Road to comprehensive estimation of antimicrobial resistance (AMR) disease burden in Japan.
Antimicrobial resistance (AMR) is currently a global health threat. Many countries have issued their own national action plans following the publication of the Global Action Plan on AMR by the World Health Organization. The government of Japan established its own National Action Plan on AMR in 2016; however, Japan's AMR countermeasures are still in the developmental stage. Recently, the AMR Clinical Reference Center (AMR CRC) in Japan estimated the disease burden of AMR in the form of number of deaths attributed to blood-stream infections caused by antimicrobial-resistant organisms. However, a more extensive and precise assessment is needed to understand the disease burden of AMR more clearly and enable us to compare these indicators with those published by other countries. Cassini and colleagues from the World Health Organization estimated the disease burden of AMR in the European Union as disability-adjusted life years (DALYs) in 2018. Their study could be considered an important milestone in terms of its thoroughness. If we hope to estimate the disease burden of AMR in a more precise manner, age-stratified patient data is needed in conjunction with a surveillance report. At present, AMR CRC is attempting to establish such data for examination at the national level - a challenging but worthwhile task.


Henry's voices: the representation of auditory verbal hallucinations in an autobiographical narrative.
The book Henry's Demons (2011) recounts the events surrounding Henry Cockburn's diagnosis of schizophrenia from the alternating perspectives of Henry himself and his father Patrick. In this paper, we present a detailed linguistic analysis of Henry's first-person accounts of experiences that could be described as auditory verbal hallucinations. We first provide a typology of Henry's voices, taking into account who or what is presented as speaking, what kinds of utterances they produce and any salient stylistic features of these utterances. We then discuss the linguistically distinctive ways in which Henry represents these voices in his narrative. We focus on the use of Direct Speech as opposed to other forms of speech presentation, the use of the sensory verbs hear and feel and the use of 'non-factive' expressions such as I thought and as if. We show how different linguistic representations may suggest phenomenological differences between the experience of hallucinatory voices and the perception of voices that other people can also hear. We, therefore, propose that linguistic analysis is ideally placed to provide in-depth accounts of the phenomenology of voice hearing and point out the implications of this approach for clinical practice and mental healthcare.


Effect of gravity on human spontaneous 10-Hz electroencephalographic oscillations during the arrest reaction.
Electroencephalographic oscillations at 10 Hz (alpha and mu rhythms) are the most prominent rhythms observed in awake, relaxed (eye-closed) subjects. These oscillations may be considered as a marker of cortical inactivity or an index of the active inhibition of the sensory information. Different cortical sources may participate in the 10-Hz oscillation and appear to be modulated by the sensory context and functional demands. In microgravity, the marked reduction in multimodal graviceptive inputs to cortical networks participating in the representation of space could be expected to affect the 10-Hz activity. The effect of microgravity on this basic oscillation has heretofore not been studied quantitatively. Because the alpha rhythm has a functional role in the regulation of network properties of the visual areas, we hypothesised that the absence of gravity would affect its strength. Here, we report the results of an experiment conducted over the course of 3 space flights, in which we quantified the power of the 10-Hz activity in relation to the arrest reaction (i.e., in 2 distinct physiological states: eyes open and eyes closed). We observed that the power of the spontaneous 10-Hz oscillation recorded in the eyes-closed state in the parieto-occipital (alpha rhythm) and sensorimotor areas (mu rhythm) increased in the absence of gravity. The suppression coefficient during the arrest reaction and the related spectral perturbations produced by eye-opening/closure state transition also increased in on orbit. These results are discussed in terms of current theories on the source and the importance of the alpha rhythm for cognitive function.


Altered coronary vascular responsiveness to leukotrienes in alloxan-diabetic rats.
Altered responsiveness to and metabolism of various eicosanoids in diabetic animals and patients has been reported by several investigators. The purpose of this investigation was to examine the coronary vascular responsiveness of alloxan-diabetic rats to the leukotrienes. Hearts from 12- to 16-week-old alloxan-diabetic rats and weight-matched controls were perfused at constant flow by the Langendorff method. Coronary vasoactivity to leukotrienes B4, C4, D4 and E4 was assessed by measuring the change in coronary perfusion pressure upon infusion of these eicosanoids. Hearts from diabetic rats showed increased responsiveness to leukotrienes C4 (4-40 nM) and D4 (10-100 nM). Both control and diabetic rat hearts were only slightly responsive to leukotriene E4, and no difference between the two groups existed in the reactivity to this leukotriene. Neither group was responsive to the chemotactic leukotriene, B4. Perfusion of the hearts with the cyclooxygenase inhibitor, ibuprofen, failed to alter the coronary vascular responses to the leukotrienes. The coronary constrictor effects of the leukotrienes are the primary effect of these agents on the rat heart, since heart rate does not change significantly, and changes in contractile force are secondary to the coronary vascular constriction. These alterations in responsiveness to leukotrienes may play a role in the cardiovascular complications associated with diabetes.


Intracellular calcium mishandling leads to cardiac dysfunction and ventricular arrhythmias in a mouse model of propionic acidemia.
Propionic acidemia (PA) is a rare metabolic disease associated with mutations in genes encoding the α and β subunits of the enzyme propionyl-CoA carboxylase. The accumulation of toxic metabolites results in mitochondrial dysfunction, increased reactive oxygen species production and oxidative damage, which have been associated with the disease pathophysiology. Clinical symptoms are heterogeneous and include cardiac complications, mainly cardiac dysfunction and arrhythmias, which are recognized as one of the major life-threatening manifestations in patients. We aimed to investigate the molecular mechanisms underlying the cardiac phenotype using a hypomorphic mouse model (Pcca-/-(A138T)) that recapitulates some biochemical and clinical characteristics of PA. We demonstrate that Pcca-/-(A138T) mice present with depressed cardiac function along with impaired cell contractility when compared to the wild-type mice. Cardiac dysfunction in Pcca-/-(A138T) mice was associated with lower systolic Ca2+ release ([Ca2+]i transients), impairment in the sarcoplasmic reticulum (SR) Ca2+ load and decreased Ca2+ re-uptake by SR-Ca2+ ATPase (SERCA2a). These functional changes correlated well with the depressed activity of SERCA2a, the elevated ROS levels and SERCA2a oxidation rate in cardiomyocytes isolated from Pcca-/-(A138T) mice. In addition, decreased SR-Ca2+ load in Pcca-/-(A138T) cardiomyocytes was associated with increased diastolic Ca2+ release. The increase in Ca2+ sparks, Ca2+ waves and spontaneous [Ca2+]i transients in Pcca-/-(A138T) cardiomyocytes could be responsible for the induction of ventricular arrhythmias detected in these mice. Overall, our results uncover the role of impaired Ca2+ handling in arrhythmias and cardiac dysfunction in PA, and identify new targets for the development of therapeutic approaches for this devastating metabolic disease.


The E-Coach technology-assisted care transition system: a pragmatic randomized trial.
Care transitions from the hospital to home remain a vulnerable time for many patients, especially for those with heart failure (CHF) and chronic obstructive pulmonary disease (COPD). Despite regular use in chronic disease management, it remains unclear how technology can best support patients during their transition from the hospital. We sought to evaluate the impact of a technology-supported care transition support program on hospitalizations, days out of the community and mortality. Using a pragmatic randomized trial, we enrolled patients (511 enrolled, 478 analyzed) hospitalized with CHF/COPD to "E-Coach," an intervention with condition-specific customization and in-hospital and post-discharge support by a care transition nurse (CTN), interactive voice response post-discharge calls, and CTN follow-up versus usual post-discharge care (UC). The primary outcome was 30-day rehospitalization. Secondary outcomes included (1) rehospitalization and death and (2) days in the hospital and out of the community. E-Coach and UC groups were similar at baseline except for gender imbalance (p = 0.02). After adjustment for gender, our primary outcome, 30-day rehospitalization rates did not differ between the E-Coach and UC groups (15.0 vs. 16.3 %, adjusted hazard ratio [95 % confidence interval]: 0.94 [0.60, 1.49]). However, in the COPD subgroup, E-Coach was associated with significantly fewer days in the hospital (0.5 vs. 1.6, p = 0.03). E-Coach, an IVR-augmented care transition intervention did not reduce rehospitalization. The positive impact on our secondary outcome (days in hospital) among COPD patients, but not in CHF, may suggest that E-Coach may be more beneficial among patients with COPD.NIH trial registry number: NCT01135381Trial Protocol: http://dx.doi.org/ 10.1016/j.cct.2012.08.007.


The Pseudomonas aeruginosa sensor kinase KinB negatively controls alginate production through AlgW-dependent MucA proteolysis.
Mucoidy, or overproduction of the exopolysaccharide known as alginate, in Pseudomonas aeruginosa is a poor prognosticator for lung infections in cystic fibrosis. Mutation of the anti-sigma factor MucA is a well-accepted mechanism for mucoid conversion. However, certain clinical mucoid strains of P. aeruginosa have a wild-type (wt) mucA. Here, we describe a loss-of-function mutation in kinB that causes overproduction of alginate in the wt mucA strain PAO1. KinB is the cognate histidine kinase for the transcriptional activator AlgB. Increased alginate production due to inactivation of kinB was correlated with high expression at the alginate-related promoters P(algU) and P(algD). Deletion of alternative sigma factor RpoN (sigma(54)) or the response regulator AlgB in kinB mutants decreased alginate production to wt nonmucoid levels. Mucoidy was restored in the kinB algB double mutant by expression of wt AlgB or phosphorylation-defective AlgB.D59N, indicating that phosphorylation of AlgB was not required for alginate overproduction when kinB was inactivated. The inactivation of the DegS-like protease AlgW in the kinB mutant caused loss of alginate production and an accumulation of the hemagglutinin (HA)-tagged MucA. Furthermore, we observed that the kinB mutation increased the rate of HA-MucA degradation. Our results also indicate that AlgW-mediated MucA degradation required algB and rpoN in the kinB mutant. Collectively, these studies indicate that KinB is a negative regulator of alginate production in wt mucA strain PAO1.


Chronic Stroke Survivors Improve Reaching Accuracy by Reducing Movement Variability at the Trained Movement Speed.
Recovery from stroke is often said to have "plateaued" after 6 to 12 months. Yet training can still improve performance even in the chronic phase. Here we investigate the biomechanics of accuracy improvements during a reaching task and test whether they are affected by the speed at which movements are practiced. We trained 36 chronic stroke survivors (57.5 years, SD ± 11.5; 10 females) over 4 consecutive days to improve endpoint accuracy in an arm-reaching task (420 repetitions/day). Half of the group trained using fast movements and the other half slow movements. The trunk was constrained allowing only shoulder and elbow movement for task performance. Before training, movements were variable, tended to undershoot the target, and terminated in contralateral workspace (flexion bias). Both groups improved movement accuracy by reducing trial-to-trial variability; however, change in endpoint bias (systematic error) was not significant. Improvements were greatest at the trained movement speed and generalized to other speeds in the fast training group. Small but significant improvements were observed in clinical measures in the fast training group. The reduction in trial-to-trial variability without an alteration to endpoint bias suggests that improvements are achieved by better control over motor commands within the existing repertoire. Thus, 4 days' training allows stroke survivors to improve movements that they can already make. Whether new movement patterns can be acquired in the chronic phase will need to be tested in longer term studies. We recommend that training needs to be performed at slow and fast movement speeds to enhance generalization.


The use of mushroom glucans and proteoglycans in cancer treatment.
Immunoceuticals can be considered as substances having immunotherapeutic efficacy when taken orally. More than 50 mushroom species have yielded potential immunoceuticals that exhibit anticancer activity in vitro or in animal models and of these, six have been investigated in human cancers. All are non-toxic and very well tolerated. Lentinan and schizophyllan have little oral activity. Active Hexose Correlated Compound (AHCC) is poorly defined but has shown early clinical promise. Maitake D-Fraction has limited proof of clinical efficacy to date, but controlled research is underway. Two proteoglycans from Coriolus versicolor - PSK (Polysaccharide-K) and PSP (Polysaccharide-Peptide - have demonstrated the most promise. In Japanese trials since 1970, PSK significantly extended survival at five years or beyond in cancers of the stomach, colon-rectum, esophagus, nasopharynx, and lung (non-small cell types), and in a HLA B40-positive breast cancer subset. PSP was subjected to Phase II and Phase III trials in China. In double-blind trials, PSP significantly extended five-year survival in esophageal cancer. PSP significantly improved quality of life, provided substantial pain relief, and enhanced immune status in 70-97 percent of patients with cancers of the stomach, esophagus, lung, ovary, and cervix. PSK and PSP boosted immune cell production, ameliorated chemotherapy symptoms, and enhanced tumor infiltration by dendritic and cytotoxic T-cells. Their extremely high tolerability, proven benefits to survival and quality of life, and compatibility with chemotherapy and radiation therapy makes them well suited for cancer management regimens.


Current rectification by nanoparticle blocking in single cylindrical nanopores.
Blocking of a charged pore by an oppositely charged nanoparticle can support rectifying properties in a cylindrical nanopore, as opposed to the usual case of a fixed asymmetry in the pore geometry and charge distribution. We present here experimental data and model calculations to confirm this fundamental effect. The nanostructure imaging and the effects of nanoparticle concentration, pore radius, and salt concentration on the electrical conductance-voltage (G-V) curves are discussed. Logic responses based on chemical and electrical inputs/outputs could also be implemented with a single pore acting as an effective nanofluidic diode. To better show the generality of the results, different charge states and relative sizes of the nanopore and the nanoparticle are considered, emphasizing those physical concepts that are also found in the ionic drug blocking of protein ion channels.


Autosomal recessive hypercholesterolemia protein interacts with and regulates the cell surface level of Alzheimer's amyloid beta precursor protein.
The familial Alzheimer's disease gene product amyloid beta protein precursor (A beta PP) is sequentially processed by beta- and gamma-secretases to generate the A beta peptide. Although much is known about the biochemical pathway leading to A beta formation, because extracellular aggregates of A beta peptides are considered the cause of Alzheimer's disease, the biological role of A beta PP processing is only recently being investigated. Cleavage of A beta PP by gamma-secretase releases, together with A beta, a COOH-terminal A beta PP intracellular domain, termed AID. Hoping to gain clues about proteins that regulates A beta PP processing and function, we used the yeast two-hybrid system to identify proteins that interact with the AID region of A beta PP. One of the interactors isolated is the autosomal recessive hypercholesterolemia (ARH) adapter protein. This molecular interaction is confirmed in vitro and in vivo by fluorescence resonance energy transfer and in cell lysates. Moreover, we show that reduction of ARH expression by RNA interference results in increased levels of cell membrane A beta PP. These data assert a physiological role for ARH in A beta PP internalization, transport, and/or processing.


Endurance training per se increases metabolic health in young, moderately overweight men.
Health benefits of physical activity may depend on a concomitant weight loss. In a randomized, controlled trial, we compared the effects of endurance training with or without weight loss to the effect of weight loss induced by an energy-reduced diet in 48 sedentary, moderately overweight men who completed a 12-week intervention program of training (T), energy-reduced diet (D), training and increased diet (T-iD), or control (C). An energy deficit of 600 kcal/day was induced by endurance training or diet in T and D and a similar training regimen plus an increased dietary intake of 600 kcal/day defined the T-iD group. Primary end point was insulin sensitivity as evaluated by HOMA-IR (mainly reflecting hepatic insulin sensitivity) and hyperinsulinemic, isoglycemic clamps (primarily reflecting peripheral insulin sensitivity). Body mass decreased in T and D by 5.9 ± 0.7 and 5.3 ± 0.7 kg, respectively, whereas T-iD and C remained weight stable. Total and abdominal fat mass were reduced in an additive manner in the T-iD, D, and T groups by 1.9 ± 0.3/0.2 ± 0.1, 4.4 ± 0.7/0.5 ± 0.1, and 7.7 ± 0.8/0.9 ± 0.1 kg, respectively. HOMA-IR was improved in T, D, and T-iD, whereas insulin-stimulated glucose clearance and suppression of plasma nonesterified fatty acids (NEFAs) were increased only in the two training groups. Thus, loss of fat mass (diet or training induced) improves hepatic insulin sensitivity, whereas peripheral insulin sensitivity in skeletal muscle and adipose tissue is increased by endurance training only. This demonstrates that endurance training per se increases various metabolic health parameters and that endurance training should preferably always be included in any intervention regimen for improving metabolic health in moderately overweight men.


A deletion map of the human immunoglobulin heavy chain variable region.
Analysis of VH gene segments deleted in the process of immunoglobulin heavy chain (IGH) variable region assembly in three series of monoclonal B cell lines has been used to determine the human VH region organization. A deletion map of the relative positions of 21 different VH gene segments has been determined. The characterization of B cell lines from three unrelated adults of two racial groups yielded the same relative VH gene segment order, suggesting that the overall order of VH genes in the normal population is constant. This VH gene segment order was consistent with what we had previously generated from physical mapping techniques. DH segments from the second DH cluster, distinct from the major DH locus 3' of the VH region, were not observed to be used in 32 different rearrangements. Approximately 77% of the VH-(D)JH rearrangements involved VH gene segments within 500 kb of the JH region, indicating that human B cell lines preferentially rearrange JH-proximal VH gene segments. The switch, observed in mice, from the fetal use of JH-proximal VH gene segments to an adult VH use dependent upon VH family size may therefore not occur in humans. This detailed map of the VH gene segments is a necessary prerequisite for understanding VH usage in development and disease.


The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial.
Transcranial Doppler ultrasound (TCD) and magnetic resonance angiography (MRA) can identify intracranial atherosclerosis but have not been rigorously validated against the gold standard, catheter angiography. The WASID trial (Warfarin Aspirin Symptomatic Intracranial Disease) required performance of angiography to verify the presence of intracranial stenosis, allowing for prospective evaluation of TCD and MRA. The aims of Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial were to define abnormalities on TCD/MRA to see how well they identify 50 to 99% intracranial stenosis of large proximal arteries on catheter angiography. SONIA standardized the performance and interpretation of TCD, MRA, and angiography. Study-wide cutpoints defining positive TCD/MRA were used. Hard copy TCD/MRA were centrally read, blind to the results of angiography. SONIA enrolled 407 patients at 46 sites in the United States. For prospectively tested noninvasive test cutpoints, positive predictive values (PPVs) and negative predictive values (NPVs) were TCD, PPV 36% (95% CI: 27 to 46); NPV, 86% (95% CI: 81 to 89); MRA, PPV 59% (95% CI: 54 to 65); NPV, 91% (95% CI: 89 to 93). For cutpoints modified to maximize PPV, they were TCD, PPV 50% (95% CI: 36 to 64), NPV 85% (95% CI: 81 to 88); MRA PPV 66% (95% CI: 58 to 73), NPV 87% (95% CI: 85 to 89). For each test, a characteristic performance curve showing how the predictive values vary with a changing test cutpoint was obtained. Both transcranial Doppler ultrasound and magnetic resonance angiography noninvasively identify 50 to 99% intracranial large vessel stenoses with substantial negative predictive value. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis trial methods allow transcranial Doppler ultrasound and magnetic resonance angiography to reliably exclude the presence of intracranial stenosis. Abnormal findings on transcranial Doppler ultrasound or magnetic resonance angiography require a confirmatory test such as angiography to reliably identify stenosis.


Quantitative imaging reveals heterogeneous growth dynamics and treatment-dependent residual tumor distributions in a three-dimensional ovarian cancer model.
Three-dimensional tumor models have emerged as valuable in vitro research tools, though the power of such systems as quantitative reporters of tumor growth and treatment response has not been adequately explored. We introduce an approach combining a 3-D model of disseminated ovarian cancer with high-throughput processing of image data for quantification of growth characteristics and cytotoxic response. We developed custom MATLAB routines to analyze longitudinally acquired dark-field microscopy images containing thousands of 3-D nodules. These data reveal a reproducible bimodal log-normal size distribution. Growth behavior is driven by migration and assembly, causing an exponential decay in spatial density concomitant with increasing mean size. At day 10, cultures are treated with either carboplatin or photodynamic therapy (PDT). We quantify size-dependent cytotoxic response for each treatment on a nodule by nodule basis using automated segmentation combined with ratiometric batch-processing of calcein and ethidium bromide fluorescence intensity data (indicating live and dead cells, respectively). Both treatments reduce viability, though carboplatin leaves micronodules largely structurally intact with a size distribution similar to untreated cultures. In contrast, PDT treatment disrupts micronodular structure, causing punctate regions of toxicity, shifting the distribution toward smaller sizes, and potentially increasing vulnerability to subsequent chemotherapeutic treatment.


Ca2+ signals coordinate zygotic polarization and cell cycle progression in the brown alga Fucus serratus.
Zygotes of the fucoid brown algae provide excellent models for addressing fundamental questions about zygotic symmetry breaking. Although the acquisition of polarity is tightly coordinated with the timing and orientation of the first asymmetric division--with zygotes having to pass through a G1/S-phase checkpoint before the polarization axis can be fixed--the mechanisms behind the interdependence of polarization and cell cycle progression remain unclear. In this study, we combine in vivo Ca2+ imaging, single cell monitoring of S-phase progression and multivariate analysis of high-throughput intracellular Ca2+ buffer loading to demonstrate that Ca2+ signals coordinate polarization and cell cycle progression in the Fucus serratus zygote. Consistent with earlier studies on this organism, and in contrast to animal models, we observe no fast Ca2+ wave following fertilization. Rather, we show distinct slow localized Ca2+ elevations associated with both fertilization and S-phase progression, and we show that both S-phase and zygotic polarization are dependent on pre-S-phase Ca2+ increases. Surprisingly, this Ca2+ requirement cannot be explained by co-dependence on a single G1/S-phase checkpoint, as S phase and zygotic polarization are differentially sensitive to pre-S-phase Ca2+ elevations and can be uncoupled. Furthermore, subsequent cell cycle progression through M phase is independent of localized actin polymerization and zygotic polarization. This absence of a morphogenesis checkpoint, together with the observed Ca2+-dependences of S phase and polarization, show that the regulation of zygotic division in the brown algae differs from that in other eukaryotic model systems, such as yeast and Drosophila.


The spice sage and its active ingredient rosmarinic acid protect PC12 cells from amyloid-beta peptide-induced neurotoxicity.
Traditional use and clinical reports suggest that the culinary herb sage (Salvia officinalis) may be effective for patients with mild to moderate Alzheimer's disease (AD). In this study, we evaluated the effect of a standardized extract from the leaves of S. officinalis (SOE) and its active ingredient rosmarinic acid on Alzheimer amyloid-beta peptide (Abeta)-induced toxicity in cultured rat pheochromocytoma (PC12) cells. Incubation of PC12 cells with Abeta (fragment 1-42) for 24 h caused cell death, and this effect was reduced by SOE and its active ingredient, rosmarinic acid. Rosmarinic acid reduced a number of events induced by Abeta. These include reactive oxygen species formation, lipid peroxidation, DNA fragmentation, caspase-3 activation, and tau protein hyperphosphorylation. Moreover, rosmarinic acid inhibited phosphorylated p38 mitogen-activated protein kinase but not glycogen synthase kinase 3beta activation. These data show the neuroprotective effect of sage against Abeta-induced toxicity, which could validate the traditional use of this spice in the treatment of AD. Rosmarinic acid could contribute, at least in part, for sage-induced neuroprotective effect.


Comprehension of signs by dolphins (Tursiops truncatus).
The authors assessed the ability of 6 captive dolphins (Tursiops truncatus) to comprehend without explicit training 3 human communicative signs (pointing, directed gaze, and replica). Pointing consisted of indicating the target item with the index finger and a fully extended arm. Directed gaze consisted of orienting the head and eyes toward the target item while the rest of the body remained stationary. The replica signal consisted of holding up an exact duplicate of the target item. On the initial series of 12 trials for each condition, 3 dolphins performed above chance on pointing, 2 on gaze, and none for replica. With additional trials, above chance performance increased to 4 dolphins for pointing, 6 for gazing, and 2 for replica. The replica sign seemed to be the most taxing for them (only 2 dolphins achieved results significantly above chance). Taken together, these results indicate that dolphins are able to interpret untrained communicative signs successfully.


Unconventional superconductivity on a topological insulator.
We study proximity-induced superconductivity on the surface of a topological insulator (TI), focusing on unconventional pairing. We find that the excitation spectrum becomes gapless for any spin-triplet pairing, such that both subgap bound states and Andreev reflection is strongly suppressed. For spin-singlet pairing, the zero-energy surface state in the d(xy)-wave case becomes a Majorana fermion, in contrast with the situation realized in the topologically trivial high-T(c) cuprates. We also study the influence of a Zeeman field on the surface states. Both the magnitude and direction of this field are shown to strongly influence the transport properties, in contrast with the case without TI. We predict an experimental signature of the Majorana states via conductance spectroscopy.


NirF is a periplasmic protein that binds d₁ heme as part of its essential role in d₁ heme biogenesis.
The cytochrome cd₁ nitrite reductase from Paracoccus pantotrophus catalyses the one electron reduction of nitrite to nitric oxide using two heme cofactors. The site of nitrite reduction is the d₁ heme, which is synthesized under anaerobic conditions by using nirECFD-LGHJN gene products. In vivo studies with an unmarked deletion strain, ΔnirF, showed that this gene is essential for cd₁ assembly and consequently for denitrification, which was restored when the ΔnirF strain was complemented with wild-type, plasmid-borne, nirF. Removal of a signal sequence and deletion of a conserved N-terminal Gly-rich motif from the NirF coded on a plasmid resulted in loss of in vivo NirF activity. We demonstrate here that the product of the nirF gene is a periplasmic protein and, hence, must be involved in a late stage of the cofactor biosynthesis. In vitro studies with purified NirF established that it could bind d₁ heme. It is concluded that His41 of NirF, which aligns with His200 of the d₁ heme domain of cd₁, is essential both for this binding and for the production of d₁ heme; replacement of His41 by Ala, Cys, Lys and Met all gave nonfunctional proteins. Potential functions of NirF are discussed.


Histogenesis of retinal dysplasia in trisomy 13.
Although often associated with holoprosencephaly, little detail of the histopathology of cyclopia is available. Here, we describe the ocular findings in a case of trisomy 13 to better understand the histogenesis of the rosettes, or tubules, characteristic of the retinal dysplasia associated with this condition. A full pediatric autopsy was performed of a near term infant who died shortly after birth from multiple congenital anomalies including fused facial-midline structures. A detailed histopathological study of the ocular structures was performed. The expression of interphotoreceptor retinoid-binding protein (IRBP), cellular retinal-binding protein (CRALBP), rod opsin, and Sonic Hedgehog (Shh) were studied by immunohistochemistry. Holoprosencephaly, and a spectrum of anatomical findings characteristic of Patau's syndrome, were found. Cytogenetic studies demonstrated trisomy 13 [47, XY, +13]. The eyes were fused but contained two developed separate lenses. In contrast, the cornea, and angle structures were hypoplastic, and the anterior chamber had failed to form. The retina showed areas of normally laminated neural retina, whereas in other areas it was replaced by numerous neuronal rosettes. Histological and immunohistochemical studies revealed that the rosettes were composed of differentiated retinal neurons and Müller cell glia. In normally laminated retina, Shh expression was restricted to retinal-ganglion cells, and to a population of neurons in the inner zone of the outer nuclear layer. In contrast, Shh could not be detected in the dysplastic rosettes. The histopathology of cyclopia appears to be more complex than what may have been previously appreciated. In fact, the terms "cyclopia" and "synophthalmia" are misnomers as the underlying mechanism is a failure of the eyes to form separately during development. The rosettes found in the dysplastic retina are fundamentally different than those of retinoblastoma, being composed of a variety of differentiated cell types. The dysplastic rosettes are essentially laminated retina failing to establish a polarized orientation, resulting in the formation of tubules. Finally, our findings suggest that defective ganglion cell Shh expression may contribute to the ocular pathology of cyclopia.


Monocyte chemoattractant protein-1 plays a critical role in neuroblast migration after focal cerebral ischemia.
Transient focal ischemia is known to induce proliferation of neural progenitors in adult rodent brain. We presently report that doublecortin positive neuroblasts formed in the subventricular zone (SVZ) and the posterior peri-ventricle region migrate towards the cortical and striatal penumbra after transient middle cerebral artery occlusion (MCAO) in adult rodents. Cultured neural progenitor cells grafted into the non-infarcted area of the ipsilateral cortex migrated preferentially towards the infarct. As chemokines are known to induce cell migration, we investigated if monocyte chemoattractant protein-1 (MCP-1) has a role in post-ischemic neuroblast migration. Transient MCAO induced an increased expression of MCP-1 mRNA in the ipsilateral cortex and striatum. Immunostaining showed that the expression of MCP-1 was localized in the activated microglia and astrocytes present in the ischemic areas between days 1 and 3 of reperfusion. Furthermore, infusion of MCP-1 into the normal striatum induced neuroblast migration to the infusion site. The migrating neuroblasts expressed the MCP-1 receptor CCR2. In knockout mice that lacked either MCP-1 or its receptor CCR2, there was a significant decrease in the number of migrating neuroblasts from the ipsilateral SVZ to the ischemic striatum. These results show that MCP-1 is one of the factors that attract the migration of newly formed neuroblasts from neurogenic regions to the damaged regions of brain after focal ischemia.


Scapholunate Ligament: Comparing the Native Strength of the Ligament to an All-suture Anchor Construct.
Our aim was to compare the tensile strength of the native scapholunate ligament (SLL) with that of an all-suture anchor construct in a cadaveric model. The scaphoid and lunate were isolated, preserving all segments of the SLL. Using a servohydraulic testing machine, we increased the load until peak load-to-failure of the native SLL was reached in nine specimens (mean ± standard deviation, 273 ± 132 N). Using the same specimens, two JuggerKnot 1.4-mm suture anchors (Zimmer Biomet) were placed into the lunate and tensioned through transosseous tunnels in the scaphoid. Sutures were tied over the radial nonarticular aspect of the scaphoid. Load-to-failure testing was repeated. The mean peak load-to-failure for the all-suture anchor constructs was 172 ± 59 N versus 231 ± 117 N for the native group (p = 0.157). This represents approximately 75% of the native ligament strength. (Journal of Surgical Orthopaedic Advances 29(3):169-172, 2020).


Plasma Lipid Profiling Identifies Biomarkers of Cerebral Microvascular Disease.
Brain-specific sphingolipids (SLs) may serve as effective biomarkers of white matter hyperintensities (WMH). Here, we investigate the efficacy of SLs as a novel fluid-based biomarker to identify WMH reflective of chronic ischemia. Patients presenting to our stroke center for evaluation of acute neurological deficits were enrolled in the Advanced Serum Profiling in Recent Stroke (ASPIRE) study. From this cohort of 202 individuals, 58 patients who underwent an MRI and did not have a clinical stroke event were included in this study. Plasma samples were collected at the time of MRI, and targeted SL profiling was performed by HPLC/tandem mass spectrometry. T2 FLAIR imaging was evaluated for WMH and scored according to the Fazekas scoring (FS) method and manually quantified. Twenty two SLs were definitively identified, consisting of ceramide (Cer) and sphingomyelin (SM) species. Of these, two sphingolipids, SM 38:1 and Cer 34:1, significantly correlated with high FS (r = 0.287, p = 0.029, and r = 0.356, p = 0.006, respectively) and were used in subsequent analysis. SM 38:1 (OR 1.129, 95% CI 1.032, 1.236, p = 0.008) and Cer 34:1 (OR 1.118, 95% CI 1.031, 1.212, p = 0.007), accurately differentiated between FS 0-2 vs. 2.5-6 in regression analysis. A combined lipid score demonstrated fair discrimination in ROC analysis (AUC = 0.729, p = 0.003) and was cross-validated using leave-one-out analysis. Plasma levels of brain-specific SLs may serve as effective biomarkers of subacute white matter disease.


tRNAs marked with CCACCA are targeted for degradation.
The CCA-adding enzyme [ATP(CTP):tRNA nucleotidyltransferase] adds CCA to the 3' ends of transfer RNAs (tRNAs), a critical step in tRNA biogenesis that generates the amino acid attachment site. We found that the CCA-adding enzyme plays a key role in tRNA quality control by selectively marking structurally unstable tRNAs and tRNA-like small RNAs for degradation. Instead of adding CCA to the 3' ends of these transcripts, CCA-adding enzymes from all three kingdoms of life add CCACCA. In addition, hypomodified mature tRNAs are subjected to CCACCA addition as part of a rapid tRNA decay pathway in vivo. We conjecture that CCACCA addition is a universal mechanism for controlling tRNA levels and preventing errors in translation.


Anterior Capsulotomy Outcomes: A Comparison Between Two Femtosecond Laser Cataract Surgery Platforms.
To compare capsulotomy outcomes between two femtosecond laser platforms for cataract surgery. This retrospective case series included 205 eyes of 162 consecutive patients (75 male and 87 female) aged 68.32 ± 10.27 years (range: 38 to 92 years) who underwent femtosecond laser-assisted cataract surgery (FLACS) using either the LenSx (Alcon Laboratories, Inc., Fort Worth, TX) or the Catalys (Abbott Medical Optics, Abbott Park, IL) laser platform. Intraoperative assessment of the capsulotomy was performed and graded as one of the following four types: complete treatment pattern (type 1), microadhesions (type 2), incomplete treatment pattern (type 3), and complete pattern but not continuous (type 4). Ninety-seven eyes underwent FLACS using the LenSx platform and 108 eyes using the Catalys platform. Ninety-four capsulotomies in the LenSx group were graded as type 1 (96.91%), and three were graded as type 2 (3.09%); all capsulotomies in the Catalys group were graded as type 1 (100%). There was no statistically significant difference between the LenSx and Catalys groups (P > .05). No intraoperative complications (specifically, no posterior capsular extension or vitreous loss) were noticed in any of the eyes included in the study. The LenSx and Catalys laser platforms demonstrate similar capsulotomy outcomes. The microadhesions that were demonstrated in three cases in the LenSx group did not lead to intraoperative or postoperative complications.


Signatures of environmental genetic adaptation pinpoint pathogens as the main selective pressure through human evolution.
Previous genome-wide scans of positive natural selection in humans have identified a number of non-neutrally evolving genes that play important roles in skin pigmentation, metabolism, or immune function. Recent studies have also shown that a genome-wide pattern of local adaptation can be detected by identifying correlations between patterns of allele frequencies and environmental variables. Despite these observations, the degree to which natural selection is primarily driven by adaptation to local environments, and the role of pathogens or other ecological factors as selective agents, is still under debate. To address this issue, we correlated the spatial allele frequency distribution of a large sample of SNPs from 55 distinct human populations to a set of environmental factors that describe local geographical features such as climate, diet regimes, and pathogen loads. In concordance with previous studies, we detected a significant enrichment of genic SNPs, and particularly non-synonymous SNPs associated with local adaptation. Furthermore, we show that the diversity of the local pathogenic environment is the predominant driver of local adaptation, and that climate, at least as measured here, only plays a relatively minor role. While background demography by far makes the strongest contribution in explaining the genetic variance among populations, we detected about 100 genes which show an unexpectedly strong correlation between allele frequencies and pathogenic environment, after correcting for demography. Conversely, for diet regimes and climatic conditions, no genes show a similar correlation between the environmental factor and allele frequencies. This result is validated using low-coverage sequencing data for multiple populations. Among the loci targeted by pathogen-driven selection, we found an enrichment of genes associated to autoimmune diseases, such as celiac disease, type 1 diabetes, and multiples sclerosis, which lends credence to the hypothesis that some susceptibility alleles for autoimmune diseases may be maintained in human population due to past selective processes.


Heparin monitoring: clinical outcome and practical approach.
Traditional anticoagulant agents such as unfractionated heparin (UFH), low molecular weight heparins (LMWHs), fondaparinux, danaparoid and bivalirudine are used in the prevention and treatment of thromboembolic diseases. However, these agents have limitations: their constraining parenteral route of administration and the need for regular coagulation monitoring for HNF. The LMWHs, with their more predictable anticoagulant response, don't require a systematic monitoring. The usefulness of LMWHs monitoring in several clinical situations such as pregnancy, obesity and renal insufficiency is a matter of debate. Indeed, there is no agreement between French and American recommendations on this question. Others aspects are also controversial: the measure of trough anti-Xa activity during pregnancy and the optimal monitoring of LMWHs for patients with antithrombin deficiency (hepatic disease, new-borns). Different tests are available to ensure the monitoring of these drugs, we will see in this review their principle, their advantages and inconvenients. The management of heparin induced thrombocytopenia also needs parenteral anticoagulants: danaparoïd, bivalirudine or argatroban. The modalities of their monitoring are relatively unknown and are presented. Furthermore, platelet monitoring is capital. This article aims to provide guidance about laboratory testing of classic parenteral anticoagulants.


Indirect Mitral Annuloplasty Using the Carillon Device.
Patients with functional, or secondary, mitral regurgitation (FMR, SMR) often face significant symptoms that lead to functional decline as well as hospitalization and even death. Traditional mitral annuloplasty is an important treatment option for patients with FMR, but surgical risk and durability are important limitations. Percutaneous strategies are therefore a welcome alternative. The Carillon device utilizes the relationship of the coronary sinus and the mitral annulus to effect an "indirect" annuloplasty. Early series' and recent randomized trials suggest echocardiographic and clinical benefit with a relatively straight-forward implantation technique and low rate of significant complications.


Mixed-Cropping Between Field Pea Varieties Alters Root Bacterial and Fungal Communities.
Modern agricultural practices have vastly increased crop production but negatively affected soil health. As such, there is a call to develop sustainable, ecologically-viable approaches to food production. Mixed-cropping of plant varieties can increase yields, although impacts on plant-associated microbial communities are unclear, despite their critical role in plant health and broader ecosystem function. We investigated how mixed-cropping between two field pea (Pisum sativum L.) varieties (Winfreda and Ambassador) influenced root-associated microbial communities and yield. The two varieties supported significantly different fungal and bacterial communities when grown as mono-crops. Mixed-cropping caused changes in microbial communities but with differences between varieties. Root bacterial communities of Winfreda remained stable in response to mixed-cropping, whereas those of Ambassador became more similar to Winfreda. Conversely, root fungal communities of Ambassador remained stable under mixed-cropping, and those of Winfreda shifted towards the composition of Ambassador. Microbial co-occurrence networks of both varieties were stronger and larger under mixed-cropping, which may improve stability and resilience in agricultural soils. Both varieties produced slightly higher yields under mixed-cropping, although overall Ambassador plants produced higher yields than Winfreda plants. Our results suggest that variety diversification may increase yield and promote microbial interactions.


Quinone emissions from gasoline and diesel motor vehicles.
Gas- and particle-phase emissions from gasoline and diesel vehicles operated on chassis dynamometers were collected using annular denuders, quartz filters, and PUF substrates. Quinone species were measured using O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine derivatization in conjunction with gas chromatography-mass spectrometry and high-performance liquid chromatography-mass spectrometry. Nine quinones were observed, ranging from C6 to C16. New species identified in motor vehicle exhaust include methyl-1,4-benzoquinone, 2-methyl-1,4-naphthoquinone (MNQN), and aceanthrenequinone. Gas-phase motor vehicle emissions of quinones are also reported for the first time. Six gas-phase quinones were quantified with emission rates of 2-28 000 microg L(-1) fuel consumed. The most abundant gas-phase quinones were 1,4-benzoquinone (BON) and MNQN. The gas-phase fraction was > or = 69% of quinone mass for light-duty gasoline emissions, and > or = 84% for heavy-duty diesel emissions. Eight particle-phase quinones were observed between 2 and 1600 microg L(-1), with BQN the most abundant species followed by 9,10-phenanthrenequinone and 1,2-naphthoquinone. Current particle-phase quinone measurements agree well with the few available previous results. Further research is needed concerning the gas-particle partitioning behavior of quinones in ambient and combustion source conditions.


A novel method to detect the Mexican founder mutation BRCA1 ex9‑12del associated with breast and ovarian cancer using quantitative polymerase chain reaction and TaqMan® probes.
In 2015, according to the National Institute of Statistics and Geography (INEGI), malignant breast tumors were the first cause of cancer fatality in women (6,273 fatalities) in Mexico, whereas 2,793 fatalities in women were due to ovarian cancer. A total of 5‑10% of breast cancer and 10‑15% of ovarian cancer cases are caused by a hereditary breast‑ovarian cancer syndrome, with mutations predominantly identified in the BRCA1 and BRCA2 genes. Recently, the Mexican founder mutation BRCA1 ex9‑12del was identified (deletion of exons 9‑12 with recombination between introns 8‑12). This is the most frequently reported mutation in hereditary breast/ovarian cancer in Mexico. Current detection methods include end‑point polymerase chain reaction (PCR) and Multiplex Ligation‑dependent Probe Amplification (MLPA). In the present study a cheap, sensitive and fast detection method was developed based on quantitative PCR and two TaqMan® probes, one to detect the deletion (recombination region between introns 8 and 12), and the other one a region from exon 11. With this assay, 90 samples were able to be analyzed in 2 h using 2.5 ng of DNA/reaction at a cost of ~2‑3 USD. This method is capable of detecting positive samples for DNA deletion and excluding negative ones. Therefore, the method proposed may be a useful high‑throughput diagnostic option that could be useful in future association or prevalence studies that use large populations.


Pharmacological Management of Cancer-Related Pain.
Pain occurs in 50% of patients with cancer at the time of diagnosis, and nearly 80% of patients with advanced stage cancer have moderate to severe pain. Assessment of pain requires the health care professional to measure pain intensity, delineate opioid responsiveness, and clarify the impact of pain on a patient's psychological, social, spiritual, and existential domains. To this end, the World Health Organization (WHO) has developed a 3-step pain ladder to help the health care professional effectively manage pain, classifying pain intensity according to severity and recommending analgesic agents based on their strength. Health care professionals should follow the WHO guidelines to manage cancer-related pain in their patients. With regard to opioids, dosing, equianalgesic conversions, the management of adverse events, and the identification of new agents are discussed. Integrating adjuvant analgesics and interventional pain techniques into the management of cancer-related pain is also discussed. The WHO analgesic ladder is an effective tool for managing cancer-related pain. Successful pain management in patients with cancer relies upon the health care professional to pay attention to detail, especially during the introduction of new drugs and in identifying potential adverse events. Health care professionals must assess opioid responsiveness to determine whether adjuvant analgesics should also play a role in a patient's treatment plan. Adherence to the WHO pain ladder and understanding proper use of interventional pain techniques complement the pharmacological management of cancer-related pain.


Intramyocellular lipid and glycogen content are reduced following resistance exercise in untrained healthy males.
Resistance exercise has recently been shown to improve whole-body insulin sensitivity in healthy males. Whether this is accompanied by an exercise-induced decline in skeletal muscle glycogen and/or lipid content remains to be established. In the present study, we determined fibre-type-specific changes in skeletal muscle substrate content following a single resistance exercise session. After an overnight fast, eight untrained healthy lean males participated in a approximately 45 min resistance exercise session. Muscle biopsies were collected before, following cessation of exercise, and after 30 and 120 min of post-exercise recovery. Subjects remained fasted throughout the test. Conventional light and (immuno)fluorescence microscopy were applied to assess fibre-type-specific changes in intramyocellular triacylglycerol (IMTG) and glycogen content. A significant 27+/-7% net decline in IMTG content was observed in the type I muscle fibres (P<0.05), with no net changes in the type IIa and IIx fibres. Muscle glycogen content decreased with 23+/-6, 40+/-7 and 44+/-7% in the type I, IIa and IIx muscle fibres, respectively (P<0.05). Fibre-type-specific changes in intramyocellular lipid and/or glycogen content correlated well with muscle fibre-type oxidative capacity. During post-exercise recovery, type I muscle fibre lipid content returned to pre-exercise levels within 120 min. No changes in muscle glycogen content were observed during recovery. We conclude that intramyocellular lipid and glycogen stores are readily used during resistance exercise and this is likely associated with the reported increase in whole-body insulin sensitivity following resistance exercise.


The effect of urban air pollution on inflammation, oxidative stress, coagulation, and autonomic dysfunction in young adults.
The biological mechanisms linking air pollution to cardiovascular events still remain largely unclear. To investigate whether biological mechanisms linking air pollution to cardiovascular events occurred concurrently in human subjects exposed to urban air pollutants. We recruited a panel of 76 young, healthy students from a university in Taipei. Between April and June of 2004 or 2005, three measurements were made in each participant of high-sensitivity C-reactive protein (hs-CRP), 8-hydroxy-2'-deoxyguanosine (8-OHdG), plasminogen activator fibrinogen inhibitor-1 (PAI-1), tissue-type plasminogen activator (tPA) in plasma, and heart rate variability (HRV). Gaseous air pollutants were measured at one air-monitoring station inside their campus, and particulate air pollutants were measured at one particulate matter supersite monitoring station 1 km from their campus. We used linear mixed-effects models to associate biological endpoints with individual air pollutants averaged over 1- to 3-day periods before measurements were performed. We found that increases in hs-CRP, 8-OHdG, fibrinogen, and PAI-1, and decreases in HRV indices were associated with increases in levels of particles with aerodynamic diameters less than 10 microm and 2.5 microm, sulfate, nitrate, and ozone (O(3)) in single-pollutant models. The increase in 8-OHdG, fibrinogen, and PAI-1, and the reduction in HRV remained significantly associated with 3-day averaged sulfate and O(3) levels in two-pollutant models. There were moderate correlations (r = -0.3) between blood markers of hs-CRP, fibrinogen, PAI-1, and HRV indices. Urban air pollution is associated with inflammation, oxidative stress, blood coagulation and autonomic dysfunction simultaneously in healthy young humans, with sulfate and O(3) as two major traffic-related pollutants contributing to such effects.


Testosterone replacement elevates the serum uric acid levels in patients with female to male gender identity disorder.
Gender identity disorder (GID) results from a disagreement between a person's biological sex and the gender to which he or she identifies. With respect to the treatment of female to male GID, testosterone replacement therapy (TRT) is available. The uric acid (UA) level can be influenced by testosterone; however, the early effects and dose-dependency of TRT on the serum UA concentration have not been evaluated in this population. We herein conducted a dose-response analysis of TRT in 160 patients with female to male GID. The TRT consisted of three treatment groups who received intramuscular injections of testosterone enanthate: 125 mg every two weeks, 250 mg every three weeks and 250 mg every two weeks. Consequently, serum UA elevation was observed after three months of TRT and there was a tendency toward testosterone dose-dependency. The onset of hyperuricemia was more prevalent in the group who received the higher dose. We also demonstrated a positive correlation between increased levels of serum UA and serum creatinine. Since the level of serum creatinine represents an individual's muscle volume and the muscle is a major source of purine, which induces UA upregulation, the serum UA elevation observed during TRT is at least partially attributed to an increase in muscle mass. This is the first study showing an association between serum UA elevation and a TRT-induced increase in muscle mass. The current study provides important information regarding TRT for the follow-up and management of the serum UA levels in GID patients.


Evaluation of a spectrophotometric method for measurement of activity of diamine oxidase in newborn infants.
Diamine oxidase (DAO) is an enzyme synthesized primarily in the gastrointestinal mucosal cells. Serum levels of DAO have been used as an indicator of the integrity and/or functional mass of the intestinal mucosa. The enzyme is also produced by the placenta and is elevated in newborn serum. Previous radiometric methods for DAO used tritiated putrescine or cadaverine as substrate. A simple and rapid spectrophotometric procedure for DAO with use of histamine as substrate was developed, and this assay was utilized to evaluate the developmental pattern of activity of DAO in umbilical cord blood of newborn full-term and premature infants, in sequential samples from premature infants, and in samples from infants with necrotizing enterocolitis. The spectrophotometric assay was linear to 200 U per L and was also precise with total imprecision (CV) of 11.9 percent and 3.7 percent at DAO activities of 25.6 U per 1 and 126.1 U per L, respectively. Triglycerides above 275 mg per dL caused a significant reduction in measured activity of DAO; however, this effect could be eliminated by use of ultracentrifugation to remove lipemia. Plasma samples with heparin or ethylenediamine tetraacetic acid (EDTA) as anticoagulant were unsuitable for analysis since DAO activity showed a 24 percent and 32 percent decrease in activity at concentrations of 20 U per mL (heparin) and two mg per mL (EDTA), respectively. Serum samples are the specimen of choice. In infants it was found that the serum activity declined to adult levels by day 12 of life and that this decline is not affected by necrotizing arterocolitis.


Comparison between estimation of breeding values and fixed effects using Bayesian and empirical BLUP estimation under selection on parents and missing pedigree information.
Bayesian (via Gibbs sampling) and empirical BLUP (EBLUP) estimation of fixed effects and breeding values were compared by simulation. Combinations of two simulation models (with or without effect of contemporary group (CG)), three selection schemes (random, phenotypic and BLUP selection), two levels of heritability (0.20 and 0.50) and two levels of pedigree information (0% and 15% randomly missing) were considered. Populations consisted of 450 animals spread over six discrete generations. An infinitesimal additive genetic animal model was assumed while simulating data. EBLUP and Bayesian estimates of CG effects and breeding values were, in all situations, essentially the same with respect to Spearman's rank correlation between true and estimated values. Bias and mean square error (MSE) of EBLUP and Bayesian estimates of CG effects and breeding values showed the same pattern over the range of simulated scenarios. Methods were not biased by phenotypic and BLUP selection when pedigree information was complete, albeit MSE of estimated breeding values increased for situations where CG effects were present. Estimation of breeding values by Bayesian and EBLUP was similarly affected by joint effect of phenotypic or BLUP selection and randomly missing pedigree information. For both methods, bias and MSE of estimated breeding values and CG effects substantially increased across generations.


Population-based survey on STI-associated symptoms and health-seeking behaviours among Iranian adults.
Qualified decision-making for the improved management of sexually transmitted infections (STIs) requires various sources of information. We aimed to estimate the STI-associated symptom prevalence and care-seeking patterns in the general population of Iran. In 2014, using a street-based survey with a standard gender-specific questionnaire on STI-associated symptoms and willingness to seek treatment, we interviewed 9166 Iranian participants, who were selected from among the 18-60-year-old population using multistage sampling. Data were analysed via generalised estimating equation and survey analysis, taking into account a 95% confidence coefficient. About 67.3% of participants, mean age 33 years, were 'assumed sexually active' and were therefore eligible for inclusion. Approximately 39.9% (95% CI 28.4% to 51.4%) of women and 17.6% (95% CI 13.9% to 21.6%) of men reported at least one STI-associated symptom in the current week. The occurrence of symptoms decreased with an increase in age in both genders (p<0.05). About 21.2% (95% CI 13.3% to 29.1%) of women and 7.1% (95% CI 5.4% to 7.8%) of men treated symptoms themselves after symptoms first appeared. Of the women and men with symptoms, 37.4% (95% CI 24.8% to 50.0%) and 46.8% (95% CI 39.7% to 51.4%), respectively, sought care. Most women visited a gynaecologist and midwife; men tended to visit a general practitioner and urologist after their symptoms appeared. The prevalence of STI-associated symptoms in Iranian adults is considerable. The results emphasise the need for appropriate and timely STI care and more attention to sexual health promotion to mitigate onward and future infections. Attention to the care-seeking pattern is fundamental to policymaking and planning.


Chitosan-coated alginate microspheres for embolization and/or chemoembolization: in vivo studies.
In this study, chitosan-coated alginate microspheres were prepared by the ionic complexation of alginate and chitosan biopolymers to use in embolization and/or chemoembolization studies. Biopolymeric microspheres were prepared by the ionic gelation technique of alginate with a suitable divalent cation (i.e. CaCl2) in a suspension medium composed of mineral oil and petroleum ether including emulsifier (i.e. Tween-80) and then obtained microspheres were coated with chitosan in an aqueous chitosan solution while the medium was magnetically stirred. The obtained microspheres are in the size range of 100-400 microm and they can be prepared as required by changing the preparation conditions (i.e. stirring rate, concentration of biopolymers, molecular weight and concentration of chitosan, etc.). In the in vivo studies, New Zealand rabbits were used as the test animals. Both complete and partial embolization of the kidney were achieved by using the microspheres. The renal angiograms obtained before/after embolization and the histopathological observations showed the feasibility of the chitosan-coated alginate microspheres as an alternative embolization and/or chemoembolization agent.


Serotonin and human cancer: A critical view.
Besides its classical functions as a neurotransmitter in the central nervous system, local mediator in the gastrointestinal tract and vasoactive agent in the blood, serotonin has more recently emerged as a growth factor for human tumor cells of different origins (carcinomas, glioma and carcinoids). Several data are also available on serotonin involvement in cancer cell migration, metastatic dissemination and tumor angiogenesis. The serotonin-induced signaling pathways that promote tumor progression are complex and only partly understood in some cancer types. The results of several studies showed that serotonin levels in the tumor played a crucial role in cancer progression. A serotonin production and secretion by neuroendocrine cells have been shown in the progression of several solid tumors and the involvement of a serotoninergic autocrine loop was proposed. Specific receptor subtypes are associated with different fundamental stages of tumor progression and the pattern of receptors expression becomes dysregulated in several human tumors when compared with normal cells or tissues. Serotonin receptors, selective serotonin transporter and serotonin synthesis pathways are potential chemotherapeutic targets for the treatment of several cancers in which therapeutic approaches are limited. Through several asked questions, this critical mini-review discusses the relevance of the involvement of serotonin in human cancer progression.


Do facial fractures protect the brain or are they a marker for severe head injury?
Facial fractures (FF) have been suggested to protect the brain from severe injury. However, others have stated that facial fractures are a marker for increased risk of brain injury. The aim of this study is to evaluate the association between facial fractures, brain injury, and functional outcome. A retrospective review of our prospective trauma database was performed for blunt trauma patients during a 7-year period (January 1993 through December 1999) at the University of Louisville Hospital. We identified 7324 blunt trauma patients at a Level 1 trauma center. Severity of head injury in patients with and without FF was compared. The severity of brain injury was evaluated by admission Glasgow Coma Score (GCS) as well as specific head, neck, cervical spine, and face Acute Injury Score (AIS). Length of intensive care unit (ICU) stay, hospital stay, and Functional Independence Measures (FIM) score were also identified. A total of 1068 (14.6%) patients were diagnosed with FF; of these 848 (79.4%) patients suffered some form of brain injury by CT abnormality, clinical examination, or both. A total of 2192 patients were treated for head injury without FF; 220 patients were treated for FF without head injury. FF with traumatic brain injury (TBI) were found to occur significantly greater than FFs without TBI (P < 0.001). The mean GCS on admission for FF with head injury was 12, which was similar to that of patients with head injury alone with a GCS of 10 but was significantly less than that of patients with FF alone with a GCS of 15 (P < 0.05). Injury Severity Score for patients with FF and head injury was significantly worse compared with patients with head injury alone and those with FF alone (P < 0.0001). Mean ICU stay and hospital stay were similar for all three groups (ranges 3-6 and 6-12 days); and were not significant (P < 0.06). FIM score was significantly lower for patients with FF and head injury compared with FF alone (P = 0.0003) and similar to that of patients with head injury. FF were found to have a significantly greater incidence of TBI. FF with TBI had a similar severity of head injury when compared with patients with head injury alone by demonstrating similar GCS, AIS of the head and neck, and early functional recovery. This analysis does not support the hypothesis that the face provides a protective effect for the brain and therefore leading to a more favorable short-term outcome. Thus patients with facial fractures should be treated with the same caution as patients with significant blunt head trauma.


Porcine induced pluripotent stem cells produce chimeric offspring.
Ethical and moral issues rule out the use of human induced pluripotent stem cells (iPSCs) in chimera studies that would determine the full extent of their reprogrammed state, instead relying on less rigorous assays such as teratoma formation and differentiated cell types. To date, only mouse iPSC lines are known to be truly pluripotent. However, initial mouse iPSC lines failed to form chimeric offspring, but did generate teratomas and differentiated embryoid bodies, and thus these specific iPSC lines were not completely reprogrammed or truly pluripotent. Therefore, there is a need to address whether the reprogramming factors and process used eventually to generate chimeric mice are universal and sufficient to generate reprogrammed iPSC that contribute to chimeric offspring in additional species. Here we show that porcine mesenchymal stem cells transduced with 6 human reprogramming factors (POU5F1, SOX2, NANOG, KLF4, LIN28, and C-MYC) injected into preimplantation-stage embryos contributed to multiple tissue types spanning all 3 germ layers in 8 of 10 fetuses. The chimerism rate was high, 85.3% or 29 of 34 live offspring were chimeras based on skin and tail biopsies harvested from 2- to 5-day-old pigs. The creation of pluripotent porcine iPSCs capable of generating chimeric offspring introduces numerous opportunities to study the facets significantly affecting cell therapies, genetic engineering, and other aspects of stem cell and developmental biology.


Efficacy and Safety of Natalizumab and Vedolizumab for the Management of Crohn's Disease: A Systematic Review and Meta-analysis.
We assessed the risk-benefit profile of anti-α4-integrins, natalizumab (NAT), and vedolizumab (VEDO), in Crohn's disease through a systematic review and meta-analysis of randomized controlled trials. We searched multiple electronic databases through July 2014 and identified 8 randomized controlled trials in adults with Crohn's disease comparing NAT (5 trials) or VEDO (3 trials) with placebo. Efficacy outcomes were induction of remission, response, and improvement in quality of life; safety outcomes were serious adverse events, infusion reactions, infections, and treatment discontinuation. We performed subgroup analysis based on anti-tumor necrosis factor (TNF)-α exposure and estimated summary relative risk (RR) or mean difference, with 95% confidence intervals (CIs). Anti-α4-integrins were superior to placebo for induction of remission (RR, 0.87; 95% CI, 0.84-0.91), with similar estimates for NAT (RR, 0.86; 95% CI, 0.80-0.93) and VEDO (RR, 0.87; 95% CI, 0.79-0.95). Both NAT and VEDO were equally efficacious for anti-TNF-naive (NAT: RR, 0.87; 95% CI, 0.75-1.00; VEDO: RR, 0.86; 95% CI, 0.79-0.94) and anti-TNF-exposed patients (NAT: RR, 0.86; 95% CI, 0.76-0.99; VEDO: RR, 0.89; 95% CI, 0.78-1.01). Anti-α4-integrins were effective in inducing clinical response and improving quality of life, with no significant difference between NAT and VEDO. Rates of serious adverse events, infusion reactions, infections, and treatment discontinuation were similar for NAT and VEDO. No cases of progressive multifocal leukoencephalopathy have been observed with VEDO to date. NAT and VEDO are effective in inducing remission and response in patients with Crohn's disease, with similar efficacy in anti-TNF-naive and anti-TNF-exposed patients.


Psychosomatic problems and countermeasures in Japanese children and adolescents.
In Japan there are a number of children and adolescents with emotion-related disorders including psychosomatic diseases (orthostatic dysregulation, anorexia nervosa, recurrent pains), behavior problems and school absenteeism. According to our previous report, the Japanese children had significantly higher score of physical symptoms and psychiatric complaints than did the Swedish children, and these were more strongly influenced by school-related stress than by home-related stress. To enforce countermeasures for psychosomatic problems in children, the Japanese Society of Psychosomatic Pediatrics (established in 1982) have started several new projects including multi-center psychosomatic researches and society-based activities. In this article, we present an outline of our study on mental health in Japanese children in comparison with Swedish children. Countermeasures including clinical guidelines for child psychosomatic diseases are reviewed and discussed.


Retinal segmented layers with strong aquaporin-4 expression suffered more injuries in neuromyelitis optica spectrum disorders compared with optic neuritis with aquaporin-4 antibody seronegativity detected by optical coherence tomography.
To evaluate retinal segmented layer alterations in optic neuritis (ON) in an AQP4-Ab seropositive (AQP4-Ab+/ON) cohort and in neuromyelitis optica (NMO) with ON eyes (NMO-ON) compared with an AQP4-Ab seronegative ON (AQP4-Ab-/ON) cohort using optical coherence tomography (OCT). We recruited 109 patients with ON (161 eyes) and 47 healthy controls. All patients with ON were subdivided into three subcohorts: 37 patients (54 eyes) with AQP4-Ab+/ON, 45 patients (65 eyes) with AQP4-Ab-/ON and 27 patients (42 eyes) with NMO-ON. All subjects were evaluated for their peripapillary retinal nerve fibre layer (pRNFL) and inner macular segmented layer using OCT. AQP4-Ab+/patients with ON had the same structural injury patterns as patients with NMO-ON, and the injury patterns were distinct from those of AQP4-Ab-/patients with ON. NMO-ON and AQP4-Ab+/ON preferentially damaged the pRNFL (all p=0.000), the macular retinal nerve fibre layer (mRNFL; p=0.000 and 0.032, respectively), and the inner plexiform layer (IPL; p=0.000 and 0.006, respectively) without differences in the retinal ganglion cell layer (p=0.106 and 0.374, respectively) compared with AQP4-Ab-/patients with ON. The thickness of the inner nuclear layer (INL) increased in NMO-ON (p=0.043) compared with that of AQP4-Ab-/ON without a significant difference in AQP4-Ab+/ON versus AQP4-Ab-/ON (p=0.353). When the thickness of the inferior nasal quadrant (NI) of the pRNFL was reduced to ≤46.5 μm (area under the curve 0.772, sensitivity 89.2% and specificity 57.5%) 6 months after ON onset, NMO was considered. AQP4-Ab+/ON produced similar structural injury patterns as NMO-ON. The pRNFL, mRNFL and IPL in the two types of ON and the INL in NMO-ON suffered more damage than those in AQP4-Ab-/ON, which could be associated with strong aquaporin-4 expression. The thickness of the NI of the pRNFL could be a potential clue for predicting ON progression to definite NMO.


NeuroD-null mice are deaf due to a severe loss of the inner ear sensory neurons during development.
A key factor in the genetically programmed development of the nervous system is the death of massive numbers of neurons. Therefore, genetic mechanisms governing cell survival are of fundamental importance to developmental neuroscience. We report that inner ear sensory neurons are dependent on a basic helix-loop-helix transcription factor called NeuroD for survival during differentiation. Mice lacking NeuroD protein exhibit no auditory evoked potentials, reflecting a profound deafness. DiI fiber staining, immunostaining and cell death assays reveal that the deafness is due to the failure of inner ear sensory neuron survival during development. The affected inner ear sensory neurons fail to express neurotrophin receptors, TrkB and TrkC, suggesting that the ability of NeuroD to support neuronal survival may be directly mediated through regulation of responsiveness to the neurotrophins.


Maximization of acoustic energy difference between two spaces.
There has recently been an increasing interest in the generation of a sound field that is audible in one spatial region and inaudible in an adjacent region. The method proposed here ensures the control of the amplitude and phase of multiple acoustic sources in order to maximize the acoustic energy difference between two adjacent regions while also ensuring that evenly distributed source strengths are used. The performance of the method proposed is evaluated by computer simulations and experiments with real loudspeaker arrays in the shape of a circle and a sphere. The proposed method gives an improvement in the efficiency of radiation into the space in which the sound should be audible, while maintaining the acoustic pressure difference between two acoustic spaces. This is shown to give an improvement of performance compared to the contrast control method previously proposed.


Transforming the healthcare response to intimate partner violence and taking best practices to scale.
Intimate partner violence (IPV) is prevalent among adolescent and adult women, with significant physical, sexual, and mental health consequences. In 2011, the Institute of Medicine's Clinical Preventive Services for Women consensus report recommended universal screening for violence as a component of women's preventive services; this policy has been adopted by the Health Resources and Services Administration (HRSA). These policy developments require that effective clinic-based interventions be identified, easily implemented, and taken to scale. To foster dialogue about implementing effective interventions, we convened a symposium entitled "Responding to Violence Against Women: Emerging Evidence, Implementation Science, and Innovative Interventions," on May 21, 2012. Drawing on multidisciplinary expertise, the agenda integrated data on the prevalence and health impact of IPV violence, with an overview of the implementation science framework, and a panel of innovative IPV screening interventions. Recommendations were generated for developing, testing, and implementing clinic-based interventions to reduce violence and mitigate its health impact. The strength of evidence supporting specific IPV screening interventions has improved, but the optimal implementation and dissemination strategies are not clear. Implementation science, which seeks to close the evidence to program gap, is a useful framework for improving screening and intervention uptake and ensuring the translation of research findings into routine practice. Findings have substantial relevance to the broader research, clinical, and practitioner community. Our conference proceedings fill a timely gap in knowledge by informing practitioners as they strive to implement universal IPV screening and guiding researchers as they evaluate the success of implementing IPV interventions to improve women's health and well-being.


Soluble VCAM-1 impairs human brain endothelial barrier integrity via integrin α-4-transduced outside-in signalling.
Human brain microvascular endothelial cells forming the blood-brain barrier (BBB) release soluble vascular cell adhesion molecule-1 (sVCAM-1) under inflammatory conditions. Furthermore, sVCAM-1 serum levels in untreated patients with multiple sclerosis (MS) correlate with a breakdown of the BBB as measured by gadolinium-enhanced MRI. To date, it is unknown whether sVCAM-1 itself modulates BBB permeability. Here, we provide evidence that human brain endothelium expresses integrin α-4/β-1, the molecular binding partner of sVCAM-1, and that sVCAM-1 directly impairs BBB function by inducing intracellular signalling events through integrin α-4. Primary human brain microvascular endothelial cells showed low to moderate integrin α-4 and strong β-1 but no definite β-7 expression in vitro and in situ. Increased brain endothelial integrin α-4 expression was observed in active MS lesions in situ and after angiogenic stimulation in vitro. Exposure of cultured primary brain endothelial cells to recombinant sVCAM-1 significantly increased their permeability to the soluble tracer dextran, which was paralleled by formation of actin stress fibres and reduced staining of tight junction-associated molecules. Soluble VCAM-1 was also found to activate Rho GTPase and p38 MAP kinase. Chemical inhibition of these signalling pathways partially prevented sVCAM-1-induced changes of tight junction arrangement. Importantly, natalizumab, a neutralising recombinant monoclonal antibody against integrin α-4 approved for the treatment of patients with relapsing-remitting MS, partially antagonised the barrier-disturbing effect of sVCAM-1. In summary, we newly characterised sVCAM-1 as a compromising factor of brain endothelial barrier function that may be partially blocked by the MS therapeutic natalizumab.


Application of physiologically based modelling and transcriptomics to probe the systems toxicology of aldicarb for Caenorhabditis elegans (Maupas 1900).
The toxicity of aldicarb on movement, life cycle, population growth rate and resource allocation, and the gene expression changes underpinning these effects, were investigated for Caenorhabditis elegans. A clear effect of aldicarb on nematode movement was found suggesting that this pesticide acts as a neurotoxicant. Aldicarb also had an effect on life cycle traits including low concentration life-span extension; high concentration brood size reduction and a high concentration extension of time to first egg. All life-cycle and growth data were integrated into a biology-based model (DEBtox) to characterise aldicarb effects on life-history traits, resource allocation and population growth rate within a single modelling framework. The DEBtox fits described concentration dependent effects on individual traits and population growth rate and indicated that the most probable mechanism of action of the pesticide was an increase in energy demands for somatic and reproductive tissue maintenance. Transcriptomic profiling indicated that aldicarb was associated with changes in amino acid metabolism, DNA structure, fatty acid metabolism and cytochrome P450 mediated xenobiotic metabolism. The changes in the amino acid and fatty acid pathways suggest an effect of aldicarb on protein integrity; while effects on DNA suggests that aldicarb influence DNA morphology or replication. Both these effects have the potential to incur increased costs for structural maintenance of macromolecules. These effects, coupled to the effect on biotransformation enzymes also seen, represent the materialisation of the maintenance costs indicated by DEBtox modelling.


Homograft Versus Conventional Prosthesis for Surgical Management of Aortic Valve Infective Endocarditis: A Systematic Review and Meta-analysis.
Surgical management of aortic valve infective endocarditis (IE) with cryopreserved homograft has been associated with lower risk of recurrent IE, but there is equipoise with regard to the optimal prosthesis. This systematic review and meta-analysis were performed to compare outcomes between homograft and conventional prosthesis for aortic valve IE. We searched MEDLINE database to September 2017 for studies comparing homograft versus conventional prosthesis. The main outcomes were all-cause mortality, recurrent IE, and reoperation. There were 18 included comparative observational studies with 2232 patients (median follow up = 5 [interquartile range: 2-7] years, 30% prosthetic valve endocarditis); four studies were adjusted for baseline differences. There were no differences in perioperative mortality or stroke despite a greater proportion of staphylococcal endocarditis, abscess, and root replacements but less multivalve involvement in the homograft group. Long-term outcomes of all-cause mortality [incidence rate ratio (IRR) = 1.03, 95% confidence interval (CI) = 0.81-1.31, P = 0 .83, for unmatched, and IRR = 0.82, 95% CI = 0.36-1.84, P = 0.63, for matched studies], recurrent endocarditis (IRR = 1.01, 95% CI = 0.53-1.93, P = 0.96, for unmatched, and IRR = 1.04, 95% CI = 0.49-2.19, P = 0.92, for matched studies), and reoperation (IRR = 1.60, 95% CI = 0.80-3.21, P = 0.18, for unmatched, and IRR = 3.17, 95% CI = 0.52-19.44, P = 0.21, for matched studies) were not different comparing homograft versus conventional prosthesis. There was a significantly increased need for reoperation with homograft versus mechanical prosthetic valves, but this comparison was based on limited data. Homografts and conventional prostheses offer similar survival and freedom from recurrent endocarditis and reoperation for aortic valve IE. Homografts may be associated with greater risk of reoperation compared with mechanical valves.


Learning-induced ribosomal RNA is required for memory consolidation in mice-Evidence of differentially expressed rRNA variants in learning and memory.
The transition from short-term to long-term forms of synaptic plasticity requires protein synthesis and new gene expression. Most efforts to understand experience-induced changes in neuronal gene expression have focused on the transcription products of RNA polymerase II-primarily mRNAs and the proteins they encode. We recently showed that nucleolar integrity and activity-dependent ribosomal RNA (rRNA) synthesis are essential for the maintenance of hippocampal long-term potentiation (LTP). Consequently, the synaptic plasticity and memory hypothesis predicts that nucleolar integrity and activity dependent rRNA synthesis would be required for Long-term memory (LTM). We tested this prediction using the hippocampus-dependent, Active Place Avoidance (APA) spatial memory task and found that training induces de novo rRNA synthesis in mouse dorsal hippocampus. This learning-induced increase in nucleolar activity and rRNA synthesis persists at least 24 h after training. In addition, intra-hippocampal injection of the Pol I specific inhibitor, CX-5461 prior to training, revealed that de novo rRNA synthesis is required for 24 h memory, but not for learning. Using qPCR to assess activity-dependent changes in gene expression, we found that of seven known rRNA expression variants (v-rRNAs), only one, v-rRNA IV, is significantly upregulated right after training. These data indicate that learning induced v-rRNAs are crucial for LTM, and constitute the first evidence that differential rRNA gene expression plays a role in memory.


An Approach to Spatiotemporally Resolve Protein Interaction Networks in Living Cells.
Cells operate through protein interaction networks organized in space and time. Here, we describe an approach to resolve both dimensions simultaneously by using proximity labeling mediated by engineered ascorbic acid peroxidase (APEX). APEX has been used to capture entire organelle proteomes with high temporal resolution, but its breadth of labeling is generally thought to preclude the higher spatial resolution necessary to interrogate specific protein networks. We provide a solution to this problem by combining quantitative proteomics with a system of spatial references. As proof of principle, we apply this approach to interrogate proteins engaged by G-protein-coupled receptors as they dynamically signal and traffic in response to ligand-induced activation. The method resolves known binding partners, as well as previously unidentified network components. Validating its utility as a discovery pipeline, we establish that two of these proteins promote ubiquitin-linked receptor downregulation after prolonged activation.


Effects of rectally administered paracetamol on infants delivered by vacuum extraction.
To evaluate whether paracetamol (20 mg/kg rectally) relieves pain in infants delivered by vacuum extraction, and improves clinical condition. Prospective, randomised, double-blind, placebo-controlled study. Infants delivered by vacuum extraction were randomised either to the study group (n=61) and given paracetamol or to the control group (n=61) receiving placebo. Pain assessment was performed by a validated pain score and by scoring the clinical condition. Both scores and clinical symptoms in these groups were compared with symptoms in a reference group (n=66) with uncomplicated pregnancy and delivery in vertex position without vacuum extraction. Pain score did not differ between groups; clinical condition in the study group improved only after the first dose. There was a significant difference (P<0.05) in objective clinical symptoms in the vacuum extraction groups, compared to the reference group. One dose of paracetamol given to neonates delivered by vacuum extraction significantly improved their clinical condition, but did not result in a significant change in objective pain scores. Subsequent doses of paracetamol did not show any effect on the clinical symptoms or appearance of the neonates studied.


Prediction of thrombus resolution after intravenous thrombolysis assessed by CT-based thrombus imaging.
The degree of thrombus resolution directly indicates the effectiveness of a thrombolytic drug. We investigated the degree of thrombus resolution and factors associated with thrombus resolution after intravenous (IV) recombinant tissue plasminogen activator (rt-PA) using thin-section noncontrast computed tomography (NCT). Thin-section NCTs were performed before and immediately after IV rt-PA infusion in acute stroke patients. The thrombus volume and Hounsfield unit were measured using three-dimensional imaging software. Immediate recanalisation was assessed immediately after IV rt-PA infusion using CT angiography. During a three-year study period, 130 patients were prospectively enrolled. On baseline thin-section NCT, no thrombi were found in 30 patients (23%). Among the 100 patients with confirmed thrombus, the median volume decreased by 20% on the follow-up NCT. The thrombus was completely resolved in 8%. Of note, an increase in thrombus volume was observed in 20 patients. Independent predictors of thrombus resolution were total rt-PA dose, thrombus location in the M2 segment of the middle cerebral artery, and time from baseline to follow-up NCT. Thrombus resolution increased by 9% per each 10-mg increase in rt-PA (p = 0.045). Immediate complete recanalisation was achieved in 12% of patients. Total dose of rt-PA was independently associated with complete recanalisation [odds ratio [OR] 4.52, 95% confidence interval [CI] 1.345-15.184) and good functional outcome at three months (modified Rankin scale score <3, OR 2.34, 95% CI 1.104-4.962). In conclusion, rt-PA dose was associated with the degree of thrombus resolution, immediate complete recanalisation, and good outcome at three months. CT-based thrombus imaging may be helpful in determining thrombolysis effectiveness.


Sequential motions of body segments in striking and throwing skills: descriptions and explanations.
The motions of segments participating in striking and throwing skills are generally sequenced in a proximal-to-distal fashion. These sequences are often described in terms of the linear velocities of the segment endpoints, joint angular velocities or segment angular velocities. While each method of description has its own merit, the latter is recommended since it leads to an intuitively pleasing way of explaining segment motions. Explanations of segment motion sequences are dependent not only on a knowledge of the joint moments driving the system of linked segments, but on the way the segments interact as functions of their motions and orientations. The motion-dependent interaction among segments is significant and offers an explanation of the sequencing of segment motions. As illustrated by the thigh and lower leg in kicking and by the upper arm and forearm in overarm pitching, the forward acceleration of the proximal segment plays a large role in causing the distal segment to lag behind. The subsequent forward acceleration of the distal segment is largely a result of the way the proximal segment interacts with the distal segment as a function of the proximal segment's angular velocity. The proximal segment is subsequently slowed down largely due to the motion-dependent effect of the distal segment on the proximal segment. Differences in the way segments interact in striking and throwing skills can account for variations in the timing of segment actions and these differences need to be examined before establishing general principles governing striking and throwing.


Is it worth continuing sexual rehabilitation after radical prostatectomy with intracavernous injection of alprostadil for more than 1 year?
Intracavernous alprostadil injection (IAI) is a widely used treatment for sexual rehabilitation (SR) after radical prostatectomy (RP). It is unknown whether the continuation of IAI beyond 1 year continues to improve erectile function. To assess evolution of sexual function in patients using IAI who are nonresponsive to phosphodiesterase type 5 inhibitors (PDE5i) between 12 (M12) and 24 (M24) months after RP. We retrospectively studied 75 men with a nerve-sparing laparoscopic RP, who had normal preoperative erectile function, and who regularly used IAI for SR for at least 24 months. At M12, no patients had responded to PDE5i. At 12 and 24 months, sexual function was assessed with the UCLA Prostate Cancer Index (UCLA-PCI), International Index of Erectile Function (IIEF)-15, and erection hardness score (EHS) with and without IAI. We also assessed the satisfaction rate with IAI, injection-related penile pain, and satisfaction of treatment. Statistical analysis was performed by using t-tests for paired data and Spearman's rho correlation coefficients to assess the relationships between scores at M12 and M24. Improvement of nocturnal erection was noted (UCLA-PCI, question 25); however, no significant difference was found for IIEF-erectile function with (19.60 ± 9.80 vs. 18.07 ± 10.44) and without IAI (4.63 ± 2.93 vs. 4.92 ± 4.15), UCLA-PCI-sexual bother (37.14 ± 21.45 vs. 37.54 ± 19.67), nor the EHS score with (2.97 ± 1.30 vs. 2.57 ± 1.30) and without IAI (0.67 ± 1.11 vs. 0.76 ± 0.10). The rate of satisfaction with treatment decreased over time (66.6% vs. 46.7%, P = 0.013). Improved response to IAI at M12 was not correlated to improvement in spontaneous erections at M24. The response to IAI remained stable after 2 years of treatment, and no significant improvement of spontaneous erections during intercourse attempts was found between M12 and M24. Patients should be informed of the limited effect of IAI on natural erections after 1 year. Yiou R, Bütow Z, Parisot J, Binhas M, Lingombet O, Augustin D, de la Taille A, and Audureau E. Is it worth continuing sexual rehabilitation after radical prostatectomy with intracavernous injection of alprostadil for more than 1 year? Sex Med 2015;3:42-48.


Socioeconomic and racial/ethnic differences in the discussion of cancer screening: "between-" versus "within-" physician differences.
To determine the extent to which socioeconomic and racial/ethnic differences in cancer screening discussion between a patient and his/her primary care physician are due to "within-physician" differences (the fact that patients were treated differently by the same physicians) versus "between-physician" differences (that they were treated by a different group of physicians). We use data from the baseline patient and physician surveys of two community trials from the Communication in Medical Care (CMC) research series. The two studies combined provide an analysis sample of 5,978 patients ages 50-80 nested within 191 primary care physicians who practiced throughout Southern California. Our main outcomes of interest are whether the physician has ever talked to the patient about fecal occult blood test (FOBT; for colorectal cancer screening), mammogram (for breast cancer screening, female patients only) and the prostate-specific antigen test (PSA, male patients only). We consider five racial/ethnic groups: non-Hispanic white, non-Hispanic black, Hispanic, Asian, and other race/ethnicity. We measure socioeconomic status by both income and education. For each type of cancer screening discussion, we first estimate a probit model that includes patient characteristics as the only covariates to assess the overall differences. We then add physician fixed effects to derive estimates of "within-" versus "between-" physician differences. There was a strong education gradient in the discussion of all three types of cancer screening and most of the education differences arose within physicians. Disparities by income were less consistent across different screening methods, but seemed to have arisen mainly because of "between-physician" differences. Asians were much less likely, compared with whites, to have received discussion about FOBT and PSA and these differences were mainly "within-physician" differences. Black female patients, however, were much more likely, compared with whites treated by the same physicians, to have discussed mammogram with their physicians. Differences in cancer screening discussion along the different dimensions of patient SES may have arisen because of very different mechanisms and therefore call for a combination of interventions. Physicians need to be aware of the persistent disparities by patient education in clinical communication regarding cancer screening and tailor their efforts to the needs of low-education patients. Quality-improvement efforts targeted at physicians practicing in low-income communities may also be effective in addressing disparities in cancer screening communication by patient income.


The combination of tamoxifen with amphotericin B, but not with fluconazole, has synergistic activity against the majority of clinical isolates of Cryptococcus neoformans.
Cryptococcal meningitis has fatality rates of 40%-70%, resulting in 200 000 deaths each year. The best outcomes are achieved with amphotericin combined with flucytosine but flucytosine is expensive and unavailable where most disease occurs. More effective and affordable treatments are needed. Tamoxifen, a selective oestrogen receptor modulator frequently indicated for breast cancer, has been found to have synergistic activity against the Cryptococcus neoformans type strain when combined with amphotericin or fluconazole. It is cheap, off-licence, widely available and well-tolerated, and thus a pragmatic potential treatment for cryptococcal disease. We wanted to determine the susceptibility of clinical isolates of C. neoformans to tamoxifen alone and in combination with other antifungals, to determine whether there is sufficient evidence of activity to justify a clinical trial. We used the CLSI broth microdilution protocol to test the susceptibility of 30 randomly selected clinical isolates of C. neoformans to tamoxifen, in dual combination with amphotericin, fluconazole or flucytosine, and in triple combination with amphotericin and fluconazole. Evidence of drug interactions was assessed using the fractional inhibitory concentration index. The MIC50 and MIC90 of tamoxifen were 4 and 16 mg/L, respectively. The combination of tamoxifen and amphotericin suggested a synergistic interaction in 20 of 30 (67%) isolates. There was no interaction between tamoxifen and either fluconazole or flucytosine. Synergy was maintained in 3-Dimensional chequerboard testing. There was no evidence of antagonism. Tamoxifen may be a useful addition to treatment with amphotericin and fluconazole for cryptococcal meningitis; a trial is justified.


Prospective study of pulmonary function and lung cancer.
The role of pulmonary function as an independent predictor of lung cancer risk was studied in a community-based cohort of 6,317 Japanese-American men who were aged 45 to 68 at the time of examination. After a follow-up period of about 22 yr, 172 incident cases of lung cancer were identified. The percentage of the predicted FEV1 was inversely related to lung cancer (p value for trend = 0.01) after adjustment for age and cigarette smoking history. The subjects in the lowest quartile of pulmonary function (% predicted FEV1 less than 84.5) had a relative risk of 2.1 (95% confidence interval = 1.3 to 3.5) for lung cancer compared with subjects in the highest quartile (% predicted FEV1 = 103.5+). For the 84 cases with a squamous or small cell histologic type of lung cancer, the subjects in the lowest quartile had a relative risk of 2.5 (95% Cl = 1.2 to 5.6) compared with subjects in the highest quartile of pulmonary function. For the 84 patients with lung cancer whose tumors were located within 4 cm of the pulmonary hilum, the subjects in the lowest quartile had a relative risk of 4.0 (95% Cl = 1.7 to 9.7). The results suggest that impaired pulmonary function in a community-based population is a predictor of lung cancer.