Vascular, inflammatory, and metabolic factors associated with cognition in aging persons with chronic epilepsy.
We examined cognition in aging persons with chronic epilepsy; characterized targeted vascular, inflammatory, and metabolic risk factors associated with abnormal cognitive aging in the general population; and examined associations between cognition and vascular, inflammatory, and metabolic health. Participants included 40 persons with chronic localization-related epilepsy and 152 controls, aged 54.6 and 55.3, respectively. Participants underwent neuropsychological assessment, clinical examination, and fasting blood evaluation for quantification of vascular status (systolic and diastolic blood pressure, obesity/body mass index [BMI], total and high-density lipoprotein [HDL] cholesterol level, and homocysteine), inflammatory markers (high sensitivity C-reactive protein [hs-CRP], and interleukin-6 [IL-6]), and metabolic status (insulin resistance [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], glucose). Epilepsy participants exhibited impairment across all cognitive factor scores (all p's < 0.0001); abnormalities in BMI (p = 0.049), hs-CRP (p = 0.046), HOMA-IR (p = 0.0040), and fasting glucose (p = 0.03), with significant relationships between higher HOMA-IR with poorer Immediate Memory (p = 0.03) and Visuospatial Ability (0.03); elevated hs-CRP with poorer Visuospatial (p = 0.035) and Verbal Ability (p = 0.06); elevated BMI with poorer Speed/Flexibility (p = 0.04), Visuospatial (p = 0.001) and Verbal Ability (p = 0.02); and lower HDL with poorer Verbal Learning/Delayed Memory (p = 0.01), Speed/Flexibility (p = 0.043), and Working Memory (p = 0.008). Aging persons with chronic epilepsy exhibit multiple abnormalities in metabolic, inflammatory, and vascular health that are associated with poorer cognitive function.


Learning curves and teaching when acquiring nut-cracking in humans and chimpanzees.
Humans are considered superior to other species in their tool using skills. However, most of our knowledge about animals comes from observations in artificial conditions with individuals removed from their natural environment. We present a first comparison of humans and chimpanzees spontaneously acquiring the same technique as they forage in their natural environment. We compared the acquisition of the Panda nut-cracking technique between Mbendjele foragers from the Republic of Congo and the Taï chimpanzees from Côte d'Ivoire. Both species initially acquire the technique slowly with similar kinds of mistakes, with years of practice required for the apprentice to become expert. Chimpanzees more rapidly acquired the technique when an apprentice, and reached adult efficiency earlier than humans. Adult efficiencies in both species did not differ significantly. Expert-apprentice interactions showed many similar instances of teaching in both species, with more variability in humans due, in part to their more complex technique. While in humans, teaching occurred both vertically and obliquely, only the former existed in chimpanzees. This comparison of the acquisition of a natural technique clarifies how the two species differed in their technical intelligence. Furthermore, our observations support the idea of teaching in both species being more frequent for difficult skills.


International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors.
The Adhesion family forms a large branch of the pharmacologically important superfamily of G protein-coupled receptors (GPCRs). As Adhesion GPCRs increasingly receive attention from a wide spectrum of biomedical fields, the Adhesion GPCR Consortium, together with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification, proposes a unified nomenclature for Adhesion GPCRs. The new names have ADGR as common dominator followed by a letter and a number to denote each subfamily and subtype, respectively. The new names, with old and alternative names within parentheses, are: ADGRA1 (GPR123), ADGRA2 (GPR124), ADGRA3 (GPR125), ADGRB1 (BAI1), ADGRB2 (BAI2), ADGRB3 (BAI3), ADGRC1 (CELSR1), ADGRC2 (CELSR2), ADGRC3 (CELSR3), ADGRD1 (GPR133), ADGRD2 (GPR144), ADGRE1 (EMR1, F4/80), ADGRE2 (EMR2), ADGRE3 (EMR3), ADGRE4 (EMR4), ADGRE5 (CD97), ADGRF1 (GPR110), ADGRF2 (GPR111), ADGRF3 (GPR113), ADGRF4 (GPR115), ADGRF5 (GPR116, Ig-Hepta), ADGRG1 (GPR56), ADGRG2 (GPR64, HE6), ADGRG3 (GPR97), ADGRG4 (GPR112), ADGRG5 (GPR114), ADGRG6 (GPR126), ADGRG7 (GPR128), ADGRL1 (latrophilin-1, CIRL-1, CL1), ADGRL2 (latrophilin-2, CIRL-2, CL2), ADGRL3 (latrophilin-3, CIRL-3, CL3), ADGRL4 (ELTD1, ETL), and ADGRV1 (VLGR1, GPR98). This review covers all major biologic aspects of Adhesion GPCRs, including evolutionary origins, interaction partners, signaling, expression, physiologic functions, and therapeutic potential.


The maintenance of lymphatic vessels in the cornea is dependent on the presence of macrophages.
It has been shown previously that the presence in the cornea of antigen-presenting cells (APC), such as macrophages (MPS) and lymphangiogenesis, is a risk for corneal transplantation. We sought to determine whether the existence of lymphatic vessels in the non-inflamed cornea is associated with the presence of MPS. Flat mounts were prepared from corneas of untreated C57BL/6, CD11b(-/-), F4/80(-/-), and BALB/c mice, and after suture placement or corneal transplantation, observed by immunofluorescence for the presence of lymphatic vessels using LYVE-1 as a marker of lymphatic endothelium. Innate immune cells were detected in normal mouse corneas using CD11b, F4/80, CD40, as well as MHC-class II. Digital images of the flat mounts were taken using a spot image analysis system, and the area covered by lymphatic vessels was measured using NIH Image software. The number of spontaneous lymphatic vessels in C57BL/6 corneas was significantly greater than in BALB/c corneas (P = 0.03). There were more CD11b(+) (P < 0.01) and CD40(+), MHC-class II (+) cells in the C57BL/6 corneas than in BALB/c mouse corneas. MPS depletion via clodronate liposome in C57BL/6 mice led to fewer spontaneous lymphatic vessels and reduced inflammation-induced lymphangiogenesis relative to control mice. Mice deficient in CD11b or F4/80 had fewer spontaneous lymphatic vessels and less lymphangiogenesis than control C57BL/6 mice. C57BL/6 mouse corneas have more endogenous CD11b(+) cells and lymphatic vessels. The endogenous lymphatic vessels, along with pro-inflammatory MPS, account for the high risk of corneal graft rejection in C57BL/6 mice. CD11b(+) and F4/80(+) MPS appear to have an important role in of the formation of new lymphatic vessels.


Creatine kinase knockout mice show left ventricular hypertrophy and dilatation, but unaltered remodeling post-myocardial infarction.
Creatine kinase (CK) is responsible for the transport of high-energy phosphates in excitable tissue and is of central importance in myocardial energy homeostasis. Significant changes in myocardial energetics have been reported in mice lacking the various CK isoenzymes. Our hypothesis was that ablation of CK isoenzymes leads to cardiac hypertrophy, impaired function, and aggravation of left ventricular remodeling post-myocardial infarction. CK-deficient mice (CK KO) were examined by cardiac magnetic resonance imaging (MRI) to determine left ventricular volumes, ejection fraction, and mass: ten wild-type (WT), 6 mitochondrial CK KO (Mito-CK-/-), 10 cytosolic CK KO (M-CK-/-), and 10 mice with combined KO (M/Mito-CK-/-). While ejection fraction was similar in all groups, there was significant LV dilatation with a approximately 30% increase in LV end-diastolic volumes in Mito-CK-/- and in M/Mito-CK-/-. Compared to WT, there was a striking 73% and 64% increase of LV mass in Mito-CK-/- and in M/Mito-CK-/- mice, respectively, but no significant increase of LV mass (+33%; p=n.s.) in M-CK-/-. Furthermore, significant re-expression of beta-MHC, a marker of myocardial hypertrophy, was found in all CK-deficient hearts. LV remodeling was investigated by MRI in hearts of 7 WT and 10 M/Mito-CK-/- mice 4 weeks postmyocardial infarction (MI). Four weeks post-LAD ligation (MI size approximately 32%), WT and M/Mito-CK-/- showed a similar degree of cardiac dysfunction, dilatation, and hypertrophy. Mito-CK-/- and M/Mito-CK-/- mice show significant LV dilatation and marked LV hypertrophy, but LV remodeling post-MI is not aggravated. CK ablation leads to substantial adaptational changes in heart.


Cost analysis of enhancing linkages to HIV care following jail: a cost-effective intervention.
We are not aware of published cost-effectiveness studies addressing community transitional programs for HIV-infected jail detainees. To address this gap, data from 9 sites of EnhanceLink, a project that enrolled HIV-infected releasees from jails across the US, were examined. Figures on the number of clients served, cost of linkage services, number of linkages and 6-month sustained linkages to community HIV care, and number of clients achieving viral suppression were assessed for subjects released in the first quarter of 2010 (n = 543). The cost analysis included all costs that participating service agencies incurred. A cost-effectiveness analysis was conducted to estimate the new HIV cases averted by EnhanceLink and the cost per quality-adjusted life year saved by the program. The mean cost per linked client was $4,219; the mean cost per 6-month sustained linkage was $4,670; and the mean cost per client achieving viral suppression was $8,432. Compared to standard care, the cost per additional quality-adjusted life year saved was $72,285, suggesting that the EnhanceLink interventions were cost-effective from the societal perspective.


Racial/Ethnic Differences in Incidence and Persistence of Childhood Atopic Dermatitis.
Although previous studies have explored racial/ethnic differences in incident atopic dermatitis (AD) in childhood, few studies have examined risk factors associated with AD persistence. As such, we sought to examine differences in incidence and persistence of childhood AD by race/ethnicity accounting for sociodemographic characteristics and perinatal vitamin D levels. Using data from Project Viva, a prospective prebirth cohort in eastern Massachusetts, we studied 1,437 mother-child pairs with known AD status to examine the associations of race/ethnicity with maternally reported child AD. We used multivariable logistic regression, adjusting for sociodemographic factors and maternal plasma vitamin D, to estimate adjusted odds ratios (aORs) of AD incidence at early childhood and persistence at mid-childhood. Compared to non-Hispanic whites, non-Hispanic blacks (aOR = 2.71, 95% confidence interval = 1.75-4.19) and other non-Hispanics (aOR = 1.80, 95% confidence interval = 1.16-2.80) were more likely to have incident AD. Non-Hispanic blacks (aOR = 6.26, 95% confidence interval = 2.32-16.88) and Hispanics (aOR = 6.42, 95% CI = 1.93-21.41) with early childhood AD were more likely to have persistent AD. In conclusion, compared with non-Hispanic whites, AD incidence and persistence are higher among certain nonwhite racial/ethnic subgroups. Further research is warranted to identify environmental, socioeconomic, and genetic factors that may be responsible for the observed differences.


Spontaneous activity, economy of activity, and resistance to diet-induced obesity in rats bred for high intrinsic aerobic capacity.
Though obesity is common, some people remain resistant to weight gain even in an obesogenic environment. The propensity to remain lean may be partly associated with high endurance capacity along with high spontaneous physical activity and the energy expenditure of activity, called non-exercise activity thermogenesis (NEAT). Previous studies have shown that high-capacity running rats (HCR) are lean compared to low-capacity runners (LCR), which are susceptible to cardiovascular disease and metabolic syndrome. Here, we examine the effect of diet on spontaneous activity and NEAT, as well as potential mechanisms underlying these traits, in rats selectively bred for high or low intrinsic aerobic endurance capacity. Compared to LCR, HCR were resistant to the sizeable increases in body mass and fat mass induced by a high-fat diet; HCR also had lower levels of circulating leptin. HCR were consistently more active than LCR, and had lower fuel economy of activity, regardless of diet. Nonetheless, both HCR and LCR showed a similar decrease in daily activity levels after high-fat feeding, as well as decreases in hypothalamic orexin-A content. The HCR were more sensitive to the NEAT-activating effects of intra-paraventricular orexin-A compared to LCR, especially after high-fat feeding. Lastly, levels of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) in the skeletal muscle of HCR were consistently higher than LCR, and the high-fat diet decreased skeletal muscle PEPCK-C in both groups of rats. Differences in muscle PEPCK were not secondary to the differing amount of activity. This suggests the possibility that intrinsic differences in physical activity levels may originate at the level of the skeletal muscle, which could alter brain responsiveness to neuropeptides and other factors that regulate spontaneous daily activity and NEAT.


Parental obesity and offspring serum alanine and aspartate aminotransferase levels: the Framingham heart study.
Obesity is an important correlate of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. We sought to examine the relations between parental obesity and the serum ALT and AST levels among offspring in a community-based sample. Participants (n = 1732) of the Framingham Offspring Study (50% women; mean age, 42 years) who had serum ALT and AST measurements and both parents in the original Framingham cohort were studied. Study participants were grouped into early-onset parental obesity (n = 193) (at least one parent obese), later-onset parental obesity (n = 460), and no parental obesity (n = 1079) subgroups. The association between elevated ALT or AST levels and parental obesity was tested using generalized estimating equations to account for familial correlations. In multivariable analysis including adjustment for offspring obesity, significantly higher ALT levels were observed among individuals with paternal early-onset obesity as compared with those without paternal obesity (P = .02). Offspring with early-onset paternal obesity were more likely to have elevated ALT levels compared with those without paternal obesity (odds ratio, 1.75; 95% confidence interval, 1.06-2.89; P = .03). There was no association with elevated ALT levels among offspring with maternal early-onset obesity (odds ratio, 1.10; 95% confidence interval, 0.76-1.59; P = .61). There was no association between parental obesity and serum AST levels. Early-onset paternal obesity, but not maternal obesity, increases the odds of elevated serum ALT levels in offspring, suggesting a predisposition to developing elevated serum ALT levels that may be mediated through familial early-onset obesity.


Excretory calcinosis: a new fatal disease of wild American lobsters Homarus americanus.
A significant number of moribund and dead lobsters Homarus americanus were reported to New York state authorities by lobster fishers in Long Island Sound (LIS) during the summer of 2002. Morbid lobsters were characterised by an orange discolouration of the abdomen, lethargy, an excess of epibionts and poor post-capture survival. On necropsy, severe extensive multifocal or diffuse mineralised granulomatous inflammation of the gills and antennal glands was the most striking pathology. In the gills, granulomas often occluded the lumen of filaments, resulting in congestion, ischemia and coagulative necrosis of gill tissues. In the antennal glands, granulomas were concentrated along the border between the coelomosac and labyrinth. No significant pathogens were recovered from diseased individuals. In prechronic individuals, however, it was evident that granulomas were focused around calcium carbonate (aragonite) crystals. This disease may result from anomalously high sea-bottom temperatures in LIS (approximately 23 degrees C) during the summer of 2002 and associated disruptions of the calcium chemistry of lobsters in favour of deposition of minerals in soft tissues. The ultimate cause of death of affected lobsters is probably respiratory failure due to reduced effective surface area of the gills, exacerbated by hypermetabolic temperatures and an abundance of epibionts.


Soluble tumor necrosis factor receptors in chronic hepatitis C: a correlation with histological fibrosis and activity.
Tumor necrosis factor-alpha (TNF) is a mediator of inflammation and cellular immune response. Soluble TNF receptors (sTNFR) sTNF-R55 and sTNF-R75, which compete with cellular receptors for the binding of TNF, have been detected at high levels in infectious diseases including human immunodeficiency virus and HBV infection. In order to investigate the activation of the TNF system in HCV infection, we have analyzed the balance between TNF and sTNF-R in 60 HCV-infected subjects according to their clinical, biological, virological and histological characteristics. Serum TNF, sTNF-R55 and sTNF-R75 levels were determined by ELISA before any therapy and were compared to a control group of 60 healthy subjects and a group of 34 HBV-infected patients. Mean TNF levels were 50.5+/-4.5 pg/ml in HCV patients, and undetectable (<5 pg/ml) in the control subjects. sTNF-R55 and sTNF-R75 levels were significantly higher in HCV-infected patients than in the controls: 2.88+/-0.14 ng/ml vs. 1.30+/-0.05, (p = 0.0001), and 9.54+/-0.58 ng/ml vs. 4.19+/-016, (p = 0.0001), respectively. sTNF-R55 and TNF-alpha levels in HCV patients were not significantly different from levels in HBV patients. sTNF-R75 levels were slightly lower than in HBV patients (9.54+/-0.58 vs. 11.4+/-0.79 ng/ml, p = 0.03). In contrast to other infectious diseases, there was no correlation between levels of sTNF-R and TNF. sTNF-R75 but not TNF levels were correlated with aminotransferases levels (p = 0.0001 and p = 0.0015 for aspartate and alanine aminotransferase, respectively), while sTNF-R55 levels were significantly correlated only with aspartate aminotransferase levels (p = 0.003). sTNF-R75 levels were significantly correlated with the Metavir activity index (p = 0.01), and sTNF-R55 and sTNF-R75 levels were significantly higher in patients with vs. without cirrhosis (3.22+/-0.21 vs. 2.54+/-0.17 ng/ml (p<0.02) and 11.6+/-0.86 vs. 7.5+/-0.53 ng/ml (p<0.001), respectively). sTNF-R55, sTNF-R75 and TNF levels were not correlated with viral load, genotype or response to interferon therapy. Levels of soluble TNF receptors, and particularly sTNF-R75, are significantly correlated with the severity of the disease but not with virological parameters such as quantitative viremia and genotype. High TNF-R production could thus suggest that HCV-related liver disease involves immunological mechanisms, including activation of the TNF system.


Chylous ascites as a complication of left sided robot-assisted laparoscopic partial nephrectomy.
The aim of the study was to present a case series of the sparsely reported complication of chylous ascites (CA) after left sided robot-assisted laparoscopic partial nephrectomy (RALPN), identify possible risk factors for the development of postoperative CA, and explore current recommendations for identification, management and prevention of CA. A retrospective review of patients that were treated with a RALPN during a one year time period (August 2012 to August 2013) by one surgeon at our institution was conducted. A total of 12 patients were included in the study. Demographics, tumor characteristics, and perioperative outcomes were assessed. Three patients in the study experienced postoperative CA. All three patients had left sided surgery. The initial clinical suspicion for CA was raised due to complaints of abdominal pain with increased milky appearance of JP fluid. JP triglycerides were elevated in all three patients. The patients responded to conservative measures, with two patients treated with medium chain triglyceride diets and one patient treated with total parenteral nutrition (TPN). Among the patients treated with RALPN, the group that was diagnosed with postoperative CA (CA group) was found to have a statistically significant lower average body mass index (BMI) as compared to the group that did not have CA (non-CA group) (24.67 kg/m2 in the CA group versus 31.77 kg/m2 in the non-CA group; P = 0.026). Other demographic data, tumor characteristics, and perioperative outcomes were similar in both groups. CA as a result of RALPN is a newly reported and rare postoperative complication. As utilization of RALPN continues to increase, urologists should be aware of this possible complication and be adept at diagnosing and managing CA. We suggest that left sided retroperitoneal surgery and a lower BMI preoperatively be considered risk factors for developing this complication.


CPP-directed oligonucleotide exon skipping in animal models of Duchenne muscular dystrophy.
Antisense oligonucleotides (AOs) are effective splice switching agents and have potential as therapeutics via the exclusion or inclusion of specific target gene exons to ameliorate and modify disease progression. The leading example is Duchenne muscular dystrophy (DMD), a fatal muscle degenerative disease, where AO-mediated skipping of specific DMD gene exons can restore the disrupted DMD open reading frame, leading to the production of functional dystrophin protein and ameliorate the DMD phenotype in animal models. Clinical proof-of-concept has recently been shown in two successful, independent Phase I clinical trials. These trials both followed local intramuscular treatments, and the challenge now is to develop and test systemic protocols, which will be required for treatment-aimed disease modification. Recently, a number of groups have demonstrated the promise of AOs directly conjugated to cell-penetrating peptides (CPPs) as having significant potential for systemic delivery and therapeutic correction in DMD animal models. Here, we review the background to this work and describe in detail the experimental protocols used in studies aimed at investigating CPP-conjugated AOs as systemic splice correcting agents in animal models of DMD.


The extent and genetic basis of phenotypic divergence in life history traits in Mimulus guttatus.
Differential natural selection acting on populations in contrasting environments often results in adaptive divergence in multivariate phenotypes. Multivariate trait divergence across populations could be caused by selection on pleiotropic alleles or through many independent loci with trait-specific effects. Here, we assess patterns of association between a suite of traits contributing to life history divergence in the common monkey flower, Mimulus guttatus, and examine the genetic architecture underlying these correlations. A common garden survey of 74 populations representing annual and perennial strategies from across the native range revealed strong correlations between vegetative and reproductive traits. To determine whether these multitrait patterns arise from pleiotropic or independent loci, we mapped QTLs using an approach combining high-throughput sequencing with bulk segregant analysis on a cross between populations with divergent life histories. We find extensive pleiotropy for QTLs related to flowering time and stolon production, a key feature of the perennial strategy. Candidate genes related to axillary meristem development colocalize with the QTLs in a manner consistent with either pleiotropic or independent QTL effects. Further, these results are analogous to previous work showing pleiotropy-mediated genetic correlations within a single population of M. guttatus experiencing heterogeneous selection. Our findings of strong multivariate trait associations and pleiotropic QTLs suggest that patterns of genetic variation may determine the trajectory of adaptive divergence.


Identification of a Substrate Recognition Domain in the Replication Stress Response Protein Zinc Finger Ran-binding Domain-containing Protein 3 (ZRANB3).
DNA damage and other forms of replication stress can cause replication forks to stall. Replication stress response proteins stabilize and resolve stalled forks by mechanisms that include fork remodeling to facilitate repair or bypass of damaged templates. Several enzymes including SMARCAL1, HLTF, and ZRANB3 catalyze these reactions. SMARCAL1 and HLTF utilize structurally distinct accessory domains attached to an ATPase motor domain to facilitate DNA binding and catalysis of fork remodeling reactions. Here we describe a substrate recognition domain within ZRANB3 that is needed for it to recognize forked DNA structures, hydrolyze ATP, catalyze fork remodeling, and act as a structure-specific endonuclease. Thus, substrate recognition domains are a common feature of fork remodeling, SNF2-family, DNA-dependent ATPases, and our study provides further mechanistic understanding of how these enzymes maintain genome integrity during DNA replication.


Resting-brain functional connectivity predicted by analytic measures of network communication.
The complex relationship between structural and functional connectivity, as measured by noninvasive imaging of the human brain, poses many unresolved challenges and open questions. Here, we apply analytic measures of network communication to the structural connectivity of the human brain and explore the capacity of these measures to predict resting-state functional connectivity across three independently acquired datasets. We focus on the layout of shortest paths across the network and on two communication measures--search information and path transitivity--which account for how these paths are embedded in the rest of the network. Search information is an existing measure of information needed to access or trace shortest paths; we introduce path transitivity to measure the density of local detours along the shortest path. We find that both search information and path transitivity predict the strength of functional connectivity among both connected and unconnected node pairs. They do so at levels that match or significantly exceed path length measures, Euclidean distance, as well as computational models of neural dynamics. This capacity suggests that dynamic couplings due to interactions among neural elements in brain networks are substantially influenced by the broader network context adjacent to the shortest communication pathways.


Enhancing & Mobilizing the POtential for Wellness & Emotional Resilience (EMPOWER) among Surrogate Decision-Makers of ICU Patients: study protocol for a randomized controlled trial.
Critical illness increases the risk for poor mental health outcomes among both patients and their informal caregivers, especially their surrogate decision-makers. Surrogates who must make life-and-death medical decisions on behalf of incapacitated patients may experience additional distress. EMPOWER (Enhancing & Mobilizing the POtential for Wellness & Emotional Resilience) is a novel cognitive-behavioral, acceptance-based intervention delivered in the intensive care unit (ICU) setting to surrogate decision-makers designed to improve both patients' quality of life and death and dying as well as surrogates' mental health. Clinician stakeholder and surrogate participant feedback (n = 15), as well as results from an open trial (n = 10), will be used to refine the intervention, which will then be evaluated through a multisite randomized controlled trial (RCT) (n = 60) to examine clinical superiority to usual care. Feasibility, tolerability, and acceptability of the intervention will be evaluated through self-report assessments. Hierarchical linear modeling will be used to adjust for clustering within interventionists to determine the effect of EMPOWER on surrogate differences in the primary outcome, peritraumatic stress. Secondary outcomes will include symptoms of post-traumatic stress disorder, prolonged grief disorder, and experiential avoidance. Exploratory outcomes will include symptoms of anxiety, depression, and decision regret, all measured at 1 and 3 months from post-intervention assessment. Linear regression models will examine the effects of assignment to EMPOWER versus the enhanced usual care group on patient quality of life or quality of death and intensity of care the patient received during the indexed ICU stay assessed at the time of the post-intervention assessment. Participant exit interviews will be conducted at the 3-month assessment time point and will be analyzed using qualitative thematic data analysis methods. The EMPOWER study is unique in its application of evidence-based psychotherapy targeting peritraumatic stress to improve patient and caregiver outcomes in the setting of critical illness. The experimental intervention will be strengthened through the input of a variety of ICU stakeholders, including behavioral health clinicians, physicians, bereaved informal caregivers, and open trial participants. Results of the RCT will be submitted for publication in a peer-reviewed journal and serve as preliminary data for a larger, multisite RCT grant application. ClinicalTrials.gov, NCT03276559 . Retrospectively registered on 8 September 2017.


Discrimination of gastric cancer from normal by serum RNA based on surface-enhanced Raman spectroscopy (SERS) and multivariate analysis.
Here, the authors explore the feasibility of discriminating cancer patients from healthy controls by serum RNA detection based on surface-enhanced Raman spectroscopy (SERS) and multivariate analysis. MgSO(4)-aggregated silver nanoparticles (Ag NP) as the SERS-active substrate presented strong SERS signals to RNA. SERS measurements were performed on two groups of serum RNA samples: one group from patients (n = 31) with gastric cancer and the other group from healthy volunteers (n = 34). Tentative assignments of the Raman bands in the normalized SERS spectra demonstrated that there are differential expressions of circulating RNA between the gastric cancer group and the control group. Principal component analysis (PCA) combined with linear discriminate analysis (LDA) was introduced to differentiate gastric cancer from normal and achieved sensitivity of 100% and specificity of 94.1%. This exploratory study demonstrated potential for developing serum RNA SERS analysis into a useful clinical tool for noninvasive screening and detection of cancer.


Oligomycin A-induced inhibition of mitochondrial ATP-synthase activity suppresses boar sperm motility and in vitro capacitation achievement without modifying overall sperm energy levels.
Incubation of boar spermatozoa in a capacitation medium with oligomycin A, a specific inhibitor of the F0 component of the mitochondrial ATP synthase, induced an immediate and almost complete immobilisation of cells. Oligomycin A also inhibited the ability of spermatozoa to achieve feasible in vitro capacitation (IVC), as measured through IVC-compatible changes in motility patterns, tyrosine phosphorylation levels of the acrosomal p32 protein, membrane fluidity and the ability of spermatozoa to achieve subsequent, progesterone-induced in vitro acrosome exocytosis (IVAE). Both inhibitory effects were caused without changes in the rhythm of O2 consumption, intracellular ATP levels or mitochondrial membrane potential (MMP). IVAE was accompanied by a fast and intense peak in O2 consumption and ATP levels in control spermatozoa. Oligomycin A also inhibited progesterone-induced IVAE as well as the concomitant peaks of O2 consumption and ATP levels. The effect of oligomycin on IVAE was also accompanied by concomitant alterations in the IVAE-induced changes on intracellular Ca(2+) levels and MMP. Our results suggest that the oligomycin A-sensitive mitochondrial ATP-synthase activity is instrumental in the achievement of an adequate boar sperm motion pattern, IVC and IVAE. However, this effect seems not to be linked to changes in the overall maintenance of adequate energy levels in stages other than IVAE.


ECHO: health care performance assessment in several European health systems.
Strengthening health-care effectiveness, increasing accessibility and improving resilience are key goals in the upcoming European Union health-care agenda. European Collaboration for Health-Care Optimization (ECHO), an international research project on health-care performance assessment funded by the seventh framework programme, has provided evidence and methodology to allow the attainment of those goals. This article aims at describing ECHO, analysing its main instruments and discussing some of the ECHO policy implications. Using patient-level administrative data, a series of observational studies (ecological and cross-section with associated time-series analyses) were conducted to analyze population and patients' exposure to health care. Operationally, several performance dimensions such as health-care inequalities, quality, safety and efficiency were analyzed using a set of validated indicators. The main instruments in ECHO were: (i) building a homogeneous data infrastructure; (ii) constructing coding crosswalks to allow comparisons between countries; (iii) making geographical units of analysis comparable; and (iv) allowing comparisons through the use of common benchmarks. ECHO has provided some innovations in international comparisons of health-care performance, mainly derived from the massive pooling of patient-level data and thus: (i) has expanded the usual approach based on average figures, providing insight into within and across country variation at various meaningful policy levels, (ii) the important effort made on data homogenization has increased comparability, increasing stakeholders' reliance on data and improving the acceptance of findings and (iii) has been able to provide more flexible and reliable benchmarking, allowing stakeholders to make critical use of the evidence.


Cholecystokinin (CCK) and related adjunct peptide therapies for the treatment of obesity and type 2 diabetes.
Cholecystokinin (CCK) is a hormone secreted from I-cells of the gut, as well as neurons in the enteric and central nervous system, that binds and activates CCK-1 and CCK-2 receptors to mediate its biological actions. To date knowledge relating to the physiological significance of CCK has predominantly focused around induction of short-term satiety. However, CCK has also been highlighted to possess important actions in relation to the regulation of insulin secretion, as well as overall beta-cell function and survival. Consequently, this has led to the development of enzymatically stable, biologically active, CCK peptide analogues with proposed therapeutic promise for both obesity and type 2 diabetes. In addition, several studies have demonstrated metabolic, and therapeutically relevant, complementary biological actions of CCK with those of the incretin hormones GIP and GLP-1, as well as with amylin and leptin. Thus, stable CCK derivatives not only offer promise as potential independent weight-reducing and glucose-lowering drugs, but also as effective adjunctive therapies. This review focuses on the recent and ongoing developments of CCK in the context of new therapies for obesity and type 2 diabetes.


MicroScope--an integrated microbial resource for the curation and comparative analysis of genomic and metabolic data.
MicroScope is an integrated platform dedicated to both the methodical updating of microbial genome annotation and to comparative analysis. The resource provides data from completed and ongoing genome projects (automatic and expert annotations), together with data sources from post-genomic experiments (i.e. transcriptomics, mutant collections) allowing users to perfect and improve the understanding of gene functions. MicroScope (http://www.genoscope.cns.fr/agc/microscope) combines tools and graphical interfaces to analyse genomes and to perform the manual curation of gene annotations in a comparative context. Since its first publication in January 2006, the system (previously named MaGe for Magnifying Genomes) has been continuously extended both in terms of data content and analysis tools. The last update of MicroScope was published in 2009 in the Database journal. Today, the resource contains data for >1600 microbial genomes, of which ∼300 are manually curated and maintained by biologists (1200 personal accounts today). Expert annotations are continuously gathered in the MicroScope database (∼50 000 a year), contributing to the improvement of the quality of microbial genomes annotations. Improved data browsing and searching tools have been added, original tools useful in the context of expert annotation have been developed and integrated and the website has been significantly redesigned to be more user-friendly. Furthermore, in the context of the European project Microme (Framework Program 7 Collaborative Project), MicroScope is becoming a resource providing for the curation and analysis of both genomic and metabolic data. An increasing number of projects are related to the study of environmental bacterial (meta)genomes that are able to metabolize a large variety of chemical compounds that may be of high industrial interest.


Glutamine suppresses PGE2 synthesis and breast cancer growth.
Reduced natural killer (NK) activity found in tumor-bearing hosts has been associated with high levels of prostaglandin E2 (PGE2) produced by monocytes in vitro. We have previously demonstrated a dependence of NK cell activity on glutamine (GLN) levels in vitro and in vivo. Further, glutathione (GSH) is antagonistic to PGE2 synthesis. We hypothesized that GLN, through increased GSH production, leads to decreased PGE2 synthesis and upregulation of NK cytotoxic activity. To test this, we examined the effects of oral GLN on GSH and PGE2 concentrations, NK activity and tumor growth in a rat breast cancer model. Starting on the day of MTF-7 tumor implantation 18 Fisher 344 rats were pair-fed chow and gavaged with 1 g/kg/day GLN (n = 9) or an isonitrogenous amount of Freamine (FA) (n = 9). Seven weeks after tumor implantation rats were sacrificed. Tumors were measured, weighed, and processed for tumor morphometrics. Spleens were removed, lymphocytes isolated and assayed for NK activity. Blood GLN, GSH, and PGE2 concentrations were measured. Over the 7-week study period tumor growth was decreased by approximately 40% in the GLN-supplemented group. This decrease in growth was associated with a 2.5 fold greater NK activity in the GLN-fed rats vs FA-fed rats. This correlated with a 25% rise in GSH concentration and a proportional decrease in PGE2 synthesis. Decreased tumor volume in rats fed GLN was not associated with changes in morphometrics. Oral GLN supplementation enhances NK activity resulting in decreased tumor growth. The enhanced NK activity seen with oral GLN supplementation in the tumor-bearing host is associated with GSH mediated suppression of PGE2 synthesis.


Prepubertal exposure to commercial formulation of the herbicide glyphosate alters testosterone levels and testicular morphology.
Glyphosate is a herbicide widely used to kill weeds both in agricultural and non-agricultural landscapes. Its reproductive toxicity is related to the inhibition of a StAR protein and an aromatase enzyme, which causes an in vitro reduction in testosterone and estradiol synthesis. Studies in vivo about this herbicide effects in prepubertal Wistar rats reproductive development were not performed at this moment. Evaluations included the progression of puberty, body development, the hormonal production of testosterone, estradiol and corticosterone, and the morphology of the testis. Results showed that the herbicide (1) significantly changed the progression of puberty in a dose-dependent manner; (2) reduced the testosterone production, in semineferous tubules' morphology, decreased significantly the epithelium height (P < 0.001; control = 85.8 +/- 2.8 microm; 5 mg/kg = 71.9 +/- 5.3 microm; 50 mg/kg = 69.1 +/- 1.7 microm; 250 mg/kg = 65.2 +/- 1.3 microm) and increased the luminal diameter (P < 0.01; control = 94.0 +/- 5.7 microm; 5 mg/kg = 116.6 +/- 6.6 microm; 50 mg/kg = 114.3 +/- 3.1 microm; 250 mg/kg = 130.3 +/- 4.8 microm); (4) no difference in tubular diameter was observed; and (5) relative to the controls, no differences in serum corticosterone or estradiol levels were detected, but the concentrations of testosterone serum were lower in all treated groups (P < 0.001; control = 154.5 +/- 12.9 ng/dL; 5 mg/kg = 108.6 +/- 19.6 ng/dL; 50 mg/dL = 84.5 +/- 12.2 ng/dL; 250 mg/kg = 76.9 +/- 14.2 ng/dL). These results suggest that commercial formulation of glyphosate is a potent endocrine disruptor in vivo, causing disturbances in the reproductive development of rats when the exposure was performed during the puberty period.


Evidence for a GPR18 Role in Diurnal Regulation of Intraocular Pressure.
The diurnal cycling of intraocular pressure (IOP) was first described in humans more than a century ago. This cycling is preserved in other species. The physiologic underpinning of this diurnal variation in IOP remains a mystery, even though elevated pressure is indicated in most forms of glaucoma, a common cause of blindness. Once identified, the system that underlies diurnal variation would represent a natural target for therapeutic intervention. Using normotensive mice, we measured the regulation of ocular lipid species by the enzymes fatty acid amide hydrolase (FAAH) and N-arachidonoyl phosphatidylethanolamine phospholipase (NAPE-PLD), mRNA expression of these enzymes, and their functional role in diurnal regulation of IOP. We now report that NAPE-PLD and FAAH mice do not exhibit a diurnal cycling of IOP. These enzymes produce and break down acylethanolamines, including the endogenous cannabinoid anandamide. The diurnal lipid profile in mice shows that levels of most N-acyl ethanolamines and, intriguingly, N-arachidonoyl glycine (NAGly), decline at night: NAGly is a metabolite of arachidonoyl ethanolamine and a potent agonist at GPR18 that lowers intraocular pressure. The GPR18 blocker O1918 raises IOP during the day when pressure is low, but not at night. Quantitative PCR analysis shows that FAAH mRNA levels rise with pressure, suggesting that FAAH mediates the changes in pressure. Our results support FAAH-dependent NAGly action at GPR18 as the physiologic basis of the diurnal variation of intraocular pressure in mice.


Different substrate specificities of the two ADPR binding sites in TRPM2 channels of Nematostella vectensis and the role of IDPR.
NvTRPM2 (Nematostella vectensis Transient Receptor Potential Melastatin 2), the species variant of the human apoptosis-related cation channel hTRPM2, is gated by ADP-ribose (ADPR) independently of the C-terminal NUDT9H domain that mediates ADPR-directed gating in hTRPM2. The decisive binding site in NvTRPM2 is likely to be identical with the N-terminal ADPR binding pocket in zebra fish DrTRPM2. Our aim was a characterization of this binding site in NvTRPM2 with respect to its substrate specificity, in comparison to the classical ADPR interaction site within NUDT9H that is highly homologous in hTRPM2 and NvTRPM2, although only in NvTRPM2, catalytic (ADPRase) activity is conserved. With various ADPR analogues, key differences of the two sites were identified. Particularly, two reported antagonists on hTRPM2 were agonists on NvTRPM2. Moreover, IDP-ribose (IDPR) induced currents both in hTRPM2 and NvTRPM2 but not in NvTRPM2 mutants in which NUDT9H was absent. Thus, IDPR acts on NUDT9H rather than N-terminally, revealing a regulatory function of NUDT9H in NvTRPM2 opposed to that in hTRPM2. We propose that IDPR competitively inhibits the ADPRase function of NUDT9H and evokes ADPR accumulation. The findings provide important insights into the structure-function relationship of NvTRPM2 and will allow further characterization of the novel ADPR interaction site.


The novel membrane protein TMEM59 modulates complex glycosylation, cell surface expression, and secretion of the amyloid precursor protein.
Ectodomain shedding of the amyloid precursor protein (APP) by the two proteases alpha- and beta-secretase is a key regulatory event in the generation of the Alzheimer disease amyloid beta peptide (Abeta). At present, little is known about the cellular mechanisms that control APP shedding and Abeta generation. Here, we identified a novel protein, transmembrane protein 59 (TMEM59), as a new modulator of APP shedding. TMEM59 was found to be a ubiquitously expressed, Golgi-localized protein. TMEM59 transfection inhibited complex N- and O-glycosylation of APP in cultured cells. Additionally, TMEM59 induced APP retention in the Golgi and inhibited Abeta generation as well as APP cleavage by alpha- and beta-secretase cleavage, which occur at the plasma membrane and in the endosomes, respectively. Moreover, TMEM59 inhibited the complex N-glycosylation of the prion protein, suggesting a more general modulation of Golgi glycosylation reactions. Importantly, TMEM59 did not affect the secretion of soluble proteins or the alpha-secretase like shedding of tumor necrosis factor alpha, demonstrating that TMEM59 did not disturb the general Golgi function. The phenotype of TMEM59 transfection on APP glycosylation and shedding was similar to the one observed in cells lacking conserved oligomeric Golgi (COG) proteins COG1 and COG2. Both proteins are required for normal localization and activity of Golgi glycosylation enzymes. In summary, this study shows that TMEM59 expression modulates complex N- and O-glycosylation and suggests that TMEM59 affects APP shedding by reducing access of APP to the cellular compartments, where it is normally cleaved by alpha- and beta-secretase.


Implementation of central venous catheter bundle in an intensive care unit in Kuwait: Effect on central line-associated bloodstream infections.
Central line-associated bloodstream infection (CLABSIs) is an important healthcare-associated infection in the critical care units. It causes substantial morbidity, mortality and incurs high costs. The use of central venous line (CVL) insertion bundle has been shown to decrease the incidence of CLABSIs. Our aim was to study the impact of CVL insertion bundle on incidence of CLABSI and study the causative microbial agents in an intensive care unit in Kuwait. Surveillance for CLABSI was conducted by trained infection control team using National Health Safety Network (NHSN) case definitions and device days measurement methods. During the intervention period, nursing staff used central line care bundle consisting of (1) hand hygiene by inserter (2) maximal barrier precautions upon insertion by the physician inserting the catheter and sterile drape from head to toe to the patient (3) use of a 2% chlorohexidine gluconate (CHG) in 70% ethanol scrub for the insertion site (4) optimum catheter site selection. (5) Examination of the daily necessity of the central line. During the pre-intervention period, there were 5367 documented catheter-days and 80 CLABSIs, for an incidence density of 14.9 CLABSIs per 1000 catheter-days. After implementation of the interventions, there were 5052 catheter-days and 56 CLABSIs, for an incidence density of 11.08 per 1000 catheter-days. The reduction in the CLABSI/1000 catheter days was not statistically significant (P=0.0859). This study demonstrates that implementation of a central venous catheter post-insertion care bundle was associated with a reduction in CLABSI in an intensive care area setting.


Freshmen at a University in Appalachia Experience a Higher Rate of Campus than Family Food Insecurity.
Food insecurity means having limited or uncertain access, in socially acceptable ways, to an adequate and safe food supply. Ample evidence has identified college students as vulnerable to this problem, but little research has focused on freshmen. This cross-sectional study examined family and campus food insecurity among freshmen at a university in Appalachia. An online questionnaire contained sociodemographic items and scales that measured food security status, academic progress, coping strategies for accessing food, and social support. T-tests and Chi square analyses compared food insecure and food secure students. Statistical significance was p < .05. Participants were 456 freshmen, 118 males (26%) and 331 females (73%). Family and campus food insecurity were experienced by 32 (7.1%) and 98 (21.5%) of the freshmen, respectively, and 42.5% of those who experienced campus food insecurity believed their food access had worsened since starting college. Family and campus coping strategies, respectively, included stretching food (72.9 vs. 18.4%) and purchasing cheap, processed food (68.8 vs. 16.3%). Food secure students scored significantly higher on self-rated measures of academic progress (p < .01), and greater proportions of food secure students (60.7 vs. 43.9%, p < .01) perceived their eating habits since starting college as "healthy/very healthy," and perceived their health status as "good/excellent" (86.0 vs. 71.4%, p < .01). Students requested assistance with job opportunities (19.4%), affordable meal plans (18.4%), money management (13.3%), and eating healthy (11.2%). Findings suggest that college student food insecurity begins during the freshmen year, and that there is a need for campus and community-based interventions to increase food access among these freshmen and their families.


Effects of work-related factors on the breastfeeding behavior of working mothers in a Taiwanese semiconductor manufacturer: a cross-sectional survey.
In recent years, the creation of supportive environments for encouraging mothers to breastfeed their children has emerged as a key health issue for women and children. The provision of lactation rooms and breast pumping breaks have helped mothers to continue breastfeeding after returning to work, but their effectiveness is uncertain. The aim of this study was to assess the effects of worksite breastfeeding-friendly policies and work-related factors on the behaviour of working mothers. This study was conducted at a large Taiwanese semiconductor manufacturer in August-September 2003. Questionnaires were used to collect data on female employees' breastfeeding behaviour, child rearing and work status when raising their most recently born child. A total of 998 valid questionnaires were collected, giving a response rate of 75.3%. The results showed that 66.9% of survey respondents breastfed initially during their maternity leave, which averaged 56 days. Despite the provision of lactation rooms and breast pumping breaks, only 10.6% mothers continued to breastfeed after returning to work, primarily office workers and those who were aware of their company's breastfeeding-friendly policies. In conclusion, breastfeeding-friendly policies can significantly affect breastfeeding behaviour. However, an unfavourable working environment, especially for fab workers, can make it difficult to implement breastfeeding measures. With health professionals emphasizing that the importance of breastfeeding for infant health, and as only females can perform lactation, it is vital that women's work "productive role" and family "reproductive role" be respected and accommodated by society.


Very low protein diet enhances inflammation, malnutrition, and vascular calcification in uremic rats.
Clinical studies have shown that very low protein diet (VLPD) has negative effects on long-term survival. It remains unclear why VLPD induces premature death. The present study determined the underlying mechanism whereby VLPD exerts its harmful effects on uremic rats. Rats were divided into four groups and fed a normal diet or diets containing 0.3% adenine and low/normal protein with high/low phosphate. After 6 weeks, body weight, urinary biochemistry (creatinine and phosphate), serum biochemical parameters (urea, creatinine, fibroblast growth factor 23, albumin, and fetuin-A), systemic inflammatory markers (serum tumor necrosis factor-alpha and urinary 8-hydroxy-2'-deoxyguanosine), calcium content in the aorta, and serum calcium-phosphate precipitates were evaluated. Hepatic mRNA levels were also determined. Rats fed the diet containing 0.3% adenine developed severe azotemia. Rats fed VLPD developed malnutrition (decreases in body weight, serum albumin and fetuin-A levels, and urinary creatinine excretion) and systemic inflammation (increases in serum tumor necrosis factor-α and urinary 8-hydroxy-2'-deoxyguanosine) independent of phosphate status. VLPD decreased the serum fetuin-A level and hepatic fetuin-A synthesis and increased serum calcium-phosphate precipitates, a marker of calciprotein particle. A high-phosphate diet induced arterial medial calcification, which was enhanced by VLPD. Serum calcium-phosphate precipitate levels were correlated with the degree of inflammation, malnutrition, and aortic calcium content. Dietary phosphate restriction prevented VLPD-enhanced vascular calcification, but could not halt inflammation and malnutrition induced by VLPD. VLPD enhances inflammation, malnutrition, and vascular calcification in uremic rats, among which only vascular calcification is prevented by dietary phosphate restriction.


Incidence and bone biopsy findings of atypical femoral fractures.
Bisphosphonates are widely used in the treatment of osteoporosis. It has been suggested that bisphosphonate treatment may be associated with atypical femoral fractures (AFFs), severely suppressed bone turnover rate, and decreased mineralization. We studied bone properties using bone quantitative histomorphometry and Fourier transform infrared spectroscopic imaging (FTIRI) on patients with AFFs. Further, the incidence of AFFs was estimated. Patient records of Kuopio University Hospital, Finland from January 2007 to June 2009 were reviewed to identify all patients who had sustained and had been operated for AFF (n = 8). The incidence of AFFs among patients on bisphosphonates was 0.61 fractures/1,000 patients per year, compared to 0.0067/1,000 per year among untreated patients. The patients that underwent bone biopsy (n = 4) were postmenopausal women (aged 55.5-81.1 years) who had been treated with bisphosphonates for over 4 years. Histomorphometry revealed low trabecular bone volume. Bone formation and resorption parameters tended to be low. Trabecular bone single labels were detected in one patient in the region of interest. In the extended label search, trabecular bone double labels were found in two patients. Based on FTIRI results, higher phosphate-to-amide I ratio and collagen maturity were found compared to normal samples. The heterogeneity of phosphate-to-amide I ratio was low. Overall incidence of atypical femoral fractures is low. The poor fracture resistance in some patients on long-term bisphosphonate-therapy could be explained by low bone formation, and changes in bone composition, i.e., higher degree of mineralization, increased collagen maturity, and decreased heterogeneity of the degree of mineralization.


A double-blind placebo-controlled clinical evaluation of MultiStem for the treatment of ischemic stroke.
There is growing interest in neurorestorative and reparative therapies after acute stroke. MultiStem is an allogeneic cell therapy treatment comprising a population of multipotent adherent bone marrow cells that has shown safety in clinical trials of myocardial infarction and graft vs. host disease, as well as preclinical evidence of activity in stroke and other neurological damage models. MultiStem is now being evaluated in a clinical trial in patients that have suffered an ischemic stroke, in which the product is administered intravenously 24-36 h after the ischemic event. The Phase 2 randomized, double-blind, placebo-controlled, multicenter dose-escalation trial will consist of three treatment cohorts, including a placebo group, and two treatment groups involving dose tiers of either 400 million or 1200 million cells per patient. Patients will be treated at 24-36 h after stroke. The two primary objectives are to determine the highest well-tolerated and safe single dose of MultiStem up to a maximum of 1200 million total cells in subjects with ischemic stroke and to determine the efficacy of MultiStem on functional outcome in subjects with stroke as measured by the modified Rankin Scale at 90 days. Patients will also be evaluated using the National Institutes of Health Stroke Scale and Barthel Index. The study will explore other aspects including, uniquely, the measurement of spleen size after stroke by magnetic resonance imaging or computed tomography imaging. If MultiStem is safe and there is a signal of efficacy, a late stage phase IIb-III trial is planned.


The gibberellin biosynthetic genes AtGA20ox1 and AtGA20ox2 act, partially redundantly, to promote growth and development throughout the Arabidopsis life cycle.
The activity of the gibberellin (GA) biosynthetic enzymes GA 20-oxidases (GA20ox) is of particular importance in determining GA concentration in many plant species. In Arabidopsis these enzymes are encoded by a family of five genes: AtGA20ox1-AtGA20ox5. Transcript analysis indicated that they have different expression patterns and may thus participate differentially in GA-regulated developmental processes. We have used reverse genetics to determine the physiological roles of AtGA20ox1 and AtGA20ox2, the most highly expressed GA20ox genes during vegetative and early reproductive development. AtGA20ox1 and AtGA20ox2 act redundantly to promote hypocotyl and internode elongation, flowering time, elongation of anther filaments, the number of seeds that develop per silique and elongation of siliques, with AtGA20ox1 making the greater contribution to internode and filament elongation, and AtGA20ox2 making the greater contribution to flowering time and silique length. Pollination of the double mutant with wild-type pollen indicated that the GA promoting silique elongation is of maternal origin. The ga20ox2 phenotype revealed that GA promotes the number of stem internodes that elongate upon bolting, and does so independently of its effect on internode elongation. Comparison of the phenotype of the double mutant with that of the highly GA-deficient ga1-3 mutant indicates that other GA20ox genes contribute to all the developmental processes examined, and, in some cases such as root growth and leaf expansion, make major contributions, as these processes were unaffected in the double mutant. In addition, the effects of the mutations are mitigated by the homeostatic mechanism that acts on expression of other GA dioxygenase and GID1 receptor genes.


Despite improved quality of care in the Veterans Affairs health system, racial disparity persists for important clinical outcomes.
Both government and private health care systems have engaged in efforts to improve quality, but the effect of these initiatives on racial and ethnic disparities has not been well studied. In the decade following an organizational transformation, the Veterans Affairs (VA) health care system achieved substantial improvements in quality of care with minimal racial disparities for most process-of-care measures, such as rates of cholesterol screenings. However, in our study we observed a striking disconnect between high levels of performance on widely used process measures and modest levels of improvement in clinical outcomes, such as control of blood pressure, blood glucose, and cholesterol levels. We also observed a gap in clinical outcomes of as much as nine percentage points between African American veterans and white veterans. Almost all of the disparity in outcomes in the VA was explained by within-facility disparity, which suggests that VA medical centers need to measure and address racial gaps in care for their patient populations. Moreover, because cardiovascular disease and diabetes are major contributors to racial disparities in life expectancy, the findings of this study and others underscore the urgency of focused efforts to improve intermediate outcomes among African Americans in the VA and other settings.


Disclosure of cancer diagnosis and prognosis: a survey of the general public's attitudes toward doctors and family holding discretionary powers.
This study aimed to ask a sample of the general population about their preferences regarding doctors holding discretionary powers in relation to disclosing cancer diagnosis and prognosis. The researchers mailed 443 questionnaires to registered voters in a ward of Tokyo which had a socio-demographic profile similar to greater Tokyo's average and received 246 responses (response rate 55.5%). We describe and analysed respondents' attitudes toward doctors and family members holding discretionary powers in relation to cancer diagnoses disclose. Amongst respondents who wanted full disclosure about the diagnosis without delay, 117 (69.6 %) respondents agreed to follow the doctor's discretion, whilst 111 (66.1 %) respondents agreed to follow the family member's decision. For respondents who preferred to have the diagnosis and prognosis withheld, 59 (26.5 %) agreed to follow the doctor's decision, and 79 (35.3 %) of respondents agreed with following family member's wishes. The greater proportion of respondents wants or permits disclosure of cancer diagnosis and prognosis. In patients who reveal negative attitudes toward being given a cancer disclosure directly, alternative options exist such as telling the family ahead of the patient or having a discussion of the cancer diagnosis with the patient together with the family. It is recommended that health professionals become more aware about the need to provide patients with their cancer diagnosis and prognosis in a variety of ways.


Minimally invasive percutaneous screw fixation of traumatic spondylolisthesis of the axis.
OBJECT Most cases of traumatic spondylolisthesis of the axis (hangman's fracture) can be treated nonoperatively with reduction and subsequent immobilization in a rigid cervical collar or halo. However, in some instances, operative management is necessary and can be accomplished by using either anterior or posterior fusion techniques. Because open posterior procedures can result in significant blood loss, pain, and limited cervical range of motion, other less invasive options for posterior fixation are needed. The authors describe a minimally invasive, navigation-guided technique for surgical treatment of Levine-Edwards (L-E) Type II hangman's fractures. METHODS For 5 patients with L-E Type II hangman's fracture requiring operative reduction and internal fixation, percutaneous screw fixation directed through the fracture site was performed. This technique was facilitated by use of intraoperative 3D fluoroscopy and neuronavigation. RESULTS Of the 5 patients, 2 were women, 3 were men, and age range was 46-67 years. No intraoperative or postoperative complications occurred. All patients wore a rigid cervical collar, and flexion-extension radiographs were obtained at 6 months. For all patients, dynamic imaging demonstrated a stable construct. CONCLUSIONS L-E type II hangman's fractures can be safely repaired by using percutaneous minimally invasive surgical techniques. This technique may be appropriate, depending on circumstances, for all L-E Type I and II hangman's fractures; however, the degree of associated ligament injury and disc disruption must be accounted for. Percutaneous fixation is not appropriate for L-E Type III fractures because of significant displacement and ligament and disc disruption. This report is meant to serve as a feasibility study and is not meant to show superiority of this procedure over other surgical options.


Biophysical and computational fragment-based approaches to targeting protein-protein interactions: applications in structure-guided drug discovery.
Drug discovery has classically targeted the active sites of enzymes or ligand-binding sites of receptors and ion channels. In an attempt to improve selectivity of drug candidates, modulation of protein-protein interfaces (PPIs) of multiprotein complexes that mediate conformation or colocation of components of cell-regulatory pathways has become a focus of interest. However, PPIs in multiprotein systems continue to pose significant challenges, as they are generally large, flat and poor in distinguishing features, making the design of small molecule antagonists a difficult task. Nevertheless, encouragement has come from the recognition that a few amino acids - so-called hotspots - may contribute the majority of interaction-free energy. The challenges posed by protein-protein interactions have led to a wellspring of creative approaches, including proteomimetics, stapled α-helical peptides and a plethora of antibody inspired molecular designs. Here, we review a more generic approach: fragment-based drug discovery. Fragments allow novel areas of chemical space to be explored more efficiently, but the initial hits have low affinity. This means that they will not normally disrupt PPIs, unless they are tethered, an approach that has been pioneered by Wells and co-workers. An alternative fragment-based approach is to stabilise the uncomplexed components of the multiprotein system in solution and employ conventional fragment-based screening. Here, we describe the current knowledge of the structures and properties of protein-protein interactions and the small molecules that can modulate them. We then describe the use of sensitive biophysical methods - nuclear magnetic resonance, X-ray crystallography, surface plasmon resonance, differential scanning fluorimetry or isothermal calorimetry - to screen and validate fragment binding. Fragment hits can subsequently be evolved into larger molecules with higher affinity and potency. These may provide new leads for drug candidates that target protein-protein interactions and have therapeutic value.


Platelet rich plasma for the management of hair loss: Better alone or in combination?
Platelet-rich plasma (PRP) and autologous protein-based treatments have recently emerged as a potential therapeutic approach for hair loss-related disorders including androgenetic alopecia and alopecia areata. The safety and efficacy of repeated intradermal injections of PRP has proved to promote hair growth in a number of randomized clinical trials. Biologically active proteins and cytokines released upon platelet activation have shown to induce folliculogenesis and activate the anagen growing phase of dormant bulbs. Interestingly, further studies have revealed that combining PRP with other hair loss-related products may enhance the final performance of the treatment. These synergistic approaches include Food and Drug Administration (FDA) approved drugs such as finasteride or minoxidil, bioactive macromolecules and cell-based therapies. Here, recent research involving alone or combined therapy with platelet-rich plasma for the management of hair loss-related disorders are outlined and future prospects are discussed.


Dynamic chromosome movements during meiosis: a way to eliminate unwanted connections?
Dramatic chromosome motion is a characteristic of mid-prophase of meiosis that is observed across broadly divergent eukaryotic phyla. Although the specific mechanisms underlying chromosome motions vary among organisms studied to date, the outcome is similar in all cases: vigorous back-and-forth movement (as fast as approximately 1mum/sec for budding yeast), led by chromosome ends (or near-end regions), and directed by cytoskeletal components via direct association through the nuclear envelope. The exact role(s) of these movements remains unknown, although an idea gaining currency is that movement serves as a stringency factor, eliminating unwanted inter-chromosomal associations or entanglements that have arisen as part of the homolog pairing process and, potentially, unwanted associations of chromatin with the nuclear envelope. Turbulent chromosome movements observed during bipolar orientation of chromosomes for segregation could also serve similar roles during mitosis. Recent advances shed light on the contribution of protein complexes involved in the meiotic movements in chromosome dynamics during the mitotic program.


Casein kinase 1 family proteins promote Slimb-dependent Expanded degradation.
Hippo signalling integrates diverse stimuli related to epithelial architecture to regulate tissue growth and cell fate decisions. The Hippo kinase cascade represses the growth-promoting transcription co-activator Yorkie. The FERM protein Expanded is one of the main upstream Hippo signalling regulators in Drosophila as it promotes Hippo kinase signalling and directly inhibits Yorkie. To fulfil its function, Expanded is recruited to the plasma membrane by the polarity protein Crumbs. However, Crumbs-mediated recruitment also promotes Expanded turnover via a phosphodegron-mediated interaction with a Slimb/β-TrCP SCF E3 ligase complex. Here, we show that the Casein Kinase 1 (CKI) family is required for Expanded phosphorylation. CKI expression promotes Expanded phosphorylation and interaction with Slimb/β-TrCP. Conversely, CKI depletion in S2 cells impairs Expanded degradation downstream of Crumbs. In wing imaginal discs, CKI loss leads to elevated Expanded and Crumbs levels. Thus, phospho-dependent Expanded turnover ensures a tight coupling of Hippo pathway activity to epithelial architecture.


Posthospital course and outcome in schizophrenia.
To study the early course of schizophrenia, we assessed 79 early phase, young, DSM-III schizophrenic patients at two successive posthospital follow-ups, 2.5 and 5.0 years after index hospitalization. More than 50% of the sample had poor overall outcome, with either severe impairment in functioning and symptoms, or suicide, in the follow-up period. Rehospitalization rates decreased significantly during the course of the two posthospital assessments, despite the sample showing persisting psychosis. Only a small group of schizophrenic patients showed complete remission: 10% at the first follow-up and 17% at the second follow-up, when patients who suicided are excluded from consideration. While progressive deterioration is not common in schizophrenia, our relatively negative findings challenge the conclusions of some other longitudinal studies. Implications of our data on schizophrenic course are discussed.


Mechanical properties of bulk carbon nanostructures: effect of loading and temperature.
Carbon-based bulk nanostructures are believed to entail certain advantages over their parent low-dimensional materials and are promising candidates for supercapacitors due to their unique properties such as extremely high specific surface area and high conductivity. Herein the mechanical and structural properties of four types of carbon nanopolymorph-based nanomaterials were calculated using molecular dynamics simulations. Bulk carbon nanostructures composed of structural units of bent graphene flakes, short carbon nanotubes, fullerenes and their mixture were considered. The effect of the loading scheme and temperature was studied and constitutive relationships describing the deformation of the materials were given. The simulation results revealed that the effect of the loading scheme significantly depends on the type of structural units, and was slightly affected by the temperature especially for high densities. The constitutive equations obtained in this work can be applied to describe the mechanical behavior of new bulk carbon nanostructures.


First Report of Phytophthora palmivora Causing Fruit Rot of Fig (Ficus carica L.) in China.
Fresh fig (Ficus carica L.) has been grown on a large scale in Beijing, China, since 2011. In late July 2012, a rot disease occurred on immature fruit of fig after a heavy rain (average daily rainfall 170 mm) in Fangshan District, Beijing, which caused about 30% incidence of green fruit on trees. The symptom first appeared as a water-soaked lesion that was covered with a white, fluffy mass of mycelia, followed by a soft, mushy rot of infected area on the fruit. To isolate the causal agent, mycelia and sporangia from 10 symptomatic fruits were suspended in sterile water, spread on potato dextrose agar (PDA) plates, and incubated at 25°C for 18 h. The isolates from each diseased fruit showed the same colonial characteristics. A single sporangium was isolated under a dissecting microscope and transferred onto PDA to obtain a pure culture. On carrot agar, the colony was white and homogeneous with tidy edge, with a few aerial hyphae. Sporangia were obpyriform with obvious papillae and measured 54.7 to 63.8 (59.3) × 26.5 to 36.3 (30.7) μm. The chlamydospores produced in culture were spherical. The pathogen was identified as Phytophthora palmivora based on the morphological characteristics (3) and confirmed with ITS sequences by PCR amplification using rDNA universal primers ITS1 and ITS4. The resulting sequence (Accession No. KC131229) had a 99% identity to that of P. palmivora (JQ354937) isolated from Pachira aquatica. Koch's postulates were conducted by inoculating six surface-sterilized figs with a PDA plug from a 7-day-old culture, with six noninoculated (PDA plugs only) fruits serving as controls. The inoculated fruits were incubated at room temperature in a plastic box covered with film. Symptoms similar to those on the naturally infected fruits began on wounded fruits 48 h after inoculation and on non-wounded fruits 60 h after inoculation, while the six control fruits remained healthy. P. palmivora was reisolated from the symptomatic fruit tissue. P. palmivora is one of the most severe pathogens on edible figs, being reported by Japanese in 1941 (2). Fruit rot of fig caused by the pathogen was reported in Florida in 1984 (1). To our knowledge, this is the first report of P. palmivora leading to fruit rot on fig in China. References: (1) N. E. El-Gholl and S. A. Alfieri, Jr. Proc. Fla. State Hort. Soc. 97:327, 1984. (2) Y. Nisikado et al. Ber. Ohara Inst. 8:427, 1941. (3) Y. N. Yu. Flora Fungorum Sinicorum: Peronosporales (in Chinese) Vol. 6. Science Press, Beijing, 1998.


Missed diagnosis and misdiagnosis of infectious diseases in hematopoietic cell transplant recipients: an autopsy study.
Hematopoietic cell transplantation (HCT) is potentially curative for patients with hematologic disorders, but carries significant risks of infection-related morbidity and mortality. Infectious diseases are the second most common cause of death in HCT recipients, surpassed only by progression of underlying disease. Many infectious diseases are difficult to diagnose and treat, and may only be first identified by autopsy. However, autopsy rates are decreasing despite their value. The clinical and autopsy records of adult HCT recipients at our center who underwent autopsy between 1 January 2000 and 31 December 2017 were reviewed. Discrepancies between premortem clinical diagnoses and postmortem autopsy diagnoses were evaluated. Of 185 patients who underwent autopsy, 35 patients (18.8%) had a total of 41 missed infections. Five patients (2.7%) had >1 missed infection. Of the 41 missed infections, 18 (43.9%) were viral, 16 (39.0%) were fungal, 5 (12.2%) were bacterial, and 2 (4.9%) were parasitic. According to the Goldman criteria, 31 discrepancies (75.6%) were class I, 5 (12.2%) were class II, 1 (2.4%) was class III, and 4 (9.8%) were class IV. Autopsies of HCT recipients frequently identify clinically significant infectious diseases that were not suspected premortem. Had these infections been suspected, a change in management might have improved patient survival in many of these cases. Autopsy is underutilized and should be performed regularly to help improve infection-related morbidity and mortality. Illustrative cases are presented and the lessons learned from them are also discussed.


A receptor and binding protein interplay in the detection of a distinct pheromone component in the silkmoth Antheraea polyphemus.
Male moths respond to conspecific female-released pheromones with remarkable sensitivity and specificity, due to highly specialized chemosensory neurons in their antennae. In Antheraea silkmoths, three types of sensory neurons have been described, each responsive to one of three pheromone components. Since also three different pheromone binding proteins (PBPs) have been identified, the antenna of Antheraea seems to provide a unique model system for detailed analyzes of the interplay between the various elements underlying pheromone reception. Efforts to identify pheromone receptors of Antheraea polyphemus have led to the identification of a candidate pheromone receptor (ApolOR1). This receptor was found predominantly expressed in male antennae, specifically in neurons located beneath pheromone-sensitive sensilla trichodea. The ApolOR1-expressing cells were found to be surrounded by supporting cells co-expressing all three ApolPBPs. The response spectrum of ApolOR1 was assessed by means of calcium imaging using HEK293-cells stably expressing the receptor. It was found that at nanomolar concentrations ApolOR1-cells responded to all three pheromones when the compounds were solubilized by DMSO and also when DMSO was substituted by one of the three PBPs. However, at picomolar concentrations, cells responded only in the presence of the subtype ApolPBP2 and the pheromone (E,Z)-6,11-hexadecadienal. These results are indicative of a specific interplay of a distinct pheromone component with an appropriate binding protein and its related receptor subtype, which may be considered as basis for the remarkable sensitivity and specificity of the pheromone detection system.


Clinical prediction rule for identifying patients with vancomycin-resistant enterococci (VRE) at the time of admission to the intensive care unit in a low VRE prevalence setting.
The purpose of this study was to develop and validate a clinical prediction rule to screen patients at risk of vancomycin-resistant enterococci (VRE) carriage at intensive care unit (ICU) admission in a hospital setting with low VRE prevalence. This study was retrospectively conducted in the ICUs of a university-affiliated hospital in Korea, where active surveillance cultures for VRE had been run at ICU admission and weekly thereafter. In the derivation cohort from April 2008 to September 2010, risk factors for VRE carriage at ICU admission were determined and assigned weighted point values using a multivariate logistic regression model. In the validation cohort from October 2010 to March 2011, predictability of the prediction rule was evaluated. Of a total of 4445 cultures taken from patients at ICU admission, 153 (3.4%) patients carried VRE. In the derivation cohort, independent risk factors (assigned points) for VRE carriage at ICU admission were ICU readmission during hospitalization (1 point), chronic obstructive lung disease (2 points), recent antibiotic treatment (3 points) and recent vancomycin use (2 points). In the validation cohort, the sensitivity, specificity, and positive and negative predictive values of the prediction rule, on the basis of risk scores ≥3 points, were 84.2%, 82.5%, 15.2% and 99.3%, respectively. This clinical prediction rule for identifying VRE carriage at the time of ICU admission is expected to markedly reduce the screening volume (by 80.1%) in our healthcare facility. For use in clinical practice, the rule needs to be prospectively validated in other settings.


Model for MLL translocations in therapy-related leukemia involving topoisomerase IIβ-mediated DNA strand breaks and gene proximity.
Topoisomerase poisons such as the epipodophyllotoxin etoposide are widely used effective cytotoxic anticancer agents. However, they are associated with the development of therapy-related acute myeloid leukemias (t-AMLs), which display characteristic balanced chromosome translocations, most often involving the mixed lineage leukemia (MLL) locus at 11q23. MLL translocation breakpoints in t-AMLs cluster in a DNase I hypersensitive region, which possesses cryptic promoter activity, implicating transcription as well as topoisomerase II activity in the translocation mechanism. We find that 2-3% of MLL alleles undergoing transcription do so in close proximity to one of its recurrent translocation partner genes, AF9 or AF4, consistent with their sharing transcription factories. We show that most etoposide-induced chromosome breaks in the MLL locus and the overall genotoxicity of etoposide are dependent on topoisomerase IIβ, but that topoisomerase IIα and -β occupancy and etoposide-induced DNA cleavage data suggest factors other than local topoisomerase II concentration determine specific clustering of MLL translocation breakpoints in t-AML. We propose a model where DNA double-strand breaks (DSBs) introduced by topoisomerase IIβ into pairs of genes undergoing transcription within a common transcription factory become stabilized by antitopoisomerase II drugs such as etoposide, providing the opportunity for illegitimate end joining and translocation.


Quantitative optical determination of the viability of platelet concentrates.
An optical method to assess platelet viability in platelet transfusion concentrates has been developed which is based on the observation that healthy, discoid platelets transmit more light in shear flow than aged, spherical cells. Using a specially designed glass channel, the rise in transmission of light through platelet samples with agitation is referenced against a measurement of transmission without flow. Referencing the measurements may minimize the effects of red blood cell contamination, as well as other variations among platelet packs such as plasma characteristics and plastic container variability. At an optimal frequency of agitation, the ratio of the transmission of light with agitation to that of the sample at rest is found to correlate highly with the concentration of discoid platelets, r = 0.92 to 0.95 (P less than 0.001), for light sources including a HeNe laser and two LEDs. Using this index, the discoid platelet counts of twelve platelet packs are estimated and compared with manual counts. The mean difference between the two methods was 0.009 x 10(9) discoid platelets ml-1 with a standard deviation of 0.11 x 10(9) cells ml-1. We conclude that the method may be applied to the development of a non-invasive device to monitor the concentration of viable, discoid platelets in storage.


The effect of intravenous iron therapy on long-term survival in anaemic colorectal cancer patients: Results from a matched cohort study.
Intravenous iron therapy has been shown to be advantageous in treating anaemia and reducing the need for blood transfusions. Iron treatment, however, may also be hazardous by supporting cancer growth. Present clinical study explores, for the first time, the effect of preoperative intravenous iron therapy on tumour prognosis in anaemic colorectal cancer patients. A retrospective cohort study was performed on consecutive patients who underwent surgery for colorectal cancer between 2010 and 2016 in a single teaching hospital. The primary outcomes were 5-year overall survival (OS) and disease-free survival (DFS). Survival estimates were calculated using the Kaplan-Meier method and patients were matched based on propensity score. 320 (41.0%) of all eligible patients were anaemic, of whom 102 patients received preoperative intravenous iron treatment (31.9%). After propensity score matching 83 patients were included in both intravenous and non-intravenous iron group. The estimated 1-, 3-, and 5-year OS (91.6%, 73.1%, 64.3%, respectively) and DFS (94.5%, 86.7%, 83.4%, respectively) in the intravenous iron group were comparable with the non-intravenous iron group (p = 0.456 and p = 0.240, respectively). In comparing patients with an event (death or recurrence) and no event in the intravenous iron group, a distinct trend was found for decreased transferrin in the event group (median 2.53 g/L vs 2.83 g/L, p = 0.052). The present study illustrates that a dose of 1000-2000 mg preoperative intravenous iron therapy does not have a profound effect on long-term overall and disease-free survival in anaemic colorectal cancer patients. Future randomised trials with sufficient power are required to draw definite conclusions on the safety of intravenous iron therapy.


Time for reform in transplant program-specific reporting: AST/ASTS transplant metrics taskforce.
In accordance with the National Organ Transplant Act and Department of Health and Human Services' Final Rule, the Scientific Registry of Transplant Recipients (SRTR) publicly releases biannual program-specific reports that include analyses of transplant centers' risk-adjusted waitlist mortality, organ acceptance ratios, transplant rates, and graft and patient survival. Since the inception of these center metrics, 1-year posttransplant graft and patient survival have improved, and center variation has decreased, casting uncertainty on their clinical relevance. The SRTR has recently modified center evaluations by ranking centers into 5 tiers rather than 3 tiers in an attempt to discriminate between programs performing within a tight range, further exacerbating this uncertainty. The American Society of Transplantation/American Society of Transplant Surgeons convened an expert taskforce to examine both the utility and unintended consequences of transplant center metrics. Estimates of center variation in outcomes in adjacent tiers are imprecise and fleeting, but can result in consequential changes in clinician and center behavior. The taskforce has concerns that current metrics, based principally on 1-year graft and patient survival, provide minimal if any benefit in informing patient choice and access to transplantation, with the untoward effect of decreased utilization of organs and restriction of research and innovation.


[The importance of genetics in the public health care system: report on the closing down of a genetics division in São Paulo, Brazil].
The availability of genetics services in hospitals should be an issue of public concern. Having genetics services helps shorten the time spent in making diagnoses and reduces the average number of inpatient days; it also helps accelerate the choice of adequate treatments, prevents or minimizes sequelae, and, ultimately, reduces costs. The objective of the present study was to describe the closing down in 1996 of the genetics division at the Menino Jesus Children's Hospital, a pediatric institution located in the city of São Paulo, SP, Brazil. A retrospective analysis was carried out of the work performed by this division between 1992 and 1996, with an emphasis on the detection of chromosomal abnormalities. Of all cases assessed during the study period, 571 were entered into a database. Some kind of chromosomal abnormality was observed in 20% of the 350 karyotypes performed. The existence of genetics services in hospitals helps minimize the appearance of clinical symptoms in carriers of genetic abnormalities, improves the quality of life of these patients, and enables them to receive information regarding risk of recurrence, while preventing the waste of resources that results from tests that are costly and unnecessary. Such benefits amply justify the investment in setting up genetics services of the type described here.


Watching the dynamics of electrons and atoms at work in solar energy conversion.
The photochemical reactions performed by transition metal complexes have been proposed as viable routes towards solar energy conversion and storage into other forms that can be conveniently used in our everyday applications. In order to develop efficient materials, it is necessary to identify, characterize and optimize the elementary steps of the entire process on the atomic scale. To this end, we have studied the photoinduced electronic and structural dynamics in two heterobimetallic ruthenium-cobalt dyads, which belong to the large family of donor-bridge-acceptor systems. Using a combination of ultrafast optical and X-ray absorption spectroscopies, we can clock the light-driven electron transfer processes with element and spin sensitivity. In addition, the changes in local structure around the two metal centers are monitored. These experiments show that the nature of the connecting bridge is decisive for controlling the forward and the backward electron transfer rates, a result supported by quantum chemistry calculations. More generally, this work illustrates how ultrafast optical and X-ray techniques can disentangle the influence of spin, electronic and nuclear factors on the intramolecular electron transfer process. Finally, some implications for further improving the design of bridged sensitizer-catalysts utilizing the presented methodology are outlined.


Compact in-line laser radial shear interferometer.
A compact in-line radial shearing interferometer using laser as a light source is presented. The interferometer is made out of a cube-type beam splitter so that the two opposite surfaces are generated with different curvatures while the normal to the entrance and exit surfaces are in the same line. The interferometer is simple to make and easy to align. Aberration analysis of the interferometer is also presented. Some applications of the interferometer for testing lenses and infrared optical systems and for accessing the quality of an emerging wave front from the exit slit of a monochromator are suggested.


Comparative interaction of cimetidine and ranitidine with racemic warfarin in man.
Cimetidine potentiates the anticoagulant effect of warfarin sodium, but in one small study ranitidine hydrochloride did not. Furthermore, these drugs have not been compared in the same subjects. Eleven normal subjects received single oral doses of 1.5 mg/kg racemic warfarin sodium alone, with cimetidine (1,200 mg/day orally), or with ranitidine (300 mg/day orally), beginning three days before the warfarin and daily thereafter for the duration of hypoprothrombinemia. Blood samples were obtained daily for determination of prothrombin times and warfarin concentrations. Cimetidine augmented both the hypoprothrombinemia and the blood concentrations of warfarin, but ranitidine did not. Substituted imidazoles like cimetidine inhibit hepatic microsomal activity, which may cause reduced metabolic clearance of warfarin and augment its anticoagulant effect. Ranitidine, lacking these effects, may be safer for patients undergoing anticoagulation who require H2-receptor antagonists.


Perspectives on model forecasts of the 2014-2015 Ebola epidemic in West Africa: lessons and the way forward.
The unprecedented impact and modeling efforts associated with the 2014-2015 Ebola epidemic in West Africa provides a unique opportunity to document the performances and caveats of forecasting approaches used in near-real time for generating evidence and to guide policy. A number of international academic groups have developed and parameterized mathematical models of disease spread to forecast the trajectory of the outbreak. These modeling efforts often relied on limited epidemiological data to derive key transmission and severity parameters, which are needed to calibrate mechanistic models. Here, we provide a perspective on some of the challenges and lessons drawn from these efforts, focusing on (1) data availability and accuracy of early forecasts; (2) the ability of different models to capture the profile of early growth dynamics in local outbreaks and the importance of reactive behavior changes and case clustering; (3) challenges in forecasting the long-term epidemic impact very early in the outbreak; and (4) ways to move forward. We conclude that rapid availability of aggregated population-level data and detailed information on a subset of transmission chains is crucial to characterize transmission patterns, while ensemble-forecasting approaches could limit the uncertainty of any individual model. We believe that coordinated forecasting efforts, combined with rapid dissemination of disease predictions and underlying epidemiological data in shared online platforms, will be critical in optimizing the response to current and future infectious disease emergencies.


Neurosurgical resident research education: a survey of United States residency program directors.
The application of evidence-based medicine (EBM) has played an increasing role within neurosurgical education over the last several decades. The Accreditation Council for Graduate Medical Education (ACGME) has mandated that residents are now required to demonstrate academic productivity and mastery of EBM principles. The goal of this study was to assess how neurosurgery programs around the US are dealing with the challenges of fulfilling these program requirements from the ACGME in addition to standard neurosurgical education. A 20-question survey was developed and electronically delivered to residency program directors of the 110 ACGME-approved MD and DO training programs in the US. Data regarding journal club and critical appraisal skills, research requirements, and protected research time were collected. Linear regression was used to determine significant associations between these data and reported resident academic productivity. Responses were received from 102 of the 110 (92.7%) neurosurgical training programs in the US. Ninety-eight programs (96.1%) confirmed a regularly scheduled journal club. Approximately half of programs (51.5%) indicated that the primary goal of their journal club was to promote critical appraisal skills. Only 58.4% of programs reported a formal EBM curriculum. In 57.4% of programs an annual resident publication requirement was confirmed. Multivariate regression models demonstrated that greater protected research time (p = 0.001), journal club facilitator with extensive training in research methods (p = 0.029), and earlier research participation during residency (p = 0.049) all increased the number of reported publications per resident. Although specific measures are important, and should be tailored to the program, the overall training culture with faculty mentorship and provision of time and resources for research activity are probably the most important factors. ACGME = Accreditation Council for Graduate Medical Education; EBM = evidence-based medicine; PGY = postgraduate year.


Comparative study of cinnamon oil and clove oil on some oral microbiota.
A comparative study was carried out between cinnamon oil and clove oil on the oral micro-biota causing dental caries. Cinnamon oil was found to be more effective than clove oil exhibiting broad spectrum of antibacterial activity inhibiting all the ten test bacterial species involved in dental caries. Cinnamon oil produced maximum inhibition zone of diameter (IZD) of 24.0 mm against Streptococcus mutans (major causative bacteria of dental plaque) as compared to clove oil (IZD = 13.0mm). This is contrary to the popular belief that clove oil is effective in tooth decay and dental plaque. This study shows the potential of cinnamon oil over clove oil in the treatment of dental caries. (www.actabiomedica.it).


Influence of a probiotic strain of Enterococcus faecium on Salmonella enterica serovar Typhimurium DT104 infection in a porcine animal infection model.
The beneficial effects of probiotic Enterococcus spp. in different hosts, such as mice and humans, have previously been reported in several studies. However, studies of large domestic animals, as well as challenge studies with pathogenic microorganisms, are very rare. Here, we investigated the influence of oral treatment of pigs with the probiotic bacterium Enterococcus faecium NCIMB 10415 on Salmonella enterica serovar Typhimurium DT104 infections in weaning piglets. Clinical symptoms, fecal excretion, the organ distribution of Salmonella, and the humoral immune response (immunoglobulin G [IgG], IgM, and IgA levels) in serum were examined. A pool of 89 piglets was randomly divided into probiotic and control groups. The probiotic group received a feed supplement containing E. faecium starting on day 14 postpartum prior to challenge with Salmonella serovar Typhimurium DT104 at 28 days postpartum. After challenge with Salmonella serovar Typhimurium DT104, piglets in both groups showed no severe clinical signs of salmonellosis. However, fecal excretion and colonization of Salmonella in organs were significantly greater in piglets fed E. faecium. Likewise, the humoral immune response against Salmonella (serum IgM and IgA levels) was significantly greater in the probiotic group animals than in control animals. The results of this study suggest that E. faecium NCIMB 10415 treatment enhanced the course of infection in weaning piglets challenged with Salmonella serovar Typhimurium DT104. However, the probiotic treatment also appeared to result in greater production of specific antibodies against Salmonella serovar Typhimurium DT104.


Highly variable Northern Hemisphere temperatures reconstructed from low- and high-resolution proxy data.
A number of reconstructions of millennial-scale climate variability have been carried out in order to understand patterns of natural climate variability, on decade to century timescales, and the role of anthropogenic forcing. These reconstructions have mainly used tree-ring data and other data sets of annual to decadal resolution. Lake and ocean sediments have a lower time resolution, but provide climate information at multicentennial timescales that may not be captured by tree-ring data. Here we reconstruct Northern Hemisphere temperatures for the past 2,000 years by combining low-resolution proxies with tree-ring data, using a wavelet transform technique to achieve timescale-dependent processing of the data. Our reconstruction shows larger multicentennial variability than most previous multi-proxy reconstructions, but agrees well with temperatures reconstructed from borehole measurements and with temperatures obtained with a general circulation model. According to our reconstruction, high temperatures--similar to those observed in the twentieth century before 1990--occurred around ad 1000 to 1100, and minimum temperatures that are about 0.7 K below the average of 1961-90 occurred around ad 1600. This large natural variability in the past suggests an important role of natural multicentennial variability that is likely to continue.