One-atom-thick 2D copper oxide clusters on graphene.
The successful isolation and remarkable properties of graphene have recently triggered investigation of two-dimensional (2D) materials from layered compounds; however, one-atom-thick 2D materials without bulk layered counterparts are scarcely reported. Here we report the structure and properties of novel 2D copper oxide studied by experimental and theoretical methods. Electron microscopy observations reveal that copper oxide can form monoatomic layers with an unusual square lattice on graphene. Density functional theory calculations suggest that oxygen atoms at the centre of the square lattice stabilizes the 2D Cu structure, and that the 2D copper oxide sheets have unusual electronic and magnetic properties different from 3D bulk copper oxide.


A case of Pott's disease with epidural abscess and probable cerebral tuberculoma following Bacillus Calmette-Guérin therapy for superficial bladder cancer.
Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy is an accepted treatment for transitional cell carcinoma of the bladder. Carcinoma in situ of the bladder progresses to invasive muscular disease in approximately 54% of untreated patients, mandating early initiation of therapy once the diagnosis is confirmed. Should BCG treatment fail, an additional course of BCG combined with interferon-alpha, both administered intravesically, is a promising second-line immunotherapy. In greater than 95% of patients, BCG is tolerated without significant morbidity or mortality. However, both early (within three months of the original treatment) and late presentations of systemic infection resulting from intravesical BCG treatment have been described. The present study describes the course of a 75-year-old man with a late presentation of BCG vertebral osteomyelitis, discitis, epidural abscess, bilateral psoas abscesses and probable cerebral tuberculoma, following treatment regimens of intravesical BCG followed by intravesical BCG plus interferon-alpha 2b.


Phosphodiesterases and subcellular compartmentalized cAMP signaling in the cardiovascular system.
Phosphodiesterases are key enzymes in the cAMP signaling cascade. They convert cAMP in its inactive form 5'-AMP and critically regulate the intensity and the duration of cAMP-mediated signals. Multiple isoforms exist that possess different intracellular distributions, different affinities for cAMP, and different catalytic and regulatory properties. This complex repertoire of enzymes provides a multiplicity of ways to modulate cAMP levels, to integrate more signaling pathways, and to respond to the specific needs of the cell within distinct subcellular domains. In this review we summarize key findings on phosphodiesterase compartmentalization in the cardiovascular system.


When do health care decisions discriminate against persons with disabilities?
Recent interpretations of laws prohibiting discrimination against persons with disabilities indicate that these laws will play a greater role in health care decision making than previously anticipated. This article employs lessons from other areas of antidiscrimination law to examine these developments and to provide a framework for making health care decisions that are consistent with these new legal interpretations. This article addresses decisions in individual cases, treatment policies adopted by health care providers, and coverage programs of third-party payers, both public and private.


CUTICULAR DRUSEN IN AN INDIGENOUS AUSTRALIAN.
To report a case of cuticular drusen in an indigenous Australian. A 37-year-old indigenous (aboriginal) Australian woman from a remote Western Australian town presented with a 2-month history of vision loss. Clinical history, examination, and multimodal retinal imaging data from spectral domain optical coherence tomography, fundus autofluorescence, fluorescein angiography, and indocyanine green angiography were analyzed. Multimodal imaging confirmed cuticular drusen complicated by a right choroidal neovascularization with pigment epithelial detachment and a left foveal vitelliform lesion. An unusual "negative-staining" pattern was noted on late phase indocyanine green angiography and this spared the regions affected by cuticular drusen. To the best of our knowledge, this is the first published report of cuticular drusen in an indigenous Australian. We hypothesize that this may be secondary to ancestral mixing of the gene pool. An unusual staining pattern witnessed on indocyanine green angiography suggests widespread disturbance of lipoprotein deposition in the Bruch membrane.


Effects of angiotensin II AT1-receptor blockade on coronary dynamics, function, and structure in postischemic heart failure in rats.
Angiotensin II AT1-receptor blockers (AT1-s) prolong survival in experimental postischemic (coronary artery ligation) heart failure (CHF) in rats. The goal of this study was to investigate whether potential beneficial effects of short- and/or long-term treatment with AT1-s on coronary dynamics, function, and structure develop along with the drug-induced survival prolongation in this model. Coronary blood flow was measured (fluorescent microspheres) in conscious sham, untreated, and irbesartan-treated (50 mg/kg daily for 6 weeks or 6 months, starting 8 days after surgery) CHF rats at baseline and at maximal vasodilatation induced by dipyridamole, and coronary dilatation reserve (CDR) was calculated as the ratio of maximal to baseline coronary flow. Coronary endothelial function was assessed in vitro by measuring the coronary relaxant responses to acetylcholine in the three groups of animals. Finally, cardiac hypertrophy and pericoronary fibrosis also were investigated. In CHF rats, left (LV) and right (RV) ventricular CDR were markedly depressed at both 7 weeks and 6 months after ligation, whereas coronary endothelial function was significantly impaired only after 6 months. Short-term AT1-receptor blockade with irbesartan did not prevent CDR deterioration at 7 weeks, nor did it significantly oppose cardiac hypertrophy and pericoronary fibrosis development. Prolonged AT1-receptor blockade prevented both RV CDR deterioration and coronary endothelial function impairment. It also limited significantly the increase in LV end diastolic pressure and the development of cardiac hypertrophy and pericoronary fibrosis. In conclusion, in postischemic CHF in rats, alterations of CDR precede those of coronary endothelial function. Long-, but not short-term AT1-receptor blockade prevents endothelial function degradation, opposes RV CDR impairment, prevents pericoronary fibrosis development, and improves systemic hemodynamics. These effects of AT1-s on coronary dynamics, function, and structure (i.e., on myocardial perfusion) may contribute to the drug-induced survival prolongation in this model.


Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity.
Emerging evidence suggests cancer stem cells sustain neoplasms; however, little is understood of the normal cell initially targeted and the resultant cancer stem cells. We show here, by tracking individual human leukemia stem cells (LSCs) in nonobese diabetic-severe combined immunodeficiency mice serially transplanted with acute myeloid leukemia cells, that LSCs are not functionally homogeneous but, like the normal hematopoietic stem cell (HSC) compartment, comprise distinct hierarchically arranged LSC classes. Distinct LSC fates derived from heterogeneous self-renewal potential. Some LSCs emerged only in recipients of serial transplantation, indicating they divided rarely and underwent self-renewal rather than commitment after cell division within primary recipients. Heterogeneity in LSC self-renewal potential supports the hypothesis that they derive from normal HSCs. Furthermore, normal developmental processes are not completely abolished during leukemogenesis. The existence of multiple stem cell classes shows the need for LSC-targeted therapies.


Analysis of flavivirus NS5 methyltransferase cap binding.
The flavivirus 2'-O-nucleoside N-terminal RNA methyltransferase (MTase) enzyme is responsible for methylating the viral RNA cap structure. To increase our understanding of the mechanism of viral RNA cap binding we performed a detailed structural and biochemical characterization of the guanosine cap-binding pocket of the dengue (DEN) and yellow fever (YF) virus MTase enzymes. We solved an improved 2.1 A resolution crystal structure of DEN2 Mtase, new 1.5 A resolution crystal structures of the YF virus MTase domain in apo form, and a new 1.45 A structure in complex with guanosine triphosphate and RNA cap analog. Our structures clarify the previously reported DEN MTase structure, suggest novel protein-cap interactions, and provide a detailed view of guanine specificity. Furthermore, the structures of the DEN and YF proteins are essentially identical, indicating a large degree of structural conservation amongst the flavivirus MTases. Guanosine triphosphate analog competition assays and mutagenesis analysis, performed to analyze the biochemical characteristics of cap binding, determined that the major interaction points are (i) guanine ring via pi-pi stacking with Phe24, N1 hydrogen interaction with the Leu19 backbone carbonyl via a water bridge, and C2 amine interaction with Leu16 and Leu19 backbone carbonyls; (ii) ribose 2' hydroxyl interaction with Lys13 and Asn17; and (iii) alpha-phosphate interactions with Lys28 and Ser215. Based on our mutational and analog studies, the guanine ring and alpha-phosphate interactions provide most of the energy for cap binding, while the combination of the water bridge between the guanine N1 and Leu19 carbonyl and the hydrogen bonds between the C2 amine and Leu16/Leu19 carbonyl groups provide for specific guanine recognition. A detailed model of how the flavivirus MTase protein binds RNA cap structures is presented.


Anatomical flow phantoms of the nonplanar carotid bifurcation, part I: computer-aided design and fabrication.
Doppler ultrasound is widely used in the diagnosis and monitoring of arterial disease. Current clinical measurement systems make use of continuous and pulsed ultrasound to measure blood flow velocity; however, the uncertainty associated with these measurements is great, which has serious implications for the screening of patients for treatment. Because local blood flow dynamics depend to a great extent on the geometry of the affected vessels, there is a need to develop anatomically accurate arterial flow phantoms with which to assess the accuracy of Doppler blood flow measurements made in diseased vessels. In this paper, we describe the computer-aided design and manufacturing (CAD-CAM) techniques that we used to fabricate anatomical flow phantoms based on images acquired by time-of-flight magnetic resonance imaging (TOF-MRI). Three-dimensional CAD models of the carotid bifurcation were generated from data acquired from sequential MRI slice scans, from which solid master patterns were made by means of stereolithography. Thereafter, an investment casting procedure was used to fabricate identical flow phantoms for use in parallel experiments involving both laser and Doppler ultrasound measurement techniques.


Cellular selectivity of AAV serotypes for gene delivery in neurons and astrocytes by neonatal intracerebroventricular injection.
The non-pathogenic parvovirus, adeno-associated virus (AAV), is an efficient vector for transgene expression in vivo and shows promise for treatment of brain disorders in clinical trials. Currently, there are more than 100 AAV serotypes identified that differ in the binding capacity of capsid proteins to specific cell surface receptors that can transduce different cell types and brain regions in the CNS. In the current study, multiple AAV serotypes expressing a GFP reporter (AAV1, AAV2/1, AAVDJ, AAV8, AAVDJ8, AAV9, AAVDJ9) were screened for their infectivity in both primary murine astrocyte and neuronal cell cultures. AAV2/1, AAVDJ8 and AAV9 were selected for further investigation of their tropism throughout different brain regions and cell types. Each AAV was administered to P0-neonatal mice via intracerebroventricular injections (ICV). Brains were then systematically analyzed for GFP expression at 3 or 6 weeks post-infection in various regions, including the olfactory bulb, striatum, cortex, hippocampus, substantia nigra (SN) and cerebellum. Cell counting data revealed that AAV2/1 infections were more prevalent in the cortical layers but penetrated to the midbrain less than AAVDJ8 and AAV9. Additionally, there were differences in the persistence of viral transgene expression amongst the three serotypes examined in vivo at 3 and 6 weeks post-infection. Because AAV-mediated transgene expression is of interest in neurodegenerative diseases such as Parkinson's Disease, we examined the SN with microscopy techniques, such as CLARITY tissue transmutation, to identify AAV serotypes that resulted in optimal transgene expression in either astrocytes or dopaminergic neurons. AAVDJ8 displayed more tropism in astrocytes compared to AAV9 in the SN region. We conclude that ICV injection results in lasting expression of virally encoded transgene when using AAV vectors and that specific AAV serotypes are required to selectively deliver transgenes of interest to different brain regions in both astrocytes and neurons.


Bombesin inhibits LH release in ovariectomized (OVX), estrogen primed rats.
Bombesin, 14-amino acid peptide, discovered in the gastrointestinal tract, is widely distributed in the central nervous system (CNS). The specific receptors of bombesin in the pituitary have been characterized. Bombesin plays an important role in the gastric and pancreatic secretion, in the mechanism of food intake, thermoregulation and in pituitary hormone secretion. There are contentious opinions about the effect of bombesin on hormone secretion. The aim of this study was to evaluate the effect of estrogens in the modulation of bombesin action on LH release. Female Wistar-Kyoto rats, two weeks after ovariectomy (OVX), were implanted with a cannula being located in the third cerebroventricle. Thereafter, the rats were primed with 17beta estradiol in a dose of 25microg/0.2ml s.c. for three consecutive days. On the day of the experiment, bombesin at a concentration of 0.5 microg in 5microl vehicle (artificial cerebrospinal fluid) or equal volume of the vehicle was infused into the third ventricle with an automatic pump. At 60 or 120 min after the infusion the animals were decapitated, and the trunk blood was collected. Rat serum LH was measured by RIA kit supplied by Dr A.F. Parlow from NIDDK Baltimore, MD. Bombesin inhibited LH release at 120 min and it did not change LH release at 60 min after icv administration. The response of LH release after central injection of bombesin is modified by estrogens.


A public health response against Strongyloides stercoralis: time to look at soil-transmitted helminthiasis in full.
Strongyloides stercoralis infections have a worldwide distribution with a global burden in terms of prevalence and morbidity that is largely ignored. A public health response against soil-transmitted helminth (STH) infections should broaden the strategy to include S. stercoralis and overcome the epidemiological, diagnostic, and therapeutic challenges that this parasite poses in comparison to Ascaris lumbricoides, Trichuris trichiura, and hookworms. The relatively poor sensitivity of single stool evaluations, which is further lowered when quantitative techniques aimed at detecting eggs are used, also complicates morbidity evaluations and adequate drug efficacy measurements, since S. stercoralis is eliminated in stools in a larval stage. Specific stool techniques for the detection of larvae of S. stercoralis, like Baermann's and Koga's agar plate, despite superiority over direct techniques are still suboptimal. New serologies using recombinant antigens and molecular-based techniques offer new hopes in those areas. The use of ivermectin rather than benzimidazoles for its treatment and the need to have curative regimens rather than lowering the parasite burden are also unique for S. stercoralis in comparison to the other STH due to its life cycle, which allows reproduction and amplification of the worm burden within the human host. The potential impact on STH of the benzimidazoles/ivermectin combinations, already used for control/elimination of lymphatic filariasis, should be further evaluated in public health settings. While waiting for more effective single-dose drug regimens and new sensitive diagnostics, the evidence and the tools already available warrant the planning of a common platform for STH and S. stercoralis control.


Coccolithophore calcification studied by single-cell impedance cytometry: Towards single-cell PIC:POC measurements.
Since the industrial revolution 30% of the anthropogenic CO2 is absorbed by oceans, resulting in ocean acidification, which is a threat to calcifying algae. As a result, there has been profound interest in the study of calcifying algae, because of their important role in the global carbon cycle. The coccolithophore Emiliania huxleyi is considered to be globally the most dominant calcifying algal species, which creates a unique exoskeleton from inorganic calcium carbonate platelets. The PIC (particulate inorganic carbon): POC (particulate organic carbon) ratio describes the relative amount of inorganic carbon in the algae and is a critical parameter in the ocean carbon cycle. In this research we explore the use of microfluidic single-cell impedance spectroscopy in the field of calcifying algae. Microfluidic impedance spectroscopy enables us to characterize single-cell electrical properties in a non-invasive and label-free way. We use the ratio of the impedance at high frequency vs. low frequency, known as opacity, to discriminate between calcified coccolithophores and coccolithophores with a calcite exoskeleton dissolved by acidification (decalcified). We have demonstrated that using opacity we can discriminate between calcified and decalcified coccolithophores with an accuracy of 94.1%. We have observed a correlation between the measured opacity and the cell height in the channel, which is supported by FEM simulations. The difference in cell density between calcified and decalcified cells can explain the difference in cell height and therefore the measured opacity.


Increase in cholesterol predicts survival advantage in renal cell carcinoma patients treated with temsirolimus.
Temsirolimus is an effective treatment for renal cell carcinoma. It is associated with increases in serum cholesterol, triglyceride, and glucose. We investigated whether changes of these biomarkers could predict its efficacy. We examined serial measurements of cholesterol, triglycerides, and glucose from patients randomized to IFN or temsirolimus in the Global Advanced Renal Cell Carcinoma Trial. Using time-dependent proportional hazards models, we quantified the association between changes in these biomarkers from baseline with overall survival (OS) and progression-free survival (PFS). We also assess the extent to which changes of these biomarkers predict the effects of temsirolimus on survival. Temsirolimus was associated with larger mean increases in cholesterol (1.02 mmol/L; P < 0.0001), triglycerides (0.32 mmol/L; P = 0.0008), and glucose (1.28 mmol/L; P < 0.0001) compared with IFN and improved survival rate (OS: HR = 0.76, P = 0.02; PFS: HR = 0.70, P = 0.001). Cholesterol increase during study was associated with longer survival (OS: HR = 0.77 per mmol/L, P < 0.0001; PFS: HR = 0.81 per mmol/L; P < 0.0001). Temsirolimus effect on cholesterol predicted its effect on survival with no additional survival advantage observed after adjusting for cholesterol change during study (OS: HR = 1.14, P = 0.37; PFS: HR = 0.88, P = 0.35). Temsirolimus effect on triglycerides or glucose did not predict its effect on survival, with survival advantage in favor of temsirolimus still observed after adjusting for these factors (P = 0.003 and P = 0.002). Cholesterol increase is a potential predictor for temsirolimus efficacy. Longer survival in patients treated with temsirolimus was observed in those with larger increases in cholesterol. Prospectively designed biomarker studies of temsirolimus or other mTOR inhibitors are recommended.


Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures.
Swelling of primary astrocyte cultures by exposing them to hypotonic media caused release of label after the cells had been allowed to accumulate 3H-L-glutamate, 3H-D-aspartate, or 3H-taurine. Comparable release of endogenous L-glutamate or taurine, as measured by high-pressure liquid chromatography (HPLC), was also found. Release of label was not affected by treating the cells with cytochalasin B, indicating that microfilament polymerization was not significantly involved. Hypotonic-induced release did not appear to principally involve reversal of the Na(+)-dependent uptake system since increasing external K+ to depolarize the cells by replacement of external Na+, thus maintaining isotonic conditions, increased release to a lesser extent. Threo beta-hydroxyaspartate, a potent 3H-L-glutamate uptake blocker, added externally stimulated efflux of 3H-L-glutamate independently of the swelling-induced efflux. Upon restoration of swollen cells to isotonic medium they showed an unimpaired ability to take up 3H-L-glutamate. The swelling-induced release of label was inhibited by a number of anion transport inhibitors, one of which has been shown to significantly improve outcome in an experimental brain trauma/hypoxia model in which astrocyte swelling is an early event.


Quantitative proteomics identifies altered O-GlcNAcylation of structural, synaptic and memory-associated proteins in Alzheimer's disease.
Protein modification by O-linked β-N-acetylglucosamine (O-GlcNAc) is emerging as an important factor in the pathogenesis of sporadic Alzheimer's disease (AD); however, detailed molecular characterization of this important protein post-translational modification at the proteome level has been highly challenging, owing to its low stoichiometry and labile nature. Herein, we report the most comprehensive, quantitative proteomics analysis for protein O-GlcNAcylation in postmortem human brain tissues with and without AD by the use of isobaric tandem mass tag labelling, chemoenzymatic photocleavage enrichment, and liquid chromatography coupled to mass spectrometry. A total of 1850 O-GlcNAc peptides covering 1094 O-GlcNAcylation sites were identified from 530 proteins in the human brain. One hundred and thirty-one O-GlcNAc peptides covering 81 proteins were altered in AD brains as compared with controls (q < 0.05). Moreover, alteration of O-GlcNAc peptide abundance could be attributed more to O-GlcNAcylation level than to protein level changes. The altered O-GlcNAcylated proteins belong to several structural and functional categories, including synaptic proteins, cytoskeleton proteins, and memory-associated proteins. These findings suggest that dysregulation of O-GlcNAcylation of multiple brain proteins may be involved in the development of sporadic AD. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


JSAP1, a novel jun N-terminal protein kinase (JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway.
The major components of the mitogen-activated protein kinase (MAPK) cascades are MAPK, MAPK kinase (MAPKK), and MAPKK kinase (MAPKKK). Recent rapid progress in identifying members of MAPK cascades suggests that a number of such signaling pathways exist in cells. To date, however, how the specificity and efficiency of the MAPK cascades is maintained is poorly understood. Here, we have identified a novel mouse protein, termed Jun N-terminal protein kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1), by a yeast two-hybrid screen, using JNK3 MAPK as the bait. Of the mammalian MAPKs tested (JNK1, JNK2, JNK3, ERK2, and p38alpha), JSAP1 preferentially coprecipitated with the JNKs in cotransfected COS-7 cells. JNK3 showed a higher binding affinity for JSAP1, compared with JNK1 and JNK2. In similar cotransfection studies, JSAP1 also interacted with SEK1 MAPKK and MEKK1 MAPKKK, which are involved in the JNK cascades. The regions of JSAP1 that bound JNK, SEK1, and MEKK1 were distinct from one another. JNK and MEKK1 also bound JSAP1 in vitro, suggesting that these interactions are direct. In contrast, only the activated form of SEK1 associated with JSAP1 in cotransfected COS-7 cells. The unstimulated SEK1 bound to MEKK1; thus, SEK1 might indirectly associate with JSAP1 through MEKK1. Although JSAP1 coprecipitated with MEK1 MAPKK and Raf-1 MAPKKK, and not MKK6 or MKK7 MAPKK, in cotransfected COS-7 cells, MEK1 and Raf-1 do not interfere with the binding of SEK1 and MEKK1 to JSAP1, respectively. Overexpression of full-length JSAP1 in COS-7 cells led to a considerable enhancement of JNK3 activation, and modest enhancement of JNK1 and JNK2 activation, by the MEKK1-SEK1 pathway. Deletion of the JNK- or MEKK1-binding regions resulted in a significant reduction in the enhancement of the JNK3 activation in COS-7 cells. These results suggest that JSAP1 functions as a scaffold protein in the JNK3 cascade. We also discuss a scaffolding role for JSAP1 in the JNK1 and JNK2 cascades.


Interaction of vitamin E isoforms on asthma and allergic airway disease.
Prospective epidemiological studies, observational cross-sectional studies and some randomised prevention trials have demonstrated inconsistent findings of the impact of vitamin E on asthma risk. The goals of this study were to explore whether this differing association of vitamin E on asthma risk is due to an interaction of vitamin E isoforms. To address this question, in a population-based asthma incidence study we assessed the interaction between the plasma concentrations of vitamin E isoforms α-tocopherol and γ-tocopherol on asthma risk. Second, to understand the mechanisms of any interaction of these isoforms, we conducted experimental supplementation of α-tocopherol and γ-tocopherol isoforms in mice on the outcome of allergic airway inflammation. We found that in the highest γ-tocopherol tertile, low levels of α-tocopherol were associated with increased asthma risk, while highest tertile α-tocopherol levels trended to be protective. Similarly, in a mouse model of asthma, diet supplementation with α-tocopherol decreased lung inflammation in response to house dust mite (HDM) challenge. In contrast, diet supplementation with γ-tocopherol increased lung inflammation in response to HDM. These human and animal studies provide evidence for the competing effects of the vitamin E isoforms, in physiological concentrations, on asthma and allergic airway disease.


Interferon regulatory factor 3 inhibits astrocyte inflammatory gene expression through suppression of the proinflammatory miR-155 and miR-155*.
Astrocytes, together with microglia and macrophages, participate in innate inflammatory responses in the CNS. Although inflammatory mediators such as interferons generated by astrocytes may be critical in the defense of the CNS, sustained unopposed cytokine signaling could result in harmful consequences. Interferon regulatory factor 3 (IRF3) is a transcription factor required for IFNβ production and antiviral immunity. Most cells express low levels of IRF3 protein, and the transcriptional mechanism that upregulates IRF3 expression is not known. In this study, we explored the consequence of adenovirus-mediated IRF3 gene transfer (Ad-IRF3) in primary human astrocytes. We show that IRF3 transgene expression suppresses proinflammatory cytokine gene expression upon challenge with IL-1/IFNγ and alters astrocyte activation phenotype from a proinflammatory to an anti-inflammatory one, akin to an M1-M2 switch in macrophages. This was accompanied by the rescue of neurons from cytokine-induced death in glial-neuronal co-cultures. Furthermore, Ad-IRF3 suppressed the expression of microRNA-155 and its star-form partner miR-155*, immunoregulatory miRNAs highly expressed in multiple sclerosis lesions. Astrocyte miR-155/miR155* were induced by cytokines and TLR ligands with a distinct hierarchy and involved in proinflammatory cytokine gene induction by targeting suppressor of cytokine signaling 1, a negative regulator of cytokine signaling and potentially other factors. Our results demonstrate a novel proinflammatory role for miR-155/miR-155* in human astrocytes and suggest that IRF3 can suppress neuroinflammation through regulating immunomodulatory miRNA expression. © 2011 Wiley-Liss, Inc.


Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice.
Endothelins act on two subtypes of G protein-coupled receptors, termed endothelin-A and endothelin-B receptors. We report a targeted disruption of the mouse endothelin-B receptor (EDNRB) gene that results in aganglionic megacolon associated with coat color spotting, resembling a hereditary syndrome of mice, humans, and other mammalian species. Piebald-lethal (sl) mice exhibit a recessive phenotype identical to that of the EDNRB knockout mice. In crossbreeding studies, the two mutations show no complementation. Southern blotting revealed a deletion encompassing the entire EDNRB gene in the sl chromosome. A milder allele, piebald (s), which produces coat color spotting only, expresses low levels of structurally intact EDNRB mRNA and protein. These findings indicate an essential role for EDNRB in the development of two neural crest-derived cell lineages, myenteric ganglion neurons and epidermal melanocytes. We postulate that defects in the human EDNRB gene cause a hereditary form of Hirschsprung's disease that has recently been mapped to human chromosome 13, in which EDNRB is located.


Magnetic resonance imaging for the assessment of myocardial viability.
The identification of myocardial viability in the setting of left ventricular (LV) dysfunction is crucial for the prediction of functional recovery following revascularization. Although echocardiography, positron emission tomography (PET), and nuclear imaging have validated roles, recent advances in cardiac magnetic resonance (CMR) technology and availability have led to increased experience in CMR for identification of myocardial viability. CMR has unique advantages in the ability of magnetic resonance spectroscopy (MRS) to measure subcellular components of myocardium, and in the image resolution of magnetic resonance proton imaging. As a result of excellent image resolution and advances in pulse sequences and coil technology, magnetic resonance imaging (MRI) can be used to identify the transmural extent of myocardial infarction (MI) in vivo for the first time. This review of the role of CMR in myocardial viability imaging describes the acute and chronic settings of ventricular dysfunction and concepts regarding the underlying pathophysiology. Recent advances in MRS and MRI are discussed, including the potential for dobutamine MRI to identify viable myocardium and a detailed review of the technique of delayed gadolinium (Gd) contrast hyperenhancement for visualization of viable and nonviable myocardium.


Uncertainty Reduction for Stochastic Processes on Complex Networks.
Many real-world systems are characterized by stochastic dynamical rules where a complex network of interactions among individual elements probabilistically determines their state. Even with full knowledge of the network structure and of the stochastic rules, the ability to predict system configurations is generally characterized by a large uncertainty. Selecting a fraction of the nodes and observing their state may help to reduce the uncertainty about the unobserved nodes. However, choosing these points of observation in an optimal way is a highly nontrivial task, depending on the nature of the stochastic process and on the structure of the underlying interaction pattern. In this paper, we introduce a computationally efficient algorithm to determine quasioptimal solutions to the problem. The method leverages network sparsity to reduce computational complexity from exponential to almost quadratic, thus allowing the straightforward application of the method to mid-to-large-size systems. Although the method is exact only for equilibrium stochastic processes defined on trees, it turns out to be effective also for out-of-equilibrium processes on sparse loopy networks.


Longitudinal changes in sedentary time and physical activity during adolescence.
Low levels of physical activity and high time spent in sedentary activities have been associated with unfavourable health outcomes in adolescents. During adolescence, physical activity declines and sedentary time increases, however little is known about whether the magnitude of these changes differs within or between school-time, after-school time, or at weekends. Adolescents (n = 363) participating in the PEACH (Personal and Environmental Associations with Children's Health) project provided accelerometer data at 12 and 15 years of age. Data were collected in 2008/2009 and 2012/2013. Time spent sedentary (<100 cpm), in light physical activity (LPA (100-2295 cpm) and in moderate to vigorous physical activity (MVPA: ≥ 2296 cpm) were generated for school-time, after-school time and for weekends using school-specific start and finish times. All data were analysed in 2014. The proportion of time spent sedentary significantly increased during school (+8.23%, 95% CI = 7.35 to 9.13), after-school (+6.99%, 95% CI = 5.91 to 8.07) and at weekends (+6.86%, 95% CI = 5.10 to 8.62). A parallel decrease was found in the proportion of time spent in LPA during school (-7.62%, 95% CI = -8.26 to -6.98), after-school (-7.01%, 95% CI = -7.74 to -6.28) and at weekends (-6.72%, 95% CI = -7.80 to -5.65). The proportion of time spent in MVPA remained relatively stable during school (-0.64, 95% CI = -1.11 to -0.18), after-school (0.04%, 95% CI = -0.58 to 0.67) and at weekends (-0.14%, 95% CI = -1.18 to 0.90). Objectively measured sedentary time increased between 12 and 15 years of age during-school, after-school, and at weekends, suggesting that interventions aiming to reduce the age-associated changes in sedentary time are needed in all three time contexts. Future work should identify which sedentary activities change more than others to inform interventions which aim to minimise the increase in time spent sedentary during adolescence.


Rapid deployment of the five founding Amerind mtDNA haplogroups via coastal and riverine colonization.
Numerous studies of variation in mtDNA in Amerindian populations established that four haplogroups are present throughout both North and South America. These four haplogroups (A, B, C, and D) and perhaps a fifth (X) in North America are postulated to be present in the initial founding migration to the Americas. Furthermore, studies of ancient mtDNA in North America suggested long-term regional continuity of the frequencies of these founding haplogroups. Present-day tribal groups possess high frequencies of private mtDNA haplotypes (variants within the major haplogroups), consistent with early establishment of local isolation of regional populations. Clearly these patterns have implications for the mode of colonization of the hemisphere. Recently, the earlier consensus among archaeologists for an initial colonization by Clovis hunters arriving through an ice-free corridor and expanding in a "blitzkrieg " wave was shown to be inconsistent with extensive genetic variability in Native Americans; a coastal migration route avoids this problem. The present paper demonstrates through a computer simulation model how colonization along coasts and rivers could have rapidly spread the founding lineages widely through North America.


Galantamine improves sustained attention in chronic cocaine users.
Chronic cocaine users are known to have cognitive deficits that are predictive of poor treatment response. Whether these deficits improve with medications targeting specific cognitive functions has not been examined in previous studies. The goal of this study was to evaluate galantamine's efficacy on selected cognitive outcomes, including measures of sustained attention, response inhibition, and attentional bias in recently abstinent cocaine users. Galantamine, a reversible and competitive inhibitor of acetylcholinesterase, is used clinically in the treatment of Alzheimer's dementia. In a randomized, double-blind, parallel-group study, 34 participants were randomized to galantamine (8 mg/day) or placebo treatment for 10 days. Cognitive and self-report mood measures were obtained at baseline and on Days 5 and 10 after the initiation of treatment. Galantamine treatment, compared to placebo, improved the reaction time, F(2, 50) = 8.6, p < .01, detection sensitivity (A'), F(2, 50) = 4.9, p < .03, number of hits, F(2, 50) = 4.2, p < .04, and number of correct rejections, F(2, 50) = 5.6, p < .02, on the Rapid Visual Information Processing task. With the exception of speeding the reaction time on the Stroop, galantamine did not affect performance on other tasks, (p > .05). These results demonstrate that medications can enhance cognitive function (e.g., sustained attention) in abstinent cocaine users. The potential efficacy of galantamine as a treatment for cocaine abuse needs to be further evaluated in clinical trials.


Alkylation base damage is converted into repairable double-strand breaks and complex intermediates in G2 cells lacking AP endonuclease.
DNA double-strand breaks (DSBs) are potent sources of genome instability. While there is considerable genetic and molecular information about the disposition of direct DSBs and breaks that arise during replication, relatively little is known about DSBs derived during processing of single-strand lesions, especially for the case of single-strand breaks (SSBs) with 3'-blocked termini generated in vivo. Using our recently developed assay for detecting end-processing at random DSBs in budding yeast, we show that single-strand lesions produced by the alkylating agent methyl methanesulfonate (MMS) can generate DSBs in G2-arrested cells, i.e., S-phase independent. These derived DSBs were observed in apn1/2 endonuclease mutants and resulted from aborted base excision repair leading to 3' blocked single-strand breaks following the creation of abasic (AP) sites. DSB formation was reduced by additional mutations that affect processing of AP sites including ntg1, ntg2, and, unexpectedly, ogg1, or by a lack of AP sites due to deletion of the MAG1 glycosylase gene. Similar to direct DSBs, the derived DSBs were subject to MRX (Mre11, Rad50, Xrs2)-determined resection and relied upon the recombinational repair genes RAD51, RAD52, as well as on the MCD1 cohesin gene, for repair. In addition, we identified a novel DNA intermediate, detected as slow-moving chromosomal DNA (SMD) in pulsed field electrophoresis gels shortly after MMS exposure in apn1/2 cells. The SMD requires nicked AP sites, but is independent of resection/recombination processes, suggesting that it is a novel structure generated during processing of 3'-blocked SSBs. Collectively, this study provides new insights into the potential consequences of alkylation base damage in vivo, including creation of novel structures as well as generation and repair of DSBs in nonreplicating cells.


A narrative study of refugee women who have experienced violence in the context of war.
Although women are rarely on the frontlines of battle, as in many other realms of contemporary life they bear a disproportionate burden of the consequences of war. Many have experienced torture firsthand or been witnesses to the torture or killing of family, friends, and loved ones. The use of rape and other forms of sexual torture has been well documented. For those who are forced to flee their homes and countries, separation from spouses, children, and other family members is common. Because of the sheer magnitude of global conflict, the number of refugees and displaced persons throughout the world has risen exponentially. It has been estimated that women constitute more than half of the world's refugee population. The purpose of this narrative study was to examine the experiences of refugee women who experienced violence in the context of war. Data analysis revealed 8 themes: lives forever changed, new notions of normality, a pervasive sense of fear, selves obscured, living among and between cultures, a woman's place in Canada, bearing heavy burdens--the centrality of children, and an uncaring system of care. Implications for research and practice, including limitations associated with individualized Western approaches, are discussed.


Effects of preoperative leukocytapheresis on inflammatory cytokines following surgery for ulcerative colitis: a prospective randomized study.
Targeted extracorporeal granulocyte and monocyte apheresis (GMA) has produced clinical efficacy together with down modulation of specific inflammatory cytokines in patients with ulcerative colitis (UC). This study was to investigate if preoperative GMA produces immunological effect on dysregulated immune activity after restorative proctocolectomy (RPC) in patients with UC. Forty patients requiring RPC were included. Twenty randomly selected patients received five GMA sessions with the Adacolumn over two consecutive weeks before RPC (GMA group). RPC was performed within 2 weeks following the last GMA session. The other 20 patients did not receive GMA before RPC (non-GMA group). Blood samples were obtained immediately before surgery, at 1 h after surgery, and on postoperative Days 1, 3, and 7 from all patients. Abdominal exudate was obtained from the drainage tube at 1 h after surgery, and on postoperative Days 1, 3, and 7. Concentrations of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in plasma and peritoneal fluid from a drainage tube were measured by enzyme linked immunosorbent assay. Between the two groups, patients were matched with respect to age, sex, UC duration, severity, extent and the dose of prednisolone at surgery. IL-1β, IL-6, and TNF-α levels in plasma and peritoneal fluid were not significantly different between the two groups during the entire study period. Based on the assays of IL-1β, IL-6, and TNF-α levels in the plasma and the peritoneal fluid, this study did not find any effect on these inflammatory cytokines by preoperative GMA in patients with UC who underwent RPC.


Mitotic bookmarking in development and stem cells.
The changes imposed on the nucleus, chromatin and its regulators during mitosis lead to the dismantlement of most gene regulatory processes. However, an increasing number of transcriptional regulators are being identified as capable of binding their genomic targets during mitosis. These so-called 'mitotic bookmarking factors' encompass transcription factors and chromatin modifiers that are believed to convey gene regulatory information from mother to daughter cells. In this Primer, we review mitotic bookmarking processes in development and stem cells and discuss the interest and potential importance of this concept with regard to epigenetic regulation and cell fate transitions involving cellular proliferation.


Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic.
: MR-Egger regression has recently been proposed as a method for Mendelian randomization (MR) analyses incorporating summary data estimates of causal effect from multiple individual variants, which is robust to invalid instruments. It can be used to test for directional pleiotropy and provides an estimate of the causal effect adjusted for its presence. MR-Egger regression provides a useful additional sensitivity analysis to the standard inverse variance weighted (IVW) approach that assumes all variants are valid instruments. Both methods use weights that consider the single nucleotide polymorphism (SNP)-exposure associations to be known, rather than estimated. We call this the `NO Measurement Error' (NOME) assumption. Causal effect estimates from the IVW approach exhibit weak instrument bias whenever the genetic variants utilized violate the NOME assumption, which can be reliably measured using the F-statistic. The effect of NOME violation on MR-Egger regression has yet to be studied. An adaptation of the I2 statistic from the field of meta-analysis is proposed to quantify the strength of NOME violation for MR-Egger. It lies between 0 and 1, and indicates the expected relative bias (or dilution) of the MR-Egger causal estimate in the two-sample MR context. We call it IGX2 . The method of simulation extrapolation is also explored to counteract the dilution. Their joint utility is evaluated using simulated data and applied to a real MR example. In simulated two-sample MR analyses we show that, when a causal effect exists, the MR-Egger estimate of causal effect is biased towards the null when NOME is violated, and the stronger the violation (as indicated by lower values of IGX2 ), the stronger the dilution. When additionally all genetic variants are valid instruments, the type I error rate of the MR-Egger test for pleiotropy is inflated and the causal effect underestimated. Simulation extrapolation is shown to substantially mitigate these adverse effects. We demonstrate our proposed approach for a two-sample summary data MR analysis to estimate the causal effect of low-density lipoprotein on heart disease risk. A high value of IGX2 close to 1 indicates that dilution does not materially affect the standard MR-Egger analyses for these data. : Care must be taken to assess the NOME assumption via the IGX2 statistic before implementing standard MR-Egger regression in the two-sample summary data context. If IGX2 is sufficiently low (less than 90%), inferences from the method should be interpreted with caution and adjustment methods considered.


Stem cell research: a novel boulevard towards improved bovine mastitis management.
The dairy industry is a multi-billion dollar industry catering the nutritional needs of all age groups globally through the supply of milk. Clinical mastitis has a severe impact on udder tissue and is also an animal welfare issue. Moreover, it significantly reduces animal value and milk production. Mammary tissue damage reduces the number and activity of epithelial cells and consequently contributes to decreased milk production. The high incidence, low cure rate of this highly economic and sometimes deadly disease is an alarming for dairy sector as well as policy makers. Bovine mammary epithelial cells (MECs) and their stem cells are very important in milk production and bioengineering. The adult mammary epithelium consists of two main cell types; an inner layer of luminal epithelial cells, which produce the milk during lactation, and an outer layer of myoepithelial cells resting on a basement membrane, which are responsible for pushing the milk through the ductal network to the teat cistern. Inner layer of columner/luminal cells of bovine MECs, is characterized by cytokeratin18, 19 (CK18, CK19) and outer layer such as myoepithelial cells which are characterized by CK14, α-smooth muscle actin (α-SMA) and p63. Much work has been done in mouse and human, on mammary gland stem cell research, particularly in cancer therapy, but stem cell research in bovine is still in its infancy. Such stem/progenitor cell discoveries in human and mouse mammary gland bring some hope for application in bovines. These progenitors may be therapeutically adopted to correct the structural/cytological defects in the bovine udder due to mastitis. In the present review we focused on various kinds of stem/progenitor cells which can have therapeutic utility and their possibilities to use as a potential stem cell therapy in the management of bovine post-mastitis damage in orders to restore milk production. The possibilities of bovine mammary stem cell therapy offers significant potential for regeneration of tissues that can potentially replace/repair diseased and damaged tissue through differentiation into epithelial, myoepithelial and/or cuboidal/columnar cells in the udder with minimal risk of rejection and side effects.


[Colestasic toxic hepatitis caused by terbinafine: case report].
Trichophytic onychomycosis of the feet represents an important and serious medical problem. Until recent years, there was not cure for this unpleasant pathology. It is only at the beginning of the 50s, especially at the onset of the antimycotic systemic therapy that a cure is available offering high rate of clinical and mycological therapy. The purpose of this report is to better inform on the undesirable side-effects of antimycotic agents which are currently so largely disseminated. The case of a young patient is presented who was enjoying good health and who after 6 weeks of starting therapy with terbinafine on a doses of 1 pill of 250 mg a day, to treat a trichophytic onychomycosis in both feet, developed severe symptoms of toxic colostatic hepatitis duly corroborated after pertinent testing. Patient had a full recovery after a few months of having interrupted her therapy, apparently without any sequel. The literature in this regard has been revised and a close monitoring of the hepatic function is recommended prior and during treatment with this drug. The need to continue research to find an ideal antimycotic still not found is also recommended.


In planta gene targeting.
The development of designed site-specific endonucleases boosted the establishment of gene targeting (GT) techniques in a row of different species. However, the methods described in plants require a highly efficient transformation and regeneration procedure and, therefore, can be applied to very few species. Here, we describe a highly efficient GT system that is suitable for all transformable plants regardless of transformation efficiency. Efficient in planta GT was achieved in Arabidopsis thaliana by expression of a site-specific endonuclease that not only cuts within the target but also the chromosomal transgenic donor, leading to an excised targeting vector. Progeny clonal for the targeted allele could be obtained directly by harvesting seeds. Targeted events could be identified up to approximately once per 100 seeds depending on the target donor combination. Molecular analysis demonstrated that, in almost all events, homologous recombination occurred at both ends of the break. No ectopic integration of the GT vector was found.


Survey of developmental milestones in internal medicine among residents and faculty.
The published Accreditation Council for Graduate Medical Education (ACGME) milestones represent a novel method of evaluation of trainees in graduate medical education. We surveyed agroup of teaching faculty and residents, regarding the new ACGME milestones project. We obtained their input on the expected timeline for the developmental milestones and compared their responses to the ACGME recommendations. A 42-item survey questionnaire, derived from the original 142 item publication, was completed by 26 internal medicine teaching faculty and 34 internal medicine residents. We found statistically significant differences in the responses given by residents and faculty compared to those in the standard recommendations. The differences were more pronounced with the residents than with the faculty. The results of our survey showed significantly different responses as compared to the standard recommended timelines. Since this is a novel evaluation process, substantial faculty development and resident education regarding the process can help improve its implementation. Future studies should focus on how learners might better understand and refine the milestone evaluation process.


Lacking control increases illusory pattern perception.
We present six experiments that tested whether lacking control increases illusory pattern perception, which we define as the identification of a coherent and meaningful interrelationship among a set of random or unrelated stimuli. Participants who lacked control were more likely to perceive a variety of illusory patterns, including seeing images in noise, forming illusory correlations in stock market information, perceiving conspiracies, and developing superstitions. Additionally, we demonstrated that increased pattern perception has a motivational basis by measuring the need for structure directly and showing that the causal link between lack of control and illusory pattern perception is reduced by affirming the self. Although these many disparate forms of pattern perception are typically discussed as separate phenomena, the current results suggest that there is a common motive underlying them.


Determining the reliability of a custom built seated stadiometry set-up for measuring spinal height in participants with chronic low back pain.
Indirect measurement of disc hydration can be obtained through measures of spinal height using stadiometry. However, specialised stadiometers for this are often custom-built and expensive. Generic wall-mounted stadiometers alternatively are common in clinics and laboratories. This study examined the reliability of a custom set-up utilising a wall-mounted stadiometer for measurement of spinal height using custom built wall mounted postural rods. Twelve participants with non-specific chronic low back pain (CLBP; females n = 5, males n = 7) underwent measurement of spinal height on three separate consecutive days at the same time of day where 10 measurements were taken at 20 s intervals. Comparisons were made using repeated measures analysis of variance for 'trial' and 'gender'. There were no significant effects by trial or interaction effects of trial x gender. Intra-individual absolute standard error of measurement (SEM) was calculated for spinal height using the first of the 10 measures, the average of 10 measures, the total shrinkage, and the rate of shrinkage across the 10 measures examined as the slope of the curve when a linear regression was fitted. SEMs were 3.1 mm, 2.8 mm, 2.6 mm and 0.212, respectively. Absence of significant differences between trials and the reported SEMs suggests this custom set-up for measuring spinal height changes is suitable use as an outcome measure in either research or clinical practice in participants with CLBP.


Stressful life events, social health issues and low birthweight in an Australian population-based birth cohort: challenges and opportunities in antenatal care.
Investment in strategies to promote 'a healthy start to life' has been identified as having the greatest potential to reduce health inequalities across the life course. The aim of this study was to examine social determinants of low birthweight in an Australian population-based birth cohort and consider implications for health policy and health care systems. Population-based survey distributed by hospitals and home birth practitioners to >8000 women six months after childbirth in two states of Australia. Participants were women who gave birth to a liveborn infant in Victoria and South Australia in September/October 2007. Main outcome measures included stressful life events and social health issues, perceived discrimination in health care settings, infant birthweight. 4,366/8468 (52%) of eligible women returned completed surveys. Two-thirds (2912/4352) reported one or more stressful life events or social health issues during pregnancy. Women reporting three or more social health issues (18%, 768/4352) were significantly more likely to have a low birthweight infant (< 2500 grams) after controlling for smoking and other socio-demographic covariates (Adj OR = 1.77, 95% CI 1.1-2.8). Mothers born overseas in non-English speaking countries also had a higher risk of having a low birthweight infant (Adj OR = 1.85, 95% CI 1.2-2.9). Women reporting three or more stressful life events/social health issues were more likely to attend antenatal care later in pregnancy (OR = 2.06, 95% CI 1.3-3.1), to have fewer antenatal visits (OR = 2.17, 95% CI 1.4-3.4) and to experience discrimination in health care settings (OR = 2.69, 95% CI 2.2-3.3). There is a window of opportunity in antenatal care to implement targeted preventive interventions addressing potentially modifiable risk factors for poor maternal and infant outcomes. Developing the evidence base and infrastructure necessary in order for antenatal services to respond effectively to the social circumstances of women's lives is long overdue.


Cardiocirculatory coupling during sinusoidal baroreceptor stimulation and fixed-frequency breathing.
The question of whether respiratory sinus arrhythmia (RSA) originates mainly from a central coupling between respiration and heart rate, or from baroreflex mechanisms, is a subject of controversy. If there is a major contribution of baroreflexes to RSA, cardiocirculatory coupling during breathing and during cyclic baroreflex stimulation should show similarities. We applied a sinusoidal stimulus to the carotid baroreceptors and generated heart rate fluctuations of the same magnitude as RSA with a frequency similar to, but different from, the breathing frequency (0.2 Hz, compared with 0.25 Hz), and at 0.1 Hz, in 17 supine healthy subjects (age 28-39 years). The data were analysed using discrete Fourier-transform and transfer function analysis. Respiratory fluctuations in systolic blood pressure preceded RSA with a time lag equal to that between baroreceptor stimulation and oscillations in RR interval (0.62+/-0.18 s compared with 0.57+/-0.28 s at 0.2 Hz neck suction). The response of systolic blood pressure to neck suction at 0.2 Hz was 5 times less than the respiratory blood pressure fluctuations. Neck suction at 0.1 Hz largely increased fluctuations in blood pressure and RR interval, whereas the spontaneous phase relationship between blood pressure and RR interval remained unchanged. Our results are not consistent with the hypothesis that the origin of RSA is predominantly a central phenomenon which secondarily generates fluctuations in blood pressure, but suggest that, under the condition of fixed-frequency breathing at 0.25 Hz, baroreflex mechanisms contribute to respiratory fluctuations in RR interval.


The variable-pressure neck-chamber method for studying the carotid baroreflex in man.
1. The variable-pressure neck-chamber method was analysed in ten healthy volunteer subjects to determine its suitability for the study of the carotid baroreceptor reflex in man. 2. Positive and negative pressures applied to the neck (range +/- 60 mmHg) were always transmitted linearly to a tissue catheter outside the carotid sinus, but only 86% of positive pressure, and 64% of negative pressure. Tissue pressures were confirmed by simultaneous measurement in the internal jugular vein adjacent to the carotid sinus. 3. Positive and negative pressure changes within the above range did not alter PO2 of internal jugular venous blood, suggesting that cerebral blood flow was unaltered. 4. Positive pressure changes induced reflex pressor responses of similar magnitude at arterial PO2 12-8 and 70-1 kPa (96 and 527 mmHg), suggesting that the carotid chemoreceptors were not involved. 5. It is concluded that the variable-pressure neck chamber is a valid method for selectively studying the carotid baroreceptor reflex in man. However, transmission of external pneumatic pressure to the carotid sinus is imperfect and greater for positive than for negative pressure. This must be recognized to avoid underestimation of gain and distortion of shape of the reflex.


A New RNA-Based Adjuvant Enhances Virus-Specific Vaccine Responses by Locally Triggering TLR- and RLH-Dependent Effects.
Among innovative adjuvants conferring a Th1-shift, RNAdjuvant is a promising candidate. This adjuvant consists of a 547-nt uncapped noncoding ssRNA containing polyU repeats that is stabilized by a cationic carrier peptide. Whereas vaccination of mice with an influenza subunit vaccine induced moderate virus-specific IgG1, vaccination together with RNAdjuvant significantly enhanced this IgG1 and additionally promoted the formation of IgG2b/c, which is indicative of Th1 responses. Furthermore, such sera neutralized influenza virus, whereas this effect was not detected upon vaccination with the subunit vaccine alone. Similarly, upon vaccination with virus-like particles displaying vesicular stomatitis virus G protein, RNAdjuvant promoted the formation of virus-specific IgG2b/c and enhanced neutralizing IgG responses to an extent that mice were protected against lethal virus infection. RNAdjuvant induced dendritic cells to upregulate activation markers and produce IFN-I. Although these effects were strictly TLR7 dependent, RNAdjuvant-mediated augmentation of vaccine responses needed concurrent TLR and RIG-I-like helicase signaling. This was indicated by the absence of the adjuvant effect in vaccinated MyD88-/-Cardif-/- mice, which are devoid of TLR (with the exception of TLR3) and RIG-I-like helicase signaling, whereas in vaccinated MyD88-/- mice the adjuvant effect was reduced. Notably, i.m. RNAdjuvant injection induced local IFN-I responses and did not induce systemic effects, implying good tolerability and a favorable safety profile for RNAdjuvant.


Effects of the side of arteriovenous fistula on outcomes after coronary artery bypass surgery in hemodialysis-dependent patients.
The aim of the study was to determine whether using the in situ internal thoracic artery (ITA) graft ipsilateral to the arteriovenous fistula adversely affects the outcomes after isolated coronary artery bypass grafting (CABG) in the dialysis-dependent patients to answer the concerns of a possible steal and consequent myocardial ischemia. We categorized 155 dialysis patients undergoing isolated CABG between January 1993 and December 2011 into 108 patients (70%, ipsilateral group) whose left anterior descending artery (LAD) was revascularized with the ITA ipsilateral to the arteriovenous fistula and 47 patients (contralateral group) whose LAD was grafted with the ITA opposite to the fistula, to compare their early and late outcomes. While 94% of the ipsilateral group had left fistula, 55% of the contralateral group had left fistulas. The LAD was grafted with the left ITA in 94% of the ipsilateral group, whereas it was grafted with left (49%) or right (51%) ITAs in the contralateral group. There was no significant difference in hospital mortality between the groups (ipsilateral 10.2% vs contralateral 10.6%). After follow-up for 55 ± 42 months, the overall survival (ipsilateral 58% vs contralateral 65% at 5 years) and cardiac event-free rates (ipsilateral 74% vs contralateral 68% at 5 years) were also similar between the groups by log-rank tests (P = .90 and P = .07). Revascularization of the LAD using the in situ ITA graft ipsilateral to the arteriovenous fistula increases neither the operative mortality nor the risks of late death and cardiac events after isolated CABG in dialysis patients.


Lactobacillus rhamnosus HN001 and Lactobacillus acidophilus La-14 Attenuate Gardnerella vaginalis-Infected Bacterial Vaginosis in Mice.
Oral administration of a probiotic mixture (PM; Respecta®) consisting of Lactobacillus rhamnosus HN001 (L1), Lactobacillus acidophilus La-14 (L2), and lactoferrin RCXTM results in colonization of these probiotics in the vagina of healthy women. Therefore, we examined whether vaginal colonization of the PM ingredients L1 and L2 could attenuate bacterial vaginosis (BV). BV was induced in mice via β-estradiol-3-benzoate-induced immunosuppression and intravaginal inoculation with Gardnerella vaginalis (GV). Inflammatory markers were analyzed using enzyme-linked immunosorbent assay, immunoblotting, quantitative polymerase chain reaction, and flow cytometry. Oral or intravaginal administration of PM resulted in colonization of L1 and L2 in the vagina. Oral or intravaginal administration of L1, L2, or PM significantly inhibited GV-induced epithelial cell disruption, myeloperoxidase activity, NF-κB activation, and IL-1β and TNF-α expression (p < 0.05). Administration of these probiotics also inhibited IL-17 and RORγt expression but increased IL-10 and Foxp3 expression. Of these probiotics, L2 most effectively attenuated GV-induced BV, followed by L1 and PM. Oral administration was more effective against GV-induced BV than intravaginal administration. L1 and L2 also significantly inhibited the adherence of GV to HeLa cells (a human cervical cancer cell line) and GV growth in vitro. In addition, L1 and L2 inhibited lipopolysaccharide-induced NF-κB activation in macrophages and the differentiation of splenocytes into Th17 cells in vitro, but increased their differentiation into Treg cells. Our study suggests that L1, L2, and PM attenuated GV-induced vaginosis by regulating both vaginal and systemic innate and adaptive immune responses rather than direct competition or killing of GV in the vagina.


Infusing neuroscience into the study and prevention of drug misuse and co-occurring aggressive behavior.
The etiology of behavioral precursors to substance misuse and aggression is viewed from the perspective of a developmental, multifactorial model of complex disorders. Beginning at conception, genetic and environmental interactions have potential to produce a sequence of behavioral phenotypes during development that bias the trajectory toward high-risk outcomes. One pathway is theorized to emanate from a deviation in neurological development that predisposes children to affective and cognitive delays or impairments that, in turn, generate dysregulatory behaviors. The plasticity of these neurobiological systems is highly relevant to the prevention sciences; their functions are reliant upon environmental inputs and can be altered, for better or for worse, contingent upon the nature of the inputs. Thus, social contextual factors confer significant influence on the development of this neural network and behavioral outcomes by increasing risk for, or protecting (1) against, dysregulatory outcomes. A well-designed intervention can exploit the brain's plasticity by targeting biological and social factors at sensitive time points to positively influence emergent neurobiological functions and related behaviors. Accordingly, prevention research is beginning to focus on perturbations in developmental neural plasticity during childhood that increase the likelihood of risky behaviors and may also moderate intervention effects on behavior. Given that the more complex features of neurobiological functions underlying drug misuse and aggression (e.g., executive cognitive function, coping skills, affect regulation) do not coalesce until early adulthood when prefrontal-limbic brain networks consolidate, it is critical that mechanisms underlying developmental risk factors are identified. An empirically driven prevention approach, thus, may benefit from consideration of (i) the type, effect, and developmental timing of the environmental impact on the brain, and (ii) the type and effect on brain function, and developmental timing of the intervention. This translational approach promises to eventually offer some direction for the design of effective interventions to prevent drug misuse and concomitant aggression.


Reptiles and habitat fragmentation in the box-ironbark forests of central Victoria, Australia: predictions, compositional change and faunal nestedness.
There are few published accounts addressing the impact of habitat fragmentation on biodiversity of terrestrial reptiles. Here we provide information on the saurofaunas of fragments of box-ironbark forest of central Victoria, south-eastern Australia, gathered over three years. Data for fragments of four size classes (10 ha, 20 ha, 40 ha, 80 ha) are compared with similar information for 'reference areas', which are sites of the same range of areas but set within large blocks of continuous forest (>10,000 ha). These comparisons are used to differentiate fragmentation effects from normal species-area relationships. Two sets of data are presented. One is an 'extensive' set based on 68 fragments and reference areas surveyed by using transect counts and area searches. The other 'intensive' set also included pitfall trapping, but was restricted to just 17 fragments and reference areas. The reptilian fauna generally was both depauperate and of low abundance. Differences in capture-rates and species richness between fragments and reference areas collectively are minor, but there are significant differences in species richness between area classes. While fragmentation does not seem to be influential on total numbers and richness, there are important differences in the occurrence of certain species. The two most abundant species in reference areas were very rare in fragments, while a number of species were either in much greater numbers or only occurred in fragments. Many of the observed distributions were consistent with predictions made prior to the study on differences in vulnerability between species. We show that the saurofaunas are 'nested subsets' by area, with strongest nesting apparent in the intensive data-set for reference areas.


Diversity within inc genes of clinical Chlamydia trachomatis variant isolates that occupy non-fusogenic inclusions.
The obligately intracellular chlamydiae are bacterial pathogens that occupy intracellular vacuoles, termed inclusions, as they develop and multiply. Typical Chlamydia trachomatis isolates occupy inclusions that fuse with other C. trachomatis inclusions within cells infected with multiple elementary bodies (wild-type phenotype). The authors of this study have recently described C. trachomatis isolates that form multiply-lobed, non-fusogenic inclusions within single cells infected with multiple elementary bodies (variant phenotype). Inclusions formed by these isolates uniformly lacked the protein IncA on the inclusion membrane (IM). In the present work, the study of the C. trachomatis inclusion phenotype has been expanded to include 27 variant and 13 wild-type isolates. Twenty-four of the 27 variant isolates were IncA-negative, as detected by fluorescence microscopy and immunoblotting, but three variants localized IncA to the IM. The IncA-positive variants formed inclusions that fused, at a reduced rate, with those occupied by wild-type isolates and with inclusions formed by other IncA-positive variants. Nucleotide-sequence analysis of the incA sequences from the variant isolates identified a variety of distinct sequence polymorphisms relative to incA from wild-type strains. The authors also demonstrate that a second Inc protein, CT223p, is not found in the IM in selected C. trachomatis isolates. No change in the structure or the fusogenicity of the inclusions was associated with the presence or absence of CT223p.


Investigating the nursing practitioners perspectives about undergraduate nursing internship and apprenticeship courses: is renewing required?
Nurses' professional capacity plays an important role in the health system to achieve their mission. This study aimed to investigate the perspectives of nursing practitioners about undergraduate nursing internship and apprenticeship courses and possible ways of renewing the courses. This cross sectional survey was performed over 258 bachelors and practitioners of nursing graduates of Alborz University of medical sciences in the second half of 2012. Based on a multi-stage sampling schedule, questionnaires were used to collect data about the perspectives of nursing practitioners about undergraduate nursing internship and apprenticeship courses. There were 81.4% of females and 80.6%, 17.1% and 2.3% of organizational post of participants were nurse, head nurse and supervisor respectively. The occupied posts for 60.1%, 25.6% and 14.1% of subjects, respectively were nurse, head nurse and the supervisor. The application of the internship and apprenticeship courses in bachelor of nursing were in moderate to high levels. The highest percentages of responses for internship and apprenticeship training courses were in internal surgery nursing and special nursing and the minimum percentage of responses were for community hygiene nursing and mental health nursing. Due to observing moderate to high levels of fulfillment and lack of compliance of training courses, renewing to improve the quality and effectiveness of training programs are highly recommended. This can be effective in the future of nursing career and provide a practical training environment to achieve the goals of theoretical training and can lead nurses to become specialized in their field.


The Effect of Acute Body Unloading on Somatosensory Performance, Motor Activation, and Visuomotor Tasks.
Evaluating countermeasures designed to reduce the impact of microgravity exposure on astronaut performance requires the development of effective methods of assessing changes to sensorimotor function in 1g analog systems. In this study, somatosensation at the ankle and fingers, lower leg muscle activity and visuomotor control were assessed using a full body loading and acute unloading model to simulate microgravity. It was hypothesized that the function of the hands and eyes are not constrained to 'weight bearing' postures for optimal function and would not differ between the loaded and acute unloaded conditions, whereas lower leg muscle activity and ankle somatosensation would be reduced in the acute unloaded condition. Somatosensation was recorded using the Active Movement Extent Discrimination Apparatus (AMEDA) protocol where participants were required to make an absolute judgment of joint position sense. A score closer to 1.0 demonstrates higher accuracy. Lower leg muscle activity was recorded using electromyography of major lower leg musculature to observe peak muscle activity and duration of contraction. The King Devick infrared eye tracking test was used to asses visuomotor control by monitoring saccade velocity and fixation time. In acute unloading, it was found that ankle somatosensation had decreased accuracy (loaded 0.68, unloaded 0.66, p = 0.045) while finger somatosensation improved (loaded 0.77, unloaded 0.79, p = 0.006). When acutely unloaded, peak lower leg muscle activation reduced ( > 27%) and total contraction time increased (2.02 × longer) compared to loading. Visuomotor assessment results did not vary between the loaded and acute unloaded postures, however the underlying techniques used by the participant to complete the task (saccade velocity and fixations time) did increase in acute unloaded conditions. This research provides an insight to how to the human body responds immediately to acute changes of gravitational load direction. It provides insight to the acute affects' astronauts may encounter when in microgravity.


Poor neutralization and rapid decay of antibodies to SARS-CoV-2 variants in vaccinated dialysis patients.
Patients on dialysis are at risk of severe course of SARS-CoV-2 infection. Understanding the neutralizing activity and coverage of SARS-CoV-2 variants of vaccine-elicited antibodies is required to guide prophylactic and therapeutic COVID-19 interventions in this frail population. By analyzing plasma samples from 130 hemodialysis and 13 peritoneal dialysis patients after two doses of BNT162b2 or mRNA-1273 vaccines, we found that 35% of the patients had low-level or undetectable IgG antibodies to SARS-CoV-2 Spike (S). Neutralizing antibodies against the vaccine-matched SARS-CoV-2 and Delta variant were low or undetectable in 49% and 77% of patients, respectively, and were further reduced against other emerging variants. The fraction of non-responding patients was higher in SARS-CoV-2-naïve hemodialysis patients immunized with BNT162b2 (66%) than those immunized with mRNA-1273 (23%). The reduced neutralizing activity correlated with low antibody avidity. Patients followed up to 7 months after vaccination showed a rapid decay of the antibody response with an average 21- and 10-fold reduction of neutralizing antibodies to vaccine-matched SARS-CoV-2 and Delta variant, which increased the fraction of non-responders to 84% and 90%, respectively. These data indicate that dialysis patients should be prioritized for additional vaccination boosts. Nevertheless, their antibody response to SARS-CoV-2 must be continuously monitored to adopt the best prophylactic and therapeutic strategy.


Recovery of frontal cortex-mediated visual behaviors following neurotrophic rescue of axotomized neurons in medial frontal cortex.
Unilateral lesions extending across the boundary region of visual and parietal cortex in adult rats result in the death of 20-35% of neurons in layers II-III of the caudal third of medial frontal cortex ipsilaterally, a neuron population labeled with 3H-thymidine on the 19th day of gestation (E19). Additionally, there is a consistent 15% loss of these labeled neurons in an area between 50% and 60% of the distance along the caudal-rostral extent of medial frontal cortex, an area that may function analogously to the frontal eye field of primates. All of these neurons are rescued from axotomy-induced death by delivering into the posterior cortex lesion cavity for 2 weeks a macromolecular fraction of culture medium conditioned by embryonic primordia of the frontal-occipital pathway (CM). Moreover, the rescue is apparently permanent, with normal numbers of these neurons present in CM animals 6-7 weeks after the neurotrophic factor is no longer being supplied exogenously. Behaviorally, control operates receiving a similarly prepared fraction of unconditioned medium are significantly impaired in the number of trials needed to learn two visual discrimination tasks. This deficit is attributable in part to a bias in erroneous responses to the side contralateral to the lesion. The error bias reflects a failure to inhibit repeated incorrect responding contralaterally. In contrast, the CM animals learn both visual tasks in a normal number of trials and have no contralateral error bias. Rather, all CM animals have an contralateral error bias. Rather, all CM animals have an ipsilateral error bias (interpreted as an unmasking of the contralateral neglect expected after a parietal cortex lesion).(ABSTRACT TRUNCATED AT 250 WORDS)


Color filter array demosaicking: new method and performance measures.
Single-sensor digital cameras capture imagery by covering the sensor surface with a color filter array (CFA) such that each sensor pixel only samples one of three primary color values. To render a full-color image, an interpolation process, commonly referred to as CFA demosaicking, is required to estimate the other two missing color values at each pixel. In this paper, we present two contributions to the CFA demosaicking: a new and improved CFA demosaicking method for producing high quality color images and new image measures for quantifying the performance of demosaicking methods. The proposed demosaicking method consists of two successive steps: an interpolation step that estimates missing color values by exploiting spatial and spectral correlations among neighboring pixels, and a post-processing step that suppresses noticeable demosaicking artifacts by adaptive median filtering. Moreover, in recognition of the limitations of current image measures, we propose two types of image measures to quantify the performance of different demosaicking methods; the first type evaluates the fidelity of demosaicked images by computing the peak signal-to-noise ratio and CIELAB DeltaE(*)(ab) for edge and smooth regions separately, and the second type accounts for one major demosaicking artifact-zipper effect. We gauge the proposed demosaicking method and image measures using several existing methods as benchmarks, and demonstrate their efficacy using a variety of test images.


Integration of the Drug-Gene Interaction Database (DGIdb 4.0) with open crowdsource efforts.
The Drug-Gene Interaction Database (DGIdb, www.dgidb.org) is a web resource that provides information on drug-gene interactions and druggable genes from publications, databases, and other web-based sources. Drug, gene, and interaction data are normalized and merged into conceptual groups. The information contained in this resource is available to users through a straightforward search interface, an application programming interface (API), and TSV data downloads. DGIdb 4.0 is the latest major version release of this database. A primary focus of this update was integration with crowdsourced efforts, leveraging the Drug Target Commons for community-contributed interaction data, Wikidata to facilitate term normalization, and export to NDEx for drug-gene interaction network representations. Seven new sources have been added since the last major version release, bringing the total number of sources included to 41. Of the previously aggregated sources, 15 have been updated. DGIdb 4.0 also includes improvements to the process of drug normalization and grouping of imported sources. Other notable updates include the introduction of a more sophisticated Query Score for interaction search results, an updated Interaction Score, the inclusion of interaction directionality, and several additional improvements to search features, data releases, licensing documentation and the application framework.


Interferon-Gamma Impairs Maintenance and Alters Hematopoietic Support of Bone Marrow Mesenchymal Stromal Cells.
Bone marrow (BM) mesenchymal stromal cells (MSCs) provide microenvironmental support to hematopoietic stem and progenitor cells (HSPCs). Culture-expanded MSCs are interesting candidates for cellular therapies due to their immunosuppressive and regenerative potential which can be further enhanced by pretreatment with interferon-gamma (IFN-γ). However, it remains unknown whether IFN-γ can also influence hematopoietic support by BM-MSCs. In this study, we elucidate the impact of IFN-γ on the hematopoietic support of BM-MSCs. We found that IFN-γ increases expression of interleukin (IL)-6 and stem cell factor by human BM-MSCs. IFN-γ-treated BM-MSCs drive HSPCs toward myeloid commitment in vitro, but impair subsequent differentiation of HSPC. Moreover, IFN-γ-ARE-Del mice with increased IFN-γ production specifically lose their BM-MSCs, which correlates with a loss of hematopoietic stem cells' quiescence. Although IFN-γ treatment enhances the immunomodulatory function of MSCs in a clinical setting, we conclude that IFN-γ negatively affects maintenance of BM-MSCs and their hematopoietic support in vitro and in vivo.


Electrophysiology of morphologically identified mossy cells of the dentate hilus recorded in guinea pig hippocampal slices.
A specific population of cells located in the hilus of the hippocampal fascia dentata was studied in guinea pig hippocampal slices using standard intracellular recording techniques. Twenty-one such cells were characterized using electrophysiological techniques and were identified morphologically as mossy cells following intracellular injection of the fluorescent dye Lucifer yellow. These cells had a resting membrane potential (mean, -64.6 mV), action potential amplitude (mean, 78.6 mV), action potential duration (mean, 2.2 msec), and time constant (mean, 24.2 msec) similar to those of hippocampal pyramidal cells of area CA3. Rectification seen in their I-V curves, and their ability to fire action potentials in accommodating trains or bursts in response to injected current pulses, were also similar to those of area CA3 pyramidal cells. However, these cells could be distinguished from area CA3 pyramidal cells by their higher input resistance (mean, 97.4 M omega) and higher level of spontaneous activity. The synaptic responses of mossy cells were also different from those of CA3 pyramidal cells. First, mossy cells responded to low levels of stimulation in all areas of the hippocampal slice that were tested, even areas as remote as area CA1. Second, the responses of mossy cells to stimulation consisted primarily of EPSPs. Hyperpolarizing IPSP-like events followed EPSPs in some cells, but the hyperpolarizations were small and monophasic, even after the cell was depolarized with current injection. This response contrasts with the smaller EPSP and the prominent, biphasic IPSP elicited by afferent stimulation of area CA3 pyramidal cells. The physiological and morphological characteristics of these cells suggest that they could play an important role in the integration of electrical activity in the hippocampus.


Consumption of bovine spongiform encephalopathy (BSE) contaminated beef and the risk of variant Creutzfeldt-Jakob disease.
To date, the variant Creutzfeldt-Jakob disease (vCJD) risk assessments that have been performed have primarily focused on predicting future vCJD cases in the United Kingdom, which underwent a bovine spongiform encephalopathy (BSE) epidemic between 1980 and 1996. Surveillance of potential BSE cases was also used to assess vCJD risk, especially in other BSE-prevalent EU countries. However, little is known about the vCJD risk for uninfected individuals who accidentally consume BSE-contaminated meat products in or imported from a country with prevalent BSE. In this article, taking into account the biological mechanism of abnormal prion PrP(res) aggregation in the brain, the probability of exposure, and the expected amount of ingested infectivity, we establish a stochastic mean exponential growth model of lifetime exposure through dietary intake. Given the findings that BSE agents behave similarly in humans and macaques, we obtained parameter estimates from experimental macaque data. We then estimated the accumulation of abnormal prions to assess lifetime risk of developing clinical signs of vCJD. Based on the observed number of vCJD cases and the estimated number of exposed individuals during the BSE epidemic period from 1980 to 1996 in the United Kingdom, an exposure threshold hypothesis is proposed. Given the age-specific risk of infection, the hypothesis explains the observations very well from an extreme-value distribution fitting of the estimated BSE infectivity exposure. The current BSE statistics in the United Kingdom are provided as an example.


A cis-acting mechanism mediates transcriptional memory at Polycomb target genes in mammals.
Epigenetic inheritance of gene expression states enables a single genome to maintain distinct cellular identities. How histone modifications contribute to this process remains unclear. Using global chromatin perturbations and local, time-controlled modulation of transcription, we establish the existence of epigenetic memory of transcriptional activation for genes that can be silenced by the Polycomb group. This property emerges during cell differentiation and allows genes to be stably switched after a transient transcriptional stimulus. This transcriptional memory state at Polycomb targets operates in cis; however, rather than relying solely on read-and-write propagation of histone modifications, the memory is also linked to the strength of activating inputs opposing Polycomb proteins, and therefore varies with the cellular context. Our data and computational simulations suggest a model whereby transcriptional memory arises from double-negative feedback between Polycomb-mediated silencing and active transcription. Transcriptional memory at Polycomb targets thus depends not only on histone modifications but also on the gene-regulatory network and underlying identity of a cell.


Patient advocacy: barriers and facilitators.
During the two recent decades, advocacy has been a topic of much debate in the nursing profession. Although advocacy has embraced a crucial role for nurses, its extent is often limited in practice. While a variety of studies have been generated all over the world, barriers and facilitators in the patient advocacy have not been completely identified. This article presents the findings of a study exploring the barriers and facilitators influencing the role of advocacy among Iranian nurses. This study was conducted by grounded theory method. Participants were 24 Iranian registered nurses working in a large university hospital in Tehran, Iran. Semi-structured interviews were used for data collection. All interviews were transcribed verbatim and simultaneously Constant comparative analysis was used according to the Strauss and Corbin method. Through data analysis, several main themes emerged to describe the factors that hindered or facilitated patient advocacy. Nurses in this study identified powerlessness, lack of support, law, code of ethics and motivation, limited communication, physicians leading, risk of advocacy, royalty to peers, and insufficient time to interact with patients and families as barriers to advocacy. As for factors that facilitated nurses to act as a patient advocate, it was found that the nature of nurse-patient relationship, recognizing patients' needs, nurses' responsibility, physician as a colleague, and nurses' knowledge and skills could be influential in adopting the advocacy role. Participants believed that in this context taking an advocacy role is difficult for nurses due to the barriers mentioned. Therefore, they make decisions and act as a patient's advocate in any situation concerning patient needs and status of barriers and facilitators. In most cases, they can not act at an optimal level; instead they accept only what they can do, which we called 'limited advocacy' in this study. It is concluded that advocacy is contextually complex, and is a controversial and risky component of the nursing practice. Further research is needed to determine the possibility of a correlation between identified barriers/ facilitators and the use of advocacy.


Increased intramuscular lipid storage in the insulin-resistant and endurance-trained state.
Numerous studies have reported a strong correlation between intramuscular triacylglycerol (IMTG) content and insulin resistance. However, the proposed relationship between IMTG accumulation and skeletal muscle insulin resistance is not unambiguous, as trained athletes have been shown to be markedly insulin sensitive despite an elevated IMTG storage. Though the latter has often been attributed to differences in muscle fibre type composition and/or structural characteristics of the intramyocellular lipid deposits, recent studies have failed to provide such evidence. The greater insulin sensitivity despite an elevated IMTG deposition in the endurance-trained state has often been described as a metabolic paradox. However, divergent metabolic events are responsible for the greater IMTG content in the endurance-trained versus insulin-resistant states. The greater IMTG storage in the trained athlete represents an adaptive response to endurance training, allowing a greater contribution of the IMTG pool as a substrate source during exercise. In contrast, elevated IMTG stores in the obese and/or type 2 diabetes patient seem to be secondary to a structural imbalance between plasma free fatty acid availability, fatty acid (FA) storage and oxidation. Therefore, the reported correlation between IMTG content and insulin resistance does not represent a functional relationship, as it is strongly influenced by training status and/or habitual physical activity. It can be argued that the ratio between IMTG content and muscle oxidative capacity represents a more accurate marker of insulin resistance. Interventions to augment mitochondrial density and/or function are likely to improve the balance between FA uptake and oxidation and should be applied to prevent and/or treat insulin resistance.


Sociodemographic variables affecting the health seeking behaviour of mothers in a saudi community.
Studies have shown that good antenatal care is associated with favorable outcome for both mothers and children. However, there are several factors that influence the utilization of such care even when available. The objective of this paper is to examine maternal demographic variables that influence antenatal care and the desire of mothers to consult a physician when their children aged below two are ill. This is a cross-sectional study of women living in Riyadh, Saudi Arabia. From a map of residential areas, a multi-stage sampling approach was employed to select a random sample of houses. All women with children aged less than two years were included in a house- to- house survey. A structured questionnaire was used for data collection. Epi-Info was used for statistical analysis. Results show that 96.6% of the mothers had at least one antenatal care visit, while 80.9% had had more than six visits. Delivery under medical supervision was reported by 97.8% of the sample. The use of antenatal care and the number of visits were statistically significantly associated with age, education and marital status. The last two variables were also statistically significantly associated with the place of delivery. Nearly 83% of the mothers reported one or two illnesses in their children within the last two weeks. About 90.5% of these mothers consulted a physician on the illness and there was a 12.4% severe morbidity rate as evidenced by hospital admission. Physician consultation was statistically significantly associated with nationality, education and the occupation of the mother p<0.05. Hospital admission was also statistically significantly associated with age, nationality and occupation of the mother p<0.05. The commonest illness in the children in the last two weeks was diarrhea (34.3%) followed by fever (33.4%) and breathing difficulties (16%), although the highest frequency of episodes of illness was diarrhea and fever. Nevertheless, breathing difficulties followed closely by ear infection constituted the two highest prevalences among children who were brought for medical consultation (94.4% and 93.3% respectively). The study shows a higher proportion of mothers attending antenatal care than has been previously reported for the country. The pattern of reported children's illnesses reflects what has been previously seen from hospital studies. It also shows a high rate of physician consultation. This is probably due to the extensive coverage of free government health services in Riyadh. It will be worthwhile to document other socio-demographic variables affecting health seeking behavior of mothers in other parts of the country. There is a need to educate young illiterate mothers in sound child rearing practices. This will help minimize the distress of childhood diseases.


US-guided Percutaneous Release of the Trigger Finger by Using a 21-gauge Needle: A Prospective Study of 60 Cases.
Purpose To evaluate the efficacy of ultrasonographically (US)-guided percutaneous treatment of the trigger finger by releasing the A1 pulley with a 21-gauge needle. Materials and Methods This two-part study was approved by the ethics committee, and written consent was obtained from all patients. The first part consisted of 10 procedures on cadaver digits followed by dissection to analyze the effectiveness of the A1 pulley release and detect any collateral damage to the A2 pulley, interdigital nerves, or underlying flexor tendons. The second part was performed during an 18-month period starting in March 2013. It was a prospective clinical study of 60 procedures performed in 48 patients. Outcomes were evaluated through a clinical examination at day 0 and during a 6-month follow-up visit, where the trigger digit was evaluated clinically and the Quick Disabilities of the Arm, Shoulder and Hand outcome measure, or QuickDASH, and patient satisfaction questionnaires were administered. Results No complications were found during the cadaver study. However, the release was considered "partial" in all fingers. In the clinical study, the trigger finger was completely resolved in 81.7% (49 of 60) of cases immediately after the procedure. Moderate trigger finger persisted in 10 cases, and one thumb pulley could not be released. A US-guided corticosteroid injection was subsequently performed in these 11 cases. At 6-month follow-up, only two cases still had moderate trigger finger and there were no late complications. The mean QuickDASH questionnaire score was 4; all patients said they were satisfied. Conclusion US-guided treatment of the trigger finger by using a 21-gauge needle is feasible in current practice, with minimal complications. (©) RSNA, 2016 Online supplemental material is available for this article.


Outcome-Weighted Learning for Personalized Medicine with Multiple Treatment Options.
To achieve personalized medicine, an individualized treatment strategy assigning treatment based on an individual's characteristics that leads to the largest benefit can be considered. Recently, a machine learning approach, O-learning, has been proposed to estimate an optimal individualized treatment rule (ITR), but it is developed to make binary decisions and thus limited to compare two treatments. When many treatment options are available, existing methods need to be adapted by transforming a multiple treatment selection problem into multiple binary treatment selections, for example, via one-vs-one or one-vs-all comparisons. However, combining multiple binary treatment selection rules into a single decision rule requires careful consideration, because it is known in the multicategory learning literature that some approaches may lead to ambiguous decision rules. In this work, we propose a novel and efficient method to generalize outcome-weighted learning for binary treatment to multi-treatment settings. We solve a multiple treatment selection problem via sequential weighted support vector machines. We prove that the resulting ITR is Fisher consistent and obtain the convergence rate of the estimated value function to the true optimal value, i.e., the estimated treatment rule leads to the maximal benefit when the data size goes to infinity. We conduct simulations to demonstrate that the proposed method has superior performance in terms of lower mis-allocation rates and improved expected values. An application to a three-arm randomized trial of major depressive disorder shows that an ITR tailored to individual patient's expectancy of treatment efficacy, their baseline depression severity and other characteristics reduces depressive symptoms more than non-personalized treatment strategies (e.g., treating all patients with combined pharmacotherapy and psychotherapy).