcripts of OsZIFL4, OsZIFL5, OsZIFL7, and OsZIFL12 accumulate in response to Zn-excess and Fe-deficiency in roots, two stresses with partially overlapping responses. We suggest that ZIFL genes have different evolutionary histories in monocot and dicot lineages. In rice, concerted evolution affected ZIFL duplicated genes, possibly maintaining similar expression patterns between pairs. The enrichment for IDE1 boxes in rice ZIFL gene promoters suggests a role in Zn-excess and Fe-deficiency up-regulation of ZIFL transcripts. Moreover, this is the first description of the ZIFL gene family in plants and the basis for functional studies on this family, which may play important roles in Zn and Fe homeostasis in plants.


Omega-6 and Omega-3 Fatty Acid-Derived Oxylipins from the Lipoxygenase Pathway in Maternal and Umbilical Cord Plasma at Delivery and Their Relationship with Infant Growth.
Omega-3 and omega-6 fatty acids are important for neonatal development and health. One mechanism by which omega-3 and omega-6 fatty acids exert their effects is through their metabolism into oxylipins and specialized pro-resolving mediators. However, the influence of oxylipins on fetal growth is not well understood. Therefore, the objective of this study was to identify oxylipins present in maternal and umbilical cord plasma and investigate their relationship with infant growth. Liquid chromatography-tandem mass spectrometry was used to quantify oxylipin levels in plasma collected at the time of delivery. Spearman's correlations highlighted significant correlations between metabolite levels and infant growth. They were then adjusted for maternal obesity (normal body mass index (BMI: ≤30 kg/m2) vs. obese BMI (>30 kg/m2) and smoking status (never vs. current/former smoker) using linear regression modeling. A p-value < 0.05 was considered statistically significant. Our study demonstrated a diverse panel of oxylipins from the lipoxygenase pathway present at the time of delivery. In addition, both omega-3 and omega-6 oxylipins demonstrated potential influences on the birth length and weight percentiles. The oxylipins present during pregnancy may influence fetal growth and development, suggesting potential metabolites to be used as biomarkers for infant outcomes.


Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium.
Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.


Mental disorders and their association with disability among internally displaced persons and returnees in Georgia.
There remains limited evidence on comorbidity of mental disorders among conflict-affected civilians, particularly internally displaced persons (IDPs) and former IDPs who have returned to their home areas (returnees). The study aim was to compare patterns of mental disorders and their influence on disability between IDPs and returnees in the Republic of Georgia. A cross-sectional household survey was conducted with adult IDPs from the conflicts in the 1990s, the 2008 conflict, and returnees. Posttraumatic stress disorder (PTSD), depression, anxiety, and disability were measured using cut scores on Trauma Screening Questionnaire, Patient Health Questionnaire 9, Generalised Anxiety Disorder 7, and the WHO Disability Assessment Schedule 2.0. Among the 3,025 respondents, the probable prevalence of PTSD, depression, anxiety, and comorbidity (>1 condition) was 23.3%, 14.0%, 10.4%, 12.4%, respectively. Pearson correlation coefficients (p < .001) were .40 (PTSD with depression), .38 (PTSD with anxiety), and .52 (depression with anxiety). Characteristics associated with mental disorders in regression analyses included displacement (particularly longer-term), cumulative trauma exposure, female gender, older age, poor community conditions, and bad household economic situation; coefficients ranged from 1.50 to 3.79. PTSD, depression, anxiety, and comorbidity were associated with increases in disability of 6.4%, 9.7%, 6.3%, and 15.9%, respectively. A high burden of psychiatric symptoms and disability persist among conflict-affected persons in Georgia.


Interleukin 13 (IL-13)-regulated expression of the chondroprotective metalloproteinase ADAM15 is reduced in aging cartilage.
The adamalysin metalloproteinase 15 (ADAM15) has been shown to protect against development of osteoarthritis in mice. Here, we have investigated factors that control ADAM15 levels in cartilage. Secretomes from wild-type and Adam15 -/- chondrocytes were compared by label-free quantitative mass spectrometry. mRNA was isolated from murine knee joints, either with or without surgical induction of osteoarthritis on male C57BL/6 mice, and the expression of Adam15 and other related genes quantified by RT-qPCR. ADAM15 in human normal and osteoarthritic cartilage was investigated similarly and by fluorescent immunohistochemistry. Cultured HTB94 chondrosarcoma cells were treated with various anabolic and catabolic stimuli, and ADAM15 mRNA and protein levels evaluated. There were no significant differences in the secretomes of chondrocytes from WT and Adam15 -/- cartilage. Expression of ADAM15 was not altered in either human or murine osteoarthritic cartilage relative to disease-free controls. However, expression of ADAM15 was markedly reduced upon aging in both species, to the extent that expression in joints of 18-month-old mice was 45-fold lower than in that 4.5-month-old animals. IL-13 increased expression of ADAM15 in HTB94 cells by 2.5-fold, while modulators of senescence and autophagy pathways had no effect. Expression of Il13 in the joint was reduced with aging, suggesting this cytokine may control ADAM15 levels in the joint. Expression of the chondroprotective metalloproteinase ADAM15 is reduced in aging human and murine joints, possibly due to a concomitant reduction in IL-13 expression. We thus propose IL-13 as a novel factor contributing to increased osteoarthritis risk upon aging.


Deep vein thrombosis prophylaxis in hospitalized medical patients: current recommendations, general rates of implementation, and initiatives for improvement.
Venous thromboembolism (VTE), which encompasses deep vein thrombosis and pulmonary embolism, is a leading cause of preventable morbidity and mortality following hospitalization. In the last decade, investigators have used randomized controlled trials to assess the efficacy and safety of various methods of VTE prevention for more than 20,000 medical patients. Identifying medical patients at risk for VTE and providing effective prophylaxis is now an important health care priority to reduce the burden of this morbid and sometimes fatal disease. Pharmacologic prophylaxis is the mainstay of VTE prevention. It is effective, safe, and cost effective. Multiple scientific guidelines support VTE prophylaxis in medical patients. Regulatory and accreditation agencies have mandated that hospitals use formalized systems to assess VTE risk and provide clinically appropriate prophylaxis measures to patients at risk.