Evaluation of calcium ion release and change in pH on combining calcium hydroxide with different vehicles.
Intracanal medicaments have traditionally been used in endodontics to disinfect root canals between appointments. Calcium hydroxide is widely used as an intracanal medicament for disinfection and to promote periapical healing. It is stable for long periods, harmless to the body, and bactericidal in a limited area. The efficacy of calcium hydroxide as a disinfectant is dependent on the availability of the hydroxyl ions in the solution that depends on the vehicle in which the calcium hydroxide is carried. In general, three types of vehicles are used: Aqueous, viscous or oily. Some in vitro studies have shown that the type of vehicle has a direct relationship with the concentration and the velocity of ionic liberation as well as with the antibacterial action when the paste is carried into a contaminated area. To evaluate the calcium ion release and measure the change in pH of the environment that occurred when calcium hydroxide was combined with different vehicles (distilled water, propylene glycol, calcium hydroxide containing gutta-percha points and chitosan) over different time periods. Forty single rooted mandibular first premolar teeth were decoronated for this study. Working length was established and the root canals were enlarged and irrigation accomplished with 2 ml of NaOCl solution after every file. The teeth were then randomly divided into four groups. The canals were then packed with different preparations of calcium hydroxide using the following vehicles-distilled water, propylene glycol, gutta-percha points and chitosan. Calcium ion release in different groups was analyzed using an ultraviolet spectrophotometer at 220 nm. The change in pH of was determined using a pH meter. Results were statistically evaluated using one-way ANOVA test. For calcium ion release, Group 2 showed cumulative drug release of 81.97% at the end of 15 days, whereas Group 1, 3 and 4 showed a release of 99.53, 17.98, 74.93% respectively with a significant difference among all groups. Group 1 reached the highest Ca(2+) level (39.79%) at the end of 1 day but showed almost complete release of calcium hydroxide at the end of 15 days. Group 3 showed least calcium ion release (17.98%) at 15 days. Group 4 showed a sustained release of Ca(+2) ions from 74% at 15 days to 95% at the end of 30 days. After the 1(st) h; Group 1 showed the highest pH level (11.8). However, pH reduced to 7.8 at the end of 30 days in this group. Group 2 showed the highest pH value (10.35), followed by Group 4 (10.32) after 30 days. Chitosan can be used as a promising vehicle for calcium hydroxide to maintain an alkaline pH and to allow sustained release of calcium ions in the root canal system.


Social status in pairs of male squirrel monkeys determines the behavioral response to central oxytocin administration.
Oxytocin, when administered centrally, has been associated with the modulation of various social initiatives including maternal and sexual behaviors. The nature of these effects depends on gonadal hormone status. In the present experiments, we investigated the effects of centrally administered oxytocin on the behavior of pair-housed male squirrel monkeys during interactions with a familiar female monkey. Pairs of male squirrel monkeys established reliable and persistent dominance relationships with dominant males showing increased sexual and aggressive behavior as well as higher plasma concentrations of testosterone. Oxytocin (0.1, 1.0 micrograms) increased the sexual and aggressive behavior of dominant monkeys without affecting these measures in the subordinate monkeys. In contrast to these effects in the dominant monkeys, oxytocin increased associative and marking behaviors only in subordinate monkeys. Central administration of the oxytocin receptor antagonis d(CH2)5 [Tyr(Me)2, Thr4,Tyr-NH2(9)] OVT (OTA; 0.05 microgram) had no intrinsic effect on behavior but blocked the effects of exogenous oxytocin. To investigate further the specificity of oxytocin's effects on social behavior, we administered the structurally related peptide arginine vasopressin under identical conditions. Vasopressin (0.5, 5.0 micrograms) decreased social behaviors and increased motor activity in both dominant and subordinate monkeys. Previous studies in rodents have demonstrated that oxytocin receptors are induced by gonadal steroids in a regionally specific fashion. The status-related behavioral effects of oxytocin in the squirrel monkey may reflect differences in brain oxytocin receptor density associated with the higher concentrations of testosterone in the dominant animal. Alternatively, the status-related effects may depend on the conditioned behavioral differences associated with social organization.


Origins of ultralow thermal conductivity in bulk [6,6]-phenyl-C61-butyric acid methyl ester (PCBM).
Bulk PCBM has exceptionally low thermal conductivity, 0.07 W m(-1) K(-1) at room temperature. We show that its ultralow thermal conductivity is an intrinsic property. Based on results for thermal conductivity and heat capacity measurements down to <2 K, along with Raman spectroscopy and dilatometry, a new model for minimum thermal conductivity was developed. In the model the thermal energy is transferred between entities of phonons oscillating in a range of frequencies, and limited by the atomic density and the phonon mean speed. The model accurately represents the low thermal conductivity for both PCBM and C60/C70.


A new hybrid method for image approximation using the easy path wavelet transform.
The easy path wavelet transform (EPWT) has recently been proposed by one of the authors as a tool for sparse representations of bivariate functions from discrete data, in particular from image data. The EPWT is a locally adaptive wavelet transform. It works along pathways through the array of function values and exploits the local correlations of the given data in a simple appropriate manner. However, the EPWT suffers from its adaptivity costs that arise from the storage of path vectors. In this paper, we propose a new hybrid method for image approximation that exploits the advantages of the usual tensor product wavelet transform for the representation of smooth images and uses the EPWT for an efficient representation of edges and texture. Numerical results show the efficiency of this procedure.


A cost-benefit analysis of a pellet boiler with electrostatic precipitator versus conventional biomass technology: A case study of an institutional boiler in Syracuse, New York.
Biomass facilities have received increasing attention as a strategy to increase the use of renewable fuels and decrease greenhouse gas emissions from the electric generation and heating sectors, but these facilities can potentially increase local air pollution and associated health effects. Comparing the economic costs and public health benefits of alternative biomass fuel, heating technology, and pollution control technology options provides decision-makers with the necessary information to make optimal choices in a given location. For a case study of a combined heat and power biomass facility in Syracuse, New York, we used stack testing to estimate emissions of fine particulate matter (PM2.5) for both the deployed technology (staged combustion pellet boiler with an electrostatic precipitator) and a conventional alternative (wood chip stoker boiler with a multicyclone). We used the atmospheric dispersion model AERMOD to calculate the contribution of either fuel-technology configuration to ambient primary PM2.5 in a 10km×10km region surrounding the facility, and we quantified the incremental contribution to population mortality and morbidity. We assigned economic values to health outcomes and compared the health benefits of the lower-emitting technology with the incremental costs. In total, the incremental annualized cost of the lower-emitting pellet boiler was $190,000 greater, driven by a greater cost of the pellet fuel and pollution control technology, offset in part by reduced fuel storage costs. PM2.5 emissions were a factor of 23 lower with the pellet boiler with electrostatic precipitator, with corresponding differences in contributions to ambient primary PM2.5 concentrations. The monetary value of the public health benefits of selecting the pellet-fired boiler technology with electrostatic precipitator was $1.7 million annually, greatly exceeding the differential costs even when accounting for uncertainties. Our analyses also showed complex spatial patterns of health benefits given non-uniform age distributions and air pollution levels. The incremental investment in a lower-emitting staged combustion pellet boiler with an electrostatic precipitator was well justified by the population health improvements over the conventional wood chip technology with a multicyclone, even given the focus on only primary PM2.5 within a small spatial domain. Our analytical framework could be generalized to other settings to inform optimal strategies for proposed new facilities or populations.


[Is a second reform of primary health care in Spain necessary?].
Created in 1986, the Spanish National Health System adopted Primary Health Care (PHC) as one of its building blocks. Since the beginning, the Spanish PHC model has been the subject of both praise and criticism. Nowadays, a crisis in public policy funding--including health funding policies--is resurrecting old debates and raising new ones. This paper analyzes the data available about the degree of acceptance of PHC from the perspective of Spanish citizens as well as data about the debate produced in the last five years by politicians, patients and health workers. At the end of the paper the authors seek to draw some conclusions based on the commonly acknowledged strengths and weakness of the PHC model, which decision-makers ought to take into consideration in order to avoid mistakes caused by improvised decisions elicited by the requirements of the moment.


Profiling changes in cortical astroglial cells following chronic stress.
Recent studies have suggested that cortical astroglia play an important role in depressive-like behaviors. Potential astroglial contributions have been proposed based on their known neuroplastic functions, such as glutamate recycling and synaptic plasticity. However, the specific mechanisms by which astroglial cells may contribute or protect against a depressive phenotype remain unknown. To delineate astroglial changes that accompany depressive-like behavior, we used astroglial-specific bacTRAP mice exposed to chronic variable stress (CVS) and profiled the astroglial translatome using translating ribosome affinity purification (TRAP) in conjunction with RNAseq. As expected, CVS significantly increased anxiety- and depressive-like behaviors and corticosterone levels and decreased GFAP expression in astroglia, although this did not reflect a change in the total number of astroglial cells. TRAPseq results showed that CVS decreased genes associated with astroglial plasticity: RhoGTPases, growth factor signaling, and transcription regulation, and increased genes associated with the formation of extracellular matrices such as perineuronal nets (PNNs). PNNs inhibit neuroplasticity and astroglia contribute to the formation, organization, and maintenance of PNNs. To validate our TRAPseq findings, we showed an increase in PNNs following CVS. Degradation of PNNs in the prefrontal cortex of mice exposed to CVS reversed the CVS-induced behavioral phenotype in the forced swim test. These data lend further support to the neuroplasticity hypothesis of depressive behaviors and, in particular, extend this hypothesis beyond neuronal plasticity to include an overall decrease in genes associated with cortical astroglial plasticity following CVS. Further studies will be needed to assess the antidepressant potential of directly targeting astroglial cell function in models of depression.


Sequence, distribution and chromosomal context of class I and class II pilin genes of Neisseria meningitidis identified in whole genome sequences.
Neisseria meningitidis expresses type four pili (Tfp) which are important for colonisation and virulence. Tfp have been considered as one of the most variable structures on the bacterial surface due to high frequency gene conversion, resulting in amino acid sequence variation of the major pilin subunit (PilE). Meningococci express either a class I or a class II pilE gene and recent work has indicated that class II pilins do not undergo antigenic variation, as class II pilE genes encode conserved pilin subunits. The purpose of this work was to use whole genome sequences to further investigate the frequency and variability of the class II pilE genes in meningococcal isolate collections. We analysed over 600 publically available whole genome sequences of N. meningitidis isolates to determine the sequence and genomic organization of pilE. We confirmed that meningococcal strains belonging to a limited number of clonal complexes (ccs, namely cc1, cc5, cc8, cc11 and cc174) harbour a class II pilE gene which is conserved in terms of sequence and chromosomal context. We also identified pilS cassettes in all isolates with class II pilE, however, our analysis indicates that these do not serve as donor sequences for pilE/pilS recombination. Furthermore, our work reveals that the class II pilE locus lacks the DNA sequence motifs that enable (G4) or enhance (Sma/Cla repeat) pilin antigenic variation. Finally, through analysis of pilin genes in commensal Neisseria species we found that meningococcal class II pilE genes are closely related to pilE from Neisseria lactamica and Neisseria polysaccharea, suggesting horizontal transfer among these species. Class II pilins can be defined by their amino acid sequence and genomic context and are present in meningococcal isolates which have persisted and spread globally. The absence of G4 and Sma/Cla sequences adjacent to the class II pilE genes is consistent with the lack of pilin subunit variation in these isolates, although horizontal transfer may generate class II pilin diversity. This study supports the suggestion that high frequency antigenic variation of pilin is not universal in pathogenic Neisseria.


Phosphodiesterase 4 inhibition affects both the direct and indirect pathway: an electrophysiological study examining the tri-phasic response in the substantia nigra pars reticulata.
Fronto-striatal circuits constitute the neurobiological basis of many neuropsychiatric disorders. Part of the intracellular signaling within these circuits, including its dopaminergic modulation, is regulated by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling cascade. Based on the overall expression in human fronto-striatal circuitry, we tested the effects of a cAMP selective phosphodiesterase 4 (PDE4) inhibitor on the tri-phasic response in the dorsomedial substantia nigra pars reticulata (SNr) upon stimulation of the infralimbic cortex in rats. Our results show for the first time that stimulation of the cognitive infralimbic cortex leads to a tri-phasic response in SNr neurons. In addition and in line with previous biochemical and behavioral studies, PDE4 inhibition by roflumilast affects the direct pathway as well as the indirect pathway of which the latter appears more sensitive than the former.


Death rates in HIV-positive antiretroviral-naive patients with CD4 count greater than 350 cells per microL in Europe and North America: a pooled cohort observational study.
Whether people living with HIV who have not received antiretroviral therapy (ART) and have high CD4 cell counts have higher mortality than the general population is unknown. We aimed to examine this by analysis of pooled data from industrialised countries. We merged data on demographics, CD4 cell counts, viral-load measurements, hepatitis C co-infection status, smoking status, date of death, and whether death was AIDS-related or not from 23 European and North American cohorts. We calculated standardised mortality ratios (SMRs) standardised by age, sex, and year, stratifying by risk group. Data were included for patients aged 20-59 years who had at least one CD4 count greater than 350 cells per microL while ART naive. All pre-ART CD4 counts greater than 350 cells per microL from January, 1990, to December, 2004, were included. We investigated mortality for four risk groups--men who have sex with men, heterosexual people, injecting drug users, and those at other or unknown risk. The association between CD4 cell count and death rate was investigated by use of Poisson regression methods. Data were analysed for 40,830 patients contributing 80,682 person-years of follow-up. Of 419 deaths, 401 were used in the SMR analysis: 100 men who have sex with men (SMR 1.30, 95% CI 1.06-1.58); 68 heterosexual people (2.94, 2.28-3.73); 203 injecting drug users (9.37, 8.13-10.75); and 30 in the other or unknown risk category (4.57, 3.09-6.53). Compared with CD4 counts of 350-499 cells per microL, death rate was lower in patients with counts of 500-699 cells per microL (adjusted rate ratio 0.77, 95% CI 0.61-0.95) and counts of 700 cells per microL (0.66, 0.52-0.85). In HIV-infected ART-naive patients with high CD4 cell counts, death rates were raised compared with the general population. In men who have sex with men this was modest, suggesting that a substantial proportion of the increased risk in other groups is due to confounding by other factors. Even though the increased risk is small, new studies of potential benefits of ART in this group are merited. European Commission, FP6. European AIDS Treatment Network (NEAT). Project number LSHP-CT-2006-037570.


Molecular structure of poly(methyl methacrylate) surface. I. Combination of interface-sensitive infrared-visible sum frequency generation, molecular dynamics simulations, and ab initio calculations.
The chemical composition and molecular structure of polymeric surfaces are important in understanding wetting, adhesion, and friction. Here, we combine interface-sensitive sum frequency generation spectroscopy (SFG), all-atom molecular dynamics (MD) simulations, and ab initio calculations to understand the composition and the orientation of chemical groups on poly(methyl methacrylate) (PMMA) surface as a function of tacticity and temperature. The SFG spectral features for isotactic and syndiotactic PMMA surfaces are similar, and the dominant peak in the spectra corresponds to the ester-methyl groups. The SFG spectra for solid and melt states are very similar for both syndiotactic and isotactic PMMA. In comparison, the MD simulation results show that both the ester-methyl and the α-methyl groups of syndiotactic-PMMA are ordered and tilted toward the surface normal. For the isotactic-PMMA, the α-methyl groups are less ordered compared to their ester-methyl groups. The backbone methylene groups have a broad angular distribution and are disordered, independent of tacticity and temperature. We have compared the SFG results with theoretical spectra calculated using MD simulations and ab initio calculations. Our analysis shows that the weaker intensity of α-methyl groups in SFG spectra is due to a combination of smaller molecular hyperpolarizability, lower ordering, and lower surface number density. This work highlights the importance of combining SFG spectroscopy with MD simulations and ab initio calculations in understanding polymer surfaces.


Alcohol consumption and risk of colorectal cancer: the Findrink study.
We investigated the association between alcohol consumption and colorectal cancer because previous studies have yielded conflicting results. As part of the Findrink study, data from the Kuopio Ischaemic Heart Disease (KIHD) Risk Factor Study were analysed. The KIHD study is a cohort of 2,682 men from Eastern Finland with no history of cancer at baseline. The men were grouped into five groups according to their weekly alcohol intake in grams. Association between alcohol and colorectal cancer was examined using Cox proportional hazard models. There were 59 cases of colorectal cancer during an average follow up of 16.7 years. Men within the highest quintile of alcohol consumption had a median weekly alcohol intake of 198.8 g. Age and examination year adjusted risk ratio of colorectal cancer among men within the highest quintile of alcohol consumption was 4.4 (95% CI: 1.6-11.9, P-value = 0.004). After adjusting for potential confounders, such as vegetable consumption, fibre intake, smoking, family history of cancer, socio-economic status, leisure time physical activity, men with the highest amount of alcohol consumption still had a 3.5-fold (95% CI: 1.2-9.9, P-value = 0.021) increased risk of colorectal cancer. Exclusion of men diagnosed with colorectal cancer during the first 2 years of follow up from the analyses did not alter the risk increase. In conclusion, this study gives further evidence of a positive association between alcohol consumption and the risk of colorectal cancer.


Long-term Expectations of Vagus Nerve Stimulation: A Look at Battery Replacement and Revision Surgery.
Vagus nerve stimulation (VNS) is an established surgical treatment for medically intractable epilepsy with more than 75 000 devices implanted worldwide. While there are many reports documenting efficacy, complications, and clinical use, there are very few reports concerning VNS battery replacement and revision surgeries. To review our experience with VNS battery replacement and revision surgery. We retrospectively reviewed 1144 consecutive VNS procedures performed by a single surgeon between 1998 and 2012. Six hundred forty-four of those procedures were the initial placement of the VNS device. These patients were then followed to determine when a battery change occurred and what type of revision or removal was necessary. In the study, 46% of patients required at least 1 or more type of battery replacement or revision surgery. The most common types of surgery were for generator battery depletion (27%), poor efficacy (9%), and lead malfunction (8%). Only 2% of patients were noted to have an infection. VNS battery replacement, revisions, and removals account for almost one-half of all VNS procedures. Our findings suggest important long-term expectations for VNS including expected complications, battery life, and other surgical issues. Review of the literature suggests that this is the first large review of VNS revisions by a single center. Our findings are important to better characterize long-term surgical expectations of VNS therapy. A significant portion of patients undergoing VNS therapy will eventually require revision.


Operative findings after percutaneous pulmonary balloon dilatation of the right ventricular outflow tract in tetralogy of Fallot.
Since 1983 percutaneous balloon dilatation of the right ventricular outflow tract has been performed as an alternative to surgical palliation in selected cases of tetralogy of Fallot at the Royal Liverpool Children's Hospital. From 31 December 1984 to 31 December 1988, 27 of these patients underwent subsequent surgical correction. Age at operation ranged from 7 to 58 months (median 2.7 years). The mean interval between balloon dilatation and correction was 15.6 months (range 3-39 months). Two patients had a systemic pulmonary shunt operation performed before dilatation and a further five required one afterwards. Overall 20 (74%) patients had some anatomical alteration as the result of balloon dilatation, while in seven (26%) there was no discernible change in the right ventricular outflow tract. There was no consistent relation between the ratio of balloon size to pulmonary annulus diameter and the morphological findings. Balloon dilatation may obviate the need for systemic-pulmonary shunt at the expense of some structural damage, particularly to the posterior cusp. The present data suggest that dilatation does not bring about growth of the annulus to such an extent that transannular patch is no longer needed at intracardiac repair.


Genetic engineering of hematopoiesis for targeted IFN-α delivery inhibits breast cancer progression.
The immunosuppressive tumor microenvironment represents a major hurdle to cancer therapy. We developed a gene transfer strategy into hematopoietic stem cells (HSCs) to target transgene expression to tumor-infiltrating monocytes/macrophages. Using a combination of transcriptional and microRNA-mediated control, we achieved selective expression of an interferon-α (IFN-α) transgene in differentiated monocytes of human hematochimeric mice. We show that IFN-α transgene expression does not impair engraftment and long-term multilineage repopulation of NSG (NOD/LtSz-scidIL2Rγ(null)) mice by transplanted human HSCs. By providing a source of human cytokines in the mice, we improved the functional reconstitution of human myeloid, natural killer, and T cell lineages, and achieved enhanced immune-mediated clearance of transplanted human breast tumors when hematopoiesis was engineered for tumor-targeted IFN-α expression. By applying our strategy to mouse breast cancer models, we achieved inhibition of tumor progression and experimental metastases in an autologous setting, likely through enhanced generation of effector T cells and their recruitment to the neoplastic tissues. By forcing IFN-α expression in tumor-infiltrating macrophages, we blunted their innate protumoral activity and reprogrammed the tumor microenvironment toward more effective dendritic cell activation and immune effector cell cytotoxicity. Overall, our studies validate the feasibility, safety, and therapeutic potential of a new cancer gene therapy strategy, and open the way to test this approach as adjuvant therapy in advanced breast cancer patients.


Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial.
Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US. STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7-8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes [vg]/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed). From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0-5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26-100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91-100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8-44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 [67%] of 33), upper respiratory infection (11 [33%]), and increased alanine aminotransferase (nine [27%]). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study. STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit-risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline. Novartis Gene Therapies.


Probing the structural, electronic and magnetic properties of AgnSc (n = 1-16) clusters.
The structural, electronic and magnetic properties of AgnSc (n = 1-16) clusters have been studied on the basis of density functional theory and the CALYPSO structure prediction method. The optimized geometry exhibits that the growth process of Sc-doped silver clusters have a periodic structural change. The Ag atom grows around a basically invariant cluster core in each growth cycle. The Sc atom has a tendency to occupy the most highly coordinated position in the ground state. The infrared spectra, Raman spectra and photoelectron spectra of AgnSc clusters are forecasted and can be used to identify the structures of these clusters from experiments. The global maxima of the dissociation energy, the averaged binding energy and the gap of the energy level occur at n = 15 for the most stable AgnSc clusters, implying that the Ag15Sc can be perceived as a superatom. The magnetism analysis indicates that the magnetic moment of the Sc atom in AgnSc clusters decreases with the increase of the cluster. The change of the magnetic moment is proportional to the charge transfer between the Sc and Ag atoms.


Phenotypes of caregiver distress in military and veteran caregivers: Suicidal ideation associations.
The United States (US) has been at war for almost two decades, resulting in a high prevalence of injuries and illnesses in service members and veterans. Family members and friends are frequently becoming the caregivers of service members and veterans who require long-term assistance for their medical conditions. There is a significant body of research regarding the physical, emotional, and social toll of caregiving and the associated adverse health-related outcomes. Despite strong evidence of the emotional toll and associated mental health conditions in family caregivers, the literature regarding suicidal ideation among family caregivers is scarce and even less is known about suicidal ideation in military caregivers. This study sought to identify clusters of characteristics and health factors (phenotypes) associated with suicidal ideation in a sample of military caregivers using a cross-sectional, web-based survey. Measures included the context of caregiving, physical, emotional, social health, and health history of caregivers. Military caregivers in this sample (n = 458) were mostly young adults (M = 39.8, SD = 9.9), caring for complex medical conditions for five or more years. They reported high symptomology on measures of pain, depression, and stress. Many (39%) experienced interruptions in their education and 23.6% reported suicidal ideation since becoming a caregiver. General latent variable analyses revealed three distinct classes or phenotypes (low, medium, high) associated with suicidality. Individuals in the high suicidality phenotype were significantly more likely to have interrupted their education due to caregiving and live closer (within 25 miles) to a VA medical center. This study indicates that interruption of life events, loss of self, and caring for a veteran with mental health conditions/suicidality are significant predictors of suicidality in military caregivers. Future research should examine caregiver life experiences in more detail to determine the feasibility of developing effective interventions to mitigate suicide-related risk for military caregivers.


What are the Physiological Mechanisms for Post-Exercise Cold Water Immersion in the Recovery from Prolonged Endurance and Intermittent Exercise?
Intense training results in numerous physiological perturbations such as muscle damage, hyperthermia, dehydration and glycogen depletion. Insufficient/untimely restoration of these physiological alterations might result in sub-optimal performance during subsequent training sessions, while chronic imbalance between training stress and recovery might lead to overreaching or overtraining syndrome. The use of post-exercise cold water immersion (CWI) is gaining considerable popularity among athletes to minimize fatigue and accelerate post-exercise recovery. CWI, through its primary ability to decrease tissue temperature and blood flow, is purported to facilitate recovery by ameliorating hyperthermia and subsequent alterations to the central nervous system (CNS), reducing cardiovascular strain, removing accumulated muscle metabolic by-products, attenuating exercise-induced muscle damage (EIMD) and improving autonomic nervous system function. The current review aims to provide a comprehensive and detailed examination of the mechanisms underpinning acute and longer term recovery of exercise performance following post-exercise CWI. Understanding the mechanisms will aid practitioners in the application and optimisation of CWI strategies to suit specific recovery needs and consequently improve athletic performance. Much of the literature indicates that the dominant mechanism by which CWI facilitates short term recovery is via ameliorating hyperthermia and consequently CNS mediated fatigue and by reducing cardiovascular strain. In contrast, there is limited evidence to support that CWI might improve acute recovery by facilitating the removal of muscle metabolites. CWI has been shown to augment parasympathetic reactivation following exercise. While CWI-mediated parasympathetic reactivation seems detrimental to high-intensity exercise performance when performed shortly after, it has been shown to be associated with improved longer term physiological recovery and day to day training performances. The efficacy of CWI for attenuating the secondary effects of EIMD seems dependent on the mode of exercise utilised. For instance, CWI application seems to demonstrate limited recovery benefits when EIMD was induced by single-joint eccentrically biased contractions. In contrast, CWI seems more effective in ameliorating effects of EIMD induced by whole body prolonged endurance/intermittent based exercise modalities.


SPINE: an integrated tracking database and data mining approach for identifying feasible targets in high-throughput structural proteomics.
High-throughput structural proteomics is expected to generate considerable amounts of data on the progress of structure determination for many proteins. For each protein this includes information about cloning, expression, purification, biophysical characterization and structure determination via NMR spectroscopy or X-ray crystallography. It will be essential to develop specifications and ontologies for standardizing this information to make it amenable to retrospective analysis. To this end we created the SPINE database and analysis system for the Northeast Structural Genomics Consortium. SPINE, which is available at bioinfo.mbb.yale.edu/nesg or nesg.org, is specifically designed to enable distributed scientific collaboration via the Internet. It was designed not just as an information repository but as an active vehicle to standardize proteomics data in a form that would enable systematic data mining. The system features an intuitive user interface for interactive retrieval and modification of expression construct data, query forms designed to track global project progress and external links to many other resources. Currently the database contains experimental data on 985 constructs, of which 740 are drawn from Methanobacterium thermoautotrophicum, 123 from Saccharomyces cerevisiae, 93 from Caenorhabditis elegans and the remainder from other organisms. We developed a comprehensive set of data mining features for each protein, including several related to experimental progress (e.g. expression level, solubility and crystallization) and 42 based on the underlying protein sequence (e.g. amino acid composition, secondary structure and occurrence of low complexity regions). We demonstrate in detail the application of a particular machine learning approach, decision trees, to the tasks of predicting a protein's solubility and propensity to crystallize based on sequence features. We are able to extract a number of key rules from our trees, in particular that soluble proteins tend to have significantly more acidic residues and fewer hydrophobic stretches than insoluble ones. One of the characteristics of proteomics data sets, currently and in the foreseeable future, is their intermediate size ( approximately 500-5000 data points). This creates a number of issues in relation to error estimation. Initially we estimate the overall error in our trees based on standard cross-validation. However, this leaves out a significant fraction of the data in model construction and does not give error estimates on individual rules. Therefore, we present alternative methods to estimate the error in particular rules.


Fluoroscopy only for the placement of long iliac screws: A study on 14 patients.
Iliac screw placement is challenging due to the particular anatomy of the ilium. Most series have reported the use of relatively short (≤90 mm in length) screws despite a long iliac buttress, which has an average length of 129 mm in females and 141 mm in males. This study describes a series of 14 patients who underwent placement of long iliac screws (≥100 mm in length) as part of a spinopelvic fusion utilizing fluoroscopy alone. All patients who received at least one long iliac screw were included in this study. Placement accuracy, the average distance from the screw tip to the anterior inferior iliac spine (AIIS), neurovascular injuries, acetabulum and/or sciatic notch violations, and screw prominence were all measured. Fourteen patients received 38 iliac screws, with 31 screws being ≥100 mm in length. The accuracy rate was 87.1% (27/31) for the long iliac screws. The average shortest distance from the iliac screw tip to the AIIS was 15.5 mm for the right-sided and 17.1 mm for the left-sided ilia. There were no neurovascular injuries, acetabulum, or sciatic notch violations, and no screws loosened or fractured. Of interest, only one patient required off-set connectors to link the rods to the iliac screws. Placement of long iliac screws under intraoperative fluoroscopy only was shown to be feasible, with a high accuracy rate and few complications, in this series of patients.


Use of a single-nucleotide polymorphism genotyping system to demonstrate the unique epidemiology of methicillin-resistant Staphylococcus aureus in remote aboriginal communities.
Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a major public health problem in Australia, as in many other parts of the world. High rates of CA-MRSA skin and soft tissue infection have been reported from Aboriginal communities. We used a single-nucleotide polymorphism (SNP) genotyping typing system based on the multilocus sequence type (MLST) database to investigate the epidemiology of CA-MRSA and methicillin-sensitive S. aureus (MSSA) over a 12-month period in three remote Aboriginal communities of Northern Australia. This was supplemented by real-time PCR for Panton-Valentine leukocidin (PVL) genes, staphylococcal cassette chromosome mec (SCCmec) typing, and antimicrobial susceptibility testing. S. aureus was recovered from pyoderma lesions on 221 occasions and throat swabs on 44 occasions. The median monthly recovery rate of S. aureus from skin sores was 58% (interquartile range, 62 to 78%), and there was no seasonal variation. Twenty-three percent of isolates were CA-MRSA; the proportion was similar across the communities and did not vary over the study period. Erythromycin resistance was found in 47% of CA-MRSA and 21% of MSSA. SNP-based typing identified 14 different clonal complexes (cc); however, cc75 was predominant, accounting for 71% of CA-MRSA isolates. These were confirmed as ST75-like by using an additional SNP and MLST of selected isolates. All but one of the cc75 isolates had SSCmec type IV (one had type V), and all were PVL negative. Monthly tracking of SNP-based cc types showed a highly dynamic process. ST75-MRSA-IV appears to be unique to the region and probably evolved de novo in remote Aboriginal communities.


Performance of a new HPV and biomarker assay in the management of hrHPV positive women: Subanalysis of the ongoing multicenter TRACE clinical trial (n > 6,000) to evaluate POU4F3 methylation as a potential biomarker of cervical precancer and cancer.
The ongoing Triage and Risk Assessment of Cervical Precancer by Epigenetic Biomarker (TRACE) prospective, multicenter study aimed to provide a clinical evaluation of the CONFIDENCE™ assay, which comprises a human papillomavirus (HPV) DNA and a human epigenetic biomarker test. Between 2013 and 2015 over 6,000 women aged 18 or older were recruited in Hungary. Liquid-based cytology (LBC), high-risk HPV (hrHPV) DNA detection and single target host gene methylation test of the promoter sequence of the POU4F3 gene by quantitative methylation-specific polymerase chain reaction (PCR) were performed from the same liquid-based cytology sample. The current analysis is focused on the baseline cross-sectional clinical results of 5,384 LBC samples collected from subjects aged 25 years or older. The performance of the CONFIDENCE HPV™ test was found to be comparable to the cobas® HPV test with good agreement. When applying the CONFIDENCE Marker™ test alone in hrHPV positives, it showed significantly higher sensitivity with matching specificity compared to LBC-based triage. For CIN3+ histological endpoint in the age group of 25-65 and 30-65, the methylation test of POU4F3 achieved relative sensitivities of 1.74 (95% CI: 1.25-2.33) and 1.64 (95% CI: 1.08-2.27), respectively, after verification bias adjustment. On the basis of our findings, POU4F3 methylation as a triage test of hrHPV positives appears to be a noteworthy method. We can reasonably assume that its quantitative nature offers the potential for a more objective and discriminative risk assessment tool in the prevention and diagnostics of high-grade cervical intraepithelial neoplasia (CIN) lesions and cervical cancer.


A Decomposition Framework for Image Denoising Algorithms.
In this paper, we consider an image decomposition model that provides a novel framework for image denoising. The model computes the components of the image to be processed in a moving frame that encodes its local geometry (directions of gradients and level lines). Then, the strategy we develop is to denoise the components of the image in the moving frame in order to preserve its local geometry, which would have been more affected if processing the image directly. Experiments on a whole image database tested with several denoising methods show that this framework can provide better results than denoising the image directly, both in terms of Peak signal-to-noise ratio and Structural similarity index metrics.


The meiotic behavior of an inversion in Caenorhabditis elegans.
The rearrangement hIn1(I) was isolated as a crossover suppressor for the right end of linkage group (LG) I. By inducing genetic markers on this crossover suppressor and establishing the gene order in the homozygote, hIn1(I) was demonstrated to be the first genetically proven inversion in Caenorhabditis elegans. hIn1(I) extensively suppresses recombination in heterozygotes in the right arm of chromosome I from unc-75 to unc-54. This suppression is associated with enhancement of recombination in other regions of the chromosome. The enhancement observed maintains the normal distribution of events but does not extend to other chromosomes. The genetic distance of chromosome I in inversion heterozygotes approaches 50 map units (m.u.), approximately equal to one chiasma per meiosis. This value is maintained in hIn1(I)/szT1(I;X) heterozygotes indicating that small homologous regions can pair and recombine efficiently. hIn1(I)/hT2(I;III) heterozygotes share no uninverted homologous regions and segregate randomly, suggesting the importance of chiasma formation in proper segregation of chromosomes. The genetic distance of chromosome I in these heterozygotes is less that 1 m.u., indicating that crossing over can be suppressed along an entire chromosome. Since one of our goals was to develop an efficient balancer for the right end of LGI, the effectiveness of hIn1(I) as a balancer was tested by isolating and maintaining lethal mutations. The meiotic behaviour of hIn1(I) is consistent with other genetic and cytogenetic data suggesting the meiotic chromosomes are monocentric. Rare recombinants bearing duplications and deficiencies of chromosome I were recovered from hIn1(I) heterozygotes, leading to the proposal the inversion was paracentric.


Idiopathic unilateral hyperhidrosis with Holmes-Adie syndrome: case report.
Hyperhidrosis is a disease that is characterized by excessive sweating due to hyperactivation of eccrine sweat glands. It may be localized or generalized form. Holmes-Adie syndrome is an idiopathic disease with unilateral pupil dilatation and loss of deep tendon reflexes. We present a 37-year-old female patient diagnosed with unilateral hyperhidrosis coincident with Holmes-Adie syndrome because of this unusual presentation.


The polyglutamylated lateral chain of alpha-tubulin plays a key role in flagellar motility.
To investigate whether a specific isotype of tubulin is involved in flagellar motility, we have developed and screened a panel of monoclonal antibodies (mAb) generated against sea urchin sperm axonemal proteins. Antibodies were selected for their ability to block the motility of permeabilized sperm models. The antitubulin mAb B3 completely inhibited, at low concentrations, the flagellar motility of permeabilized sperm models from four sea urchin species. On immunoblots, B3 recognized predominantly alpha-tubulin in sea urchin sperm axonemes and equally well brain alpha- and beta-tubulins. Subtilisin cleavage of tubulin removed the B3 epitope, indicating that it was restricted to the last 13 amino acid residues of the C-terminal domain of alpha-tubulin. In enzyme-linked immunosorbant assays, B3 reacted with glutamylated alpha-tubulin peptides from sea urchin or mouse brain but did not bind to the unmodified corresponding peptide, indicating that it recognized polyglutamylated motifs in the C-terminal domain of alpha-tubulin. On the other hand, other tubulin antibodies directed against various epitopes of the C-terminal domain, with the exception of the antipolyglutamylated mAb GT335, had no effect on motility while having binding properties similar to that of B3. B3 and GT335 acted by decreasing the beating amplitude without affecting the flagellar beat frequency. B3 and GT335 were also capable of inhibiting the motility of flagella of Oxyrrhis marina, a 400,000,000 year old species of dinoflagellate, and those of human sperm models. Localization of the antigens recognized by B3 and GT335 by immunofluorescence techniques revealed their presence along the whole axoneme of sea urchin spermatozoa and flagella of O. marina, except for the distal tip and the cortical microtubule network of the dinoflagellate. Taken together, the data reported here indicate that the polyglutamylated lateral chain of alpha-tubulin plays a dynamic role in a dynein-based motility process.


Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes.
beta cells sense glucose through its metabolism and the resulting increase in ATP, which subsequently stimulates insulin secretion. Uncoupling protein-2 (UCP2) mediates mitochondrial proton leak, decreasing ATP production. In the present study, we assessed UCP2's role in regulating insulin secretion. UCP2-deficient mice had higher islet ATP levels and increased glucose-stimulated insulin secretion, establishing that UCP2 negatively regulates insulin secretion. Of pathophysiologic significance, UCP2 was markedly upregulated in islets of ob/ob mice, a model of obesity-induced diabetes. Importantly, ob/ob mice lacking UCP2 had restored first-phase insulin secretion, increased serum insulin levels, and greatly decreased levels of glycemia. These results establish UCP2 as a key component of beta cell glucose sensing, and as a critical link between obesity, beta cell dysfunction, and type 2 diabetes.


The influence of running away on the risk of female sexual assault in the subsequent year.
This study explores the sexual risk trajectories of female youths and sheds light on the long-term effects of running away. It evaluates whether running away increases the risk of sexual assault in the following year, which is after runaways return home. The sample consists of 5,387 heterosexual females between the ages of 11 and 18 years from the Longitudinal Study of Adolescent Health. Nearly one quarter (23%) of runaways report a previous sexual assault in contrast to 5% of nonrunaways. In a logistic regression model, childhood neglect increases the risk of sexual assault between Waves 1 and 2 by nearly two times. Poor mental health is statistically significant. Alcohol use doubles the odds of sexual assault. The risk of sexual assault is approximately three-fold for girls with a history of sexual onset and sexual touching in a romantic relationship. Running away increases the risk by nearly two and a half times. There is evidence that alcohol use and sexual onset partially mediates the relationship between running away and sexual assault.


Myelodysplastic syndromes arising in patients with germline TP53 mutation and Li-Fraumeni syndrome.
Li-Fraumeni syndrome (LFS), characterized by predisposition to early onset of a variety of malignancies, is usually associated with germline mutation of the tumor-suppressor gene, TP53. Mutation carriers are at increased risk of multiple primary tumors, many of which arise in previous radiation-therapy sites. In patients with LFS, acute myeloid leukemia is uncommon and myelodysplastic syndrome (MDS) is rare. To evaluate the morphologic, cytogenetic, and molecular diagnostic findings of 3 unique cases of MDS arising in patients with germline TP53 mutation, 2 with classic LFS. We searched the Li-Fraumeni Syndrome Registry in the Department of Genetics at the University of Texas M. D. Anderson Cancer Center (Houston, Texas) and identified 3 patients with documented germline TP53 mutations or LFS who had developed MDS during a period of 6 years (2000-2005). The clinical, cytogenetic, and molecular diagnostic data and bone marrow aspirate smears and biopsies on all patients were reviewed. Immunohistochemical staining with antibody to p53 was also performed. Two patients met the criteria for classic LFS; one had no history of malignancy in first-degree relatives. The MDS followed chemotherapy and radiation therapy and progressed to acute myeloid leukemia in 2 patients. Cytogenetic analysis demonstrated chromosome 5 abnormalities in a complex karyotype in all cases. Two patients died, one of acute myeloid leukemia and one with glioblastoma multiforme, MDS, and persistent pancytopenia. Patients with LFS may develop MDS, which is most likely therapy-related and is associated with cytogenetic markers of poor prognosis.


[Telomere length of peripheral lymphocytes in patients with immuno-related pancytopenia].
To investigate the changes of relative telomere length (RTL) of peripheral blood (PB) CD3⁺, CD3⁺CD4⁺, CD3⁺CD8⁺T lymphocytes, CD19⁺B lymphocytes and bone marrow (BM) CD34⁺ cells and its association with disease severity in untreated patients with immuno-related pancytopenia (IRP). The PB CD3⁺ , CD3⁺ CD4⁺ , CD3⁺ CD8⁺ T lymphocytes, CD19⁺ B lymphocytes, and BM CD34⁺ cells were purified by magnetic activated cell sorting (MACS), and RTL were measured with flow-fluorescence in situ hybridization (FLOW-FISH). The RTL of CD3⁺, CD3⁺CD4⁺ , and CD3⁺CD8⁺T lymphocytes in untreated IRP patients were (27.754 ± 16.323)%, (7.526 ± 3.745)% and (25.854 ± 14.789)%, respectivly, which were significantly shorter than those in healthy-controls (54.555 ± 19.782)%, (12.096 ± 2.805)%, and (38.367 ± 4.626)% (P<0.05). The RTL of CD19⁺ lymphocytes in untreated IRP patients was (22.136 ± 16.142)%, which was significantly shorter than that in healthy controls (42.846 ± 16.353)% (P<0.01). There was no significant difference of BM CD34⁺ cells RTL between the untreated IRP patients (22.528 ± 21.601)% and the healthy controls (23.936 ± 19.822)% (P>0.05). There were significantly positive correlations between the RTL of B lymphocytes and the count of white blood cell (r=0.706, P=0.015). There were negative correlations between RTL of B lymphocytes and the clinical symptoms (r=-0.613, P=0.045) and positive correlations with therapeutic effect (r=0.775, P=0.005). The shorter RTL of CD3⁺, CD3⁺CD4⁺, CD3⁺CD8⁺, CD19⁺ lymphocytes, and the normal RTL of BM CD34⁺ cells in untreated IRP patients were identified, which might imply that IRP is a type of acquired autoimmune diseases.


Prevalence and Outcomes of Amyloid Positivity Among Persons Without Dementia in a Longitudinal, Population-Based Setting.
Brain amyloid deposition is a marker of Alzheimer disease (AD) pathology. The population-based prevalence and outcomes of amyloid positivity in a population without dementia are important for understanding the trajectory of amyloid positivity to clinically significant outcomes and for designing AD prevention trials. To determine prevalence and outcomes of amyloid positivity in a population without dementia. In the prospective, population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota, participants without dementia were randomly selected from the county population and were clinically and cognitively evaluated at baseline and every 15 months from August 1, 2008, to September 18, 2018. They were also invited to undergo carbon11-Pittburgh compound B positron emission tomography (PET) imaging. Amyloid positivity (defined as a standardized uptake value ratio >1.42 on PET). Prevalence of amyloid positivity in the Olmsted County population without dementia and risk of progression from no cognitive impairment (ie, normal cognition for age) to incident amnestic MCI (aMCI) and from MCI or aMCI to incident AD dementia. Of 3894 participants, 1671 underwent PET imaging and were included in the study; 2198 did not undergo imaging, and 25 were excluded for other reasons. The mean (SD) age of participants was 71.3 (9.8) years; 892 (53.4%) were men, and 179 (10.7%) had prevalent MCI. The prevalence of amyloid positivity without cognitive impairment in the population without dementia increased from 2.7% (95% CI, 0.5% to 4.9%) in persons aged 50 to 59 years to 41.3% (95% CI, 33.4% to 49.2%) in those aged 80 to 89 years at baseline. Prevalence of amyloid-positive MCI in the population without dementia increased from 0% in persons aged 50 to 59 years to 16.4% (95% CI, 10.3% to 22.5%) in those aged 80 to 89 years. The incident aMCI risk increased more than 2-fold in participants without cognitive impairment who were amyloid positive vs those who were amyloid negative (hazard ratio [HR], 2.26; 95% CI, 1.52 to 3.35; P < .001). The risk of AD dementia was 1.86 (95% CI, 0.89 to 3.88; P = .10) for amyloid-positive participants with MCI vs amyloid-negative participants with MCI, 1.63 (95% CI, 0.78 to 3.41; P = .20) for participants with aMCI who were amyloid positive vs amyloid negative, and 2.56 (95% CI, 1.35 to 4.88; P = .004) for amyloid-positive participants who were either without cognitive impairment or had aMCI vs those who were amyloid negative. Global cognitive and memory domain z scores declined significantly in amyloid-positive individuals during follow-up. The mean (SD) follow-up time from baseline was 3.7 (1.9) years to incident aMCI and 3.8 (2.0) years to incident AD dementia. Population-based prevalence of amyloid-positive status and progression rates of amyloid positivity provide valid information for designing AD prevention trials and assessing the public health outcomes of AD prevention and interventions.


Temporal Changes in Coronary Hyperemic and Resting Hemodynamic Indices in Nonculprit Vessels of Patients With ST-Segment Elevation Myocardial Infarction.
Percutaneous coronary intervention (PCI) of nonculprit vessels among patients with ST-segment elevation myocardial infarction (STEMI) is associated with improved clinical outcome compared with culprit vessel-only PCI. Fractional flow reserve (FFR) and coronary flow reserve are hyperemic indices used to guide revascularization. Recently, instantaneous wave-free ratio was introduced as a nonhyperemic alternative to FFR. Whether these indices can be used in the acute setting of STEMI continues to be investigated. To assess the value of hemodynamic indices in nonculprit vessels of patients with STEMI from the index event to 1-month follow-up. This substudy of the Reducing Micro Vascular Dysfunction in Revascularized STEMI Patients by Off-target Properties of Ticagrelor (REDUCE-MVI) randomized clinical trial enrolled 98 patients with STEMI who had an angiographic intermediate stenosis in at least 1 nonculprit vessel. Patient enrollment was between May 1, 2015, and September 19, 2017. After successful primary PCI, nonculprit intracoronary hemodynamic measurements were performed and repeated at 1-month follow-up. Cardiac magnetic resonance imaging was performed from 2 to 7 days and 1 month after primary PCI. The value of nonculprit instantaneous wave-free ratio, FFR, coronary flow reserve, hyperemic index of microcirculatory resistance, and resting microcirculatory resistance from the index event to 1-month follow-up. Of 73 patients with STEMI included in the final analysis, 59 (80.8%) were male, with a mean (SD) age of 60.8 (9.9) years. Instantaneous wave-free ratio (SD) did not change significantly (0.93 [0.07] vs 0.94 [0.06]; P = .12) and there was no change in resting distal pressure/aortic pressure (mean [SD], 0.94 [0.06] vs 0.95 [0.06]; P = .25) from the acute moment to 1-month follow-up. The FFR decreased (mean [SD], 0.88 [0.07] vs 0.86 [0.09]; P = .001) whereas coronary flow reserve increased (mean [SD], 2.9 [1.4] vs 4.1 [2.2]; P < .001). Hyperemic index of microcirculatory resistance decreased and resting microcirculatory resistance increased from the acute moment to follow-up. The decrease in distal pressure from rest to hyperemia was smaller at the acute moment vs follow-up (mean [SD], 10.6 [11.2] mm Hg vs 14.1 [14.2] mm Hg; P = .05). This blunted acute hyperemic response correlated with final infarct size (ρ, -0.29; P = .02). The resistive reserve ratio was lower at the acute moment vs follow-up (mean [SD], 3.4 [1.7] vs 5.0 [2.7]; P < .001). In the acute setting of STEMI, nonculprit coronary flow reserve was reduced and FFR was augmented, whereas instantaneous wave-free ratio was not altered. These results may be explained by an increased hyperemic microvascular resistance and a blunted adenosine responsiveness at the acute moment that was associated with infarct size.


Ultrafast all-optical switching in a silicon-based plasmonic nanoring resonator.
A silicon-based plasmonic nanoring resonator is proposed for ultrafast, all-optical switching applications. Full-wave numerical simulations demonstrate that the photogeneration of free carriers enables ultrafast switching of the device by shifting the transmission minimum of the resonator with a switching time of 3 ps. The compact 1.00 μm² device footprint demonstrates the potential for high integration density plasmonic circuitry based on this device geometry.


Drug-resistant bacterial infections: We need urgent action and investment that focus on the weakest link.
Despite high mortality and morbidity, drug-resistant bacterial infections remain the forgotten pandemic. We argue for strengthening of diagnostics, WASH (water, sanitation, and hygiene) and infection prevention and control to reduce drug-resistant infections, as an integral part of sustainable high-quality health services, particularly in low- and middle-income countries.


Comparison of imputation methods for missing laboratory data in medicine.
Missing laboratory data is a common issue, but the optimal method of imputation of missing values has not been determined. The aims of our study were to compare the accuracy of four imputation methods for missing completely at random laboratory data and to compare the effect of the imputed values on the accuracy of two clinical predictive models. Retrospective cohort analysis of two large data sets. A tertiary level care institution in Ann Arbor, Michigan. The Cirrhosis cohort had 446 patients and the Inflammatory Bowel Disease cohort had 395 patients. Non-missing laboratory data were randomly removed with varying frequencies from two large data sets, and we then compared the ability of four methods-missForest, mean imputation, nearest neighbour imputation and multivariate imputation by chained equations (MICE)-to impute the simulated missing data. We characterised the accuracy of the imputation and the effect of the imputation on predictive ability in two large data sets. MissForest had the least imputation error for both continuous and categorical variables at each frequency of missingness, and it had the smallest prediction difference when models used imputed laboratory values. In both data sets, MICE had the second least imputation error and prediction difference, followed by the nearest neighbour and mean imputation. MissForest is a highly accurate method of imputation for missing laboratory data and outperforms other common imputation techniques in terms of imputation error and maintenance of predictive ability with imputed values in two clinical predicative models.


Risk of hospitalization because of aseptic meningitis after measles-mumps-rubella vaccination in one- to two-year-old children: an analysis of the Vaccine Safety Datalink (VSD) Project.
To assess the level of increased risk, if any, of hospitalizations for aseptic meningitis after Jeryl-Lynn mumps strain measles-mumps-rubella (MMR) vaccine in the Vaccine Safety Datalink population. A possible increased risk of aseptic meningitis 8 to 14 days after receipt of MMR was observed in a preliminary screening analysis of automated data from the Vaccine Safety Datalink (VSD) project Year 2 analysis. To further evaluate this association a retrospective 10-year matched case-control study was undertaken in the four health maintenance organizations (HMOs) in the VSD project. Cases ascertained from a broad scan of the automated data were validated against a standard case definition. Two controls matched on age, sex, HMO and HMO membership were assigned per case. The VSD project involves the cooperative collection of automated vaccination and medical outcome data from four large HMOs that currently have 500,000 children younger than 7 years of age under surveillance. Review of automated screening results from the first 2 years of data revealed a possible increased risk of aseptic meningitis 0 to 14 days after MMR with a relative risk of 3.61 (95% confidence interval, 1.0 to 13.1) although the total number of cases was small. Although the automated data had suggested a possible association of aseptic meningitis with MMR containing the Jeryl-Lynn strain of mumps, review of validated hospitalized cases during the observation period did not reveal evidence of an increased risk of aseptic meningitis after MMR containing the Jeryl-Lynn strain of mumps (odds ratio < 1.0 for all analyses). Although it is recognized that hospitalized cases represent a minority of the total cases of aseptic meningitis, it is reassuring that in this evaluation no increased risk of aseptic meningitis after MMR vaccine was found.


Computing the carbonate chemistry of the coral calcifying medium and its response to ocean acidification.
Critical to determining vulnerability or resilience of reef corals to Ocean Acidification (OA) is a clearer understanding of the extent to which corals can control carbonate chemistry in their Extracellular Calcifying Medium (ECM) where the CaCO3 skeleton is produced. Here, we employ a mathematical framework to calculate ECM aragonite saturation state (Ωarag.(ECM)) and carbonate system ion concentration using measurements of calcification rate, seawater characteristics (temperature, salinity and pH) and ECM pH (pH(ECM)). Our calculations of ECM carbonate chemistry at current-day seawater pH, indicate that Ωarag.(ECM) ranges from ∼10 to 38 (mean 20.41), i.e. about 5 to 6-fold higher than seawater. Accordingly, Dissolved Inorganic Carbon (DIC) and Total Alkalinity (TA) were calculated to be around 3 times higher in the ECM than in seawater. We also assessed the effects of acidification on ECM chemical properties of the coral Stylophora pistillata. At reduced seawater pH our calculations indicate that Ωarag.(ECM) remains almost constant. DIC(ECM) and TA(ECM) gradually increase as seawater pH declines, reaching values about 5 to 6-fold higher than in seawater, respectively for DIC and TA. We propose that these ECM characteristics buffer the effect of acidification and explain why certain corals continue to produce CaCO3 even when seawater chemistry is less favourable.


Molecular dynamics calculations suggest a conduction mechanism for the M2 proton channel from influenza A virus.
The M2 protein of the influenza A virus is activated by low endosomal pH and performs the essential function of proton transfer into the viral interior. The resulting decrease in pH within the virion is essential for the uncoating and further replication of the viral genetic material. The x-ray crystal [Stouffer AL, et al. (2008) Nature 451:596-599] and solution NMR [Schnell JR, Chou JJ (2008) Nature 451:591-595] structures of the transmembrane region of the M2 homo-tetrameric bundle both revealed pores with narrow constrictions at one end, leaving a question as to how protons enter the channel. His-37, which is essential for proton-gating and selective conduction of protons, lies in the pore of the crystallographic and NMR structures. Here, we explore the different protonation states of the His-37 residues of the M2 bundle in a bilayer using molecular dynamics (MD) simulations. When the His-37 residues are neutral, the protein prefers an Open(out)-Closed(in) conformation in which the channel is open to the environment on the outside of the virus but closed to the interior environment of the virus. Diffusion of protons into the channel from the outside of the virus and protonation of His-37 residues in the tetramer stabilizes an oppositely gated Closed(out)-Open(in) conformation. Thus, protons might be conducted through a transporter-like mechanism, in which the protein alternates between Open(out)-Closed(in) and Closed(out)-Open(in) conformations, and His-37 is protonated/deprotonated during each turnover. The transporter-like mechanism is consistent with the known properties of the M2 bundle, including its relatively low rate of proton flux and its strong rectifying behavior.


Normal modes for large molecules with arbitrary link constraints in the mobile block Hessian approach.
In a previous paper [Ghysels et al., J. Chem. Phys. 126, 224102 (2007)] the mobile block Hessian (MBH) approach was presented. The method was designed to accurately compute vibrational modes of partially optimized molecular structures. The key concept was the introduction of several blocks of atoms, which can move as rigid bodies with respect to a local, fully optimized subsystem. The choice of the blocks was restricted in the sense that none of them could be connected, and also linear blocks were not taken into consideration. In this paper an extended version of the MBH method is presented that is generally applicable and allows blocks to be adjoined by one or two common atoms. This extension to all possible block partitions of the molecule provides a structural flexibility varying from very rigid to extremely relaxed. The general MBH method is very well suited to study selected normal modes of large macromolecules (such as proteins and polymers) because the number of degrees of freedom can be greatly reduced while still keeping the essential motions of the molecular system. The reduction in the number of degrees of freedom due to the block linkages is imposed here directly using a constraint method, in contrast to restraint methods where stiff harmonic couplings are introduced to restrain the relative motion of the blocks. The computational cost of this constraint method is less than that of an implementation using a restraint method. This is illustrated for the alpha-helix conformation of an alanine-20-polypeptide.


Unpacking the Black Box: Applications and Considerations for Using GPS Devices in Sport.
Athlete-tracking devices that include global positioning system (GPS) and microelectrical mechanical system (MEMS) components are now commonplace in sport research and practice. These devices provide large amounts of data that are used to inform decision making on athlete training and performance. However, the data obtained from these devices are often provided without clear explanation of how these metrics are obtained. At present, there is no clear consensus regarding how these data should be handled and reported in a sport context. Therefore, the aim of this review was to examine the factors that affect the data produced by these athlete-tracking devices and to provide guidelines for collecting, processing, and reporting of data. Many factors including device sampling rate, positioning and fitting of devices, satellite signal, and data-filtering methods can affect the measures obtained from GPS and MEMS devices. Therefore researchers are encouraged to report device brand/model, sampling frequency, number of satellites, horizontal dilution of precision, and software/firmware versions in any published research. In addition, details of inclusion/exclusion criteria for data obtained from these devices are also recommended. Considerations for the application of speed zones to evaluate the magnitude and distribution of different locomotor activities recorded by GPS are also presented, alongside recommendations for both industry practice and future research directions. Through a standard approach to data collection and procedure reporting, researchers and practitioners will be able to make more confident comparisons from their data, which will improve the understanding and impact these devices can have on athlete performance.


Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles.
Measles is a disease caused by the highly infectious measles virus (MeV) that results in both viremia and lymphopenia. Lymphocyte counts recover shortly after the disappearance of measles-associated rash, but immunosuppression can persist for months to years after infection, resulting in increased incidence of secondary infections. Animal models and in vitro studies have proposed various immunological factors underlying this prolonged immune impairment, but the precise mechanisms operating in humans are unknown. Using B cell receptor (BCR) sequencing of human peripheral blood lymphocytes before and after MeV infection, we identified two immunological consequences from measles underlying immunosuppression: (i) incomplete reconstitution of the naïve B cell pool leading to immunological immaturity and (ii) compromised immune memory to previously encountered pathogens due to depletion of previously expanded B memory clones. Using a surrogate model of measles in ferrets, we investigated the clinical consequences of morbillivirus infection and demonstrated a depletion of vaccine-acquired immunity to influenza virus, leading to a compromised immune recall response and increased disease severity after secondary influenza virus challenge. Our results show that MeV infection causes changes in naïve and memory B lymphocyte diversity that persist after the resolution of clinical disease and thus contribute to compromised immunity to previous infections or vaccinations. This work highlights the importance of MeV vaccination not only for the control of measles but also for the maintenance of herd immunity to other pathogens, which can be compromised after MeV infection.


Staccato/Unc-13-4 controls secretory lysosome-mediated lumen fusion during epithelial tube anastomosis.
A crucial yet ill-defined step during the development of tubular networks, such as the vasculature, is the formation of connections (anastomoses) between pre-existing lumenized tubes. By studying tracheal tube anastomosis in Drosophila melanogaster, we uncovered a key role of secretory lysosome-related organelle (LRO) trafficking in lumen fusion. We identified the conserved calcium-binding protein Unc-13-4/Staccato (Stac) and the GTPase Rab39 as critical regulators of this process. Stac and Rab39 accumulate on dynamic vesicles, which form exclusively in fusion tip cells, move in a dynein-dependent manner, and contain late-endosomal, lysosomal, and SNARE components characteristic of LROs. The GTPase Arl3 is necessary and sufficient for Stac LRO formation and promotes Stac-dependent intracellular fusion of juxtaposed apical plasma membranes, thereby forming a transcellular lumen. Concomitantly, calcium is released locally from ER exit sites and apical membrane-associated calcium increases. We propose that calcium-dependent focused activation of LRO exocytosis restricts lumen fusion to appropriate domains within tip cells.


Effects of light-dark cycle on hippocampal iNOS expression and CREB activation in rats.
Nitric oxide (NO) is one of the most important interneural signaling molecules mediating hippocampal functions for learning and memory. The diurnal expression of neuronal NO synthase (nNOS) has been well studied. However, the temporal profile and underlying mechanisms of inducible NOS (iNOS) expression in a normal photoperiod or in altered light-dark cycles remain unclear. We examined the temporal profile of iNOS expression in adult male Sprague-Dawley rats maintained in a 12h-light/ 12h-dark photoperiod (12L/12D), which were pre-synchronized for 7 days before the experiment. The protein and mRNA levels of iNOS in the cortex and hippocampus were measured to examine the photic influences on iNOS expression. The results showed rhythmically changes of the levels of iNOS mRNA and protein in the hippocampus, but not in the cerebral cortex. The iNOS mRNA levels peaked at Zeitgeber time (ZT) 6 and ZT22, and the protein levels peaked at ZT8 and ZT18. Notably, the peaks in iNOS mRNA and protein levels in the 12L/12D group were 10 to 12 h apart, and the rhythmic pattern was absent in the 24-h period of the darkness group. In addition, the level of the phosphorylated cAMP response element binding protein (phospho-CREB) was the highest at ZT18, prior to a peak in iNOS mRNA expression at ZT22. A phospho-CREB-iNOS signaling pathway was further confirmed by the interaction of phospho-CREB and the iNOS DNA in histone complexes isolated by chromatin immunoprecipitation at ZT18. In conclusion, the photoperiod affects the diurnal expression of iNOS and activation of CREB in the hippocampus, which provide clues for the possible impact of circadian changes in hippocampal functions.


CHIP functions an E3 ubiquitin ligase of Runx1.
Runx1 is a key factor in the generation and maintenance of hematopoietic stem cells. Improper expression and mutations in Runx1 are frequently implicated in human leukemia. Here, we report that CHIP, the carboxyl terminus of Hsc70-interacting protein, also named Stub1, physically interacts with Runx1 through the TPR and Charged domains in the nucleus. Over-expression of CHIP directly induced Runx1 ubiquitination and degradation through the ubiquitin-proteasome pathway. Interestingly, we found that CHIP-mediated degradation of Runx1 is independent of the molecular chaperone Hsp70/90. Taken together, we propose that CHIP serves as an E3 ubiquitin ligase that regulates Runx1 protein stability via an ubiquitination and degradation mechanism that is independent of Hsp70/90.


Ecological dissociation and re-association with a superior competitor alters host selection behavior in a parasitoid wasp.
Interspecific competition for limited resources can drive ecological specialization and trait expression. Organisms released from intense competition may exploit a broader range of resources, but if reunited with stronger competitors, survivorship may depend on foraging behaviors that reduce competition. We compared the host selection behavior of the parasitoid Cotesia glomerata from two North American populations that differ in their association with Cotesia rubecula, a superior competitor. Both parasitoids originate from Europe and attack the imported cabbageworm (a.k.a. small cabbage white) Pieris rapae, but C. glomerata was introduced into North America almost a century before C. rubecula. After re-association in North America, C. rubecula has displaced C. glomerata in several regions, but not in other regions. Host selection was measured in female C. glomerata from Maryland (MD) where it coexists with C. rubecula, and in conspecifics from Colorado (CO) where C. rubecula is absent. Unparasitized and C. rubecula-parasitized P. rapae hosts were used in choice tests to examine whether C. glomerata host selection behavior differed based on the population's association history with C. rubecula. We found that C. glomerata from MD had a higher likelihood of avoiding hosts parasitized by C. rubecula (and thus avoiding competition) than did wasps from CO. The ability of C. glomerata to avoid hosts parasitized by C. rubecula may facilitate coexistence in MD; whereas, the lack of discrimination in CO populations of C. glomerata naïve to C. rubecula could contribute to the displacement of C. glomerata were C. rubecula to enter the same habitat.


ANCA and predicting relapse in systemic vasculitis.
We studied 60 patients with ANCA-positive systemic vasculitis (SV) to assess the prognostic significance of clinical and serological features at presentation, and the value of sequential monitoring of ANCA, C-reactive protein (CRP) and ESR levels as predictors of disease relapse. Patients were recruited at the time of diagnosis, treated with a standard protocol, and assessed monthly for one year. Clinical remission was achieved in 56/60 (93%), and ANCA became undetectable in 50/60 (83%) after treatment. During the one year follow-up period, disease relapses were seen in 23 (38%) patients. No specific associations were observed between initial disease presentation, initial ANCA level or ANCA antigenic specificity and relapse. However, 13/23 (57%) of relapses were preceded by a rise in ANCA a mean of 7.8 weeks earlier, while at the time of relapse 19/23 (83%) were ANCA-positive. Rises in CRP and ESR occurred in 23/60 (38%) and 14/43 (33%), respectively, but were less closely associated with relapse than ANCA. A sustained rise in ANCA was seen in six patients without relapse while clinical relapse occurred with a negative ANCA in four. Sequential ANCA monitoring at monthly intervals during disease remission is of value, at least during the first year, in the prediction and diagnosis of relapse in SV, and is superior to measurement of CRP or ESR.


Intermittent versus continuous androgen deprivation in prostate cancer.
Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence. Men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization. A total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events. Our findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.).


Education and eminence in British medicine.
The educational background of eminent members of the British medical profession was examined by recourse to Who's Who. Substantial differences in background were found among the various medical specialties. Members of specialties enjoying high prestige within the profession-physicians, surgeons-were more likely than other members of the sample to have been to an English school as opposed to one in Scotland, Wales, or Northern Ireland, and to a headmasters' conference school as opposed to a grammar school. Educational background was also found to relate to the aspect of the patient's body on which specialists normally worked. Specialists coming from English headmasters' conference schools were more likely than others to work on living bodies rather than dead bodies or parts of bodies, on the head rather than on the lower trunk, on male bodies rather than female bodies, and on the body's surface rather than its inside.


Deletion of CFHR3 and CFHR1 genes in age-related macular degeneration.
Age-related macular degeneration (AMD) impairs vision for approximately 7.5 million Americans. Both susceptibility variants and protective haplotypes in the complement factor H (CFH) gene modulate risk for AMD. Recently, deletion of the 'CFH-related' genes CFHR1 and CFHR3 was found to be segregating with a particular CFH haplotype, which reduced the risk of AMD. We tested the deletion for association in a Caucasian population of 780 cases and 265 controls and examined its effect in the context of known AMD risk factors. The deletion did not segregate perfectly with any one SNP, as previously suggested. CFH haplotype P2 was the most frequent haplotype in deletion homozygotes (47%), and the majority (14/16) of these individuals were homozygous for the non-risk allele of Y402H. Overall, deletion homozygosity was significantly more frequent in controls than cases (2.6% controls, 0.8% cases, P = 0.025, OR = 0.29, 95% CI = 0.10-0.86). After controlling for age, Y402H, smoking and LOC387715 A69S, the protective effect of the deletion was no longer statistically significant (P = 0.27). However, using a CFH haplotype that all deletion homozygotes share as a surrogate for the deletion, this marker remained modestly associated with AMD after adjustment for known risk factors (OR = 0.63, 95% CI 0.39-1.04, P = 0.07). Therefore, deletion of CFHR1 and CFHR3 may account for a small portion of the protection from AMD associated with particular haplotypes in CFH. The presence of protective haplotypes in CFH that do not carry the deletion, suggests that other protective variants in this region have yet to be discovered.


Structure of tobacco mosaic virus at 3.6 A resolution: implications for assembly.
X-ray fiber diffraction analysis of tobacco mosaic virus (TMV) has led to the building of a molecular model of the intact virus, based on a map at 3.6 A resolution derived from five separated Bessel orders. This has been made possible by advances in the solution of the fiber diffraction phase problem. It is now possible to understand much of the chemical basis of TMV assembly, particularly in terms of intersubunit electrostatic interactions and RNA binding. Consideration of the molecular structure in conjunction with physical chemical studies by several groups of investigators suggests that the nucleating aggregate for initiation of TMV assembly is a short (about two turns) helix of protein subunits, probably inhibited from further polymerization in the absence of RNA by the disordering of peptide loop near the inner surface of the virus.


An Opinion on "Staging" of Infant Formula: A Developmental Perspective on Infant Feeding.
Breast milk is a dynamic fluid with compositional changes occurring throughout the period of lactation. Some of these changes in nutrient concentrations reflect the successively slowing growth rate and developmental changes in metabolic requirements that infants undergo during the first year of life. Infant formula, in contrast, has a static composition, intended to meet the nutritional requirements of infants from birth to 6 or 12 months of age. To better fit the metabolic needs of infants and to avoid nutrient limitations or excesses, we suggest that infant formulas should change in composition with the age of the infant, that is, different formulas are created/used for different ages during the first year of life. We propose that specific formulas for 0 to 3 months (stage 1), 3 to 6 months (stage 2), and 6 to 12 months (stage 3) of age may be nutritionally and physiologically advantageous to infants. Although this initially may impose some difficult practical/conceptual issues, we believe that this staging concept would improve nutrition of formula-fed infants and, ultimately, improve outcomes and make their performance more similar to that of breast-fed infants.


Cerebral palsy.
Cerebral palsy (CP) is a group of disorders of movement and posture resulting from nonprogressive disturbances of the fetal or neonatal brain. More than 80% of cases of CP in term infants originate in the prenatal period; in premature infants, both prenatal or postnatal causes contribute. The most prevalent pathological lesion seen in CP is periventricular white matter injury (PWMI) resulting from vulnerability of the immature oligodendrocytes (pre-OLs) before 32 wk of gestation. PWMI is responsible for the spastic diplegia form of CP and a spectrum of cognitive and behavioral disorders. Oxidative stress and excitotoxicity resulting from excessive stimulation of ionotropic glutamate receptors on preOLs are the most prominent molecular mechanisms for PWMI. Asphyxia around the time of birth in term infants accounts for less than 15% of CP in developed countries but the incidence is higher in underdeveloped areas. Asphyxia causes a different pattern of brain injury and CP than is seen after preterm injuries. This type of CP is associated with the clinical syndrome of hypoxic-ischemic encephalopathy shortly after the insult, and the cortex, basal ganglia, and brainstem are selectively vulnerable to injury. Experimental models indicate that neurons in the neonatal brain are more likely to die by delayed apoptosis extending over days to weeks than those in the adult brain. Neurons die by glutamate-mediated excitotoxicity involving downstream caspase-dependent and caspase-independent cell death pathways. Recent reports indicate that males and females preferentially utilize different pathways. Clinical trials indicate that mild hypothermia reduces death or disability in term infants following asphyxia and basic research suggests that this approach might be combined with pharmacological strategies in the future.


Dark green islands in plant virus infection are the result of posttranscriptional gene silencing.
Dark green islands (DGIs) are a common symptom of plants systemically infected with a mosaic virus. DGIs are clusters of green leaf cells that are free of virus but surrounded by yellow, virus-infected tissue. We report here on two lines of evidence showing that DGIs are caused by posttranscriptional gene silencing (PTGS). First, transcripts of a transgene derived from the coat protein of Tamarillo mosaic potyvirus (TaMV) were reduced in DGIs relative to adjacent yellow tissues when the plants were infected with TaMV. Second, nontransgenic plants coinfected with TaMV and a heterologous virus vector carrying TaMV sequences showed reduced titers of the vector in DGIs compared with surrounding tissues. DGIs also were compared with recovered tissue at the top of transgenic plants because recovery has been shown previously to involve PTGS. Cytological analysis of the cells at the junction between recovered and infected tissue was undertaken. The interface between recovered and infected cells had very similar features to that surrounding DGIs. We conclude that DGIs and recovery are related phenomena, differing in their ability to amplify or transport the silencing signal.


Effects of a bicarbonate-alkaline mineral water on digestive motility in experimental models of functional and inflammatory gastrointestinal disorders.
This study investigates the effects of Uliveto, a bicarbonate-alkaline mineral water, in experimental models of diarrhea, constipation and colitis. Rats were allowed to drink Uliveto or oligomineral water (control) for 30 days. Diarrhea and constipation were evoked by 16,16-dimethyl-prostaglandin E(2) (dmPGE(2)) or loperamide, respectively. Colitis was induced by 2,4-dinitrobenzenesulfonic acid (DNBS) or acetic acid. Gastric emptying, small-intestinal and colonic transit were evaluated. dmPGE(2)-induced diarrhea reduced gastric emptying and increased small-intestinal and colonic transit. In this setting, Uliveto water enhanced gastric emptying, and this effect was prevented by L-365,260 (gastrin receptor antagonist). Loperamide-induced constipation reduced gastric emptying, small-intestinal and colonic transit, and these effects were prevented by Uliveto water. L-365,260 counteracted the effects of Uliveto on gastric emptying, while alosetron (serotonin 5-HT(3) receptor antagonist) blunted the effect of Uliveto on colonic transit. Gastric emptying, small-intestinal and colonic transit were reduced in DNBS-induced colitis, and Uliveto water enhanced gastric emptying and normalized small-intestinal and colonic transit. Gastric emptying, small-intestinal and colonic transit were also reduced in acetic acid-induced colitis, and Uliveto increased both gastric emptying and small-intestinal transit. In conclusion, Uliveto water exerts beneficial effects on gastrointestinal motility in the presence of bowel motor dysfunctions. The effects of Uliveto water on gastric emptying depend on gastrin-mediated mechanisms, whereas the activation of serotonergic pathways accounts for the modulation of colonic functions.


Muscle Activity Patterns do not Differ Between Push-Up and Bench Press Exercises.
Popular topics for upper-body resistance training involve the differences between hand positions, open versus closed chain exercises, and movement variations for the novice to the advanced. It was hypothesized that there will be no difference between closed (push-up) versus open (bench press) chain exercises for the primary muscle group activity nor would there be a difference between push-ups on the toes versus knees with respect to the percent contribution of each muscle. Surface muscle activity was measured for 8 upper-body and core muscles during a sequence of push-up and bench press variations with a normalized weight for 12 active men. Each participant completed push-ups and bench press exercises at each of 3 hand positions. The results demonstrated that there were few differences between closed versus open chain exercises for the primary muscle groups with the exception of core activation. In addition, in general, narrow hand positions yielded greater activation, and there were no significant differences between push-ups on the toes versus knees with respect to the percent contribution for the primary muscle groups. In conclusion, closed chain exercises may be preferred for functional training, and knee push-ups may be ideal as a novice push-up variation.


Interpreting noncoding genetic variation in complex traits and human disease.
Association studies provide genome-wide information about the genetic basis of complex disease, but medical research has focused primarily on protein-coding variants, owing to the difficulty of interpreting noncoding mutations. This picture has changed with advances in the systematic annotation of functional noncoding elements. Evolutionary conservation, functional genomics, chromatin state, sequence motifs and molecular quantitative trait loci all provide complementary information about the function of noncoding sequences. These functional maps can help with prioritizing variants on risk haplotypes, filtering mutations encountered in the clinic and performing systems-level analyses to reveal processes underlying disease associations. Advances in predictive modeling can enable data-set integration to reveal pathways shared across loci and alleles, and richer regulatory models can guide the search for epistatic interactions. Lastly, new massively parallel reporter experiments can systematically validate regulatory predictions. Ultimately, advances in regulatory and systems genomics can help unleash the value of whole-genome sequencing for personalized genomic risk assessment, diagnosis and treatment.


Inaccurate official assessment of radiofrequency safety by the Advisory Group on Non-ionising Radiation.
The Advisory Group on Non-ionising Radiation (AGNIR) 2012 report forms the basis of official advice on the safety of radiofrequency (RF) electromagnetic fields in the United Kingdom and has been relied upon by health protection agencies around the world. This review describes incorrect and misleading statements from within the report, omissions and conflict of interest, which make it unsuitable for health risk assessment. The executive summary and overall conclusions did not accurately reflect the scientific evidence available. Independence is needed from the International Commission on Non-Ionizing Radiation Protection (ICNIRP), the group that set the exposure guidelines being assessed. This conflict of interest critically needs to be addressed for the forthcoming World Health Organisation (WHO) Environmental Health Criteria Monograph on Radiofrequency Fields. Decision makers, organisations and individuals require accurate information about the safety of RF electromagnetic signals if they are to be able to fulfil their safeguarding responsibilities and protect those for whom they have legal responsibility.


Cautious Hope for Cannabidiol (CBD) in Rheumatology Care.
Cannabidiol (CBD), a major metabolite of Cannabis sativa, is popularized as a medicinal product, with potential for analgesic, antiinflammatory, and antioxidant effects. CBD may hold promise as a treatment in rheumatic diseases, but evidence to date remains preclinical. Preclinical effects on pain and inflammation is encouraging, but clinical study is lacking, with only a single study in knee osteoarthritis reporting a promising effect on symptoms. CBD products are freely available over the counter and marketed as food supplements or wellness products. The World Health Organization has identified pure CBD as safe and without abuse potential, but products are not subject to drug regulatory standards, leading to inconsistency in manufacturing practices and quality of products. Not only have molecular concentrations of CBD been identified as inaccurate, but concerns exist regarding contaminants, including heavy metals, pesticides, microbes, and mycotoxins, as well as added tetrahydrocannabinol. Drug-drug interactions pose a potential risk due to metabolism via the cytochrome P450 enzyme pathway. Patients wishing to use CBD should obtain a product with certification of Good Manufacturing Practices, initiate treatment with a nighttime low dose, and have defined outcome goals within a reasonable time frame. Treatments should not be managed by nonmedical dispensary personnel. The hope that CBD may be a useful therapy must be substantiated by sound scientific study.


IsoDOT Detects Differential RNA-isoform Expression/Usage with respect to a Categorical or Continuous Covariate with High Sensitivity and Specificity.
We have developed a statistical method named IsoDOT to assess differential isoform expression (DIE) and differential isoform usage (DIU) using RNA-seq data. Here isoform usage refers to relative isoform expression given the total expression of the corresponding gene. IsoDOT performs two tasks that cannot be accomplished by existing methods: to test DIE/DIU with respect to a continuous covariate, and to test DIE/DIU for one case versus one control. The latter task is not an uncommon situation in practice, e.g., comparing the paternal and maternal alleles of one individual or comparing tumor and normal samples of one cancer patient. Simulation studies demonstrate the high sensitivity and specificity of IsoDOT. We apply IsoDOT to study the effects of haloperidol treatment on the mouse transcriptome and identify a group of genes whose isoform usages respond to haloperidol treatment.