Identification and characterization of ace2-type acetylcholinesterase in insecticide-resistant and -susceptible parasitoid wasp Oomyzus sokolowskii (Hymenoptera: Eulophidae).
A full-length acetylcholinesterase (AChE) cDNA sequence (Os-ace2.s) from insecticide-susceptible (S) parasitoid Oomyzus sokolowskii (Hymenoptera: Eulophidae) and a partial cDNA sequence (Os-ace2.r) from insecticide- resistant (R) O. sokolowskii were identified firstly. Both Os-ace2.s (encoding a protein of 639 amino acid residues) and Os-ace2.r (encoding a protein of 530 amino acid residues) contained the typical conserved motifs, including FGESAGdomains, catalytic triad, acyl pocket, three oxy-anino hole, choline binding site, peripheral anionic site, omega loop and conserved aromatic residues. The multiple alignment and Blast results indicated that Os-ace2.s were ace2 member of AChE gene. There were three replacements of the amino acid residues (Glu 115 Leu, Phe 394 Leu, and Lys 424 Arg) between Os-ace2.s and Os-ace2.r. The ace2 of O. sokolowskii was the AChE gene firstly isolated from hymenopteran parasitoid so far. R O. sokolowskii displayed about 15-20-folds resistance ratios to methamidophos and avermectin. The bimolecular rate constant (k i) value in S O. sokolowskii was 3.8-folds for methamidophos and 12.3 for dichlorvos, respectively higher than those in R O. sokolowskii. The results indicated that the insensitive AChE and replacements of the amino acid residues in Os-ace2 might be involved in the resistance to methamidophos in R O. sokolowskii.


Glutamate-sensitive imaging and evaluation of cognitive impairment in multiple sclerosis.
Cognitive impairment (CI) profoundly impacts quality of life for patients with multiple sclerosis (MS). Dysfunctional regulation of glutamate in gray matter (GM) has been implicated in the pathogenesis of MS by post-mortem pathological studies and in CI by in vivo magnetic resonance spectroscopy, yet GM pathology is subtle and difficult to detect using conventional T1- and T2-weighted magnetic resonance imaging (MRI). There is a need for high-resolution, clinically accessible imaging techniques that probe molecular changes in GM. To study cortical GM pathology related to CI in MS using glutamate-sensitive chemical exchange saturation transfer (GluCEST) MRI at 7.0 Tesla (7T). A total of 20 patients with relapsing-remitting MS and 20 healthy controls underwent cognitive testing, anatomical imaging, and GluCEST imaging. Glutamate-sensitive image contrast was quantified for cortical GM, compared between cohorts, and correlated with clinical measures of CI. Glutamate-sensitive contrast was significantly increased in the prefrontal cortex of MS patients with accumulated disability (p < 0.05). In addition, glutamate-sensitive contrast in the prefrontal cortex was significantly correlated with symbol digit modality test (rS = -0.814) and choice reaction time (rS = 0.772) scores in patients (p < 0.05), suggesting that GluCEST MRI may have utility as a marker for GM pathology and CI.


ARF6 directs axon transport and traffic of integrins and regulates axon growth in adult DRG neurons.
Integrins are involved in axon growth and regeneration. Manipulation of integrins is a route to promoting axon regeneration and understanding regeneration failure in the CNS. Expression of α9 integrin promotes axon regeneration, so we have investigated α9β1 trafficking and transport in axons and at the growth cone. We have previously found that α9 and β1 integrins traffic via Rab11-positive recycling endosomes in peripheral axons and growth cones. However, transport via Rab11 is slow, while rapid transport occurs in vesicles lacking Rab11. We have further studied α9 and β1 integrin transport and traffic in adult rat dorsal root ganglion axons and PC12 cells. Integrins are in ARF6 vesicles during rapid axonal transport and during trafficking in the growth cone. We report that rapid axonal transport of these integrins and their trafficking at the cell surface is regulated by ARF6. ARF6 inactivation by expression of ACAP1 leads to increased recycling of β1 integrins to the neuronal surface and to increased anterograde axonal transport. ARF6 activation by expression of the neuronal guanine nucleotide exchange factors, ARNO or EFA6, increases retrograde integrin transport in axons and increases integrin internalization. ARF6 inactivation increases integrin-mediated outgrowth, while activation decreases it. The coordinated changes in integrin transport and recycling resulting from ARF6 activation or inactivation are the probable mechanism behind this regulation of axon growth. Our data suggest a novel mechanism of integrin traffic and transport in peripheral axons, regulated by the activation state of ARF6, and suggest that ARF6 might be targeted to enhance integrin-dependent axon regeneration after injury.


Insight into the mechanism of a peptide inhibitor of HIV reverse transcriptase dimerization.
The biologically active forms of human immunodeficiency viruses type 1 and 2 reverse transcriptase (RT) found in infectious virions are heterodimers. We have previously shown that the dimeric nature of reverse transcriptase represents an important target for the design of a new class of antiviral agents and have designed a short peptide (Pep-7) derived from the tryptophan-rich motif of the connection subdomain that blocks dimerization of reverse transcriptase in vitro and abolishes viral infection. In the present work, we have investigated the mechanism through which this peptide inhibits RT dimerization and consequently viral propagation. We demonstrate that Pep-7 interacts preferentially with the p51 subunit within the heterodimeric reverse transcriptase, which destabilizes reverse transcriptase dimer conformation, thereby triggering dissociation. We have identified two residues Trp(24) and Phe(61), located on the fingers subdomain of p51, required for Pep-7 binding. Selective mutation of these residues on p51 to a glycine dramatically alters the stability of the RT-heterodimer suggesting that the fingers subdomain of p51 is also involved in stabilization of reverse transcriptase. We propose that the binding site of Pep-7 is located in a cleft between the fingers and the connection subdomains of p51 that contains the two highly conserved residues Phe(61) and Trp(24).


Collecting duct principal cell transport processes and their regulation.
The principal cell of the kidney collecting duct is one of the most highly regulated epithelial cell types in vertebrates. The effects of hormonal, autocrine, and paracrine factors to regulate principal cell transport processes are central to the maintenance of fluid and electrolyte balance in the face of wide variations in food and water intake. In marked contrast with the epithelial cells lining the proximal tubule, the collecting duct is electrically tight, and ion and osmotic gradients can be very high. The central role of principal cells in salt and water transport is reflected by their defining transporters-the epithelial Na(+) channel (ENaC), the renal outer medullary K(+) channel, and the aquaporin 2 (AQP2) water channel. The coordinated regulation of ENaC by aldosterone, and AQP2 by arginine vasopressin (AVP) in principal cells is essential for the control of plasma Na(+) and K(+) concentrations, extracellular fluid volume, and BP. In addition to these essential hormones, additional neuronal, physical, and chemical factors influence Na(+), K(+), and water homeostasis. Notably, a variety of secreted paracrine and autocrine agents such as bradykinin, ATP, endothelin, nitric oxide, and prostaglandin E2 counterbalance and limit the natriferic effects of aldosterone and the water-retaining effects of AVP. Considerable recent progress has improved our understanding of the transporters, receptors, second messengers, and signaling events that mediate principal cell responses to changing environments in health and disease. This review primarily addresses the structure and function of the key transporters and the complex interplay of regulatory factors that modulate principal cell ion and water transport.


[A simple and precise measurement of ocular torsion].
The instrument, derived from Mariotte's blind-spot experiment, permits the anatomical ocular torsion of each eye to be measured separately in primary position. This method was evaluated in a group of normal subjects, by comparison with measurements on fundus photographs. It was established that it was simpler and more accurate than measurement with the Goldmann perimeter and indirect ophthalmoscopy assessment. It complements subjective methods of measuring torsion by the double Maddox rod test or with the synoptophore.


Enhanced Photoinduced Carrier Separation in Fe-MOF-525/CdS for Photocatalytic Hydrogen Evolution: Improved Catalytic Dynamics with Specific Active Sites.
Single-atom metal-anchored porphyrin-based metal-organic frameworks (MOFs) have shown excellent light absorption, catalytic sites, and high stability during photocatalytic reactions, while there are still challenges for facile assembly with quantum dots to enhance catalytic dynamics. Herein, a kind of Fe single atom-doped MOF material (Fe-MOF-525) was ball milled with CdS in a proper ratio through Fe-N4 and Fe-N-C bonding, which showed the enhanced photoinduced carrier separation ability. As a result, extended light absorption ranges of CdS/Fe-MOF-5252.3 induced the promotion of the photocatalytic hydrogen (H2) value (3638.6 μmol g-1 h-1), which was 7.2 and 2.3 times higher than those of Fe-MOF-525 and CdS. In this work, the facile synthetic technique, specific active sites, and enhanced catalytic dynamics in the composite highlight the future research on MOF-based heterojunctions and their potential photocatalysis applications..


The time of metabolism: NAD+, SIRT1, and the circadian clock.
The mammalian cell contains a molecular clock that contributes, within each organism, to circadian rhythms and variety of physiological and metabolic processes. The clock machinery is constituted by interwined transcriptional-translational feedback loops that, through the action of specific transcription factors, modulate the expression of clock-controlled genes. These oscillations in gene expression necessarily implicate events of chromatin remodeling on a relatively large, global scale, considering that as many 10% of cellular transcripts oscillate in a circadian manner. CLOCK, a transcription factor crucial for circadian function, has intrinsic histone acetyltransferase activity and operates within a large nuclear complex with other chromatin remodelers. CLOCK directs the cyclic acetylation of the histone H3 and of its own partner BMAL1. A search for the histone deacetylase (HDAC) that counterbalanced CLOCK activity revealed that SIRT1, a nicotinamide adenine dinucleotide (NAD(+))-dependent HDAC, functions in a circadian manner. Importantly, SIRT1 is a regulator of several metabolic processes and was found to interact with CLOCK and to be recruited to circadian promoters in a cyclic manner. As many transcripts that oscillate in mammalian peripheral tissues encode proteins that have central roles in metabolic processes, these findings establish a functional and molecular link among energy balance, chromatin remodeling, and circadian physiology.


Modifications in parent feeding practices and child diet during family-based behavioral treatment improve child zBMI.
To examine associations between modifications in parent feeding practices, child diet, and child weight status after treatment and to evaluate dietary mediators. Children classified as overweight or obese and 7-11 years old (N = 170) completed a 16-session family-based behavioral weight loss treatment (FBT) program. Anthropometrics (standardized body mass index (zBMI)), Child Feeding Questionnaire, and 24-hr dietary recalls were collected at baseline and post-FBT. Linear regression predicted child zBMI change. Single and multiple mediation tested child dietary modifications as mediators between change in parent feeding practices and child zBMI. Restrictive parent feeding practices significantly decreased during FBT. Reductions in parent restriction, child weight concern, child's total energy intake, and percent energy from fat, and increases in parent perceived responsibility, and child percent energy from protein, predicted reductions in child zBMI. Change in child total energy intake mediated the relation between parent restriction and child zBMI change after accounting for covariates and additional dietary mediators. FBT is associated with a decrease in parental restriction, which is associated with reductions in child relative weight, which was mediated by a decrease in child energy intake. Teaching parents to reduce children's energy intake without being overly restrictive may improve child weight.


Evaluation of microhardness, surface roughness, and wear behavior of different types of resin composites polymerized with two different light sources.
The microhardness, surface roughness and wear resistance of different types of resin composites, polymerized by a Quartz Tungsten Halogen (QTH) or Light Emitting Diode (LED) light curing units (LCU) were evaluated in this in vitro study. Cylindrical blocks were prepared from composites (8 mm in diameter, and 2 mm in thickness) and polymerized by a LED or a QTH LCU. Vickers hardness was measured on the top and bottom surfaces of the specimens. Surface roughness was measured with a surface profilometer on the top of the specimens. For the wear test, specimens were tested in a conventional pin-on-disc tribology machine under 15 N loads. The statistical analyses were performed by one-way analysis of variance (ANOVA) and t-tests, including the Bonferroni correction. Nanocomposite material Clearfil Majesty Posterior showed the highest hardness values in all polymerization types at the top and bottom surfaces (p < 0.05). Microhybrid Clearfil APX and hybrid Quixfil composites demonstrated the greatest surface roughness. Wear resistance of Clearfil Majesty Posterior was found to be the highest among the other tested resin composites. The results indicated that Clearfil Majesty Posterior demonstrated higher microhardness, less surface roughness, and higher wear resistance when compared with the other tested materials for both polymerization types.


Navigation and visualisation with HoloLens in endovascular aortic repair.
Endovascular aortic repair (EVAR) is a minimal-invasive technique that prevents life-threatening rupture in patients with aortic pathologies by implantation of an endoluminal stent graft. During the endovascular procedure, device navigation is currently performed by fluoroscopy in combination with digital subtraction angiography. This study presents the current iterative process of biomedical engineering within the disruptive interdisciplinary project Nav EVAR, which includes advanced navigation, image techniques and augmented reality with the aim of reducing side effects (namely radiation exposure and contrast agent administration) and optimising visualisation during EVAR procedures. This article describes the current prototype developed in this project and the experiments conducted to evaluate it. The current approach of the Nav EVAR project is guiding EVAR interventions in real-time with an electromagnetic tracking system after attaching a sensor on the catheter tip and displaying this information on Microsoft HoloLens glasses. This augmented reality technology enables the visualisation of virtual objects superimposed on the real environment. These virtual objects include three-dimensional (3D) objects (namely 3D models of the skin and vascular structures) and two-dimensional (2D) objects [namely orthogonal views of computed tomography (CT) angiograms, 2D images of 3D vascular models, and 2D images of a new virtual angioscopy whose appearance of the vessel wall follows that shown in ex vivo and in vivo angioscopies]. Specific external markers were designed to be used as landmarks in the registration process to map the tracking data and radiological data into a common space. In addition, the use of real-time 3D ultrasound (US) is also under evaluation in the Nav EVAR project for guiding endovascular tools and updating navigation with intraoperative imaging. US volumes are streamed from the US system to HoloLens and visualised at a certain distance from the probe by tracking augmented reality markers. A human model torso that includes a 3D printed patient-specific aortic model was built to provide a realistic test environment for evaluation of technical components in the Nav EVAR project. The solutions presented in this study were tested by using an US training model and the aortic-aneurysm phantom. During the navigation of the catheter tip in the US training model, the 3D models of the phantom surface and vessels were visualised on HoloLens. In addition, a virtual angioscopy was also built from a CT scan of the aortic-aneurysm phantom. The external markers designed for this study were visible in the CT scan and the electromagnetically tracked pointer fitted in each marker hole. US volumes of the US training model were sent from the US system to HoloLens in order to display them, showing a latency of 259±86 ms (mean±standard deviation). The Nav EVAR project tackles the problem of radiation exposure and contrast agent administration during EVAR interventions by using a multidisciplinary approach to guide the endovascular tools. Its current state presents several limitations such as the rigid alignment between preoperative data and the simulated patient. Nevertheless, the techniques shown in this study in combination with fibre Bragg gratings and optical coherence tomography are a promising approach to overcome the problems of EVAR interventions.


An intraindividual study of the characteristics of erythema induced by bath and oral methoxsalen photochemotherapy and narrowband ultraviolet B.
We compared the characteristics of psoralen and ultraviolet A (PUVA) erythema in skin photosensitized by bath or oral methoxsalen in 20 subjects. Erythema was assessed visually and with a reflectance instrument at 24 h intervals for 7 days. In addition, narrowband ultraviolet B (TL-01 UVB) erythema was examined in 19 of these subjects at 4, 8, 12, 24, 48 and 72 h and in another nine subjects at 12, 15, 18, 21 and 24 h. Both bath and oral PUVA exhibited broad erythemal peaks beyond 72 h. For topical PUVA the lowest minimal phototoxic dose (MPD) occurred at 120 and 144 h (P = 0.01 and 0.03 compared with 72 h). Oral PUVA erythema peaked earlier at 96 h: the MPD was significantly lower at 96, 120 and 144 h compared with 72 h (P = 0.001, 0.01 and 0.02, respectively). At 120 h, bath PUVA had a significantly steeper slope compared with oral PUVA. The TL-01 UVB minimal erythema dose was significantly lower at 12 h compared with 24 h (P = 0.019). The majority of subjects were at maximal erythema at 12 h (22 of 28) and 15 h (eight of nine). Our results suggest that peak erythema for bath PUVA, oral PUVA and TL-01 UVB occurs at 120, 96 and 12-15 h, respectively.


Goal-directed decision making in prefrontal cortex: A computational framework.
Research in animal learning and behavioral neuroscience has distinguished between two forms of action control: a habit-based form, which relies on stored actio n values, and a goal-dir ected form, which forecasts and compares action outcomes based on a model of the environment. While habit-based control has been the subject of extensive computational research, the computational principles underlying goal-directed control in animals have so far received less attention. In the present paper, we advance a computational framework for goal-directed control in animals and humans. We take three empirically motivated points as founding premises: (1) Neurons in dorsolateral prefrontal cortex represent action policies, (2) Neurons in orbitofrontal cortex represent rewards, and (3) Neural computation, across domains, can be appropriately understood as performing structured probabilistic inference. On a purely computational level, the resulting account relates closely to previous work using Bayesian inference to solve Markov decision problems, but extends this work by introducing a new algorithm, which provably converges on optimal plans. On a cognitive and neuroscientific level, the theory provides a unifying framework for several different forms of goal-directed action selection, placing emphasis on a novel form, within which orbitofrontal reward representations directly drive policy selection.


Continuity, coordination, and transitions of care for patients with serious and advanced illness: a systematic review of interventions.
Continuity, coordination, and transitions of care are key to high-quality medical care for patients with serious and advanced illness. We conducted a systematic review to evaluate the impact of interventions targeting these areas in this population. We searched PubMed, CINAHL, PsycINFO, Cochrane, and DARE from 2000 through 2011. We included prospective controlled studies targeting continuity, coordination, and transitions for patients with advanced illness that reported patient centered outcomes. Of 13,014 citations, 23 studies met inclusion criteria. Two investigators extracted and checked data on population, interventions, methods, outcomes, and methodological quality. Four of the six studies evaluating patient satisfaction (67%) and four of the six studies evaluating caregiver satisfaction (67%) showed statistically significant improvements in these outcomes in the intervention compared to the control group. Only three of the nine studies (33%) measuring quality of life and five of the 16 (31%) measuring health care utilization showed improvement. Results were similar across different types of interventions. Many studies were limited by methodologic issues such as use of measurement tools not developed for patients with advanced disease and small sample size. Interventions and outcomes were too heterogeneous for meta-analysis. We found moderate evidence that interventions targeting continuity, coordination, and transitions in patients with advanced and serious illness improve patient and caregiver satisfaction, but low evidence for other outcomes. Further research is needed on how to target these domains for outcomes such as health care utilization.


Chemoenzymatic synthesis of GD3 oligosaccharides and other disialyl glycans containing natural and non-natural sialic acids.
In order to understand the biological importance of naturally occurring sialic acid variations on disialyl structures in nature, we developed an efficient two-step multienzyme approach for the synthesis of a series of GD3 ganglioside oligosaccharides and other disialyl glycans containing a terminal Siaalpha2-8Sia component with different natural and non-natural sialic acids. In the first step, alpha2-3- or alpha2-6-linked monosialylated oligosaccharides were obtained using a one-pot three-enzyme approach. These compounds were then used as acceptors for the alpha2-8-sialyltransferase activity of a recombinant truncated multifunctional Campylobacter jejuni sialyltransferase CstII mutant, CstIIDelta32(I53S), to produce disialyl oligosaccharides. The alpha2-8-sialyltransferase activity of CstIIDelta32(I53S) has promiscuous donor substrate specificity and can tolerate various substitutions at C-5 or C-9 of the sialic acid in CMP-sialic acid, while its acceptor substrate specificity is relatively restricted. The terminal sialic acid residues in the acceptable monosialylated oligosaccharide acceptors are restricted to Neu5Ac, Neu5Gc, KDN, and some of their C-9-modified forms but not their C-5 derivatives. The disialyl oligosaccharides obtained are valuable probes for their biological studies.


Lymphatic outflow of cerebrospinal fluid is reduced in glioma.
Glioblastoma is a malignant brain tumor with mean overall survival of less than 15 months. Blood vessel leakage and peritumoral edema lead to increased intracranial pressure and augment neurological deficits which profoundly decrease the quality of life of glioblastoma patients. It is unknown how the dynamics of cerebrospinal fluid (CSF) turnover are affected during this process. By monitoring the transport of CSF tracers to the systemic blood circulation after infusion into the cisterna magna, we demonstrate that the outflow of CSF is dramatically reduced in glioma-bearing mice. Using a combination of magnetic resonance imaging (MRI) and near-infrared (NIR) imaging, we found that the circulation of CSF tracers was hindered after cisterna magna injection with reduced signals along the exiting cranial nerves and downstream lymph nodes, which represent the major CSF outflow route in mice. Due to blockage of the normal routes of CSF bulk flow within and from the cranial cavity, CSF tracers were redirected into the spinal space. In some mice, impaired CSF clearance from the cranium was compensated by a lymphatic outflow from the sacral spine.


The Interplay Between Respiratory Microbiota and Innate Immunity in Flavor E-Cigarette Vaping Induced Lung Dysfunction.
Global usage of electronic nicotine delivery systems (ENDS) has been increasing in the last decade. ENDS are non-combustible tobacco products that heat and aerosolize a liquid containing humectants, with added flavorings and often nicotine. Though ENDS are promoted as a less harmful alternative to smoking, current evidence links their use to a wide range of deleterious health effects including acute and chronic lung damage. ENDS can elicit an inflammatory response and impair the innate immune response in the lungs. Exposure to ENDS flavorings results in abnormal activation of the lung epithelial cells and β-defensins, dysfunction of the macrophage phagocytic activity, increased levels of mucin (MUC5AC) and abnormal activation of the neutrophilic response (NETosis). ENDS menthol flavorings disrupt innate immunity and might be associated with allergies and asthma through activation of transient receptor potential ankyrin 1 (TRAP1). Recent studies have expanded our understanding of the relationship between the homeostasis of lung innate immunity and the immunomodulatory effect of the host-microbiota interaction. Alterations of the normal respiratory microbiota have been associated with chronic obstructive pulmonary disease (COPD), asthma, atopy and cystic fibrosis complications which are strongly associated with smoking and potentially with ENDS use. Little is known about the short-and long-term effects of ENDS on the respiratory microbiota, their impact on the innate immune response and their link to pulmonary health and disease. Here we review the interaction between the innate immune system and the respiratory microbiota in the pathogenesis of ENDS-induced pulmonary dysfunction and identify future areas of research.


Pituitary adenylyl cyclase-activating polypeptide is an intrinsic regulator of Treg abundance and protects against experimental autoimmune encephalomyelitis.
Pituitary adenylyl cyclase-activating polypeptide (PACAP) is a widely expressed neuropeptide originally discovered in the hypothalamus. It closely resembles vasoactive intestinal peptide (VIP), a neuropeptide well known to inhibit macrophage activity, promote Th2-type responses, and enhance regulatory T cell (Treg) production. Recent studies have shown that administration of PACAP, like VIP, can attenuate dramatically the clinical and pathological features of murine models of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis. However, specific roles (if any) of endogenous VIP and PACAP in the protection against autoimmune diseases have not been explored. Here, we subjected PACAP-deficient mice to myelin oligodendrocyte glycoprotein (MOG(35-55))-induced EAE. MOG immunization of PACAP-deficient mice triggered heightened clinical and pathological manifestations of EAE compared to wild-type mice. The increased sensitivity was accompanied by enhanced mRNA expression of proinflammatory cytokines (TNFalpha, IL-6, IFN-gamma, IL-12p35, IL-23p19, and IL-17), chemokines (MCP-1/CCL2, MIP-1alpha/CCL3, and RANTES/CCL5), and chemotactic factor receptors (CCR1, CCR2, and CCR5), but downregulation of the anti-inflammatory cytokines (IL-4, IL-10, and TGF-beta) in the spinal cord. Moreover, the abundance of CD4(+)CD25(+)FoxP3(+) Tregs in lymph nodes and levels of FoxP3 mRNA in the spinal cord were also diminished. The reduction in Tregs was associated with increased proliferation and decreased TGF-beta secretion in lymph node cultures stimulated with MOG. These results demonstrate that endogenous PACAP provides protection in EAE and identify PACAP as an intrinsic regulator of Treg abundance after inflammation.


Workplace Digital Health Is Associated with Improved Cardiovascular Risk Factors in a Frequency-Dependent Fashion: A Large Prospective Observational Cohort Study.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the US. Emerging employer-sponsored work health programs (WHP) and Digital Health Intervention (DHI) provide monitoring and guidance based on participants' health risk assessments, but with uncertain success. DHI--mobile technology including online and smartphone interventions--has previously been found to be beneficial in reducing CVD outcomes and risk factors, however its use and efficacy in a large, multisite, primary prevention cohort has not been described to date. We analyzed usage of DHI and change in intermediate markers of CVD over the course of one year in 30,974 participants of a WHP across 81 organizations in 42 states between 2011 and 2014, stratified by participation log-ins categorized as no (n = 14,173), very low (<12/yr, n = 12,260), monthly (n = 3,360), weekly (n = 651), or semi-weekly (at least twice per week). We assessed changes in weight, waist circumference, body mass index (BMI), blood pressure, lipids, and glucose at one year, as a function of participation level. We utilized a Poisson regression model to analyze variables associated with increased participation. Those with the highest level of participation were slightly, but significantly (p<0.0001), older (48.3±11.2 yrs) than non-participants (47.7±12.2 yr) and more likely to be females (63.7% vs 37.3% p<0.0001). Significant improvements in weight loss were demonstrated with every increasing level of DHI usage with the largest being in the semi-weekly group (-3.39±1.06 lbs; p = 0.0013 for difference from weekly). Regression analyses demonstrated that greater participation in the DHI (measured by log-ins) was significantly associated with older age (p<0.001), female sex (p<0.001), and Hispanic ethnicity (p<0.001). The current study demonstrates the success of DHI in a large, community cohort to modestly reduce CVD risk factors in individuals with high participation rate. Furthermore, participants previously underrepresented in WHPs (females and Hispanics) and those with an increased number of CVD risk factors including age and elevated BMI show increased adherence to DHI, supporting the use of this low-cost intervention to improve CVD health.


Social support and mental health treatment among persons with PTSD: results of a nationally representative survey.
Despite continued outreach efforts, levels of mental health care utilization for posttraumatic stress disorder (PTSD) remain low. As such, it is important to identify factors that may promote or discourage treatment engagement. This study was designed to examine the association between perceived social support and utilization of several types of PTSD services. Data came from wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions, which was administered between 2004 and 2005. PTSD was assessed via structured interview, and perceived social support was assessed via the Interpersonal Support Evaluation List-12. Participants were asked about receipt of four modalities of PTSD-specific treatment: outpatient, hospitalization, emergency department visits, and psychiatric medication prescriptions. Weighted logistic regression modeling was performed to examine associations between social support scores and the odds of receiving treatment for PTSD, and the analyses were adjusted for sociodemographic characteristics and PTSD severity. The final sample consisted of 2,811 individuals with PTSD. Social support was not associated with the odds of receiving any type of PTSD treatment. Among individuals in the general population with PTSD, perceived social support may not be related to PTSD treatment utilization. Other factors, such as sociodemographic characteristics and symptom severity, may be more important predictors of receipt of PTSD-specific treatment.


Assessment for prognosis during and after myocardial infarction. A plea for a stratified approach.
Right after the first signs and symptoms of acute myocardial infarctions the prognosis is determined by the interventions which are carried out at that time. Preservation of as much myocardial tissue is the key element. Early deobstruction and reperfusion of the myocardium at jeopardy can lead to limitation of the ultimate infarct size, improved ventricular function and a halving of the 1-year mortality. Early supportive therapy with beta-blockade and calcium antagonists may enhance this effect. Data in 533 patients randomized to either a reperfusion strategy or to conventional therapy, combined with those from the recent literature on thrombolysis and early beta-blockade, provide the basis for this point of view. Once infarction is unavoidable and in the process of completion, probably 3-4 h after onset of symptoms, only supportive therapy is recommended, which will hardly change the outcome except for interventions during clinical care such as defibrillation. In 351 other survivors of myocardial infarction the value of clinical variables, a symptom-limited bicycle stress test at discharge, radionuclide ventriculography and 24-hour ambulatory electrocardiogram was compared in predicting 1-year survival. A history of previous myocardial infarction and heart failure during the current episode proved to be the strongest clinical predictors of death. Similarly, a low ejection fraction (less than 40%) and an insufficient blood pressure rise during stress testing (less than 30 mm Hg) identified a high risk group. Stress-test-induced angina and ST depression as well as ventricular arrhythmias from 24-hour electrocardiography were less good as predictors. In these patients treatment should be individualized and may require arteriography. Patients eligible for and completing a normal bicycle stress test after myocardial infarction proved to be a low risk group, which may constitute 65% of the total, seen in tertiary referral centers and even more in community hospitals. They neither require therapy nor further investigation. A subgroup with an intermediate risk can be identified when clinical variables, stress testing and/or resting radionuclide ventriculography are abnormal. This group requires 'tailored' therapy. Therefore, after infarction recovery, we recommend a pre-discharge stress test routinely to complement the clinical evaluation, since it also provides information on physical capacity, the indication of arrhythmias and the presence of myocardial ischemia. Thus, optimal management of acute myocardial infarction requires a stratified approach, which does not require expensive testing procedures.


The practice of breast self-examination among older women.
Mammography, professional breast examination (PBE), and breast self-examination (BSE) are viewed as very important screening techniques for the early detection of breast cancer. Mammography and PBE are performed on a routine basis at healthcare facilities, while BSE can be performed in the privacy of the home. The self-care practice of monthly BSE is important for women of all ages. Older women often feel unsure about their ability to perform BSE properly, and many know very little about this self-care practice. The purpose of this research study was to explore the validity of teaching older women the practice of BSE using the method of return demonstration. The inclusion of actual practice opportunities with models into teaching sessions resulted in the older women feeling more confident about their ability to perform BSE.


Quantum state-resolved study of the four-atom reaction OH- (X1sigma+) + D2 (X1sigma(g)+, v = 0) --> HOD (X1A', v') + D- (1S).
The D+ transfer reaction between OH- (X1sigma+) and D2 was studied with crossed molecular beam experiments and quantum chemical calculations at collision energies of 89 and 68 kJ/mol. The D- product ions were observed and measured for the first time in the crossed beam experiments. The center-of-mass (c.m.) flux distributions of the D- product ions exhibit significant asymmetry, and their maxima are close to the velocity and direction of the precursor D2 beam. The data are consistent with a direct mechanism that occurs on a time scale significantly less than a rotational period of the transient complex formed by approaching reactants. The D+ transfer results primarily in the excitation of the H-O-D bending vibrational mode of the molecular product. The experimental observation is in agreement with theoretical results showing that, during the D+ transfer, the H-O-D bond angle changes significantly.


Cocultivation of Anaerobic Fungi with Rumen Bacteria Establishes an Antagonistic Relationship.
Anaerobic gut fungi (Neocallimastigomycetes) live in the digestive tract of large herbivores, where they are vastly outnumbered by bacteria. It has been suggested that anaerobic fungi challenge growth of bacteria owing to the wealth of biosynthetic genes in fungal genomes, although this relationship has not been experimentally tested. Here, we cocultivated the rumen bacteria Fibrobacter succinogenes strain UWB7 with the anaerobic gut fungi Anaeromyces robustus or Caecomyces churrovis on a range of carbon substrates and quantified the bacterial and fungal transcriptomic response. Synthetic cocultures were established for at least 24 h, as verified by active fungal and bacterial transcription. A. robustus upregulated components of its secondary metabolism in the presence of Fibrobacter succinogenes strain UWB7, including six nonribosomal peptide synthetases, one polyketide synthase-like enzyme, and five polyketide synthesis O-type methyltransferases. Both A. robustus and C. churrovis cocultures upregulated S-adenosyl-l-methionine (SAM)-dependent methyltransferases, histone methyltransferases, and an acetyltransferase. Fungal histone 3 lysine 27 trimethylation marks were more abundant in coculture, and heterochromatin protein-1 was downregulated. Together, these findings suggest that fungal chromatin remodeling occurs when bacteria are present. F. succinogenes strain UWB7 upregulated four genes in coculture encoding drug efflux pumps, which likely protect the cell against toxins. Furthermore, untargeted nonpolar metabolomics data revealed at least one novel fungal metabolite enriched in coculture, which may be a defense compound. Taken together, these data suggest that A. robustus and C. churrovis produce antimicrobials when exposed to rumen bacteria and, more broadly, that anaerobic gut fungi are a source of novel antibiotics. IMPORTANCE Anaerobic fungi are outnumbered by bacteria by 4 orders of magnitude in the herbivore rumen. Despite their numerical disadvantage, they are resilient members of the rumen microbiome. Previous studies mining the genomes of anaerobic fungi identified genes encoding enzymes to produce natural products, which are small molecules that are often antimicrobials. In this work, we cocultured the anaerobic fungus Anaeromyces robustus or Caecomyes churrovis with rumen bacteria Fibrobacter succinogenes strain UWB7 and sequenced fungal and bacterial active genes via transcriptome sequencing (RNA-seq). Consistent with production of a fungal defense compound, bacteria upregulated genes encoding drug efflux pumps, which often export toxic molecules, and fungi upregulated genes encoding biosynthetic enzymes of natural products. Furthermore, tandem mass spectrometry detected an unknown fungal metabolite enriched in the coculture. Together, these findings point to an antagonistic relationship between anaerobic fungi and rumen bacteria resulting in the production of a fungal compound with potential antimicrobial activity.


Return and other sequences of migration in the United States.
We examine repeat migration sequences in the United States especially those that entail a return, using data from the Panel Study of Income Dynamics. Our guiding hypotheses derive from the concepts of location-specific capital and imperfect information. Descriptive analysis elucidates the dynamics, tempo, and differential frequency of repeat migration among various socioeconomic groups. Results disclose difference among migrants who choose to return or move onward to a new location, or do not move again, and lend support to our analytical framework. Major findings are: (1) the propensity to return to an area varies directly with the amount of location-specific capital that is left behind and inversely with the ex-resident's length of absence, (2) which repeat migration sequence unfolds--return or onward--depends on the ex-resident's educational level and experience of unemployment.


Identification of a novel calcitonin-response element in the promoter of the human p21WAF1/CIP1 gene.
The cyclin-dependent kinase inhibitor p21/WAF1/CIP1 is induced in many cell types in response to a variety of extracellular signals and causes cell cycle arrest in both the G1 and G2/M phases of the cell cycle. We reported previously that calcitonin (CT) receptor (CTR)-mediated growth inhibition of HEK-293 cells stably transfected with the human CTR is accompanied by a rapid and sustained induction of p21 and cell cycle arrest in G2. In the present study we have shown that CT stimulates transcription from a p21 promoter-luciferase construct. Using deletion and mutation analysis of the p21 promoter we have demonstrated that transcriptional activation of p21 by CT is p53-independent and is mediated through specific activation of Sp1-binding sites in a region of the promoter between -82 and -69, relative to the transcription start site. CTR-mediated transcriptional activation of p21 was specific for the insert-negative isoform of the human CTR. Butyrate, which was shown previously to activate the same Sp1 site, synergised with CT to increase further p21 promoter activity. These results provide the first demonstration that CTR can induce gene transcription through the constitutively expressed transcription factor Sp1, and define a mechanism of cell growth suppression that may have implications for other members of the seven-transmembrane domain G protein-coupled receptor superfamily.


We don't all look the same; detailed examination of peripheral looking strategies after simulated central vision loss.
Loss of central vision can be compensated for in part by increased use of peripheral vision. For example, patients with macular degeneration or those experiencing simulated central vision loss tend to develop eccentric viewing strategies for reading or other visual tasks. The factors driving this learning are still unclear and likely involve complex changes in oculomotor strategies that may differ among people and tasks. Although to date a number of studies have examined reliance on peripheral vision after simulated central vision loss, individual differences in developing peripheral viewing strategies and the extent to which they transfer to untrained tasks have received little attention. Here, we apply a recently published method of characterizing oculomotor strategies after central vision loss to understand the time course of changes in oculomotor strategies through training in 19 healthy individuals with a gaze-contingent display obstructing the central 10° of the visual field. After 10 days of training, we found mean improvements in saccadic re-referencing (the percentage of trials in which the first saccade placed the target outside the scotoma), latency of target acquisition (time interval between target presentation and a saccade putting the target outside the scotoma), and fixation stability. These results are consistent with participants developing compensatory oculomotor strategies as a result of training. However, we also observed substantial individual differences in the formation of eye movement strategies and the extent to which they transferred to an untrained task, likely reflecting both variations in learning rates and patterns of learning. This more complete characterization of peripheral looking strategies and how they change with training may help us understand individual differences in rehabilitation after central vision loss.


Effect of soya lecithin on the enzymatic system of the white-rot fungi Anthracophyllum discolor.
The present work optimized the initial pH of the medium and the incubation temperature for ligninolytic enzymes produced by the white-rot fungus Anthracophyllum discolor. Additionally, the effect of soya lecithin on mycelial growth and the production of ligninolytic enzymes in static batch cultures were evaluated. The critical micelle concentration of soya lecithin was also studied by conductivity. The effects of the initial pH (3, 4, and 5) and incubation temperature (20, 25, and 30°C) on different enzymatic activities revealed that the optimum conditions to maximize ligninolytic activity were 26°C and pH 5.5 for laccase and manganese peroxidase (MnP) and 30°C and pH 5.5 for manganese-independent peroxidase (MiP). Under these culture conditions, the maximum enzyme production was 10.16, 484.46, and 112.50 U L(-1) for laccase, MnP, and manganese-independent peroxidase MiP, respectively. During the study of the effect of soya lecithin on A. discolor, we found that the increase in soya lecithin concentration from 0 to 10 g L(-1) caused an increase in mycelial growth. On the other hand, in the presence of soya lecithin, A. discolor produced mainly MnP, which reached a maximum concentration of 30.64 ± 4.61 U L(-1) after 25 days of incubation with 1 g L(-1) of the surfactant. The other enzymes were produced but to a lesser extent. The enzymatic activity of A. discolor was decreased when Tween 80 was used as a surfactant. The critical micelle concentration of soya lecithin calculated in our study was 0.61 g L(-1).


Conceptions of Adolescent Friendship Quality in Sport and Music Domains.
Purpose: The purposes of the present study were to (a) compare context-specific conceptions of friendship quality in youth sport and music, and (b) determine how friendship quality is related to motivational beliefs in sport and music. Method: Adolescents (N = 366; Mage = 12.9, SD = 1.0) who were involved in both organized sport and music completed measures of domain-specific friendship quality, perceived competence, enjoyment, anxiety, and motivational orientation. Results: For purpose one, a repeated-measures MANOVA revealed that (a) boys and girls rated their best sport friends higher in self-esteem enhancement and supportiveness than their best music friends, (b) boys rated their best sport friends higher in loyalty and intimacy, things in common, companionship and pleasant play, and conflict resolution than their best music friends, (c) girls rated positive friendship quality dimensions higher than boys, and (d) there were no domain or gender differences in friendship conflict. For purpose two, structural equation modeling revealed that (a) for sport, positive friendship quality dimensions were directly associated with perceived competence and indirectly associated with enjoyment, anxiety, and motivational orientation, and (b) for music, positive friendship quality and friendship conflict were related to competence motivation variables. Conclusion: Collectively, findings indicate domain differences in friendship quality and the relationship between friendship quality and motivational outcomes in sport and music. Despite some domain differences, findings demonstrate the significance of friendship quality for adolescents involved in sport and music.


Public health importance of rodents in South America.
Indigenous South American rodents are abundant, varied, and adaptable, and occupy most of the available natural habitats. Knowledge of their taxonomy and biology is generally superficial. Near human habitations the introduced Rattus and Mus are common and their contacts with man are often close. Cities in South America are expanding to keep pace with increases in the human population and hitherto virgin land is being settled or cleared for food production. Thus domestic rodents are brought into contact with indigenous species and the inevitable exchange of parasites may then produce unpredictable threats to human health. The role of both wild and domestic rodents in the transmission of certain infectious diseases, such as plague, sylvatic Venezuelan encephalitis, South American haemorrhagic fevers, murine typhus, and cutaneous leishmaniasis, is well established. The involvement of rodents in some other diseases, such as leptospirosis, American trypanosomiasis, South American hydatid disease, and vesicular stomatitis, is less well understood. In certain other infections, including bartonellosis and the South American spotted fevers, a wild rodent reservoir is inferred but not yet identified.


Tumbling of Quantum Dots: Rheo-Optics.
Linear flow dichroism is shown to be a powerful tool to characterize the hydrodynamic dimensions of extremely small nonspherical colloids in solution. Dispersions of prolate and oblate quantum dots (QDs) are employed to investigate the validity of flow dichroism as a characterization tool. Shape-anisotropic QDs are important from an application perspective, where it is necessary to have a good knowledge of their hydrodynamic dimensions to predict and control their orientation during solution processing. Flow dichroism quantifies the tumbling motion of QDs in shear flow by optical means, which provides a characteristic signature of the particle shape, hydrodynamic friction, and size distribution. The effects of particle size and shape, size polydispersity, and shear rate on the temporal evolution of the flow-induced alignment are discussed in detail on the basis of numerical solutions of the Smoluchowski equation that describes the motion for the probability of the orientation of colloids in shear flow. It is shown that the combination of flow-dichroism experiments and the theoretical approach on the basis of the Smoluchowski equation provides a means to measure hydrodynamic aspect ratios and polydispersity, which for such small particles is not feasible with standard methods similar to light scattering. Flow dichroism will be useful not only for shape-anisotropic colloidal QDs, but also for other nanoscale systems.


A profile of injury in Fiji: findings from a population-based injury surveillance system (TRIP-10).
Over 90% of injury deaths occur in low-and middle-income countries. However, the epidemiological profile of injuries in Pacific Islands has received little attention. We used a population-based-trauma registry to investigate the characteristics of all injuries in Viti Levu, Fiji. The Fiji Injury Surveillance in Hospitals (FISH) database prospectively collected data on all injury-related deaths and primary admissions to hospital (≥ 12 hours stay) in Viti Levu during 12 months commencing October 2005. The 2167 injury-related deaths and hospitalisations corresponded to an annual incidence rate of 333 per 100,000, with males accounting for twice as many cases as females. Almost 80% of injuries involved people aged less than 45 years, and 74% were deemed unintentional. There were 244 fatalities (71% died before admission) and 1994 hospitalisations corresponding to crude annual rates of 37.5 per 100,000 and 306 per 100,000 respectively. The leading cause of fatal injury was road traffic injury (29%) and the equivalent for injury admissions was falls (30%). The commonest type of injury resulting in death and admission to hospital was asphyxia and fractures respectively. Alcohol use was documented as a contributing factor in 13% of deaths and 12% of admissions. In general, indigenous Fijians had higher rates of injury admission, especially for interpersonal violence, while those of Indian ethnicity had higher rates of fatality, especially from suicide. Injury is an important public health problem that disproportionately affects young males in Fiji, with a high proportion of deaths prior to hospital presentation. This study highlights key areas requiring priority attention to reduce the burden of potentially life-threatening injuries in Fiji.


Surgery for tetralogy of Fallot - absent pulmonary valve syndrome. Technique of anterior translocation of the pulmonary artery.
Patients with absent pulmonary valve syndrome (APVS) and tetralogy of Fallot represent a particular management's challenge. The distinctive feature of APVS is the airway obstruction caused by tracheobronchial compression that results from massive dilatation of the main pulmonary artery (PA) and its first- and second-order branches. Consequential tracheomalacia and bronchomalacia determine the timing and severity of respiratory compromise, as well as the morbidity and mortality of these patients. Although several techniques have been proposed for decompression of the airways, the method of choice is still controversial. Translocation of the PA anterior to the aorta and away from the airways has the potential to reduce or eliminate bronchial compression. Overall, the intermediate-term functional outcomes using this technique have been encouraging, with zero mortality even in the youngest age group of patients and the disappearance of respiratory symptoms in the majority of them. Nevertheless, failure of the treatment could be expected in symptomatic patients in whom the pathology of the airways extends beyond the proximal PAs.


Antihyperglycemic effect of orthosiphon stamineus benth leaves extract and its bioassay-guided fractions.
Preliminary investigations were carried out to evaluate the antidiabetic effects of the leaves of O. stamineus extracted serially with solvents of increasing polarity (petroleum ether, chloroform, methanol and water); bioassay-guided purification of plant extracts using the subcutaneous glucose tolerance test (SbGTT) was also carried out. Only the chloroform extract, given at 1 g/kg body weight (b.w.), significantly reduced (P < 0.05) the blood glucose level of rats loaded subcutaneously with 150 mg/kg (b.w.) glucose. The active chloroform extract of O. stamineus was separated into five fractions using a dry flash column chromatography method. Out of the five fractions tested, only chloroform fraction 2 (Cƒ2), at the dose of 1 g/kg (b.w.) significantly inhibited (P < 0.05) blood glucose levels in SbGTT. Active Cƒ2 was split into two sub-fractions Cƒ2-A and Cƒ2-B, using a dry flash column chromatography method. The activities Cƒ2-A and Cƒ2-B were investigated using SbGTT, and the active sub-fraction was then further studied for anti-diabetic effects in a streptozotocin-induced diabetic rat model. The results clearly indicate that Cƒ2-B fraction exhibited a blood glucose lowering effect in fasted treated normal rats after glucose-loading of 150 mg/kg (b.w.). In the acute streptozotocin-induced diabetic rat model, Cƒ2-B did not exhibit a hypoglycemic effect on blood glucose levels up to 7 hours after treatment. Thus, it appears that Cƒ2-B functions similarly to metformin, which has no hypoglycemic effect but demonstrates an antihyperglycemic effect only in normogycemic models. The effect of Cƒ2-B may have no direct stimulatory effects on insulin secretion or on blood glucose levels in diabetic animal models. Verification of the active compound(s) within the active fraction (Cƒ2-B) indicated the presence of terpenoids and, flavonoids, including sinensitin.


Circulating metabolites from the choline pathway and acute coronary syndromes in a Chinese case-control study.
Accumulating evidence shows that circulating levels of trimethylamine N-oxide, which is generated from the metabolism of dietary choline, may predict cardiovascular disease among Caucasians. Acute coronary syndrome (ACS), one common presentation of cardiovascular disease, is a spectrum of signs and symptoms due to acute decreased blood flow in the coronary arteries. The relationship between the metabolites from choline pathway and ACS remains unclear. We aimed to assess the associations of circulating metabolites from the choline pathway with ACS among a Chinese population, who consume a different dietary pattern than their Western counterparts. We recruited 501 participants who were admitted to the Department of Cardiology, Zhongshan Hospital,Shanghai China between March 2017 and June 2018, including 254 ACS cases and 247 controls. Liquid chromatography-tandem mass spectrometry was used to measure circulating concentrations of metabolites in the choline pathway, including betaine, choline, trimethylamine, and trimethylamine N-oxide. A composite metabolite score using a weighted sum of these four metabolites, and the betaine/choline ratio were calculated. Multivariable logistic regressions were applied to estimate the association of metabolites with ACS, with adjustment of age, sex, body mass index, smoking index, history of diseases, and kidney function. After adjusting for traditional risk factors, per 1-standard deviation (SD) increment in choline was positively associated with the odds of ACS [odds ratio (OR), 95% confidence interval (CI), 1.77(1.44-2.18)], and the other metabolites were not associated with ACS at a statistical significance level. Compared with participants in the lowest quartile of the metabolite score, those in the highest quartile had higher odds of ACS [OR (95% CI), 3.18(1.85-5.54), p < 0.001 for trend]. Per 1-SD increment in metabolite score was positively associated with higher odds of ACS [OR (95% CI), 1.80 (1.37-2.40)], and per 1-SD increment in the betaine/choline ratio was inversely associated with the odds of ACS [OR (95% CI), 0.49 (0.39-0.60)]. Among our Chinese participants, trimethylamine N-oxide was not associated with ACS, while a composite metabolite score of metabolites from the choline pathway was associated with increased odds of ACS. The choline pathway metabolites may be related to the pathophysiology of ACS among Chinese.


Relationship between corneal topographic indices and scleral lens base curve.
To determine whether parameters of anterior corneal contour as identified by topographic analysis (steep and flat simulated keratometry, reference sphere) predict the base curve of Jupiter scleral lenses in patients with dry eye syndrome and keratoconus. We identified 33 eyes with dry eye syndrome and 21 eyes with keratoconus that were fit with Jupiter scleral lenses of standard design between June 2006 and July 2009. Steep and flat simulated keratometry powers and shape factor from axial topographic maps, reference sphere from elevation maps, and base curve of the scleral lens prescribed for each eye were recorded. Correlations between topographic indices and base curve were evaluated by using the Pearson correlation coefficient, and significances were completed by using generalized estimating equation models. In dry eye syndrome, the base curve of the final scleral lens prescribed correlated with the steep keratometric power (r = 0.70, P = 0.05, n = 33), the flat keratometric power (r = 0.71, P<0.001, n = 33), and the reference sphere (r = 0.73, P = 0.002, n = 33). In eyes with keratoconus, base curve also correlated with the steep keratometric power (r = 0.72, P<0.001, n = 19), the flat keratometric power (r = 0.70, P<0.001, n = 19), and the reference sphere (r = 0.68, P<0.001, n = 21). There were no correlations between base curve and shape factor. In eyes with normal and abnormal ocular contour, base curve of scleral lenses correlates with reference sphere and steep and flat keratometric powers, but the predictive relationship is weak (r ∼0.50). Diagnostic fitting may be the most efficient method of fitting scleral lenses at present.


Superior identification of familiar visual patterns a year after learning.
Practice improves visual performance on simple tasks in which stimuli vary along one dimension. Such learning frequently is stimulus-specific and enduring, and has been associated with plasticity in striate cortex. It is unclear if similar lasting effects occur for naturalistic patterns that vary on multiple dimensions. We measured perceptual learning in identification tasks that used faces and textures, stimuli that engage multiple stages in visual processing. Performance improved significantly across 2 consecutive days of practice. More important, the effects of practice were remarkably stable across time: Improvements were maintained approximately 1 year later, and both the relative difficulty of identifying individual stimuli and individual differences in performance were essentially constant across sessions. Finally, the effects of practice were largely stimulus-specific. Our results suggest that the characteristics of perceptual learning are similar across a spectrum of stimulus complexities.


Topoisomerases Modulate the Timing of Meiotic DNA Breakage and Chromosome Morphogenesis in Saccharomyces cerevisiae.
During meiotic prophase, concurrent transcription, recombination, and chromosome synapsis place substantial topological strain on chromosomal DNA, but the role of topoisomerases in this context remains poorly defined. Here, we analyzed the roles of topoisomerases I and II (Top1 and Top2) during meiotic prophase in Saccharomyces cerevisiae We show that both topoisomerases accumulate primarily in promoter-containing intergenic regions of actively transcribing genes, including many meiotic double-strand break (DSB) hotspots. Despite the comparable binding patterns, top1 and top2 mutations have different effects on meiotic recombination. TOP1 disruption delays DSB induction and shortens the window of DSB accumulation by an unknown mechanism. By contrast, temperature-sensitive top2-1 mutants exhibit a marked delay in meiotic chromosome remodeling and elevated DSB signals on synapsed chromosomes. The problems in chromosome remodeling were linked to altered Top2 binding patterns rather than a loss of Top2 catalytic activity, and stemmed from a defect in recruiting the chromosome remodeler Pch2/TRIP13 to synapsed chromosomes. No chromosomal defects were observed in the absence of TOP1 Our results imply independent roles for Top1 and Top2 in modulating meiotic chromosome structure and recombination.


Large variations of sucrose in constant carbohydrate diets in type II diabetes.
Several studies show that sucrose does not aggravate hyperglycemia in type II diabetes mellitus, but sucrose is still restricted in dietary recommendations. Since sucrose in high carbohydrate diets elevates fasting triglyceride levels, the effects of sucrose were evaluated in diets with fixed carbohydrate levels. Eighteen diabetic volunteers receiving no medication were given weight maintenance diets with 50 percent carbohydrate, 35 percent fat, 15 percent protein, and 120 g of sucrose for 10 days as inpatients. They were then randomly assigned diets of similar composition with either 220 g of sucrose (high sucrose diet) or less than 3 g of sucrose daily (complex carbohydrate [CHO] diet) for one additional month. There were no differences in fasting, one-, two-, and three-hour post-lunch serum glucose levels; 24-hour glycosuria; glycohemoglobin levels; fasting and postprandial serum triglyceride levels, or fasting high-density lipoprotein-cholesterol levels. Twelve patients with preexisting higher triglyceridemia had similar trends, but the postprandial triglyceride levels were lower in the high sucrose diet group of this subset (p less than 0.05 in the third week). Postprandial serum insulin levels declined in the second week on the complex CHO diet. More than 75-fold difference in sucrose intake with constant carbohydrate and fat did not affect glycemic or triglyceridemic control in type II diabetic patients. The reported high sucrose-carbohydrate-induced rise in fasting triglyceridemia was not present when a diet high in sucrose was given without changing total carbohydrate.


Patient-to-patient spread of a single strain of Corynebacterium striatum causing infections in a surgical intensive care unit.
Over a 12-month period, Corynebacterium striatum strains were isolated from clinical specimens from 14 patients admitted to a surgical intensive care unit. These isolates were identical by morphology and biotype and displayed the same antibiogram. Ten isolates were found to be the sole possible pathogen. These 10 isolates were from six patients, three of whom had signs of infection at the time of positive culture. Further typing was performed by random amplification of polymorphic DNA analysis, by which all strains were identical and were found to differ to various degrees from reference strains and from isolates found in clinical samples from other wards. In a case-control study the only independent risk factor for acquiring the strain was intubation for longer than 24 h (odds ratio, 20.09; 95% confidence interval, 2.29 to 176.09). The same strain was isolated from surfaces and from air sampled in the direct vicinity of infected patients but never from surfaces or air in other places of the ward. The strain was not isolated from the ventilators. The strain was cultured from the hands of personnel attending to infected patients, but no long-term carriers were found among members of the hospital personnel, suggesting transient carriage only. We conclude that C. striatum can cause serious nosocomial infections in surgical intensive care unit patients and may spread from patient to patient via the hands of attending personnel.


In Vitro Selection of a DNA Aptamer Targeting Degraded Protein Fragments for Biosensing.
Protein biomarkers often exist as degradation fragments in biological samples, and affinity agents derived using a purified protein may not recognize them, limiting their value for clinical diagnosis. Herein, we present a method to overcome this issue, by selecting aptamers against a degraded form of the toxin B protein, which is a marker for diagnosing toxigenic Clostridium difficile infections. This approach has led to isolation of a DNA aptamer that recognizes degraded toxin B, fresh toxin B, and toxin B spiked into human stool samples. DNA aptamers selected using intact recombinant toxin B failed to recognize degraded toxin B, which is the form present in stored stool samples. Using this new aptamer, we produced a simple paper-based analytical device for colorimetric detection of toxin B in stool samples, or in the NAP1 strain of Clostridium difficile. The combined aptamer-selection and paper-sensing strategy can expand the practical utility of DNA aptamers in clinical diagnosis.


Interleukin-10 enhances the therapeutic effectiveness of a recombinant poxvirus-based vaccine in an experimental murine tumor model.
Interleukin-10 (IL-10) has a wide range of in vivo biological activities and is a key regulatory cytokine of immune-mediated inflammation. The authors found that murine IL-10 given 12 hours after a recombinant vaccinia virus (rVV) containing the LacZ gene significantly enhanced the treatment of mice bearing 3-day-old pulmonary metastases expressing beta-galactosidase. Because IL-10 has been shown to inhibit the functions of key elements of both innate and acquired immune responses, the authors hypothesized that IL-10 might act by inhibiting clearance of the rVV, thus prolonging exposure to the experimental antigen. However, evidence that IL-10 was not acting primarily through such negative regulatory mechanisms included the following: (a) IL-10 also enhanced the therapeutic effectiveness of a recombinant fowlpox virus, which cannot replicate in mammalian cells; (b) Titers of rVV in immunized mice were lower, not higher; and (c) Although IL-10 did not alter levels of anti-vaccinia anti-bodies or natural killer cell activity, rVV-primed mice treated with IL-10 had enhanced vaccinia-specific cytotoxic T-lymphocyte activity. Thus, IL-10 enhanced the function of a recombinant poxvirus-based anti-cancer vaccine and may represent a potential adjuvant in the vaccination against human cancers using recombinant poxvirus-based vaccines.


Validation of attention-deficit-hyperactivity disorder subtypes among Taiwanese children using neuropsychological functioning.
The findings regarding the validity of attention-deficit-hyperactivity disorder (ADHD) subtypes using neuropsychological functioning have been inconsistent; and no such study has been conducted in an ethnic Chinese population. The aim of the present paper was therefore to examine the validity of attention tasks in distinguishing the ADHD-combined type (ADHD-C) from the ADHD-inattention type (ADHD-I), as compared to children without ADHD in Taiwan. Participants included 52 children with ADHD-C, 17 with ADHD-I, and 52 controls, aged 7-10 years. The clinical diagnosis of DSM-IV ADHD was further confirmed by a standardized psychiatric interview. Four attention components were examined: sensory selection, response selection, capacity/focus, and sustained attention, using the Cancellation Test, Digit Span, Trail-Making Test (TMT), Continuous Performance Test (CPT), and Circle-Tracing Test. Behaviour symptoms were rated by the parents, teachers, and investigators. Compared to children without ADHD, children with ADHD scored significantly higher in parent-reported and investigator-rated behavioural symptoms, and performed worse in the four domains of attention. Multiple comparisons indicated that children with ADHD-C had a worse performance on most tests than children with ADHD-I, except that children with ADHD-I had more off-target errors on the TMT with alphanumeric sequencing than children with ADHD-C. Attention tests can distinguish Taiwanese children with ADHD from those without ADHD, and these tests also demonstrate different profiles between the ADHD-C and ADHD-I groups. Further investigation on this topic should include the ADHD-hyperactivity-impulsivity subtype (ADHD-HI) and increase sample sizes of the children with ADHD-I and ADHD-HI.


Lateral preferences in children with intellectual deficiency of idiopathic origin.
The goal of this study was to evaluate lateral preferences in a population of children with intellectual deficiency of idiopathic origin, compared with those of typically developing (TD) children. Two groups of children with mild or moderate intellectual deficiency were observed. Handedness (using a 10-item test and Bishop's card-reaching task), eyedness and footedness were studied. The younger group consisted of sixteen 10- to 11-year olds; the older group comprised fourteen 12- to 14-year olds. A control group of fifteen TD children was matched for age with the younger group of intellectually deficient (ID) children. The results show that the occurrence of left-handedness is not higher in children with ID of unknown origin than in age-matched TD children. However, we observed a marginally reduced tendency toward right-handedness in ID than in TD children: more mixed-handers among ID than TD children; test-retest consistency of hand preference significantly lower in the 10- to 11-year-old ID children than in the age-matched TD children; greater tendency of ID children to use their nonpreferred left hand when the card was presented to the left, as compared with TD children. Left-eyedness and crossed hand-eye preference were also more frequent in ID than in age-matched TD children. No age-related difference in laterality was found in ID children. These results partially support other studies indicating that less rightward asymmetry is associated with intellectual deficiency in children.


Blue care: a systematic review of blue space interventions for health and wellbeing.
There is increasing interest in the potential use of outdoor water environments, or blue space, in the promotion of human health and wellbeing. However, therapeutic nature-based practices are currently outpacing policy and the evidence base for health or wellbeing benefits of therapeutic interventions within blue space has not been systematically assessed. This systematic review aims to address the gap in understanding the impacts of blue space within existing interventions for targeted individuals. A systematic review was carried out, searching Google Scholar, SCOPUS, PubMed, etc. through to August 2017. Only blue space interventions were included that were specifically designed and structured with a therapeutic purpose for individuals with a defined need and did not include nature-based promotion projects or casual recreation in the outdoors. Thirty-three studies met the inclusion criteria and were assessed. Overall, the studies suggest that blue care can have direct benefit for health, especially mental health and psycho-social wellbeing. The majority of papers found a positive or weak association between blue care and health and wellbeing indicators. There was also some evidence for greater social connectedness during and after interventions, but results were inconsistent and mixed across studies with very few findings for physical health. This is the first systematic review of the literature on blue care. In summary, it has been shown that mental health, especially psycho-social wellbeing, can be improved with investment in blue spaces. Key areas for future research include improving understanding of the mechanisms through which blue care can improve public health promotion.


Dietary flaxseed supplementation and experimental metastasis of melanoma cells in mice.
The present study investigated the effect of dietary supplementation of flaxseed, the richest source of lignans, on experimental metastasis of B16BL6 murine melanoma cells in C57BL/6 mice. Mice were fed a basal diet or the basal diet supplemented with 2.5, 5 or 10% flaxseed for 2 weeks before and after the intravenous injection of 0.75 x 10(5) melanoma cells. At necropsy, the number of tumors that developed in the lungs was counted, the cross-sectional area of tumors was measured and the volumes of tumors were calculated. The median number of tumors in mice fed the 2.5, 5 and 10% flaxseed-supplemented diets was 32, 54 and 63% lower than that of the controls, respectively. The addition of flaxseed to the diet also caused a dose-dependent decrease in the tumor cross-sectional area and the tumor volume. These results provide the first experimental evidence that flaxseed reduces metastasis and inhibits the growth of the metastatic secondary tumors in animals. It is concluded that flaxseed may be a useful nutritional adjuvant to prevent metastasis in cancer patients.


Bone morphogenetic protein-2 release profile modulates bone formation in phosphorylated hydrogel.
The optimal release profile of locally delivered bone morphogenetic protein-2 (BMP-2) for safe and effective clinical application is unknown. In this work, the effect of differential BMP-2 release on bone formation was investigated using a novel biomaterial oligo[(polyethylene glycol) fumarate] bis[2-(methacryloyloxy) ethyl] phosphate hydrogel (OPF-BP) containing poly(lactic-co-glycolic acid) microspheres. Three composite implants with the same biomaterial chemistry and structure but different BMP-loading methods were created: BMP-2 encapsulated in microspheres (OPF-BP-Msp), BMP-2 encapsulated in microspheres and adsorbed on the phosphorylated hydrogel (OPF-BP-Cmb), and BMP-2 adsorbed on the phosphorylated hydrogel (OPF-BP-Ads). These composites were compared with the clinically used BMP-2 carrier, Infuse® absorbable collagen sponge (ACS). Differential release profiles of bioactive BMP-2 were achieved by these composites. In a rat subcutaneous implantation model, OPF-BP-Ads and ACS generated a large BMP-2 burst release (>75%), whereas a more sustained release was seen for OPF-BP-Msp and OPF-BP-Cmb (~25% and 50% burst, respectively). OPF-BP-Ads generated significantly more bone than did all other composites, and the bone formation was 12-fold higher than that of the clinically used ACS. Overall, this study clearly shows that BMP-2 burst release generates more subcutaneous bone than do sustained release in OPF-BP-microsphere composites. Furthermore, composites should not only function as a delivery vehicle but also provide a proper framework to achieve appropriate bone formation.


Complications of colostomy closure in Zaria, Nigeria: a report of 70 cases.
The result of 70 Colostomy Closures (1979-1988) were analysed using certain factors considered to influence morbidity and mortality. 20/70 (28.5 pc) had wound infection, two patients (2.8) suffered wound dehiscence, two anastomotic leak, two intraabdominal abscesses, two small bowel obstructions, two transient large bowel obstructions (anastomotic oedema) two incisional hernias. There were two deaths, a mortality of 2.8 pc. Only the method of bowel preparation the location of colostomy and type of closure were found to significantly affect morbidity. There was an overall morbidity of 37.7 pc.


Psychological status and quality of life among primary caregivers of individuals with mental illness: a hospital based study.
This study aimed to explore the psychological status and quality of life among primary caregivers of individuals suffering from various mental illnesses including early psychosis, chronic schizophrenia, depressive disorders, anxiety disorders and dementia. A total of 350 primary caregivers with relatives seeking treatment at a tertiary psychiatric hospital were recruited for this study. Socio-demographic data was obtained and the brief version of the World Health Organisation Quality of Life instrument was used to assess caregiver's quality of life (QOL). Psychological status among primary caregivers was assessed using the General Anxiety Disorder - 7 item (GAD-7) and Patient Health Questionnaire - 9 item (PHQ-9) scales. Family Interview Schedule (FIS) was used to assess the impact of caregiving relating to social problems, interpersonal strain among family members, work related problems and financial difficulties as a result of their relative's illness. The socio-demographic and clinical correlates of QOL, PHQ-9 and GAD-7 were examined using multiple linear and logistic regression analyses. Associations between QOL domains and psychological status was examined using multiple linear regression analyses. The mean age of the primary caregivers was 49.7 years (SD = 13.2), ranging from 21 to 82 years, with a preponderance of females (67.6%), aged 50-64 years old (45.7%). Majority were of Chinese ethnicity (57.5%), had secondary level education (43.1%), were married (65.2%), and employed (64.9%). 18.3% of primary caregivers had symptoms of depression (based on PHQ-9 cut-off point of 10 or greater) while 12.7% had symptoms of anxiety (based on GAD-7 cut-off point of 10 or greater). Multiple linear and logistic regression analyses revealed that primary caregivers aged between 35-49 years and 50-64 years, unemployed, living with others, providing care to those diagnosed with dementia and who had higher FIS scores were significantly more likely to report symptoms of depression whilst those who cared for their son/daughter were less likely to be associated with symptoms of depression. Primary caregivers who had lower education, were living with others, were single or divorced/separated, were unemployed and with higher FIS scores were associated with lower QOL domain scores. Those with symptoms of depression were significantly associated with low QOL across all four domains, whilst those with symptoms of anxiety were significantly associated with low QOL in the social relationships domain. Psychological status of caregivers in the current study was associated with the various domains of QOL. In particular, caregivers' symptoms of depression were significantly associated with lower QOL across all four domains of QOL whereas symptoms of anxiety were associated with lower scores in the social relationships domain. The study suggests a need to provide caregivers with social support and psycho-education to improve the QOL as well as aid in developing healthy coping strategies.


Etched Fiber Bragg Grating Biosensor Functionalized with Aptamers for Detection of Thrombin.
A biosensor based on an etched Fiber Bragg Grating (EFBG) for thrombin detection is reported. The sensing system is based on a Fiber Bragg Grating (FBG) with a Bragg wavelength of 1550 nm, wet-etched in hydrofluoric acid (HF) for ~27 min, to achieve sensitivity to a refractive index (RI) of 17.4 nm/RIU (refractive index unit). Subsequently, in order to perform a selective detection of thrombin, the EFBG has been functionalized with silane-coupling agent 3-(aminopropyl)triethoxysilane (APTES) and a cross-linker, glutaraldehyde, for the immobilization of thrombin-binding aptamer. The biosensor has been validated for thrombin detection in concentrations ranging from 10 nM to 80 nM. The proposed sensor presents advantages with respect to other sensor configurations, based on plasmonic resonant tilted FBG or Long Period Grating (LPG), for thrombin detection. Firstly, fabricating an EFBG only requires chemical etching. Moreover, the functionalization method used in this study (silanization) allows the avoidance of complicated and expensive fabrications, such as thin film sputtering or chemical vapor deposition. Due to their characteristics, EFBG sensors are easier to multiplex and can be used in vivo. This opens new possibilities for the detection of thrombin in clinical settings.


Incidental venous thromboembolism in ambulatory cancer patients receiving chemotherapy.
While the association between cancer and symptomatic venous thromboembolism (VTE) is well established, the incidence and risk factors for incidental VTE in cancer patients remain unclear. The medical records of 1,921 consecutive cancer patients starting chemotherapy from January 2003 up to March 2009 were identified. Patients with a positive history of VTE were excluded. Pre-existing signs of VTE, kind and stage of malignancy, first and subsequent lines of chemotherapy, and all follow-up computed tomography (CT) scans were analysed. The primary outcome was incidental VTE. Overall, there were 101 (5.3%) VTE, 62 (3.2%) incidental and 39 (2.0%) symptomatic during a median of eight months (range 3-72). The incidence on CT scans was 0.58% (95%CI: 0.44-0.74). Incidental VTE included 24 pulmonary embolism, 28 deep venous thrombosis of the extremities, and 10 thromboses of the cava or splanchnic veins. Half of the incidental VTE occurred in the first 3-6 months of chemotherapy with a relatively higher incidence in gynecological and lung cancers. The presence of metastases, high leukocyte count, and platin-based chemotherapy increased the risk up to three-fold. All patients with incidental VTE regardless the location received half to full therapeutic doses of low-molecular-weight heparin for a minimum of three months. In summary, incidental VTE is a relative common finding in patients with solid tumours, especially in the first months of chemotherapy. Further research is needed to understand the natural history of incidental thrombosis in order to develop adequate management guidelines.


Overexpression of Hoxc13 in differentiating keratinocytes results in downregulation of a novel hair keratin gene cluster and alopecia.
Studying the roles of Hox genes in normal and pathological development of skin and hair requires identification of downstream target genes in genetically defined animal models. We show that transgenic mice overexpressing Hoxc13 in differentiating keratinocytes of hair follicles develop alopecia, accompanied by a progressive pathological skin condition that resembles ichthyosis. Large-scale analysis of differential gene expression in postnatal skin of these mice identified 16 previously unknown and 13 known genes as presumptive Hoxc13 targets. The majority of these targets are downregulated and belong to a subgroup of genes that encode hair-specific keratin-associated proteins (KAPs). Genomic mapping using a mouse hamster radiation hybrid panel showed these genes to reside in a novel KAP gene cluster on mouse chromosome 16 in a region of conserved linkage with human chromosome 21q22.11. Furthermore, data obtained by Hoxc13/lacZ reporter gene analysis in mice that overexpress Hoxc13 suggest negative autoregulatory feedback control of Hoxc13 expression levels, thus providing an entry point for elucidating currently unknown mechanisms that are required for regulating quantitative levels of Hox gene expression. Combined, these results provide a framework for understanding molecular mechanisms of Hoxc13 function in hair growth and development.


Protective effect of vitamin E on sperm parameters, chromatin quality, and DNA fragmentation in mice treated with different doses of ethanol: An experimental study.
Excessive consumption of alcohol induces an increase in oxidative stress production and can lead to detrimental effects on the male reproductive system. To evaluate the possible protective effects of coadministration of vitamin (vit) E on the detrimental changes in the sperm quality of mice administered ethanol. Fifty-four BALB/c mice were categorized into nine groups (n = 6/each). The control group received a basal diet while the eight experimental groups received ethanol 10%; ethanol 20%; vit. E 100 mg; vit. E 200 mg; ethanol 10% + vit. E 100 mg; ethanol 10% + vit. E 200 mg; ethanol 20% + vit. E 100 mg; ethanol 20% + vit. E 200 mg. After 35 days, the sperm parameters and sperm chromatin were assessed. The results demonstrated a significant reduction in the motility rate, normal morphology rate, viability rate, increase in abnormal DNA structure and packaging (TB staining), and DNA damage (TUNEL) in ethanol consumer groups. In addition, the findings showed a significant increase in the aforementioned parameters in ethanol- and vit. E-consumer groups compared to the ethanol-only consumer groups. The ethanol group received 20% of the most damage among the groups. The group receiving vit. E 100 mg and those receiving ethanol 10% + vit. E 200 mg gained the highest benefit among the groups. Sperm forward progressive motility, normal morphology rate, and viability decreased in the ethanol groups. Also, the rates of spermatozoa with abnormal DNA structure and DNA fragmentation increased in the ethanol groups. Our findings revealed that the coadministration of vit. E and ethanol can protect destructive changes in DNA structure and damage.


Activated dynamics in dense fluids of attractive nonspherical particles. II. Elasticity, barriers, relaxation, fragility, and self-diffusion.
In paper II of this series we apply the center-of-mass version of Nonlinear Langevin Equation theory to study how short-range attractive interactions influence the elastic shear modulus, transient localization length, activated dynamics, and kinetic arrest of a variety of nonspherical particle dense fluids (and the spherical analog) as a function of volume fraction and attraction strength. The activation barrier (roughly the natural logarithm of the dimensionless relaxation time) is predicted to be a rich function of particle shape, volume fraction, and attraction strength, and the dynamic fragility varies significantly with particle shape. At fixed volume fraction, the barrier grows in a parabolic manner with inverse temperature nondimensionalized by an onset value, analogous to what has been established for thermal glass-forming liquids. Kinetic arrest boundaries lie at significantly higher volume fractions and attraction strengths relative to their dynamic crossover analogs, but their particle shape dependence remains the same. A limited universality of barrier heights is found based on the concept of an effective mean-square confining force. The mean hopping time and self-diffusion constant in the attractive glass region of the nonequilibrium phase diagram is predicted to vary nonmonotonically with attraction strength or inverse temperature, qualitatively consistent with recent computer simulations and colloid experiments.


The role of the health care professional in bicycle safety.
Learning to ride a bicycle and enjoying the pleasures of cycling are synonymous with childhood; unfortunately, cycling does not come without risk of serious injury. Children under 15 years old account for the majority of cycling time in the United States, and on average, 1 child dies every day from a bicycle-related injury. Health care professionals can play an important role in making cycling a safe activity by encouraging and advocating for safe bicycling practices. Specific areas for physicians and health care professionals to emphasize involve the cyclist, environmental factors, and equipment factors. Helmet use by cyclists, avoidance of risk-taking, safe cycling road behavior, and proper cycling equipment fit and usage are all areas in which health care professionals can instruct families during office visits. The physician and the health care community can also be advocates for mandatory helmet legislation in order to achieve higher helmet usage rates and decreased cycling injuries. The health care professional's role in bicycle safety is an important component in building a foundation for safe cycling.


Immunological characterization and therapeutic activity of an altered-peptide ligand, NBI-6024, based on the immunodominant type 1 diabetes autoantigen insulin B-chain (9-23) peptide.
The nonobese diabetic (NOD) mouse is a good model for human type 1 diabetes, which is characterized by autoreactive T-cell-mediated destruction of insulin-producing islet beta-cells of the pancreas. The 9-23 amino acid region of the insulin B-chain [B((9-23))] is an immunodominant T-cell target antigen in the NOD mouse that plays a critical role in the disease process. By testing a series of B((9-23)) peptide analogs with single or double alanine substitutions, we identified a set of altered peptide ligands (APLs) capable of inhibiting B((9-23))-induced proliferative responses of NOD pathogenic T-cell clones. These APLs were unable to induce proliferation of these clones. However, vaccinations with the APLs induced strong cellular responses, as measured by in vitro lymphocyte proliferation and Th2 cytokine production (i.e., interleukin [IL]-4 and IL-10, but not gamma-interferon [IFN-gamma]). These responses were cross-reactive with the native antigen, B((9-23)), suggesting that the APL-induced Th2 responses may provide protection by controlling endogenous B((9-23))-specific Th1 (i.e., IFN-gamma-producing) pathogenic responses. One of these APLs that contained alanine substitutions at residues 16 and 19 (16Y-->A, 19C-->A; NBI-6024) was further characterized for its therapeutic activity because it consistently induced T-cell responses (e.g., T-cell lines and clones) that were of the Th2 type and that were cross-reactive with B((9-23)). Subcutaneous injections of NBI-6024 to NOD mice administered either before or after the onset of disease substantially delayed the onset and reduced the incidence of diabetes. This study is the first to report therapeutic activity of an APL derived from an islet beta-cell-specific antigen in type 1 diabetes.


Influence of exercise intensity in older persons with unchanged habitual nutritional intake: skeletal muscle and endocrine adaptations.
Long-term adherence to training programmes is difficult to attain. Yet, the benefits of exercise to general health and well-being are undeniable. Any measure to demonstrate the minimum required exercise for maximal benefit to a person is a promising avenue towards increasing the uptake and adherence to physical activity for the general public. The purpose of this study was to compare the effects of two different intensities of resistance training in healthy older adults. We hypothesised that compared to high-intensity resistance exercise, relatively low training intensity could also improve in vivo markers of healthy physiologic and endocrine functions in previously sedentary older individuals. Thirty (out of a possible 34 recruited) older adults were randomly assigned to low (LowR, i.e. approximately 40% one repetition maximum (1RM)) versus high-resistance training (HighR, i.e. approximately 80% 1RM) for 12 weeks. Neither intervention significantly impacted upon body composition markers including: body mass index (BMI), waist/hip ratio and bioelectric impedance. Muscle strength data showed an advantage for the HighR protocol with 51 +/- 4% and 22.4 +/- 10.2% (P < 0.05) improvements in 1RM strength and bilateral knee extension torque, respectively, compared with 17 +/- 1% and 10.3 +/- 4.7% (P < 0.05) increments in 1RM strength and bilateral torque in the LowR group. Unilateral torque did not change significantly in either group. Quadriceps muscle thickness data also showed a significantly greater benefit of the HighR protocol (5.8 +/- 2.6% increase) compared with the LowR protocol (no change). Functional ability tests, including Get-up-and-go (GUG), Standing from lying and the 6-min walk, showed changes of -11.6 +/- 4.8%, -15.6% and 8.5 +/- 1.7% (P < 0.05), respectively, in HighR compared with only one significant improvement in the LowR, namely a -10.8 +/- 3% (P < 0.05) improvement in the GUG test. Overnight fasting serum levels of IGFBP-3 increased, NPY decreased and TNF-alpha decreased significantly in the LowR group. Serum levels of glucose increased and NPY decreased significantly in HighR. Circulating levels of I, IL-6 and IGF-1 did not change with either intervention. In vivo physiologic changes show functional advantages for older persons carrying out high-resistance training. At the endocrine level, such an advantage is not clear. In fact, in terms of changes in sera levels of fasting glucose, IGFBP-3 and TNF-alpha, there appears to be an advantage to carrying out the lower intensity exercises for the aged populations where endocrine adaptations are key.


Central domain of a potyvirus VPg is involved in the interaction with the host translation initiation factor eIF4E and the viral protein HcPro.
Using recombinant proteins produced in bacteria or in infected plants, interactions between the VPg and HcPro of Lettuce mosaic potyvirus (LMV) and between LMV VPg and the lettuce translation initiation factor 4E, the cap-binding protein (eIF4E), were demonstrated in vitro. Interaction with eIF4E and HcPro both involved the same VPg central domain. The structure of this domain in the VPg context was predicted to include an amphiphilic alpha-helix, with the amino acids related to biological functions in various potyviruses exposed at the hydrophilic side.


Transforming growth factor beta in bovine placentas.
Transforming growth factor beta s (TGF beta) are a family of multifunctional growth factors that are important embryonic morphogens. Because TGF beta s may regulate the development of epitheliochorial placentas, we investigated the location, expression, secretion, and effects of TGF beta s in bovine placentomes and cell cultures derived from chorionic and endometrial epithelia. Placentomes from early second-trimester pregnancies were examined by immunohistochemistry for TGF beta 1, TGF beta 2, and TGF beta 3, and for TGF beta expression in Northern slot-blots. Effects of TGF beta s were assessed in trophoblastic and endometrial epithelial cell lines by DNA synthesis assays. Secretion of TGF beta s by trophoblastic and endometrial epithelial cells was determined using bioassays. All forms of TGF beta were immunolocalized in bovine placentomes. TGF beta mRNA was expressed in chorioallantois, caruncles, and in cultured trophoblastic and endometrial epithelial cells. Endometrial and trophoblastic cells secreted active and latent TGF beta s, and these cells had a transient proliferative response to all forms of TGF beta. These results indicate that TGF beta s are present at the fetal-maternal interface of the bovine placentome and may promote endometrial and chorionic growth.


Symptomatic malaria enhances protection from reinfection with homologous Plasmodium falciparum parasites.
A signature remains elusive of naturally-acquired immunity against Plasmodium falciparum. We identified P. falciparum in a 14-month cohort of 239 people in Kenya, genotyped at immunogenic parasite targets expressed in the pre-erythrocytic (circumsporozoite protein, CSP) and blood (apical membrane antigen 1, AMA-1) stages, and classified into epitope type based on variants in the DV10, Th2R, and Th3R epitopes in CSP and the c1L region of AMA-1. Compared to asymptomatic index infections, symptomatic malaria was associated with reduced reinfection by parasites bearing homologous CSP-Th2R (adjusted hazard ratio [aHR]:0.63; 95% CI:0.45-0.89; p = 0.008) CSP-Th3R (aHR:0.71; 95% CI:0.52-0.97; p = 0.033), and AMA-1 c1L (aHR:0.63; 95% CI:0.43-0.94; p = 0.022) epitope types. The association of symptomatic malaria with reduced hazard of homologous reinfection was strongest for rare epitope types. Symptomatic malaria provides more durable protection against reinfection with parasites bearing homologous epitope types. The phenotype represents a legible molecular epidemiologic signature of naturally-acquired immunity by which to identify new antigen targets.