E-cigarettes and Weight Loss-Product Design Innovation Insights From Industry Patents.
There is emerging evidence that e-cigarettes are being used by some to mitigate weight gain after quitting smoking, and being used to help control weight. This study sought to identify and describe patents related to innovations for e-cigarette devices associated and weight loss. Relevant patents were identified using Google Patents with the core search terms: "electronic cigarette" OR "e-cigarette" OR "vaporizer" OR "vapourizer" AND "nicotine" AND "weight loss" OR "weight control" OR "obesity" OR "hunger". Patents were reviewed to identify and classify the innovation related to weight loss or weight control. Our search identified 23 unique patents that were filed between 2004 and 2015. Patent applications were sponsored by individual inventors (n = 7), tobacco companies (n = 5), e-cigarette companies (n = 8), pharmaceutical companies (n = 2) and a cannabis company (n = 1). More than half the patents (n = 12) were filed in the United States; other countries included China, Germany, South Korea, and South Africa. Strategies included using e-cigarette devices to deliver constituents to users that support weight loss through altered metabolism, reduced nutrient absorption, suppressed appetite, or supported healthy behavior change. In most cases (n = 18), the innovations detailed in the patents were intended to be used with an e-cigarette device that delivered nicotine to the user. Companies from around the world, and from a range of industries are developing and patenting technologies related to e-cigarettes and weight loss. E-cigarettes may be presented to cigarette users as a possible solution to support smoking cessation and address the fear of weight gain. This article presents evidence that a range of industries are innovating to design e-cigarettes or constituents to be used with e-cigarettes to deliver a variety of drugs beyond nicotine including weight loss drugs, laxatives, and nutritional supplements. This study may inform surveillance studies to systematically include weight loss as a possible motivation to use e-cigarettes. Further, market surveillance of e-cigarette products needs to monitor ingredients in e-liquids including constituents that have been historically used for weight loss or weight control. Regulations around e-cigarette marketing, promotion, product design including e-liquid constituents need to consider weight loss claims.


[The Evaluation of Toxoplasma gondii (T.gondii) Serology Results Among Cases Who Admitted to the Serology Laboratory of a Hospital in Afyon City].
The aim of this study is to evaluate Toxoplasma gondii (T. gondii) serology results in different age groups among cases who admitted to the Medical Serology Laboratory of a secondary level hospital in Afyon. The patients who has positive result for Toxoplasma gondii IgG and IgM by electrochemiluminescence method (Cobas e-170 Analyzer, Roche Diagnostics) between January and December 2013 were included the study. Patients included the study were aged 1-68 years (mean age: 24 ± 9). Of the total 1887 sera tested for T. gondii IgG and IgM, 452 were found to be positive (24%) in a period of 12 months. Seropositivity was found to be 4%, 11,1%, 20,2%, 25,3%, 33,3% and 46,6% in 1-8, 9-18, 19-23, 24-28, 29-35 and 36-68 age groups, respectively. Because of the high seroprevalence in our country, the knowledge about the values of anti-Toxoplasma gondii antibodies in pre-pregnancy period has an importance for evaluation and follow-up during the pregnancy. In this study, it was determined that there is a relationship between seroprevalence and age. All people should be educated about ways to minimize exposure to T. gondii.


Escherichia coli ST131: a multidrug-resistant clone primed for global domination.
A single extra-intestinal pathogenic Escherichia coli (ExPEC) clone, named sequence type (ST) 131, is responsible for millions of global antimicrobial-resistant (AMR) infections annually. Population genetics indicate that ST131 consists of different clades (i.e. A, B, and C); however, clade C is the most dominant globally. A ST131 subclade, named C1-M27, is emerging in Japan and has been responsible for the recent increase in AMR ExPEC in that country. The sequential acquisition of several virulence and AMR genes associated with mobile genetic elements during the 1960s to 1980s primed clade C (and its subclades C1 and C2) for success in the 1990s to 2000s. IncF plasmids with F1:A2:B20 and F2:A1:B replicons have shaped the evolution of the C1 and C2 subclades. It is possible that ST131 is a host generalist with different accessory gene profiles. Compensatory mutations within the core genome of this clone have counterbalanced the fitness cost associated with IncF plasmids. ST131 clade C had dramatically changed the population structure of ExPEC, but it still remains unclear which features of this clade resulted in one of the most unprecedented AMR successes of the 2000s.


Purification, chain separation and sequence of the MRC OX-8 antigen, a marker of rat cytotoxic T lymphocytes.
The MRC OX-8 antigen is a marker of the rat cytotoxic T lymphocytes that consists of disulphide-linked chains of mol. wts. 37 and 32 kd. It is thought to be equivalent to the human T8 and mouse Lyt2,3 antigens (all now called CD8 antigens). MRC OX-8 antigen was purified from thymocytes using a monoclonal antibody column and because antigenicity was retained after reduction and alkylation the two polypeptide chains could be separated by a subsequent affinity chromatography step. Peptides were isolated from each chain and their sequences determined. A cDNA probe coding for the mouse CD8 antigen (pLY2C-1 provided by Dr L. A. Herzenberg) was used to obtain rat cDNA clones from which the sequence of the equivalent rat molecule was determined. Peptides from the 32-kd chain were identified in this translated sequence whereas peptides from the 37-kd chain were not. The 32-kd polypeptide sequence consisted of 210 amino acids and had one possible N-linked glycosylation site. The N-terminal part of the sequence was surprisingly different from both its mouse and human counterparts but, as in the other two species, it showed a clear relationship to Ig V domains.


Applying probability theory for the quality assessment of a wildfire spread prediction framework based on genetic algorithms.
This work presents a framework for assessing how the existing constraints at the time of attending an ongoing forest fire affect simulation results, both in terms of quality (accuracy) obtained and the time needed to make a decision. In the wildfire spread simulation and prediction area, it is essential to properly exploit the computational power offered by new computing advances. For this purpose, we rely on a two-stage prediction process to enhance the quality of traditional predictions, taking advantage of parallel computing. This strategy is based on an adjustment stage which is carried out by a well-known evolutionary technique: Genetic Algorithms. The core of this framework is evaluated according to the probability theory principles. Thus, a strong statistical study is presented and oriented towards the characterization of such an adjustment technique in order to help the operation managers deal with the two aspects previously mentioned: time and quality. The experimental work in this paper is based on a region in Spain which is one of the most prone to forest fires: El Cap de Creus.


Quality Evaluation of Peony Petals Based on the Chromatographic Fingerprints and Simultaneous Determination of Sixteen Bioactive Constituents Using UPLC-DAD-MS/MS.
In this study, a validated quality evaluation method with peony flower fingerprint chromatogram combined with simultaneous determination of sixteen bioactive constituents was established using UPLC-DAD-MS/MS. The results demonstrated that the method was stable, reliable, and accurate. The UPLC chemical fingerprints of 12 different varieties of peonies were established and comprehensively evaluated by similarity evaluation (SE), hierarchical cluster analysis (HCA), principal component analysis (PCA), and quantification analysis. The results of SE indicated that similar chemical components were present in these samples regardless of variety, but there were significant differences in the content of chemical components and material basis characteristics. The results of HCA and PCA showed that 12 varieties of samples were divided into two groups. Four flavonoids (11, 12, 13, and 16), five monoterpenes and their glycosides (3, 4, 6, 14, and 15), three tannins (7, 9, and 10), three phenolic acids (1, 2, and 5), and one aromatic acid (8) were identified from sixteen common peaks by standards and liquid chromatography-mass spectrometry (LC-MS). The simultaneous quantification of six types of components was conducted with the 12 samples, it was found that the sum contents of analytes varied obviously for peony flower samples from different varieties. The content of flavonoids, tannins, and monoterpenes (≥19.34 mg/g) was the highest, accounting for more than 78.45% of the total compounds. The results showed that the flavonoids, tannins, and monoterpenes were considered to be the key indexes in the classification and quality assessment of peony flower. The UPLC-DAD-MS/MS method coupled with multiple compounds determination and fingerprint analysis can be effectively applied as a feature distinguishing method to evaluate the compounds in peony flower raw material for product quality assurance in the food, pharmaceutical, and cosmetic industries. Moreover, this study provides ideas for future research and the improvement of products by these industries.


Cyanosis due to pulmonary arteriovenous malformation.
Cyanosis is frequently encountered in the neonate or infant. Most often it is due to congenital heart disease or primary lung disease. Pulmonary arteriovenous malformation is an unusual cause of cyanosis. Polycythemia and clubbing are associated findings. The treatment is excision or embolization if the disease is not too extensive.


Quantum Bohmian-Inspired Potential to Model Non-Gaussian Time Series and Its Application in Financial Markets.
We have implemented quantum modeling mainly based on Bohmian mechanics to study time series that contain strong coupling between their events. Compared to time series with normal densities, such time series are associated with rare events. Hence, employing Gaussian statistics drastically underestimates the occurrence of their rare events. The central objective of this study was to investigate the effects of rare events in the probability densities of time series from the point of view of quantum measurements. For this purpose, we first model the non-Gaussian behavior of time series using the multifractal random walk (MRW) approach. Then, we examine the role of the key parameter of MRW, λ, which controls the degree of non-Gaussianity, in quantum potentials derived for time series. Our Bohmian quantum analysis shows that the derived potential takes some negative values in high frequencies (its mean values), then substantially increases, and the value drops again for rare events. Thus, rare events can generate a potential barrier in the high-frequency region of the quantum potential, and the effect of such a barrier becomes prominent when the system transverses it. Finally, as an example of applying the quantum potential beyond the microscopic world, we compute quantum potentials for the S&P financial market time series to verify the presence of rare events in the non-Gaussian densities and demonstrate deviation from the Gaussian case.


[Experimental study on effects of mailuotong granule on anti-thromboangiitis obliterans].
Using experimental model of thromboangitis obliterans (TAO) in rats induced by injection of lauric acid into the femoral artery, the anti-thromboangitis obliterans effects of Mailuotong (MLT) Granule were observed. The results showed that MLT not only decreased significantly the lesion severity and extent of affected limb, plasma viscosity and level of fibrinogen, but also suppressed the arterial thrombosis, endotheliocytosis and inflammatory cell infiltration in vascular wall. MLT also reduced the organization of thrombus and facilitated thrombolysis. It showed that the therapeutic effect of MLT on TAO might be achieved by improving blood rheology, antithrombosis, thrombolysis, inhibiting endotheliocytosis and inflammatory reaction in vascular wall.


The sources of the nigrotectal pathway.
The nigrotectal pathway plays a role in the generation of saccade related responses by cells in the deep layers of the superior colliculus. By using a retrograde horseradish peroxidase technique that homogeneously fills neurons, the present experiments demonstrate that the source of the nigrotectal projection to the intermediate gray layer of the grey squirrel (Sciurus carolinensis) is a heterogeneous population of neurons whose somas and dendrites are concentrated in the rostral pole of pars reticulata. This region of pars reticulata receives projections from the posterior caudate, which in turn is a target of both the pulvinar and visual cortex. In addition, these experiments reveal the presence of a second, distinct set of neurons projecting to the midbrain tectum that are located in pars lateralis of the substantia nigra. These neurons can be distinguished from those in pars reticulata by their homogeneity and by their prominent basal dendrites. Furthermore, pars lateralis of the squirrel substantia nigra is, on cytoarchitectonic and immunocytochemical grounds, a distinct subdivision that does not receive projections from the posterior caudate. We conclude that both pars reticulata and lateralis are sources of the nigrotectal pathway. In addition, our results suggest, on connectional grounds, that the rostral pole of pars reticulata may be specialized to subserve the visual guidance of orienting movements.


Mechanical model analysis for resonance shear measurement.
Resonance shear measurement (RSM), which we developed based on a surface force apparatus, can investigate the structuring, and rheological and tribological properties of confined liquids as a function of the surface separation distance (D) from several μm to zero with a nanometer resolution. Using RSM, we reported that the nanoconfined liquids, including commercial lubricants, exhibited properties quite different from the bulk phase. Mechanical modeling of the resonance system is necessary to quantitatively evaluate the properties of confined liquids and/or sheared interfaces. In this study, we improved the model for RSM as follows: (1) We directly measured the movements of the upper and lower surfaces in addition to the measurement on the movement of the vertical spring to confirm the model, which could be used to estimate the parameters used in the model; (2) we proposed a modified mechanical model which considers the effect of additional motion. This model could fit the resonance curves using a identical apparatus constant for the entire measurement range, while the characteristic values of the confined liquids are the same as those obtained using our previous model, and (3) we calculated the friction (shear) force using the improved model and obtained the characteristic values (viscous and elastic parameters) of the confined liquids. This study afforded the simplicity and reliability of a mechanical model analysis of resonance curves, and the friction force calculation employing the viscous and elastic terms can be useful for studying the mechanism of friction force.


Post-ruminal effects of rumen-protected methionine supplementation with low protein diet using long-term simulation and in vitro digestibility technique.
Microbial degradation in the rumen and dietary availability of methionine amino acid have been reported as limiting in dairy ruminants. The aim of the present study was to examine the post-ruminal effects of feeding ruminants different concentrations of rumen-protected methionine (RPM) in low crude protein diets using the long-term rumen simulation method (Rusitec) followed by in vitro abomasum and ileum digestibility technique. The experiment contained four treatment groups: (1) high protein, without RPM supplementation (HP); (2) low protein, without RPM supplementation (LP); (3) low protein supplementation with low RPM (LPLM); and (4) low protein supplementation with high RPM (LPHM) mixed per 20 ± 0.04 g basal diet in every fermenter. The results showed that the LPLM and LPHM groups had significantly higher disappearance of crude protein and neutral detergent fiber in the abomasum and ileum than the HP treatment (P < 0.05) and were the same as the LP group (P > 0.05). The proportions of short-chain fatty acids and total volatile fatty acids in the abomasum and ileum were the same between the LPHM and HP groups (P > 0.05); however, the LPLM group was found to be significantly (P < 0.05) lower than the HP group and similar to the LP group (P > 0.05). Rusitec pH before or after changing feed bags and daily ammonia nitrogen production in the abomasum and ileum were non significantly (P > 0.05) different among all groups. In conclusion, RPM supplementation with low crude protein diets promoted post-ruminal digestibility and production of volatile fatty acids.


Detection and segmentation of cell nuclei in virtual microscopy images: a minimum-model approach.
Automated image analysis of cells and tissues has been an active research field in medical informatics for decades but has recently attracted increased attention due to developments in computer and microscopy hardware and the awareness that scientific and diagnostic pathology require novel approaches to perform objective quantitative analyses of cellular and tissue specimens. Model-based approaches use a priori information on cell shape features to obtain the segmentation, which may introduce a bias favouring the detection of cell nuclei only with certain properties. In this study we present a novel contour-based "minimum-model" cell detection and segmentation approach that uses minimal a priori information and detects contours independent of their shape. This approach avoids a segmentation bias with respect to shape features and allows for an accurate segmentation (precision = 0.908; recall = 0.859; validation based on ∼8000 manually-labeled cells) of a broad spectrum of normal and disease-related morphological features without the requirement of prior training.


Effect of lignocaine and nitrous oxide on hypoxic pulmonary vasoconstriction in the dog constant-flow perfused left lower lobe preparation.
The effects of lignocaine hydrochloride on hypoxic pulmonary vasoconstriction in the presence and absence of nitrous oxide were examined during constant-flow perfusion of the left lower lobe. Lignocaine had no effect on lobar pulmonary vascular resistance during lobar ventilation with oxygen or 7% oxygen in nitrogen. The substitution of nitrous oxide for nitrogen diminished the hypoxic vasoconstrictor response, whilst the subsequent infusion of lignocaine during 7% oxygen in nitrous oxide increased the response to a value which was not significantly different from that produced by 7% oxygen in nitrogen alone.


Silicosis and coal workers' pneumoconiosis.
Exposure to coal mine dust and/or crystalline silica results in pneumoconiosis with initiation and progression of pulmonary fibrosis. This review presents characteristics of simple and complicated coal workers' pneumoconiosis (CWP) as well as pathologic indices of acute and chronic silicosis by summarizing results of in vitro, animal, and human investigations. These results support four basic mechanisms in the etiology of CWP and silicosis: a) direct cytotoxicity of coal dust or silica, resulting in lung cell damage, release of lipases and proteases, and eventual lung scarring; b) activation of oxidant production by pulmonary phagocytes, which overwhelms the antioxidant defenses and leads to lipid peroxidation, protein nitrosation, cell injury, and lung scarring; c) activation of mediator release from alveolar macrophages and epithelial cells, which leads to recruitment of polymorphonuclear leukocytes and macrophages, resulting in the production of proinflammatory cytokines and reactive species and in further lung injury and scarring; d) secretion of growth factors from alveolar macrophages and epithelial cells, stimulating fibroblast proliferation and eventual scarring. Results of in vitro and animal studies provide a basis for proposing these mechanisms for the initiation and progression of pneumoconiosis. Data obtained from exposed workers lend support to these mechanisms.


Pyrazine-Fused Triterpenoids Block the TRPA1 Ion Channel in Vitro and Inhibit TRPA1-Mediated Acute Inflammation in Vivo.
TRPA1 is a nonselective cation channel, most famously expressed in nonmyelinated nociceptors. In addition to being an important chemical and mechanical pain sensor, TRPA1 has more recently appeared to have a role also in inflammation. Triterpenoids are natural products with anti-inflammatory and anticancer effects in experimental models. In this paper, 13 novel triterpenoids were created by synthetically modifying betulin, an abundant triterpenoid of the genus Betula L., and their TRPA1-modulating properties were examined. The Fluo 3-AM protocol was used in the initial screening, in which six of the 14 tested triterpenoids inhibited TRPA1 in a statistically significant manner. In subsequent whole-cell patch clamp recordings, the two most effective compounds (pyrazine-fused triterpenoids 8 and 9) displayed a reversible and dose- and voltage-dependent effect to block the TRPA1 ion channel at submicromolar concentrations. Interestingly, the TRPA1 blocking action was also evident in vivo, as compounds 8 and 9 both alleviated TRPA1 agonist-induced acute paw inflammation in mice. The results introduce betulin-derived pyrazine-fused triterpenoids as promising novel antagonists of TRPA1 that are potentially useful in treating diseases with a TRPA1-mediated adverse component.


Selection of a platinum-binding sequence in a loop of a four-helix bundle protein.
Protein-metal hybrids are functional materials with various industrial applications. For example, a redox enzyme immobilized on a platinum electrode is a key component of some biofuel cells and biosensors. To create these hybrid materials, protein molecules are bound to metal surfaces. Here, we report the selection of a novel platinum-binding sequence in a loop of a four-helix bundle protein, the Lac repressor four-helix protein (LARFH), an artificial protein in which four identical α-helices are connected via three identical loops. We created a genetic library in which the Ser-Gly-Gln-Gly-Gly-Ser sequence within the first inter-helical loop of LARFH was semi-randomly mutated. The library was then subjected to selection for platinum-binding affinity by using the T7 phage display method. The majority of the selected variants contained the Tyr-Lys-Arg-Gly-Tyr-Lys (YKRGYK) sequence in their randomized segment. We characterized the platinum-binding properties of mutant LARFH by using quartz crystal microbalance analysis. Mutant LARFH seemed to interact with platinum through its loop containing the YKRGYK sequence, as judged by the estimated exclusive area occupied by a single molecule. Furthermore, a 10-residue peptide containing the YKRGYK sequence bound to platinum with reasonably high affinity and basic side chains in the peptide were crucial in mediating this interaction. In conclusion, we have identified an amino acid sequence, YKRGYK, in the loop of a helix-loop-helix motif that shows high platinum-binding affinity. This sequence could be grafted into loops of other polypeptides as an approach to immobilize proteins on platinum electrodes for use as biosensors among other applications.


Adverse events to antiretrovirals in the Swiss HIV Cohort Study: effect on mortality and treatment modification.
Antiretroviral therapy (ART) decreases morbidity and mortality in HIV-infected patients but is associated with considerable adverse events (AEs). We examined the effect of AEs to ART on mortality, treatment modifications and drop-out in the Swiss HIV Cohort Study. A cross-sectional evaluation of prevalence of 13 clinical and 11 laboratory parameters was performed in 1999 in 1,078 patients on ART. AEs were defined as abnormalities probably or certainly related to ART. A score including the number and severity of AEs was defined. The subsequent progression to death, drop-out and treatment modification due to intolerance were evaluated according to the baseline AE score and characteristics of individual AEs. Of the 1,078 patients, laboratory AEs were reported in 23% and clinical AEs in 45%. During a median follow up of 5.9 years, laboratory AEs were associated with higher mortality with an adjusted hazard ratio (HR) of 1.3 (95% confidence interval [CI] 1.2-1.5; P < 0.001) per score point. For clinical AEs no significant association with increased mortality was found. In contrast, an increasing score for clinical AEs (HR 1.11,95% CI 1.04-1.18; P = 0.002), but not for laboratory AEs (HR 1.07, 95% CI 0.97-1.17; P = 0.17), was associated with antiretroviral treatment modification. AEs were not associated with a higher drop-out rate. The burden of laboratory AEs to antiretroviral drugs is associated with a higher mortality. Physicians seem to change treatments to relieve clinical symptoms, while accepting laboratory AEs. Minimizing laboratory drug toxicity seems warranted and its influence on survival should be further evaluated.


Delayed Open Reduction and K-Wire Fixation of Widely Displaced Supracondylar Fractures of Humerus in Children using Medial Approach.
Supracondylar fractures of humerus in children are usually treated with percutaneous pinning on emergency basis. When the operating time is delayed, percutaneous pinning is difficult due to massive swelling. Late presentation is common in developing countries. To assess the outcome of open reduction and internal fixation with K-wire of widely displaced supracondylar fracture when operated later than 2 days after the injury. A total of 52 children (aged 3-12 years) with widely displaced supracondylar fracture of humerus (Gartland type-III) who presented later than 2 days after injury were treated with open reduction through medial approach and fixation with cross K-wires. RESULTs were assessed with Flynn's criteria. A total of 40 patients completed follow-up. Mean age of all (n=52) patients was 4.8 years (range 3-12 years). Mean delay of presentation was 7.5 days (range 2-14 days). Hundred percent patients had satisfactory results according to Flynn's criteria. Two patients had pin infections. Open reduction through medial approach and fixation with two cross K-wires is a reliable method of treatment for supracondylar fractures of humerus in children when the operation is delayed.


Cambial activity and intra-annual xylem formation in roots and stems of Abies balsamea and Picea mariana.
Studies on xylogenesis focus essentially on the stem, whereas there is basically no information about the intra-annual growth of other parts of the tree. As roots strongly influence carbon allocation and tree development, knowledge of the dynamics of xylem production and maturation in roots at a short time scale is required for a better understanding of the phenomenon of tree growth. This study compared cambial activity and xylem formation in stem and roots in two conifers of the boreal forest in Canada. Wood microcores were collected weekly in stem and roots of ten Abies balsamea and ten Picea mariana during the 2004-2006 growing seasons. Cross-sections were cut using a rotary microtome, stained with cresyl violet acetate and observed under visible and polarized light. The number of cells in the cambial zone and in differentiation, plus the number of mature cells, was counted along the developing xylem. Xylem formation lasted from the end of May to the end of September, with no difference between stem and roots in 2004-2005. On the contrary, in 2006 a 1-week earlier beginning of cell differentiation was observed in the stem, with cell wall thickening and lignification in roots ending up to 22 d later than in the stem. Cell production in the stem was concentrated early in the season, in June, while most cell divisions in roots occurred 1 month later. The intra-annual dynamics of growth observed in stem and roots could be related to the different amount of cells produced by the cambium and the patterns of air and soil temperature occurring in spring.


Enhancement of extinction learning attenuates ethanol-seeking behavior and alters plasticity in the prefrontal cortex.
Addiction is a chronic relapsing disorder in which relapse is often initiated by exposure to drug-related cues. The present study examined the effects of mGluR5 activation on extinction of ethanol-cue-maintained responding, relapse-like behavior, and neuronal plasticity. Rats were trained to self-administer ethanol and then exposed to extinction training during which they were administered either vehicle or the mGluR5 positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) or CDPPB. CDPPB treatment reduced active lever responding during extinction, decreased the total number of extinction sessions required to meet criteria, and attenuated cue-induced reinstatement of ethanol seeking. CDPPB facilitation of extinction was blocked by the local infusion of the mGluR5 antagonist 3-((2-methyl-4-thiazolyl)ethynyl) pyridine into the infralimbic (IfL) cortex, but had no effect when infused into the prelimbic (PrL) cortex. Analysis of dendritic spines revealed alterations in structural plasticity, whereas electrophysiological recordings demonstrated differential alterations in glutamatergic neurotransmission in the PrL and IfL cortex. Extinction was associated with increased amplitude of evoked synaptic PrL and IfL NMDA currents but reduced amplitude of PrL AMPA currents. Treatment with CDPPB prevented the extinction-induced enhancement of NMDA currents in PrL without affecting NMDA currents in the IfL. Whereas CDPPB treatment did not alter the amplitude of PrL or IfL AMPA currents, it did promote the expression of IfL calcium-permeable GluR2-lacking receptors in both abstinence- and extinction-trained rats, but had no effect in ethanol-naive rats. These results confirm changes in the PrL and IfL cortex in glutamatergic neurotransmission during extinction learning and demonstrate that manipulation of mGluR5 facilitates extinction of ethanol cues in association with neuronal plasticity.


Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial.
Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion. Their efficacy relative to nicotine patch largely relies on indirect comparisons, and there is limited information on safety and efficacy in smokers with psychiatric disorders. We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders. We did a randomised, double-blind, triple-dummy, placebo-controlled and active-controlled (nicotine patch; 21 mg per day with taper) trial of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) for 12 weeks with 12-week non-treatment follow-up done at 140 centres (clinical trial centres, academic centres, and outpatient clinics) in 16 countries between Nov 30, 2011, and Jan 13, 2015. Participants were motivated-to-quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit. Randomisation was computer generated (1:1:1:1 ratio). Participants, investigators, and research personnel were masked to treatment assignments. The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. The main efficacy endpoint was biochemically confirmed continuous abstinence for weeks 9-12. All participants randomly assigned were included in the efficacy analysis and those who received treatment were included in the safety analysis. The trial is registered at ClinicalTrials.gov (number NCT01456936) and is now closed. 8144 participants were randomly assigned, 4116 to the psychiatric cohort (4074 included in the safety analysis) and 4028 to the non-psychiatric cohort (3984 included in the safety analysis). In the non-psychiatric cohort, 13 (1·3%) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group, 22 (2·2%) of 989 in the bupropion group, 25 (2·5%) of 1006 in the nicotine patch group, and 24 (2·4%) of 999 in the placebo group. The varenicline-placebo and bupropion-placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were -1·28 (95% CI -2·40 to -0·15) and -0·08 (-1·37 to 1·21), respectively; the RDs for comparisons with nicotine patch were -1·07 (-2·21 to 0·08) and 0·13 (-1·19 to 1·45), respectively. In the psychiatric cohort, moderate and severe neuropsychiatric adverse events were reported in 67 (6·5%) of 1026 participants in the varenicline group, 68 (6·7%) of 1017 in the bupropion group, 53 (5·2%) of 1016 in the nicotine patch group, and 50 (4·9%) of 1015 in the placebo group. The varenicline-placebo and bupropion-placebo RDs were 1·59 (95% CI -0·42 to 3·59) and 1·78 (-0·24 to 3·81), respectively; the RDs versus nicotine patch were 1·22 (-0·81 to 3·25) and 1·42 (-0·63 to 3·46), respectively. Varenicline-treated participants achieved higher abstinence rates than those on placebo (odds ratio [OR] 3·61, 95% CI 3·07 to 4·24), nicotine patch (1·68, 1·46 to 1·93), and bupropion (1·75, 1·52 to 2·01). Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo (OR 2·07 [1·75 to 2·45] and 2·15 [1·82 to 2·54], respectively). Across cohorts, the most frequent adverse events by treatment group were nausea (varenicline, 25% [511 of 2016 participants]), insomnia (bupropion, 12% [245 of 2006 participants]), abnormal dreams (nicotine patch, 12% [251 of 2022 participants]), and headache (placebo, 10% [199 of 2014 participants]). Efficacy treatment comparison did not differ by cohort. The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo. Pfizer and GlaxoSmithKline.


Quiescent hepatic stellate cells functionally contribute to the hepatic innate immune response via TLR3.
Toll-like Receptor 3 (TLR3) is a pathogen pattern recognition receptor that plays a key role in innate immunity. TLR3 signalling has numerous functions in liver, both in health and disease. Here we report that TLR3 is expressed by quiescent hepatic stellate cells (HSC) where it functions to induce transcription and secretion of functional interferons as well as a number of other cytokines and chemokines. Upon transdifferentiation into myofibroblasts, HSCs rapidly loose the ability to produce interferon gamma (IFNγ). Mechanistically, this gene silencing may be due to Polycomb complex mediated repression via methylation of histone H3 lysine 27. In contrast to wild type, quiescent HSC isolated from tlr3 knockout mice do not produce IFNγ in response to Poly(I∶C) treatment. Therefore, quiescent HSC may contribute to induction of the hepatic innate immune system in response to injury or infection.


Reduced Mortality With Antiplatelet Therapy Deescalation After Percutaneous Coronary Intervention in Acute Coronary Syndromes: A Meta-Analysis.
Antiplatelet therapy deescalation has been suggested as an alternative to standard treatment with potent dual antiplatelet therapy (DAPT) for 1 year in low bleeding risk patients with acute coronary syndromes undergoing percutaneous coronary intervention to mitigate the increased risk of bleeding. Whether this strategy preserves the ischemic and survival benefits of potent DAPT is uncertain. We performed a pairwise meta-analysis in patients with acute coronary syndrome undergoing percutaneous coronary intervention treated with either 1-year standard potent DAPT versus deescalation therapy (potent DAPT for 1-3 months followed by either reduced potency DAPT or ticagrelor monotherapy for up to 1 year). Randomized trials comparing standard DAPT versus deescalation therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention were searched through MEDLINE, EMBASE, Cochrane databases, and proceedings of international meetings. The primary end point was 1-year all-cause mortality. The meta-analysis included 6 trials in which 20 837 patients were randomized to potent DAPT for 1 to 3 months followed by deescalation therapy for up to 1 year (n=10 392) or standard potent DAPT for 1 year (n=10 445). Deescalation therapy was associated with lower 1-year rates of all-cause mortality compared with standard therapy (odds ratio, 0.75 [95% CI, 0.59-0.95]; P=0.02). Deescalation therapy was also associated with lower rates of major bleeding (odds ratio, 0.59 [95% CI, 0.48-0.72]; P<0.0001), with no significant difference in major adverse cardiac events (major adverse cardiovascular events; odds ratio, 0.89 [95% CI, 0.77-1.04]; P=0.14). In low bleeding risk patients with acute coronary syndrome undergoing percutaneous coronary intervention, compared with 1-year of potent DAPT, antiplatelet therapy deescalation therapy after 1 to 3 months was associated with decreased mortality and major bleeding with similar rates of major adverse cardiovascular events.


Using trend templates in a neonatal seizure algorithm improves detection of short seizures in a foetal ovine model.
Seizures below one minute in duration are difficult to assess correctly using seizure detection algorithms. We aimed to improve neonatal detection algorithm performance for short seizures through the use of trend templates for seizure onset and end. Bipolar EEG were recorded within a transiently asphyxiated ovine model at 0.7 gestational age, a common experimental model for studying brain development in humans of 30-34 weeks of gestation. Transient asphyxia led to electrographic seizures within 6-8 h. A total of 3159 seizures, 2386 shorter than one minute, were annotated in 1976 h-long EEG recordings from 17 foetal lambs. To capture EEG characteristics, five features, sensitive to seizures, were calculated and used to derive trend information. Feature values and trend information were used as input for support vector machine classification and subsequently post-processed. Performance metrics, calculated after post-processing, were compared between analyses with and without employing trend information. Detector performance was assessed after five-fold cross-validation conducted ten times with random splits. The use of trend templates for seizure onset and end in a neonatal seizure detection algorithm significantly improves the correct detection of short seizures using two-channel EEG recordings from 54.3% (52.6-56.1) to 59.5% (58.5-59.9) at FDR 2.0 (median (range); p < 0.001, Wilcoxon signed rank test). Using trend templates might therefore aid in detection of short seizures by EEG monitoring at the NICU.


Clinical significance of epithelial-mesenchymal transition.
The concept of epithelial-mesenchymal transition (EMT), a process where cells change their epithelial towards a mesenchymal phenotype, has gained overwhelming attention especially in the cancer research community. Thousands of scientific reports investigated changes in gene, mRNA and protein expression compatible with EMT and their possible correlation with tumor invasion, metastatic spread or patient prognosis; however, up to now, a proof of clinical significance of the concept is still missing. This review, with a main focus on the role of EMT in tumors, will summarize the basic molecular events underlying EMT including the signaling pathways capable of its induction as well as changes in EMT-associated protein expression and will very briefly touch the role of microRNAs in EMT. We then outline protein markers that are used most frequently for the assessment of EMT in research and diagnostic evaluation of tumor specimens and depict the link between EMT, a cancer stem cell (CSC) phenotype and resistance to conventional antineoplastic therapies. Furthermore, we evaluate a possible correlation between EMT marker expression and patient prognosis as well as current therapeutic concepts targeting the EMT process to slow down or prevent metastatic spread of malignant tumors.


A sensitivity leap for X-band EPR using a probehead with a cryogenic preamplifier.
Inspired by the considerable success of cryogenically cooled NMR cryoprobes, we present an upgraded X-band EPR probehead, equipped with a cryogenic low-noise preamplifier. Our setup suppresses source noise, can handle the high microwave powers typical in X-band pulsed EPR, and is compatible with the convenient resonator coupling and sample access found on commercially available spectrometers. Our approach allows standard pulsed and continuous-wave EPR experiments to be performed at X-band frequency with significantly increased sensitivity compared to the unmodified setup. The probehead demonstrates a voltage signal-to-noise ratio (SNR) enhancement by a factor close to 8× at a temperature of 6 K, and remains close to 2× at room temperature. By further suppressing room-temperature noise at the expense of reduced microwave power (and thus minimum π-pulse length), the factor of SNR improvement approaches 15 at 6 K, corresponding to an impressive 200-fold reduction in EPR measurement time. We reveal the full potential of this probehead by demonstrating such SNR improvements using a suite of typical hyperfine and dipolar spectroscopy experiments on exemplary samples.


[Pancreatic injury in abdominal trauma in children: difficult to diagnose and treat].
Traumatic injury of the pancreas is rare in children. It is often difficult to diagnose due to the lack of signs and symptoms, and shortly after trauma laboratory values may be normal. In addition, ultrasound and CT are often not specific. The treatment of grade 1 and 2 injury is non-operative. Although there seems to be a shift towards non-operative management of grade 3-5 injuries (with injury of the pancreatic duct), this is still a matter of debate. We describe 3 children, a girl of 2.5 years-old and a boy of 7 years-old, with grade 3 pancreatic injuries and an 8-year-old boy with a grade 2 injury. We demonstrate that the diagnosis is hard to establish, while the consequences of this injury can be serious. Thinking of pancreatic injury is most important to its diagnosis. We advocate referral to or consultation of specialized centres in these cases.


Clinical Course of Cervical Percutaneous Epidural Neuroplasty in Single-Level Cervical Disc Disease with 12-Month Follow-up.
Cervical disc disease is a common and occasionally disabling condition, occurring as a natural consequence of aging in the vast majority of the adult population. Percutaneous epidural neuroplasty (PEN) has been used to deliver highly concentrated drugs for chronic neck pain and to prevent scarring in cases refractory to conventional epidural blocks. However, the clinical course after PEN in cervical disc disease is not well-documented. The purpose of this study was to evaluate the efficacy of cervical PEN for single-level cervical disc disease. A retrospective observational study. A consecutive series of 100 patients who underwent cervical PEN for single-level disc disease (bulging or protrusion) were included in this study. Preoperatively, all patients underwent magnetic resonance imaging (MRI), and visual analog scale (VAS) scores as well as Odom's criteria were measured preoperatively and at post-operative follow-up visits (one, 3, 6, and 12 months). The results of this study are limited by the lack of a control group that did not undergo treatment with PEN. Additional block therapy was performed in 58 patients (58.0%). Subsequent surgery was performed in 10 patients (10.0%, excluded from data of clinical follow-up). Mean neck pain and VAS arm pain scores for all follow-up patients decreased from 6.82 and 4.74 preoperatively to 2.18 and 1.87 at 12 months after PEN (P < 0.001). More than 80% and 40% of all patients with and without additional block therapy after cervical PEN, respectively, showed good and excellent outcomes according to Odom's Criteria during 12 months of follow-up. During this follow-up period, no severe complications related to the procedure were observed. Cervical PEN was shown to be a safe and effective treatment for neck and arm pain in single-level disc disease during 12 months of follow-up. Key words: Neck pain, cervical disc disease, pain management, percutaneous epidural neuroplasty, adhesiolysis, clinical course.


The Effects of a Psychosocial Support Program on Perceived Stress of Family Caregivers of Patients with Mental Disorders.
Taking caring of patients with mental disorders is stressful and people who take care of these patients need to receive enough support and training to overcome this challenging situation. The present study was aimed at investigating the effects of a psychosocial support program on perceived stress of family caregivers of patients with mental disorders. This randomized controlled clinical trial was performed on 64 family caregivers of patients with mental disorders referred to Noor and Hazrat-e-Ali Asghar hospital in Isfahan, Iran, in 2018-19. The participants were randomly assigned to the intervention and control groups using a random number table. In the intervention group, the training program was held in 6 sessions of 90-minute training classes twice a week. Data were collected using a demographic characteristics form and the Perceived Stress Scale (PSS) before, immediately after, and 1 month after the intervention. Descriptive and inferential statistical tests such as Chi-square, Mann-Whitney, independent t-test, repeated measures ANOVA, and Kolmogorov-Smirnov test were used to analyze the data in SPSS software. The result of the study showed that the total mean score of perceived stress in the intervention group was significantly less than the control group immediately after (F2=66.29, p<0.001) and 1 month after the intervention (F2=66.29, p<0.001). Delivering a training program on the different dimensions of support family caregivers need will reduce the perceived stress of family caregivers of patients with mental disorders. Therefore, the implementation of this intervention is recommended in this group of caregivers.


Presence of hepatitis B surface antigen before primary hepatocellular carcinoma.
In a study of 7,498 men of Japanese ancestry in Hawaii, 18 incident cases of primary hepatocellular carcinoma were identified after the follow-up period of 13 years. Sixteen of the 18 patients had stored serum specimens available for analysis. Ten of the 16 had positive serum test results for hepatitis B surface antigen in their original specimens. None of 48 matched controls subjects, whose stored serum specimens were also analyzed, had similar positive test results. This finding indicates that hepatitis B surface antigenemia preceded primary hepatocellular carcinoma in many patients.


SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN COATS DISEASE.
To evaluate microstructural retinal abnormalities on spectral domain optical coherence tomography (SD-OCT) imaging of eyes with Coats disease. This is a multicenter, retrospective study in which SD-OCT images of patients with treatment-naive Coats disease were correlated with clinical examination and visual acuity and, when available, followed longitudinally over time. Macular SD-OCT of 27 eyes with Coats disease revealed intraretinal edema (59%), intraretinal exudates (67%), subretinal fluid (37%), subretinal exudate (48%), ellipsoid zone disruption (52%), external limiting membrane disruption (41%), and subfoveal nodule (26%). All these microstructural abnormalities correlated with worse baseline and final visual acuities (P < 0.05) on univariate analysis, except for intraretinal edema which exhibited a nonstatistically significant trend toward worse baseline visual acuity (P = 0.16). Within stage 2b eyes, external limiting membrane disruption and subretinal nodule on SD-OCT were associated with worse baseline visual acuity (P = 0.02 for both), and there was a trend toward worse final visual acuity with external limiting membrane disruption and subretinal nodule (P = 0.17 for both) and worse baseline (P = 0.08) and final (P = 0.13) visual acuities with ellipsoid zone disruption. No microstructural abnormalities were noted on OCT of fellow eyes. Spectral domain OCT can identify microstructural abnormalities in Coats disease that are associated on univariate analysis with worse baseline visual acuity and visual prognosis. Further larger studies are necessary.


Chemogenetic fingerprinting by analysis of cellular growth dynamics.
A fundamental goal in chemical biology is the elucidation of on- and off-target effects of drugs and biocides. To this aim chemogenetic screens that quantify drug induced changes in cellular fitness, typically taken as changes in composite growth, is commonly applied. Using the model organism Saccharomyces cerevisiae we here report that resolving cellular growth dynamics into its individual components, growth lag, growth rate and growth efficiency, increases the predictive power of chemogenetic screens. Both in terms of drug-drug and gene-drug interactions did the individual growth variables capture distinct and only partially overlapping aspects of cell physiology. In fact, the impact on cellular growth dynamics represented functionally distinct chemical fingerprints. Our findings suggest that the resolution and quantification of all facets of growth increases the informational and interpretational output of chemogenetic screening. Hence, by facilitating a physiologically more complete analysis of gene-drug and drug-drug interactions the here reported results may simplify the assignment of mode-of-action to orphan bioactive compounds.


Is younger really safer? A qualitative study of perceived risks and benefits of age-disparate relationships among women in Cape Town, South Africa.
Young women in age-asymmetric relationships may be at an elevated risk for acquisition of HIV, since relationships with older men are also correlated with other risk behaviors like less condom use. Qualitative studies have shown that women are motivated to participate in these relationships for money and emotional support. However, there is a paucity of research on women's perceived risks of these relationships, particularly in South Africa. To this end, we conducted in-depth interviews with 23 women recruited from three urban communities in Cape Town. A thematic question guide was used to direct the interviews. Thematic content analysis was used to explore women's perceived risks of age-disparate and non-age-disparate relationships, the benefits of dating older men, and risk perceptions that influence decisions around beginning or ending a relationship. A plurality of women thought that dating an older man does not bring any adverse consequences, although some thought that older men do not use condoms and may be involved in concurrent partnerships. Many women were less inclined to date same-age or younger men, because they were viewed as being disrespectful and abusive. This study points to the need for more awareness raising about the risks of age-disparate relationships. In addition to these initiatives, there is an urgent need to implement holistic approaches to relationship health, in order to curb intimate partner violence, improve gender equity and make non-age-disparate relationships more attractive.


Sudden infant death following hexavalent vaccination: a neuropathologic study.
We examined a large number of sudden infant death syndrome victims in order to point out a possible causal relationship between a previous hexavalent vaccination and the sudden infant death. We selected 110 cases submitted to in-depth histological examination of the autonomic nervous system and provided with detailed clinical and environmental information. In 13 cases (11.8%) the death occurred in temporal association with administration of the hexavalent vaccine (from 1 to 7 days). In none of these victims congenital developmental alterations of the main nervous structures regulating the vital functions were observed. Only the hypoplasia of the arcuate nucleus was present in 5 cases. In one case in particular an acquired hyperacute encephalitis of the tractus solitarii nucleus was diagnosed in the brainstem. This study does not prove a causal relationship between the hexavalent vaccination and SIDS. However, we hypothesize that vaccine components could have a direct role in sparking off a lethal outcome in vulnerable babies. In conclusion, we sustain the need that deaths occurring in a short space of time after hexavalent vaccination are appropriately investigated and submitted to a post-mortem examination particularly of the autonomic nervous system by an expert pathologist to objectively evaluate the possible causative role of the vaccine in SIDS.


Spontaneous hepatocyte migration towards an endothelial cell tube network.
A crucial part of the engineering liver tissue is contribution of nonparenchymal cells and maintenance of a complex three-dimensional (3D) structure in vitro for their normal physiology and function. We generated 3D hepatic tissue using primary isolated rat hepatocytes and an endothelial cell tube network from human endothelial vein epithelial cells (HUVECs). To create the 3D hepatic tissue, coculture of primary hepatocytes and tube-structured HUVECs was performed on a Matrigel®. After the HUVECs formed the tube structures, primary isolated rat hepatocytes were inoculated onto the HUVEC tube-structured layer and cultured for 24 hr. We investigated the cell migration, cellular interaction, and distributions of HUVEC tube structures and hepatocytes using multi cell-imaging incubator, confocal microscopy, and electron microscopy analyses. During the culture time, time-lapse imaging showed spontaneous migration of the hepatocytes in the gel, and after the 24-hr culture period, the vast majority of the hepatocytes had moved and adhered to the surface of the HUVEC tube structures. A confocal microscopy assay confirmed this unique 3D cellular interaction between hepatocytes and HUVEC tube structures. The hepatocytes were able to maintain their spherical shape, as well as HUVECs (tube-like form with tubular cavity). We speculate that coculturing of hepatocytes and endothelial cells replicates part of their normal physiology and may help induce migration in vitro and the growth of complex biological tissue structures.


Evaluation of reagin screen, a new serological test for syphilis.
A total of 1,020 serum and plasma specimens were tested using the Venereal Disease Research Laboratory (VDRL), Rapid Plasma Reagin (RPR) card, Reagin Screen (RST) and Fluorescent Treponemal Antibody-Absorption (FTA-ABS) tests. In 257 normal patients, all screening tests were nonreactive; the FTA-ABS test was reactive for one patient. In 588 patients with treated and untreated syphilis, the RST results were 91.7% in agreement with the VDRL and RPR results. In 175 patients with diseases that cause biological false reactions, the RST was 94% in agreement with the other screening tests. The titer of the RST was within one dilution of the corresponding VDRL titer in 91.7% of the 360 speciments tested and within one dilution of the RPR titer in 96.9% of 358 specimens quantitated by both tests.


Active Intervention Can Decrease Burnout In Ed Nurses.
The aim of this study was to evaluate whether active intervention can decrease job burnout and improve performance among ED nurses. This study was carried out in the emergency departments of 3 hospitals randomly selected from 8 comprehensive high-level hospitals in Jinan, China. A total of 102 nurses were enrolled and randomly divided into control and intervention groups. For 6 months, nurses in intervention groups were treated with ordinary treatment plus comprehensive management, whereas nurses in the control group were treated with ordinary management, respectively. Questionnaires were sent and collected at baseline and at the end of the study. The Student t test was used to evaluate the effect of comprehensive management in decreasing burnout. All ED nurses showed symptoms of job burnout at different levels. Our data indicated that comprehensive management significantly decreased emotional exhaustion and depersonalization (P < .01). The findings suggest that active intervention with comprehensive management may effectively reduce job burnout in ED nurses and contribute to relieving work-related stress and may further protect against potential mental health problems.


Diagnostic utility of the 23-gene expression profile test for an atypical intradermal melanocytic proliferation.
Ancillary tests such as immunohistochemistry (IHC) and gene expression profile (GEP) testing may be needed to arrive at a definitive diagnosis for some atypical melanocytic neoplasms. A 34-year-old male with a family history of melanoma presented with a large, heterogeneous melanocytic lesion on the cheek. Histopathological review of two biopsies revealed an atypical intradermal melanocytic proliferation with spitzoid features without ulceration or regression. Scattered mitotic figures were identified. In addition to performing SOX10 IHC, PRAME and HMB45 staining highlighted weak, patchy positivity that was stronger in superficial, pleomorphic melanocytes (Ki-67, 5-7% mitotic rate). Based on these concerning but ambiguous IHC results and lingering concern for melanoma reiterated by other consulting dermatopathologists, the 23-GEP was requested for both specimens, which both returned a malignant result. The inconclusive histopathological features of malignancy were resolved by 23-GEP testing, facilitating a final diagnosis of malignant melanoma (pT3a, 2.5 mm Breslow depth, Clark's level IV).


MicroRNA expression profiling of human islets from individuals with and without type 2 diabetes: promises and pitfalls.
Recent studies in mouse, involving the β-cell-specific deletion of Dicer1, have highlighted the crucial role of miRNAs (microRNAs) in regulating insulin secretion and consequently Type 2 diabetes. Identifying the individual miRNAs involved in human islet dysfunction may be of diagnostic and therapeutic interest. miRNA expression profiling of human islets isolated from donors with and without Type 2 diabetes may represent one of the first steps in the discovery of these specific miRNAs. The present review discusses some of the potential pitfalls and promises of such an approach.


A new terrestrial palaeoenvironmental record from the Bering Land Bridge and context for human dispersal.
Palaeoenvironmental records from the now-submerged Bering Land Bridge (BLB) covering the Last Glacial Maximum (LGM) to the present are needed to document changing environments and connections with the dispersal of humans into North America. Moreover, terrestrially based records of environmental changes are needed in close proximity to the re-establishment of circulation between Pacific and Atlantic Oceans following the end of the last glaciation to test palaeo-climate models for the high latitudes. We present the first terrestrial temperature and hydrologic reconstructions from the LGM to the present from the BLB's south-central margin. We find that the timing of the earliest unequivocal human dispersals into Alaska, based on archaeological evidence, corresponds with a shift to warmer/wetter conditions on the BLB between 14 700 and 13 500 years ago associated with the early Bølling/Allerød interstadial (BA). These environmental changes could have provided the impetus for eastward human dispersal at that time, from Western or central Beringia after a protracted human population standstill. Our data indicate substantial climate-induced environmental changes on the BLB since the LGM, which would potentially have had significant influences on megafaunal and human biogeography in the region.


Genetic diversity of the 28-kilodalton outer membrane protein gene in human isolates of Ehrlichia chaffeensis.
The Ehrlichia chaffeensis 28-kDa outer membrane protein (p28) gene was sequenced completely by genomic walking with adapter PCR. The DNA sequence of the p28 gene was nearly identical to the previously reported sequence (N. Ohashi, N. Zhi, Y. Zhang, and Y. Rikihisa, Infect. Immun. 66:132-139, 1998), but analysis of a further 75 bp on the 5' end of the gene revealed DNA that encoded a 25-amino-acid signal sequence. The leader sequence was removed from the N terminus of a 30-kDa precursor to generate the mature p28 protein. A monoclonal antibody (MAb), 1A9, recognizing four outer membrane proteins of E. chaffeensis (Arkansas strain) including the 25-, 26-, 27-, and 29-kDa proteins (X.-J. Yu, P. Brouqui, J. S. Dumler, and D. Raoult, J. Clin. Microbiol. 31:3284-3288, 1993) reacted with the recombinant p28 protein. This result indicated that the four proteins recognized by MAb 1A9 were encoded by the multiple genes of the 28-kDa protein family. DNA sequence alignment analysis revealed divergence of p28 among all five human isolates of E. chaffeensis. The E. chaffeensis strains could be divided into three genetic groups on the basis of the p28 gene. The first group consisted of the Sapulpa and St. Vincent strains. They had predicted amino acid sequences identical to each other. The second group contained strain 91HE17 and strain Jax, which only showed 0.4% divergence from each other. The third group contained the Arkansas strain only. The amino acid sequences of p28 differed by 11% between the first two groups, by 13.3% between the first and third groups, and by 13.1% between the second and third groups. The presence of antigenic variants of p28 among the strains of E. chaffeensis and the presence of multiple copies of heterogeneous genes suggest a possible mechanism by which E. chaffeensis might evade the host immune defenses. Whether or not immunization with the p28 of one strain of E. chaffeensis would confer cross-protection against other strains needs to be investigated.


Calcineurin and protein kinase G regulate C. elegans behavioral quiescence during locomotion in liquid.
Most rhythmic motor behaviors in nature are episodic i.e. they alternate between different behavioral states, including quiescence. Electrophysiological studies in invertebrate behavioral switching, maintenance and quiescence have elucidated several neuronal mechanisms that generate a temporal pattern in behavior. However, the genetic bases of these processes are less well studied. We have previously uncovered a novel episodic behavior exhibited by C. elegans in liquid media where they alternate between distinct phases of rhythmic swimming and quiescence. Here, we have investigated the effect of several genes and their site of action on the behavioral quiescence exhibited in liquid by the nematode C. elegans. We have previously reported that high cholinergic signaling promotes quiescence and command interneurons are critical for timing the quiescence bout durations. We have found that in addition to command interneurons, sensory neurons are also critical for quiescence. We show that the protein phosphatase calcineurin homolog tax-6 promotes swimming whereas the protein kinase G homolog egl-4 promotes quiescence. tax-6 expression in the sensory neurons is sufficient to account for its effect. egl-4 also acts in multiple sensory neurons to mediate its effect on quiescence. In addition our data is consistent with regulation of quiescence by egl-4 acting functionally downstream of release of acetylcholine (ACh) by motor neurons. Our study provides genetic evidence for mechanisms underlying the maintenance of a behavioral state operating at multiple neuronal levels through the activities of a kinase and a phosphatase. These results in a genetically tractable organism establish a framework for further dissection of the mechanism of quiescence during episodic behaviors.


Bloodstains on woven fabric: Simulations and experiments for quantifying the uncertainty on the impact and directional angles.
Bloodstain pattern analysis considers stains on various porous and non-porous surfaces, for the purpose of crime scene reconstruction. On non-porous surfaces, several studies relate the impact conditions of drops to the inspection of stain shapes. Stains on porous surfaces like fabrics have been relatively less explored. The phenomenon of imbibition of blood into the fabric after impact adds further complexity in retrieving information on the impacting conditions. The present work studies experimentally and numerically the formation of drip stains on a woven fabric. The proposed methodology first relies on Darcy's law to measure the imbibition characteristics of the fabric through a set of simple imbibition experiments. Next, the fabric properties are fed into a numerical model to predict the growth of the bloodstain after impact of a droplet. Experiments at different drop release heights and impact angles are compared with the numerical simulations. The uncertainties induced by the fabric on the determination of the impact and directional angles are explained and quantified.


Comparative analyses of two thermophilic enzymes exhibiting both beta-1,4 mannosidic and beta-1,4 glucosidic cleavage activities from Caldanaerobius polysaccharolyticus.
The hydrolysis of polysaccharides containing mannan requires endo-1,4-beta-mannanase and 1,4-beta-mannosidase activities. In the current report, the biochemical properties of two endo-beta-1,4-mannanases (Man5A and Man5B) from Caldanaerobius polysaccharolyticus were studied. Man5A is composed of an N-terminal signal peptide (SP), a catalytic domain, two carbohydrate-binding modules (CBMs), and three surface layer homology (SLH) repeats, whereas Man5B lacks the SP, CBMs, and SLH repeats. To gain insights into how the two glycoside hydrolase family 5 (GH5) enzymes may aid the bacterium in energy acquisition and also the potential application of the two enzymes in the biofuel industry, two derivatives of Man5A (Man5A-TM1 [TM1 stands for truncational mutant 1], which lacks the SP and SLH repeats, and Man5A-TM2, which lacks the SP, CBMs, and SLH repeats) and the wild-type Man5B were biochemically analyzed. The Man5A derivatives displayed endo-1,4-beta-mannanase and endo-1,4-beta-glucanase activities and hydrolyzed oligosaccharides with a degree of polymerization (DP) of 4 or higher. Man5B exhibited endo-1,4-beta-mannanase activity and little endo-1,4-beta-glucanase activity; however, this enzyme also exhibited 1,4-beta-mannosidase and cellodextrinase activities. Man5A-TM1, compared to either Man5A-TM2 or Man5B, had higher catalytic activity with soluble and insoluble polysaccharides, indicating that the CBMs enhance catalysis of Man5A. Furthermore, Man5A-TM1 acted synergistically with Man5B in the hydrolysis of beta-mannan and carboxymethyl cellulose. The versatility of the two enzymes, therefore, makes them a resource for depolymerization of mannan-containing polysaccharides in the biofuel industry. Furthermore, on the basis of the biochemical and genomic data, a molecular mechanism for utilization of mannan-containing nutrients by C. polysaccharolyticus is proposed.


EZH2-miRNA Positive Feedback Promotes Tumor Growth in Ovarian Cancer.
Enhancer of zester homolog 2 (EZH2), a histone methyl transferase that mediates H3K27me3 through polycomb repressive complex 2 (PRC2), is overexpressed in ovarian cancer and promotes malignant proliferation. However, the underlying mechanism of maintaining high EZH2 expression remains elusive. Here we showed that microRNA(miRNA) inhibited EZH2 by binding to the 3'-UTR of EZH2 mRNA; conversely, EZH2 can inhibit miRNA expression. We confirmed that a feedback loop exists between EZH2 and miRNA that maintained EZH2 overexpression, thus promoting ovarian cancer proliferation in vivo and in vitro. We further explored that EZH2 inhibited miRNA expression through PRC2, as determined by CHIP (chromatin immunoprecipitation), and EZH2 decreased the expression of p21, p53, and RUNX3. These results suggest that EZH2 inhibits the expression of Et-miRNAs (EZH2-targeting miRNAs) through the H3K27me3 pathway, thus forming an EZH2-miRNA positive feedback loop that maintains the high expression of EZH2 and promotes the malignant proliferation of cancer cells by regulating the expression of cell proliferation-related proteins.


Studies on the IgA-independent immunological responses in mice to influenza virus challenge after oral vaccination with irradiated whole virus and an erythrocyte complex.
Previous studies have described an oral influenza vaccine comprising whole irradiated virus and an erythrocyte complex (IV-EC), which gave broad-based protection against influenza virus challenge in mice. The present study examined the immune responses generated after live virus challenge of vaccinated mice, particularly to determine whether mice vaccinated with IV-EC had enhanced CTL activity to compensate for the previously reported diminution in lung IgA response. Oral vaccine groups examined were IV-EC, live virus alone (LV) or live virus-erythrocyte complex (LV-EC), compared with irradiated virus and erythrocyte alone controls. The antibody responses of IV-EC and LV-EC vaccinated mice showed significantly elevated lung and serum IgG2a levels post live virus challenge, with no comparable increases in IgG1 levels compared to controls. Spleen cells from IV-EC mice showed an enhanced post-challenge proliferative response to antigen compared with mice that had received live oral vaccines, indicating enhanced cellular activity post IV-EC immunization. However, CTL activity was not enhanced for IV-EC mice, and live virus-vaccinated mice had reduced CTL activity compared with controls, indicating that CTL were not important for post-vaccine protection. Cytokine analysis revealed a predominant IFN-gamma response in spleen cells from orally vaccinated mice, whereas IL-4 was not detected in any lung or spleen culture analysed. The results suggest, therefore, that protection from live influenza challenge after IV-EC or LV-EC vaccination was due to an IFN-mediated IgG2a response. Definitive confirmation of the role of these factors in post-vaccine protection can now be tested in IgG2a-depleted or IFN-gamma gene knockout mouse models.


The effects of the specific adsorption of anion on the reactivity of the Ru(0001) surface towards CO adsorption and oxidation: in situ FTIRS studies.
The dynamics of adsorption and oxidation of CO on Ru(0001) electrode in sulfuric acid solution have been studied using in situ FTIR spectroscopy under potential control and at open circuit, the latter at 20 and 55 degrees C. The in situ IR data show clearly that the bisulfate anion adsorbs on the Ru(0001) surface over the potential range from -200 mV to 350 mV (vs. Ag/AgCl) at 20 degrees C in the absence and presence of adsorbed CO; however, increasing the temperature to 55 degrees C and/or increasing the concentration of dissolved O(2) reduces the bisulfate adsorption. The formation of surface (hydro-) oxide at higher potentials replaces the bisulfate adsorbates. Both linear (CO(L)) and three-fold hollow bonded CO (CO(H)) adsorbates were produced following CO adsorption at Ru(0001) in H(2)SO(4), as was observed in our previous studies in HClO(4). However, the amount of adsorbed CO observed in H(2)SO(4) was ca. 10% less than that in HClO(4); in addition, the CO(L) and CO(H) frequencies were higher in H(2)SO(4), and the onset potential for CO(ads) oxidation 25 mV lower. These new results are interpreted in terms of a model in which the adsorbed bisulfate weakens the CO adlayer, allowing the active Ru oxide layer to form at lower potentials. Significantly different results were observed at open circuit in H(2)SO(4) compared both to the data under potential control and to our earlier data in HClO(4), and these observations were rationalized in terms of the adsorbed HSO(4)(-) anions (pre-adsorbed at -200 mV) inhibiting the oxidation of the surface at open circuit (after stepping from the initial potential of -200 mV), as the latter was no longer driven by the imposed electrochemical potential but via chemical oxidation by trace dissolved O(2). Results from experiments at open circuit at 55 degrees C and using oxygen-saturated H(2)SO(4) supported this model. The difference in Ru surface chemistry between imposed electrochemical control and chemical control has potential implications with respect to fuel cell electrocatalysis.


Regulation of actomyosin ATPase activity by troponin-tropomyosin: effect of the binding of the myosin subfragment 1 (S-1).ATP complex.
In our model of regulation, the observed lack of cooperativity in the binding of myosin subfragment 1 (S-1) with bound ATP to the troponin-tropomyosin-actin complex (regulated actin) is explained by S-1.ATP having about the same affinity for the conformation of the regulated actin that activates the myosin ATPase activity (turned-on form) and the conformation that does not activate the myosin ATPase activity (turned-off form). This predicts that, in the absence of Ca2+, S-1.ATP should not turn on the regulated actin filament. In the present study, we tested this prediction by using either unmodified S-1 or S-1 chemically modified with N,N'-p-phenylenedimaleimide (pPDM X S-1) so that functionally it acts like S-1.ATP, although it does not hydrolyze ATP. We found that, in the absence of Ca2+, neither S-1.ATP nor pPDM X S-1.ATP significantly turns on the ATPase activity of the regulated complex of actin and S-1 (acto X S-1). In contrast, in the presence of Ca2+, pPDM X S-1.ATP binding almost completely turns on the regulated acto.S-1 ATPase activity. These results can be explained by our original cooperativity model, with pPDM X S-1.ATP binding only approximately equal to 2-fold more strongly to the turned-on form than to the turned-off form of regulated actin. However, our results are not consistent with our alternative model, which predicts that if pPDM X S-1.ATP binds to actin in the absence of Ca2+ but does not turn on the ATPase activity, then it should also not turn on the ATPase activity in the presence of Ca2+.


Exploring Triaging and Short-Term Outcomes of Early Invasive Strategy in Non-ST Segment Elevation Acute Coronary Syndrome: A Report from Japanese Multicenter Registry.
This observational study aimed to examine the extent of early invasive strategy (EIS) utilization in patients with non-ST elevation acute coronary syndrome (NSTE-ACS) according to the National Cardiovascular Data Registry (NCDR) CathPCI risk score, and its association with clinical outcomes. Using a prospective multicenter Japanese registry, 2968 patients with NSTE-ACS undergoing percutaneous coronary intervention within 72 hours of hospital arrival were analyzed. Multivariable logistic regression analyses were performed to determine predictors of EIS utilization. Additionally, adverse outcomes were compared between patients treated with and without EIS. Overall, 82.1% of the cohort (n = 2436) were treated with EIS, and the median NCDR CathPCI risk score was 22 (interquartile range: 14-32) with an expected 0.3-0.6% in-hospital mortality. Advanced age, peripheral artery disease, chronic kidney disease or patients without elevation of cardiac biomarkers were less likely to be treated with EIS. EIS utilization was not associated with a risk of in-hospital mortality; yet, it was associated with an increased risk of acute kidney injury (AKI) (adjusted odds ratio: 1.42; 95% confidence interval: 1.02-2.01) regardless of patients' in-hospital mortality risk. Broader use of EIS utilization comes at the cost of increased AKI development risk; thus, the pre-procedural risk-benefit profile of EIS should be reassessed appropriately in patients with lower mortality risk.


Astrocytes mediate migraine-related intracranial meningeal mechanical hypersensitivity.
The genesis of the headache phase in migraine with aura is thought to be mediated by cortical spreading depression (CSD) and the subsequent activation and sensitization of primary afferent neurons that innervate the intracranial meninges and their related large vessels. Yet, the exact mechanisms underlying this peripheral meningeal nociceptive response remain poorly understood. We investigated the relative contribution of cortical astrocytes to CSD-evoked meningeal nociception using extracellular single-unit recording of meningeal afferent activity and 2-photon imaging of cortical astrocyte calcium activity, in combination with 2 pharmacological approaches to inhibit astrocytic function. We found that fluoroacetate and l-α-aminoadipate, which inhibit astrocytes through distinct mechanisms, suppressed CSD-evoked afferent mechanical sensitization, but did not affect afferent activation. Pharmacological inhibition of astrocytic function, which ameliorated meningeal afferents' sensitization, reduced basal astrocyte calcium activity but had a minimal effect on the astrocytic calcium wave during CSD. We propose that calcium-independent signaling in cortical astrocytes plays an important role in driving the sensitization of meningeal afferents and the ensuing intracranial mechanical hypersensitivity in migraine with aura.


Deep Learning-Based Image Analysis for the Quantification of Tumor-Induced Angiogenesis in the 3D In Vivo Tumor Model-Establishment and Addition to Laser Speckle Contrast Imaging (LSCI).
(1) Background: angiogenesis plays an important role in the growth and metastasis of tumors. We established the CAM assay application, an image analysis software of the IKOSA platform by KML Vision, for the quantification of blood vessels with the in ovo chorioallantoic membrane (CAM) model. We added this proprietary deep learning algorithm to the already established laser speckle contrast imaging (LSCI). (2) Methods: angiosarcoma cell line tumors were grafted onto the CAM. Angiogenesis was measured at the beginning and at the end of tumor growth with both measurement methods. The CAM assay application was trained to enable the recognition of in ovo CAM vessels. Histological stains of the tissue were performed and gluconate, an anti-angiogenic substance, was applied to the tumors. (3) Results: the angiosarcoma cells formed tumors on the CAM that appeared to stay vital and proliferated. An increase in perfusion was observed using both methods. The CAM assay application was successfully established in the in ovo CAM model and anti-angiogenic effects of gluconate were observed. (4) Conclusions: the CAM assay application appears to be a useful method for the quantification of angiogenesis in the CAM model and gluconate could be a potential treatment of angiosarcomas. Both aspects should be evaluated in further research.


The mood spectrum in unipolar and bipolar disorder: arguments for a unitary approach.
This study examined the extent to which individuals with a lifetime diagnosis of recurrent unipolar disorder endorse experiencing manic/hypomanic symptoms over their lifetimes and compared their reports with those of patients with bipolar I disorder. The study group included 117 patients with remitted recurrent unipolar depression and 106 with bipolar I. Subjects had their clinical diagnosis confirmed by the Mini International Neuropsychiatric Interview and were administered the Structured Clinical Interview for the Mood Spectrum, which assesses lifetime symptoms, traits, and lifestyles that characterize threshold and subthreshold mood episodes as well as "temperamental" features related to mood dysregulation. The patients with recurrent unipolar depression endorsed experiencing a substantial number of manic/hypomanic symptoms over their lifetimes. In both patients with recurrent unipolar depression and patients with bipolar I disorder, the number of manic/hypomanic items endorsed was related to the number of depressive items endorsed. In the group with recurrent unipolar depression, the number of manic/hypomanic items was related to an increased likelihood of endorsing paranoid and delusional thoughts and suicidal ideation. In the bipolar I group, the number of lifetime manic/hypomanic items was related to suicidal ideation and just one indicator of psychosis. The presence of a significant number of manic/hypomanic items in patients with recurrent unipolar depression seems to challenge the traditional unipolar-bipolar dichotomy and bridge the gap between these two categories of mood disorders. The authors argue that their mood spectrum approach is useful in making a more accurate diagnostic evaluation in patients with mood disorders.


[Prospects for using the Institute of Theoretical and Experimental Physics proton beam for treating gynecologic cancer patients].
Untoward side-effects of exposure of normal tissues surrounding tumor in the course of radiation treatment were avoided due to the use of a proton beam developed at the Institute of Theoretical and Experimental Physics. As a result, no post-treatment complications were observed in the surrounding tissues of the urinary bladder and rectum in 175 cancer patients (tumors of the vulva-39 and cervix uteri-136) who received a course of complex radiation treatment and preoperative irradiation.


Social exclusion and early or unwanted sexual initiation among poor urban females in Ethiopia.
Numerous studies of adolescent sexual behavior have explored factors associated with early sexual debut. However, few studies have examined the role of social exclusion and marginalization in relation to early and unwanted sexual initiation. A population-based study of 1,837 out-of-school females aged 10-19 was conducted in three low-income urban areas of Ethiopia in 2008. Descriptive and multivariate analyses were used to identify characteristics associated with having experienced coerced sexual initiation and sexual debut before age 15. Nearly half (48%) of the young women in the sample were domestic workers, and many reported significant social exclusion, including lack of friends, community support networks and group membership. Overall, 23% reported being sexually experienced and 27% of those had first had sex before age 15. Compared with other young women, domestic workers were significantly more likely to have had sex before age 15 (odds ratio, 3.3), and to have been coerced into having sex (1.8). Social exclusion was associated with significantly higher odds of coerced first sex (2.0). Programs for female adolescents should build their social capital and inclusion, as well as provide opportunities for them to stay in school and obtain positive and nonexploitive forms of work.


Multiferroic polymer composites with greatly enhanced magnetoelectric effect under a low magnetic bias.
Multiferroic laminate composites consisting of chain-end cross-linked ferroelectric polymers and magnetostrictive Metglas are reported. The composites exhibit a greatly enhanced multiferroic voltage coefficient and sensitivity relative to analogous composites. These remarkable properties are attributed to high piezoelectric and electromechanical coupling coefficients, because of the formation of larger crystalline sizes and concurrent improvement in the polarization ordering in the cross-linked polymers.


Postural Stability and Subsequent Sports Injuries during Indoor Season of Athletes.
[Purpose] The aim of this study was to analyze stabilometry in athletes during an indoor season in order to determine whether injured athletes show different stabilometric values before injury than non-injured athletes in two different training periods (volume and pre-competition periods). [Subjects] The subjects were 51 athletes from Unicaja athletic club who trained regularly. [Methods] At the end of the preseason and volume periods, athletes were subjected to bipodal and monopodal stabilometry. In addition, all injuries happening in the periods after performing stabilometry (volume and pre-competition periods) were tracked. [Results] Variance analysis of bipodal stabilometric measurements taken at the end of the preseason period showed that athletes with higher values for the center-of-pressure spread variables suffered injuries during the volume period. The right-leg monopodal stabilometric measurements taken at the end of the volume period showed that athletes with higher values in the center-of-pressure position variables suffered injuries during the pre-competition period. [Conclusion] Athletes showing the worst values for center-of-pressure spread variables are more prone to sports injuries in the subsequent training period. In monopodal measurements, athletes with poorer mediolateral stability were more prone to injuries in the subsequent training period.


Temperature Tides Across the Mid-Latitude Summer Turbopause Measured by a Sodium Lidar and MIGHTI/ICON.
Local full diurnal coverage of temperature variations across the turbopause (~90-115 km altitude) is achieved by combining the nocturnal observations of a Sodium (Na) Doppler lidar on the Utah State University (USU) campus (41.7°N, 248.2°E) and NASA Michelson interferometer for global high-resolution thermospheric imaging (MIGHTI)/Ionospheric connection explorer (ICON) daytime observations made in the same vicinity. In this study, utilizing this hybrid data set during summer 2020 between June 12th and July 15th, we retrieve the temperature signatures of diurnal and semidiurnal tides in this region. The tidal amplitudes of both components have similar vertical variation with increasing altitude: less than 5 K below ~98 km but increase considerably above, up to 19 K near 104 km. Both experience significant dissipation near turbopause altitudes, down to ~12 K up to 113 km for the diurnal tide and ~13 K for the semidiurnal tide near 110 km. In addition, while the semidiurnal tidal behavior is consistent with the theoretical predictions, the diurnal amplitude is considerably larger than what is expected in the turbopause region. The tidal phase profile shows a dominance of tidal components with a long vertical wavelength (longer than 40 km) for the semidiurnal tide. On the other hand, the diurnal tide demonstrates close to an evanescent wave behavior in the turbopause region, which is absent in the model results and Thermosphere ionosphere mesosphere energetics and dynamics (TIMED)/Sounding of the atmosphere using broadband radiometry (SABER) observations.


Endoscopic diagnosis and resection treatment for flat adenoma with severe dysplasia.
In a prospective study from 1988 to 1991, we discovered 31 flat colon adenomas in 29 patients and performed endoscopic resection of 27 of these lesions, using the strip biopsy technique. All of these lesions were safely and completely resected even in the thin walls of the colon. All 27 lesions were histologically flat adenomas confined to the mucosa, with a maximum diameter of 3-20 mm. Thirteen were identified as severe dysplasia, three as moderate dysplasia, and 11 as mild dysplasia. These lesions were more clearly defined after they were sprayed with indigo carmine endoscopically. The 13 flat adenomas with severe dysplasia were morphologically slightly depressed red lesions with elevation of the surrounding mucosa (six lesions) and flat round red lesions with no changes in the surrounding mucosa (seven lesions). Due to the high incidence of severe dysplasia found in flat adenomas, removal using strip biopsy is recommended.


Arterial spin labeling blood flow magnetic resonance imaging for the characterization of metastatic renal cell carcinoma(1).
This study sought to assess the feasibility of arterial spin labeling (ASL) blood flow (BF) magnetic resonance imaging (MRI) for the study of metastatic renal cell carcinoma (RCC) in the body, where the respiratory, cardiac, and peristaltic motions present challenges when applying ASL. ASL was performed using a background-suppressed single-section flow-alternating inversion recovery (FAIR) preparation and a single-shot fast spin-echo imaging sequence on a 3.0-T whole body imager. Tumor BF was evaluated for 26 patients with RCC metastatic to the liver, bone, lung, or lymph nodes before VEGF receptor inhibitor therapy. Two cases with tumor size change after treatment were also scanned 1 month after therapy. For validation, kidney cortex BF in five normal volunteers was measured with the same technique and compared with literature values. ASL was successfully performed in all normal volunteers and in 20 of 26 patients. The six failures resulted from a systematic error, which can be avoided in future studies. For normal volunteers, measured kidney cortex BF was 275 +/- 14 mL/min/100 g, a value consistent with the literature. ASL determined tumor BF averaged across tumor volume and subjects was 194 mL/min/100 g (intersubject SD = 100), resulting in high perfusion signal and conspicuity of lesions. Bright signal was also seen in large vessels and occasionally in bowel. In the two cases studied 1 month after therapy, ASL perfusion changes were consistent with tumor size changes. With background suppression, ASL MRI is a feasible method for quantifying BF in patients with renal cell carcinoma. This technique may be useful for evaluating tumor response to antiangiogenic agents.


Cerebral blood flow studies in the diagnosis and management of intrauterine growth restriction.
To provide evidence that fetal brain vasodilatation can be related with postnatal cerebral structural and functional complications. Most early-onset intrauterine growth restricted (IUGR) fetuses show signs of brain vasodilatation. As most of them are born prematurely, a high prevalence of short-term and long-term neurological complications is expected. However, the clinical significance of brain vasodilatation might be different. In the early stage of fetal deterioration, the risk of structural brain damage is low, but at advanced stages there is an increased risk of periventricular leukomalacia and intraventricular hemorrhage. The presence of brain vasodilatation in fetuses with an estimated fetal weight below the 10th centile but normal umbilical artery Doppler can be used to identify late-onset IUGR fetuses with latent placental insufficiency. These fetuses have an increased risk of abnormal neurological performance at birth and at 2 years of age. Changes in cerebral brain blood perfusion in IUGR fetuses can be detected by Doppler ultrasound techniques. Despite its association with structural and functional neurological damage after birth, fetal brain vasodilatation is usually not considered in the decision to deliver, with the only exception of the 'return' to normal middle cerebral artery pulsatility index, which is highly associated with an increased risk for perinatal mortality.


Photosynthetic capacity of tropical montane tree species in relation to leaf nutrients, successional strategy and growth temperature.
Photosynthetic capacity of tree leaves is typically positively related to nutrient content and little affected by changes in growth temperature. These relationships are, however, often poorly supported for tropical trees, for which interspecific differences may be more strongly controlled by within-leaf nutrient allocation than by absolute leaf nutrient content, and little is known regarding photosynthetic acclimation to temperature. To explore the influence of leaf nutrient status, successional strategy and growth temperature on the photosynthetic capacity of tropical trees, we collected data on photosynthetic, chemical and morphological leaf traits of ten tree species in Rwanda. Seven species were studied in a forest plantation at mid-altitude (~1,700 m), whereas six species were studied in a cooler montane rainforest at higher altitude (~2,500 m). Three species were common to both sites, and, in the montane rainforest, three pioneer species and three climax species were investigated. Across species, interspecific variation in photosynthetic capacity was not related to leaf nutrient content. Instead, this variation was related to differences in within-leaf nitrogen allocation, with a tradeoff between investments into compounds related to photosynthetic capacity (higher in pioneer species) versus light-harvesting compounds (higher in climax species). Photosynthetic capacity was significantly lower at the warmer site at 1,700 m altitude. We conclude that (1) within-leaf nutrient allocation is more important than leaf nutrient content per se in controlling interspecific variation in photosynthetic capacity among tree species in tropical Rwanda, and that (2) tropical montane rainforest species exhibit decreased photosynthetic capacity when grown in a warmer environment.


Reported Sexual Violence among Women and Children Seen at the Gynecological Emergency Unit of a Rural Tertiary Health Facility, Northwest Nigeria.
Various forms of sexual violence including: Coerced marriage or wife inheritance, female genital mutilation, forced exposure to pornography, rape by intimate partner or strangers, unwanted sexual advances, and sexual abuse occurs, especially in vulnerable groups. However, most of these cases are not reported. The aim was to review reported cases in the facility, determine the prevalence and pattern of presentation. This was a prospective longitudinal study undertaken at the Gynecological Emergency Unit of a Tertiary Health Facility in a rural setting Northwest Nigeria. A study of survivors of alleged sexual violence who presented to the hospital from the September 1, 2011 to August 31, 2013. During the study period, there were 24 cases of sexual violence (22 were alleged rape and 2 were others) of 973 gynecological consultations at the emergency unit, giving a prevalence of 3% (24/973) for sexual violence and 2.3% (22/973) for alleged rape. Majority 91.7% (22/24) of the cases were children < 16 years; 45.8% (11/24) had no formal education while 33.3% (8/24) hawked homemade drinks and snacks. The assailants were known in 83.3% (20/24) of the cases; of which 45.8% (11/24) were neighbors, 29.2% (7/24) were buyers of snacks and drinks while 8.3% (2/24) were family members. The prevalence of reported sexual violence in this facility was low with the majority of the survivors being children and nonstranger assailants', mostly neighbors.


Impaction grafting in revision total elbow arthroplasty due to aseptic loosening and bone loss.
With the increase in the number of total elbow arthroplasties being performed, there has been a parallel increase in revision surgery. There is limited information about the outcome of impaction grafting following failed elbow arthroplasty. We retrospectively analyzed sixteen cases of revision arthroplasty performed following aseptic loosening of a semiconstrained total elbow replacement. There were three men and thirteen women with a mean age of 58.4 years (range, twenty-eight to seventy-five years). Fourteen elbows had loosening of both the humeral and the ulnar component, and two elbows had only humeral loosening. Two elbows had perforation of the humeral cortex by the humeral component, and one had perforation of the ulnar cortex. Grade-II bone loss as described by King et al. was found in three elbows; grade III, in six elbows; and grade IV, in seven elbows. The impaction grafting was performed with only allograft in thirteen elbows, and it was done with allograft as well as autograft from the iliac crest in the other three elbows. The mean duration of follow-up was 7.4 years (range, 4.1 to 11.2 years). The mean Mayo Elbow Performance Score (MEPS) for pain significantly improved from 15.0 points preoperatively to 32.8 points at the time of latest follow-up (p = 0.003). The mean arc of flexion also significantly increased, from 60.3° to 115.6° (p < 0.01). Stability according to the MEPS significantly increased from a mean of 2.2 points to a mean of 9.4 points (p = 0.001). The mean total MEPS improved from 41.0 points to 82.8 points (p = 0.001). The result was excellent for four elbows, good for eleven, and fair for one. Follow-up radiographs demonstrated fifteen cases with grade-I resorption of the bone graft and one case with grade-II resorption. A type-I radiolucent line was observed in twelve of the elbows; type II, in three; and type IV, in one. Additional surgery was required in two cases. Impaction grafting is an effective technique when revision total elbow arthroplasty is used for the treatment of aseptic loosening with bone loss. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism.
In humans, peroxisomes harbor a complex set of enzymes acting on various lipophilic carboxylic acids, organized in two basic pathways, alpha-oxidation and beta-oxidation; the latter pathway can also handle omega-oxidized compounds. Some oxidation products are crucial to human health (primary bile acids and polyunsaturated FAs), whereas other substrates have to be degraded in order to avoid neuropathology at a later age (very long-chain FAs and xenobiotic phytanic acid and pristanic acid). Whereas total absence of peroxisomes is lethal, single peroxisomal protein deficiencies can present with a mild or severe phenotype and are more informative to understand the pathogenic factors. The currently known single protein deficiencies equal about one-fourth of the number of proteins involved in peroxisomal FA metabolism. The biochemical properties of these proteins are highlighted, followed by an overview of the known diseases.