A survey of musculoskeletal injuries associated with Zumba.
Zumba is a highly popular Latin-inspired dance fitness program with ∼14 million participants in 150 countries. However, there is little published data on the rates or types of injuries among participants. We surveyed a convenience sample of 49 adults (100% participation) in 5 Zumba classes in Hawai'i. Participants described any prior Zumba-related injuries. We used t-tests and logistic regression to determine if participant demographics or intensity of Zumba classes were associated with injuries. Participants were mostly female (82%), averaged 43.9 years of age (range 19 to 69 years), and took an average of 3 classes/week (1-2 hours/class) for an average of 11 months. Fourteen participants (29%) reported 21 prior Zumba-related injuries. Half of the 14 injured sought care from medical providers for their injuries. Of the 21 injuries, the most frequently injured sites were knees (42%), ankles (14%), and shoulders (14%). Participants with Zumba-related injuries did not differ significantly in age, months of Zumba, or hours/class compared to those who did not experience injuries. However, participants who reported injuries took significantly more classes/week (3.8 versus 2.7 classes, P = .006) than non-injured participants. In logistic regression, taking more classes/week remained significantly associated with injuries (odds ratio 3.6 [95% confidence interval 1.5 - 8.9, P = .006]) after controlling for age, gender, months of Zumba, and hours/class. Given Zumba's health benefits, our finding that 1 in 4 Zumba participants have experienced injuries indicates the need to improve Zumba routines, instructor training, and health provider counseling to reduce injury risk.


International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors.
Four adenosine receptors have been cloned and characterized from several mammalian species. The receptors are named adenosine A(1), A(2A), A(2B), and A(3). The A(2A) and A(2B) receptors preferably interact with members of the G(s) family of G proteins and the A(1) and A(3) receptors with G(i/o) proteins. However, other G protein interactions have also been described. Adenosine is the preferred endogenous agonist at all these receptors, but inosine can also activate the A(3) receptor. The levels of adenosine seen under basal conditions are sufficient to cause some activation of all the receptors, at least where they are abundantly expressed. Adenosine levels during, e.g., ischemia can activate all receptors even when expressed in low abundance. Accordingly, experiments with receptor antagonists and mice with targeted disruption of adenosine A(1), A(2A), and A(3) expression reveal roles for these receptors under physiological and particularly pathophysiological conditions. There are pharmacological tools that can be used to classify A(1), A(2A), and A(3) receptors but few drugs that interact selectively with A(2B) receptors. Testable models of the interaction of these drugs with their receptors have been generated by site-directed mutagenesis and homology-based modelling. Both agonists and antagonists are being developed as potential drugs.


[Cluster of multidrug-resistant tuberculosis cases in a school of the district of Ica, Peru].
We describe the evolution and features of a cluster of Multidrug-resistant tuberculosis (MDR TB) cases that occurred in 2001, in a school located in a sub-urban area of the district of Ica, Peru. We identified 15 students related before becoming infected with tuberculosis. The mean age of the cluster was 15 years. A total of 12 students were MDR-TB cases and 7 were drug-resistant to 5 first-line drugs (RHEZS). Five out of the 15 cases received at least 3 different anti-tuberculosis treatment schemes. The average treatment duration was 37 months (minimum 21 and maximum 59 months). A total of 13 cases recovered and 2 died. This study describes a cluster of MDR -TB cases in an educational facility, which due to the epidemiological link and time presentation, is probably an outbreak of MDR TB with a satisfactory outcome after prolonged treatment.


Patterns of chromosomal copy-number alterations in intrahepatic cholangiocarcinoma.
Intrahepatic cholangiocarcinomas (ICC) are relatively rare malignant tumors associated with a poor prognosis. Recent studies using genome-wide sequencing technologies have mainly focused on identifying new driver mutations. There is nevertheless a need to investigate the spectrum of copy number aberrations in order to identify potential target genes in the altered chromosomal regions. The aim of this study was to characterize the patterns of chromosomal copy-number alterations (CNAs) in ICC. 53 patients having ICC with frozen material were selected. In 47 cases, DNA hybridization has been performed on a genomewide SNP array. A procedure with a segmentation step and a calling step classified genomic regions into copy-number aberration states. We identified the exclusively amplified and deleted recurrent genomic areas. These areas are those showing the highest estimated propensity level for copy loss (resp. copy gain) together with the lowest level for copy gain (resp. copy loss). We investigated ICC clustering. We analyzed the relationships between CNAs and clinico-pathological characteristics. The overall genomic profile of ICC showed many alterations with higher rates for the deletions. Exclusively deleted genomic areas were 1p, 3p and 14q. The main exclusively amplified genomic areas were 1q, 7p, 7q and 8q. Based on the exclusively deleted/amplified genomic areas, a clustering analysis identified three tumors groups: the first group characterized by copy loss of 1p and copy gain of 7p, the second group characterized by 1p and 3p copy losses without 7p copy gain, the last group characterized mainly by very few CNAs. From univariate analyses, the number of tumors, the size of the largest tumor and the stage were significantly associated with shorter time recurrence. We found no relationship between the number of altered cytobands or tumor groups and time to recurrence. This study describes the spectrum of chromosomal aberrations across the whole genome. Some of the recurrent exclusive CNAs harbor candidate target genes. Despite the absence of correlation between CNAs and clinico-pathological characteristics, the co-occurence of 7p gain and 1p loss in a subgroup of patients may suggest a differential activation of EGFR and its downstream pathways, which may have a potential effect on targeted therapies.


Isotope Effect in the Activation of a Mechanophore.
In mechanochemistry, molecules under tension can react in unexpected ways. The reactivity of mechanophores (mechanosensitive molecules) can be controlled using various geometric or electronic factors. Often these factors affect the rate of mechanical activation but sometimes give rise to alternative reaction pathways. Here we show that a simple isotope substitution (H to D) leads to a reversal of selectivity in the activation of a mechanophore. Remarkably this isotope effect is not kinetic in nature but emerges from dynamic effects in which deuteration reduces the ability of the reactant to follow a post-transition-state concerted trajectory on the bifurcated force-modified potential energy surface. These results give a new insight into the reactivity of molecules under tension.


Opposing Contributions of GABAergic and Glutamatergic Ventral Pallidal Neurons to Motivational Behaviors.
The ventral pallidum (VP) is critical for invigorating reward seeking and is also involved in punishment avoidance, but how it contributes to such opposing behavioral actions remains unclear. Here, we show that GABAergic and glutamatergic VP neurons selectively control behavior in opposing motivational contexts. In vivo recording combined with optogenetics in mice revealed that these two populations oppositely encode positive and negative motivational value, are differentially modulated by animal's internal state, and determine the behavioral response during motivational conflict. Furthermore, GABAergic VP neurons are essential for movements toward reward in a positive motivational context but suppress movements in an aversive context. In contrast, glutamatergic VP neurons are essential for movements to avoid a threat but suppress movements in an appetitive context. Our results indicate that GABAergic and glutamatergic VP neurons encode the drive for approach and avoidance, respectively, with the balance between their activities determining the type of motivational behavior.


Resource implications of bortezomib therapy in a large UK cohort: An evaluation study.
Bortezomib is a cornerstone in the management of multiple myeloma. It remains an attractive treatment option because it is efficacious, reasonably well tolerated and easy to administer. However, data on resource implications in the UK for both patients and healthcare providers are limited. We conducted a retrospective study of 127 patients to assess implications of bortezomib therapy on patients and healthcare resources. A patient-episode was defined as a patient attending the chemotherapy day treatment unit solely for bortezomib administration. Data were collected for the duration of therapy as follows: cost of drug calculated using the UK's bortezomib indicative price as per British National Formulary, cost of drug administration in the chemotherapy day treatment unit calculated using the National Health Service's schedule of service cost, time from check-in to drug administration, patient travel time and distance calculated using Google maps, and cost of travel. Median drug cost and administration cost per patient were £8336 (£2084-£108,368) and £4640 (£290-£15,080), respectively. Median time from check-in to administration was 63 min (range 5-433), median travel time was 90 min (range 8-270) and 80 min (range 8-280) during peak and off-peak periods, respectively. Median return travel distance was 33.4 miles (range 1.2-224) for travel cost per patient per trip was £8.35-£13.20. Our real-world resource analysis demonstrated that delivering bortezomib therapy can be associated with significant cost and time implications for patients and healthcare providers. Our study method sets a basis for evaluating resource implications of other novel approaches to myeloma therapy.


Inter- and intraspecific genetic analysis of the genus Saccharomonospora with 16S to 23S ribosomal DNA (rDNA) and 23S to 5S rDNA internally transcribed spacer sequences.
In order to clarify interspecific relationships and to investigate the intraspecific phylogenetic structure of the genus Saccharomonospora, 16S to 23S ribosomal DNA (16S-23S) and 23S to 5S ribosomal DNA (23S-5S) internally transcribed spacers (ITSs) were used for sequence analyses. The 16S-23S and 23S-5S ITSs from 22 Saccharomonospora strains were amplified by PCR and directly sequenced. The average levels of nucleotide similarity of the 16S-23S and 23S-5S ITSs for the four valid species were 87.6% +/- 3.9% and 83% +/- 2.2%, respectively. For the most part, intraspecific sequence differences were not found in the two ITSs; the only exception was Saccharomonospora glauca K194, which differed from other S. glauca strains by 1 bp in the 23S-5S ITS. The Saccharomonospora viridis strains had a smaller 16S-23S ITS region than the other strains, which may be useful for differentiating these organisms from other Saccharomonospora species. The characteristics of the two ITS regions make them more useful than 16S rRNA sequences as a tool for defining and identifying Saccharomonospora strains. However, Saccharomonospora azurea K161T had two types of 23S-5S ITSs; rrnB, separated by XhoI digestion, had two additional nucleotides inserted between positions 52 and 55. Most of the 16S-23S and 23S-5S ITS sequences of S. azurea K161T and strains of "Saccharomonospora caesia" were identical; the only exception was rrnB in S. azurea K161T. The lengths and levels of sequence divergence of the two ITSs of Saccharomonospora sp. strain K180 were different from the lengths and levels of sequence divergence of the ITSs of other species. These findings suggest that a taxonomic revision of the genus Saccharomonospora is necessary. Two trees based on 16S-23S and 23S-5S ITS sequences revealed distinct interspecific relationships in the genus Saccharomonospora.


Mujer Mas Segura (Safer Women): a combination prevention intervention to reduce sexual and injection risks among female sex workers who inject drugs.
Female sex workers who inject drugs (FSW-IDUs) are at risk of acquiring HIV, sexually transmitted infections (STI) and blood-borne infections through unprotected sex and sharing injection equipment. We conducted a 2×2 factorial randomized controlled trial to evaluate combination interventions to simultaneously reduce sexual and injection risks among FSW-IDUs in Tijuana and Ciudad Juarez, Mexico. FSW-IDUs ≥18 years reporting sharing injection equipment and unprotected sex with clients within the last month were randomized to one of four conditions based on an a priori randomization schedule, blinding interviewer/counselors to assignment. Due to the extreme vulnerability of this population, we did not include a control group that would deny some women access to preventive information. All women received similar information regardless of group allocation; the difference was in the way the information was delivered and the extent to which women had an interactive role. Each condition was a single 60-minute session, including either an interactive or didactic version of an injection risk intervention and sexual risk intervention. Women underwent interviewer-administered surveys and testing for HIV, syphilis, gonorrhea, Chlamydia, and Trichomonas at baseline and quarterly for 12 months. Combined HIV/STI incidence will be the primary outcome. Secondary outcomes are proportionate reductions in sharing of injection equipment and unprotected sex with clients. Of 1,132 women, 548 (48.4%) were excluded (88.9% were ineligible; 11.1% refused to participate or did not return); 584 eligible women enrolled (284 in Tijuana; 300 in Ciudad Juarez). All 584 participants completed the baseline interview, provided biological samples and were randomized to one of the four groups. During follow-up, 17 participants (2.9%) were lost to follow-up, of whom 10 (58.8%) had died, leaving 567 participants for analysis. This study appears to be the first intervention to attempt to simultaneously reduce injection and sexual risk behaviors among FSW-IDUs. The factorial design will permit analysis to determine whether the combination of the two interactive interventions and/or its respective components are effective in reducing injection and/or sexual risks, which will have direct, tangible policy implications for Mexico and potentially other resource-poor countries. NCT00840658.


Atrial fibrillation or flutter on initial electrocardiogram is associated with worse outcomes in patients admitted for worsening heart failure with reduced ejection fraction: findings from the EVEREST Trial.
Heart failure (HF) complicated by atrial fibrillation/flutter (AF/AFL) is associated with worse outcomes. However, the clinical profile and outcomes of patients following hospitalization for HF with AF/AFL on initial electrocardiogram (ECG) has not been well studied. EVEREST was a randomized trial of vasopressin-2 receptor blockade, in addition to standard therapy, in 4133 patients hospitalized with HF with ejection fraction ≤40%. A post hoc analysis was performed comparing the clinical characteristics and outcomes [all-cause mortality and cardiovascular mortality/HF hospitalization] of patients with AF/AFL versus sinus rhythm (SR) on baseline ECG, which were centrally analyzed. Times to events were compared using log-rank tests and Cox regression models. Of the 4133 patients, 1195 (29%) were classified with AF/AFL and 2071(50%) with SR. The remaining patients (21%) were excluded because ECGs were unavailable (n = 106), rhythm was paced (n = 727), or junctional/other supraventricular (n = 34). AF/AFL patients were older, with increased weight, faster heart rate, higher blood urea nitrogen, and natriuretic peptide levels compared to SR patients. Anticoagulation was prescribed in 67% of AF/AFL patients on discharge. AF/AFL patients were less likely to receive β-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (all P < .05). After risk adjustment, AF/AFL was associated with increased mortality (hazard ratio 1.23; 95% CI, 1.04-1.46) and cardiovascular mortality/HF hospitalization (hazard ratio 1.26; 95% CI, 1.07-1.47). AF/AFL on initial ECG in patients hospitalized with HF with reduced ejection fraction is associated with lower use of evidence-based therapies and increased mortality and rehospitalization compared to patients in SR.


The reactivity of natural organic matter to disinfection by-products formation and its relation to specific ultraviolet absorbance.
Five natural waters with a broad range of DOC concentrations were fractionated using various coal- and wood-based granular activated carbons (GAC) and alum coagulation. Adsorption and alum coagulation fractionated NOM solutions by preferentially removing components having high specific ultraviolet absorbance (SUVA). UV absorbing fractions of NOM were found to be the major contributors to DBP formation. SUVA appears to be an accurate predictor of reactivity with chlorine in terms of DBP yield; however, it was also found that low-SUVA components of NOM have higher bromine incorporation. SUVA has promise as a parameter for on-line monitoring and control of DBP formation in practical applications; however, the effects of bromide concentration may also need to be considered. Understanding how reactivity is correlated to SUVA may allow utilities to optimize the degree of treatment required to comply with DBP regulations. The reactive components that require removal, and the degree of treatment necessary to accomplish this removal, may be directly obtained from the relationship between SUVA removal and the degree of treatment (e.g., alum dose).


Smart Garment Fabrics to Enable Non-Contact Opto-Physiological Monitoring.
Imaging photoplethysmography (iPPG) is an emerging technology used to assess microcirculation and cardiovascular signs by collecting backscattered light from illuminated tissue using optical imaging sensors. The aim of this study was to study how effective smart garment fabrics could be capturing physiological signs in a non-contact mode. The present work demonstrates a feasible approach of, instead of using conventional high-power illumination sources, integrating a grid of surface-mounted light emitting diodes (LEDs) into cotton fabric to spotlight the region of interest (ROI). The green and the red LEDs (525 and 660 nm) placed on a small cotton substrate were used to locally illuminate palm skin in a dual-wavelength iPPG setup, where the backscattered light is transmitted to a remote image sensor through the garment fabric. The results show that the illuminations from both wavelength LEDs can be used to extract heart rate (HR) reaching an accuracy of 90% compared to a contact PPG probe. Stretching the fabric over the skin surface alters the morphology of iPPG signals, demonstrating a significantly higher pulsatile amplitude in both channels of green and red illuminations. The skin compression by the fabric could be potentially utilised to enhance the penetration of illumination into cutaneous microvascular beds. The outcome could lead a new avenue of non-contact opto-physiological monitoring and assessment with functional garment fabrics.


Experimental inoculation of Louisiana red swamp crayfish Procambarus clarkii with white spot syndrome virus (WSSV).
The red swamp crayfish Procambarus clarkii represents an important aquaculture species responsible for over half of all commercial aquaculture profits in Louisiana, USA. White spot syndrome virus (WSSV) is highly pathogenic in crustacean species and induces mass mortality in aquaculture operations worldwide. Natural outbreaks of WSSV occur yearly in cultured populations of crayfish in Louisiana. The goal of this study was to better understand the infectivity of WSSV in P. clarkii, by determining the minimum lethal dose necessary to initiate infection and to measure the resulting cumulative mortality following infection with different doses. A real time quantitative PCR (qPCR) method was used to detect WSSV in DNA extracted from gill tissue to ensure P. clarkii study populations were WSSV-free before the start of trials. Viable viral particles were isolated from naturally infected P. clarkii gill tissue and quantified using a novel digital PCR approach. Three infectivity trials were performed, and WSSV inocula were created by serial dilution, generating 5 treatments per trial. Five crayfish (weighing ~25 g) per dilution per trial received viral inoculations. Mortality was monitored daily for the duration of the trial in order to construct a median lethal dose (LD50) curve, and probit regression analysis was used to determine LD50 concentrations of viral particles. Knowledge of the infectivity of WSSV in native crayfish populations is of critical importance to the management of the commercial crayfish aquaculture industry in Louisiana. This is the first study to investigate the infectivity and to determine the LD50 of the Louisiana strain of WSSV in native crayfish.


Nanoparticle imaging. Electron microscopy of gold nanoparticles at atomic resolution.
Structure determination of gold nanoparticles (AuNPs) is necessary for understanding their physical and chemical properties, but only one AuNP larger than 1 nanometer in diameter [a 102-gold atom NP (Au102NP)] has been solved to atomic resolution. Whereas the Au102NP structure was determined by x-ray crystallography, other large AuNPs have proved refractory to this approach. Here, we report the structure determination of a Au68NP at atomic resolution by aberration-corrected transmission electron microscopy, performed with the use of a minimal electron dose, an approach that should prove applicable to metal NPs in general. The structure of the Au68NP was supported by small-angle x-ray scattering and by comparison of observed infrared absorption spectra with calculations by density functional theory.


The 1918 influenza pandemic in New York City: age-specific timing, mortality, and transmission dynamics.
The 1918 influenza pandemic caused disproportionately high mortality among certain age groups. The mechanisms underlying these differences are not fully understood. To explore the dynamics of the 1918 pandemic and to identify potential age-specific transmission patterns. We examined 1915-1923 daily mortality data in New York City (NYC) and estimated the outbreak duration and initial effective reproductive number (Re ) for each 1-year age cohort. Four pandemic waves occurred from February 1918 to April 1920. The fractional mortality increase (i.e. ratio of excess mortality to baseline mortality) was highest among teenagers during the first wave. This peak shifted to 25- to 29-year-olds in subsequent waves. The distribution of age-specific mortality during the last three waves was strongly correlated (r = 0·94 and 0·86). With each wave, the pandemic appeared to spread with a comparable early growth rate but then attenuate with varying rates. For the entire population, Re estimates made assuming 2-day serial interval were 1·74 (1·27), 1·74 (1·43), 1·66 (1·25), and 1·86 (1·37), respectively, during the first week (first 3 weeks) of each wave. Using age-specific mortality, the average Re estimates over the first week of each wave were 1·62 (95% CI: 1·55-1·68), 1·68 (1·65-1·72), 1·67 (1·61-1·73), and 1·69 (1·63-1·74), respectively; Re was not significantly different either among age cohorts or between waves. The pandemic generally caused higher mortality among young adults and might have spread mainly among school-aged children during the first wave. We propose mechanisms to explain the timing and transmission dynamics of the four NYC pandemic waves.


The Proteomic Profile of Deleted in Breast Cancer 1 (DBC1) Interactions Points to a Multifaceted Regulation of Gene Expression.
Deleted in breast cancer 1 (DBC1) has emerged as an important regulator of multiple cellular processes, ranging from gene expression to cell cycle progression. DBC1 has been linked to tumorigenesis both as an inhibitor of histone deacetylases, HDAC3 and sirtuin 1, and as a transcriptional cofactor for nuclear hormone receptors. However, despite mounting interest in DBC1, relatively little is known about the range of its interacting partners and the scope of its functions. Here, we carried out a functional proteomics-based investigation of DBC1 interactions in two relevant cell types, T cells and kidney cells. Microscopy, molecular biology, biochemistry, and mass spectrometry studies allowed us to assess DBC1 mRNA and protein levels, localization, phosphorylation status, and protein interaction networks. The comparison of DBC1 interactions in these cell types revealed conserved regulatory roles for DBC1 in gene expression, chromatin organization and modification, and cell cycle progression. Interestingly, we observe previously unrecognized DBC1 interactions with proteins encoded by cancer-associated genes. Among these interactions are five components of the SWI/SNF complex, the most frequently mutated chromatin remodeling complex in human cancers. Additionally, we identified a DBC1 interaction with TBL1XR1, a component of the NCoR complex, which we validated by reciprocal isolation. Strikingly, we discovered that DBC1 associates with proteins that regulate the circadian cycle, including DDX5, DHX9, and SFPQ. We validated this interaction by colocalization and reciprocal isolation. Functional assessment of this association demonstrated that DBC1 protein levels are important for regulating CLOCK and BMAL1 protein oscillations in synchronized T cells. Our results suggest that DBC1 is integral to the maintenance of the circadian molecular clock. Furthermore, the identified interactions provide a valuable resource for the exploration of pathways involved in DBC1-associated tumorigenesis.


A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study.
To assess the long-term efficacy of a variable-dosing regimen with ranibizumab in the Prospective Optical Coherence Tomography (OCT) Imaging of Patients with Neovascular Age-Related Macular Degeneration (AMD) Treated with intraOcular Ranibizumab (PrONTO) Study, patients were followed for 2 years. A 2-year prospective, uncontrolled, variable-dosing regimen with intravitreal ranibizumab based on OCT. In this open-label, prospective, single-center, uncontrolled clinical study, AMD patients with neovascularization involving the central fovea and a central retinal thickness (CRT) of at least 300 microm as measured by OCT were enrolled to receive 3 consecutive monthly intravitreal injections of ranibizumab (0.5 mg) [Lucentis; Genentech Inc, South San Francisco, California, USA]. During the first year, retreatment with ranibizumab was performed at each monthly visit if any criterion was fulfilled such as an increase in OCT-CRT of at least 100 microm or a loss of 5 letters or more. During the second year, the retreatment criteria were amended to include retreatment if any qualitative increase in the amount of fluid was detected using OCT. Forty patients were enrolled and 37 completed the 2-year study. At month 24, the mean visual acuity (VA) improved by 11.1 letters (P < .001) and the OCT-CRT decreased by 212 microm (P < .001). VA improved by 15 letters or more in 43% of patients. These VA and OCT outcomes were achieved with an average of 9.9 injections over 24 months. The PrONTO Study using an OCT-guided variable-dosing regimen with intravitreal ranibizumab resulted in VA outcomes comparable with the outcomes from the phase III clinical studies, but fewer intravitreal injections were required.


Concurrent and predictive validity of physical activity measurement items commonly used in clinical settings--data from SCAPIS pilot study.
As the understanding of how different aspects of the physical activity (PA) pattern relate to health and disease, proper assessment is increasingly important. In clinical care, self-reports are the most commonly used assessment technique. However, systematic comparisons between questions regarding concurrent or criterion validity are rare, as are measures of predictive validity. The aim of the study was to examine the concurrent (using accelerometry as reference) and predictive validity (for metabolic syndrome) of five PA questions. A sample of 948 middle-aged Swedish men and women reported their PA patterns via five different questions and wore an accelerometer (Actigraph GT3X) for a minimum of 4 days. Concurrent validity was assessed as correlations and ROC-analyses. Predictive validity was assessed using logistic regression, controlling for potential confounders. Concurrent validity was low-to-moderate (r <0.35 and ROC AUC <0.7) with large misclassifications regarding time spent sitting/sedentary and in moderate-to vigorous PA. The predictive validity of the questions was good, and one question (PHAS) showed an 80 % decreased odds-ratio of having metabolic syndrome, after taking potential confounders into consideration. In this mixed sample of adults, both concurrent and predictive validity vaired between items and between measures of the physical activity pattern. The PHAS and WALK items are proposed for assessment of adherence to PA recommendations. Assessing PA patterns using self-report measures results in methodological problems when trying to predict individual risk for the metabolic syndrome, as the concurrent validity generally was low. However, several of the investigated questions may be useful for assessing risk at a group level, showing better predictive validity.


Perfluoroalkyl substances measured in breast milk and child neuropsychological development in a Norwegian birth cohort study.
Perfluoroalkyl substances (PFASs) are chemicals with potential neurotoxic effects although the current evidence is still limited. This study investigated the association between perinatal exposure to perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) and neuropsychological development assessed at 6, 12 and 24 months. We measured PFOS and PFOA in breast milk samples collected one month after delivery by mothers of children participating in the HUMIS study (Norway). Cognitive and psychomotor development was measured at 6 and at 24 months using the Ages and Stages Questionnaire (ASQ-II). Behavioral development was assessed using the infant-toddler symptom checklist (ITSC) at 12 and at 24 months. Weighted logistic regression and weighted negative binomial regression models were applied to analyze the associations between PFASs and ASQ-II and ITSC, respectively. The median concentration of PFOS was 110 ng/L, while the median for PFOA was 40 ng/L. We did not detect an increased risk of having an abnormal score in ASQ-II at 6 months or 24 months. Moreover, no consistent increase in behavioral problems assessed at 12 and 24 months by ITSC questionnaire was detected. We observed no association between perinatal PFOS and PFOA exposure and early neuropsychological development. Further longitudinal studies are needed to confirm the effects of these compounds on neuropsychological development in older children.


Does the concept of safety culture help or hinder systems thinking in safety?
The concept of safety culture has become established in safety management applications in all major safety-critical domains. The idea that safety culture somehow represents a "systemic view" on safety is seldom explicitly spoken out, but nevertheless seem to linger behind many safety culture discourses. However, in this paper we argue that the "new" contribution to safety management from safety culture never really became integrated with classical engineering principles and concepts. This integration would have been necessary for the development of a more genuine systems-oriented view on safety; e.g. a conception of safety in which human, technological, organisational and cultural factors are understood as mutually interacting elements. Without of this integration, researchers and the users of the various tools and methods associated with safety culture have sometimes fostered a belief that "safety culture" in fact represents such a systemic view about safety. This belief is, however, not backed up by theoretical or empirical evidence. It is true that safety culture, at least in some sense, represents a holistic term-a totality of factors that include human, organisational and technological aspects. However, the departure for such safety culture models is still human and organisational factors rather than technology (or safety) itself. The aim of this paper is to critically review the various uses of the concept of safety culture as representing a systemic view on safety. The article will take a look at the concepts of culture and safety culture based on previous studies, and outlines in more detail the theoretical challenges in safety culture as a systems concept. The paper also presents recommendations on how to make safety culture more systemic.


Crystal structures of Escherichia coli glycerol kinase variant S58-->W in complex with nonhydrolyzable ATP analogues reveal a putative active conformation of the enzyme as a result of domain motion.
Escherichia coli glycerol kinase (GK) displays "half-of-the-sites" reactivity toward ATP and allosteric regulation by fructose 1, 6-bisphosphate (FBP), which has been shown to promote dimer-tetramer assembly and to inhibit only tetramers. To probe the role of tetramer assembly, a mutation (Ser58-->Trp) was designed to sterically block formation of the dimer-dimer interface near the FBP binding site [Ormo, M., Bystrom, C., and Remington, S. J. (1998) Biochemistry 37, 16565-16572]. The substitution did not substantially change the Michaelis constants or alter allosteric regulation of GK by a second effector, the phosphocarrier protein IIAGlc; however, it eliminated FBP inhibition. Crystal structures of GK in complex with different nontransferable ATP analogues and glycerol revealed an asymmetric dimer with one subunit adopting an open conformation and the other adopting the closed conformation found in previously determined structures. The conformational difference is produced by a approximately 6.0 degrees rigid-body rotation of the N-terminal domain with respect to the C-terminal domain, similar to that observed for hexokinase and actin, members of the same ATPase superfamily. Two of the ATP analogues bound in nonproductive conformations in both subunits. However, beta, gamma-difluoromethyleneadenosine 5'-triphosphate (AMP-PCF2P), a potent inhibitor of GK, bound nonproductively in the closed subunit and in a putative productive conformation in the open subunit, with the gamma-phosphate placed for in-line transfer to glycerol. This asymmetry is consistent with "half-of-the-sites" reactivity and suggests that the inhibition of GK by FBP is due to restriction of domain motion.


The effect of long-term homocysteine-lowering on carotid intima-media thickness and flow-mediated vasodilation in stroke patients: a randomized controlled trial and meta-analysis.
Experimental and epidemiological evidence suggests that homocysteine (tHcy) may be a causal risk factor for atherosclerosis. B-vitamin supplements reduce tHcy and improve endothelial function in short term trials, but the long-term effects of the treatment on vascular structure and function are unknown. We conducted a sub-study of VITATOPS, a randomised, double-blind, placebo-controlled intervention trial designed to test the efficacy of long term B-vitamin supplementation (folic acid 2 mg, vitamin B6 25 mg and vitamin B12 0.5 mg) in the prevention of vascular events in patients with a history of stroke. We measured carotid intima-medial thickness (CIMT) and flow-mediated dilation (FMD) at least two years after randomisation in 162 VITATOPS participants. We also conducted a systematic review and meta-analysis of studies designed to test the effect of B-vitamin treatment on CIMT and FMD. After a mean treatment period of 3.9 +/- 0.9 years, the vitamin-treated group had a significantly lower mean plasma homocysteine concentration than the placebo-treated group (7.9 micromol/L, 95% CI 7.5 to 8.4 versus 11.8 micromol/L, 95% CI 10.9 to 12.8, p < 0.001). Post-treatment CIMT (0.84 +/- 0.17 mm vitamins versus 0.83 +/- 0.18 mm placebo, p = 0.74) and FMD (median of 4.0%, IQR 0.9 to 7.2 vitamins versus 3.0%, IQR 0.6 to 6.6 placebo, p = 0.48) did not differ significantly between groups. A meta-analysis of published randomised data, including those from the current study, suggested that B-vitamin supplements should reduce CIMT (-0.10 mm, 95% CI -0.20 to -0.01 mm) and increase FMD (1.4%, 95% CI 0.7 to 2.1%). However, the improvement in endothelial function associated with homocysteine-lowering treatment was significant in short-term studies but not in longer trials. Although short-term treatment with B-vitamins is associated with increased FMD, long-term homocysteine-lowering did not significantly improve FMD or CIMT in people with a history of stroke.


Community impacts of Prosopis juliflora invasion: biogeographic and congeneric comparisons.
We coordinated biogeographical comparisons of the impacts of an exotic invasive tree in its native and non-native ranges with a congeneric comparison in the non-native range. Prosopis juliflora is taxonomically complicated and with P. pallida forms the P. juliflora complex. Thus we sampled P. juliflora in its native Venezuela, and also located two field sites in Peru, the native range of Prosopis pallida. Canopies of Prosopis juliflora, a native of the New World but an invader in many other regions, had facilitative effects on the diversity of other species in its native Venezuela, and P. pallida had both negative and positive effects depending on the year, (overall neutral effects) in its native Peru. However, in India and Hawaii, USA, where P. juliflora is an aggressive invader, canopy effects were consistently and strongly negative on species richness. Prosopis cineraria, a native to India, had much weaker effects on species richness in India than P. juliflora. We carried out multiple congeneric comparisons between P. juliflora and P. cineraria, and found that soil from the rhizosphere of P. juliflora had higher extractable phosphorus, soluble salts and total phenolics than P. cineraria rhizosphere soils. Experimentally applied P. juliflora litter caused far greater mortality of native Indian species than litter from P. cineraria. Prosopis juliflora leaf leachate had neutral to negative effects on root growth of three common crop species of north-west India whereas P. cineraria leaf leachate had positive effects. Prosopis juliflora leaf leachate also had higher concentrations of total phenolics and L-tryptophan than P. cineraria, suggesting a potential allelopathic mechanism for the congeneric differences. Our results also suggest the possibility of regional evolutionary trajectories among competitors and that recent mixing of species from different trajectories has the potential to disrupt evolved interactions among native species.


A cell-free assay for the insertion of a viral glycoprotein into the plasma membrane.
A cell-free assay has been developed for the delivery of influenza virus neuraminidase to the plasma membrane. Two types of postnuclear supernatant, which acted as donor and acceptor of the enzyme, were prepared from baby hamster kidney cells. Donor preparations were obtained from cells infected with influenza virus and containing neuraminidase en route to the plasma membrane. Acceptor preparations were obtained from cells containing, bound to their plasma membranes, Semliki Forest virus with envelope glycoproteins bearing [3H]N-acetylneuraminic acid. Fusion between vesicles from these two preparations permits access of the enzyme to its substrate, which results in the release of free [3H]N-acetylneuraminic acid. This release was detected through the transfer of radioactivity from a trichloroacetic acid-insoluble to a trichloroacetic acid-soluble fraction. An ATP-dependent component of release was found, which appears to be a consequence of vesicle fusion. This component was enhanced when the donor was prepared from cells in which the enzyme had been concentrated in a compartment between the Golgi complex and the plasma membrane, which indicates that a specific exocytic fusion event has been reconstituted. The extent of fusion is greatly reduced by pre-treatment of donor and acceptor preparations with trypsin, which points to the involvement of proteins in the fusion reaction.


Fabrication of biofunctionalized microfluidic structures by low-temperature wax bonding.
In this work, a new fabrication technology for microfluidics based on the use of wax is described. Microfluidic structures are assembled using wax as both a thermoplastic adhesive layer between two glass substrates and a spacer layer defining the microchannels. Wax patterns with dimensions down to 25 μm are easily produced on glass substrates using specially developed decal-transfer microlithography. A complete microfluidic system is created by bonding the wax patterned layer with an additional glass substrate. On the basis of the special melting behavior of waxes, an effective glass-wax bonding is achieved at 40 °C by applying a soft pressure and without the requirement of any glass pretreatment. Wax bonding provides an effective sealing of the fluidic networks even on nonflat glass substrates (i.e., containing metal electrodes). The mild conditions required for the bonding process enables the fabrication of lab-on-a-chip devices incorporating biomolecules, as is demonstrated with the implementation of a simple heterogeneous immunoassay in a microfluidic device with amperometric detection.


Reverse Dynamization Accelerates Bone-Healing in a Large-Animal Osteotomy Model.
Reverse dynamization is a mechanical manipulation regimen designed to accelerate bone-healing and remodeling. It is based on the hypothesis that a fracture that is initially stabilized less rigidly allows micromotion to encourage initial cartilaginous callus formation. Once substantial callus has formed, the stabilization should then be converted to a rigid configuration to prevent the disruption of neovascularization. The aim of the present study was to investigate whether bone-healing can be accelerated using a regimen of reverse dynamization in a large-animal osteotomy model. Transverse 2-mm tibial osteotomies were created in 18 goats, stabilized using circular external fixation, and divided into groups of 6 goats each: static fixation (rigid fixation), dynamic fixation (continuous micromotion using dynamizers), and reverse dynamization (initial micromotion using dynamizers followed by rigid fixation at 3 weeks postoperatively). Healing was assessed with the use of radiographs, micro-computed tomography, and mechanical testing. Radiographic evaluation showed earlier and more robust callus formation in the dynamic fixation and reverse dynamization groups compared with the static fixation group. After 8 weeks of treatment, the reverse dynamization group had reduced callus size, less bone volume, higher bone mineral density, and no evidence of radiolucent lines compared with the static fixation and dynamic fixation groups. This appearance is characteristic of advanced remodeling, returning closest to the values of intact bone. Moreover, the tibiae in the reverse dynamization group were significantly stronger in torsion compared with those in the static fixation and dynamic fixation groups. These findings confirmed that tibial osteotomies under reverse dynamization healed faster, healed objectively better, and were considerably stronger, all suggesting an accelerated healing and remodeling process. This study demonstrates that the concept of reverse dynamization challenges the current understanding regarding the optimal fixation stability necessary to maximize the regenerative capacity of bone-healing. When reverse dynamization is employed in the clinical setting, it may be able to improve the treatment of fractures by reducing the time to union and potentially lowering the risk of delayed union and nonunion.


Variational multiscale models for charge transport.
This work presents a few variational multiscale models for charge transport in complex physical, chemical and biological systems and engineering devices, such as fuel cells, solar cells, battery cells, nanofluidics, transistors and ion channels. An essential ingredient of the present models, introduced in an earlier paper (Bulletin of Mathematical Biology, 72, 1562-1622, 2010), is the use of differential geometry theory of surfaces as a natural means to geometrically separate the macroscopic domain from the microscopic domain, meanwhile, dynamically couple discrete and continuum descriptions. Our main strategy is to construct the total energy functional of a charge transport system to encompass the polar and nonpolar free energies of solvation, and chemical potential related energy. By using the Euler-Lagrange variation, coupled Laplace-Beltrami and Poisson-Nernst-Planck (LB-PNP) equations are derived. The solution of the LB-PNP equations leads to the minimization of the total free energy, and explicit profiles of electrostatic potential and densities of charge species. To further reduce the computational complexity, the Boltzmann distribution obtained from the Poisson-Boltzmann (PB) equation is utilized to represent the densities of certain charge species so as to avoid the computationally expensive solution of some Nernst-Planck (NP) equations. Consequently, the coupled Laplace-Beltrami and Poisson-Boltzmann-Nernst-Planck (LB-PBNP) equations are proposed for charge transport in heterogeneous systems. A major emphasis of the present formulation is the consistency between equilibrium LB-PB theory and non-equilibrium LB-PNP theory at equilibrium. Another major emphasis is the capability of the reduced LB-PBNP model to fully recover the prediction of the LB-PNP model at non-equilibrium settings. To account for the fluid impact on the charge transport, we derive coupled Laplace-Beltrami, Poisson-Nernst-Planck and Navier-Stokes equations from the variational principle for chemo-electro-fluid systems. A number of computational algorithms is developed to implement the proposed new variational multiscale models in an efficient manner. A set of ten protein molecules and a realistic ion channel, Gramicidin A, are employed to confirm the consistency and verify the capability. Extensive numerical experiment is designed to validate the proposed variational multiscale models. A good quantitative agreement between our model prediction and the experimental measurement of current-voltage curves is observed for the Gramicidin A channel transport. This paper also provides a brief review of the field.


Association of Diabetes Subgroups With Race/Ethnicity, Risk Factor Burden and Complications: The MASALA and MESA Studies.
There are known disparities in diabetes complications by race and ethnicity. Although diabetes subgroups may contribute to differential risk, little is known about how subgroups vary by race/ethnicity. Data were pooled from 1293 (46% female) participants of the Mediators of Atherosclerosis in South Asians Living in America (MASALA) and the Multi-Ethnic Study of Atherosclerosis (MESA) who had diabetes (determined by diabetes medication use, fasting glucose, and glycated hemoglobin [HbA1c]), including 217 South Asian, 240 non-Hispanic white, 125 Chinese, 387 African American, and 324 Hispanic patients. We applied k-means clustering using data for age at diabetes diagnosis, body mass index, HbA1c, and homeostatic model assessment measures of insulin resistance and beta cell function. We assessed whether diabetes subgroups were associated with race/ethnicity, concurrent cardiovascular disease risk factors, and incident diabetes complications. Five diabetes subgroups were characterized by older age at diabetes onset (43%), severe hyperglycemia (26%), severe obesity (20%), younger age at onset (1%), and requiring insulin medication use (9%). The most common subgroup assignment was older onset for all race/ethnicities with the exception of South Asians where the severe hyperglycemia subgroup was most likely. Risk for renal complications and subclinical coronary disease differed by diabetes subgroup and, separately, race/ethnicity. Racial/ethnic differences were present across diabetes subgroups, and diabetes subgroups differed in risk for complications. Strategies to eliminate racial/ethnic disparities in complications may need to consider approaches targeted to diabetes subgroup.


Fat utilization during exercise: adaptation to a fat-rich diet increases utilization of plasma fatty acids and very low density lipoprotein-triacylglycerol in humans.
1. This study was carried out to test the hypothesis that the greater fat oxidation observed during exercise after adaptation to a high-fat diet is due to an increased uptake of fat originating from the bloodstream. 2. Of 13 male untrained subjects, seven consumed a fat-rich diet (62 % fat, 21 % carbohydrate) and six consumed a carbohydrate-rich diet (20 % fat, 65 % carbohydrate). After 7 weeks of training and diet, 60 min of bicycle exercise was performed at 68 +/- 1 % of maximum oxygen uptake. During exercise [1-(13)C]palmitate was infused, arterial and venous femoral blood samples were collected, and blood flow was determined by the thermodilution technique. Muscle biopsy samples were taken from the vastus lateralis muscle before and after exercise. 3. During exercise, the respiratory exchange ratio was significantly lower in subjects consuming the fat-rich diet (0.86 +/- 0.01, mean +/- S.E.M.) than in those consuming the carbohydrate-rich diet (0.93 +/- 0.02). The leg fatty acid (FA) uptake (183 +/- 37 vs. 105 +/- 28 micromol min(-1)) and very low density lipoprotein-triacylglycerol (VLDL-TG) uptake (132 +/- 26 vs. 16 +/- 21 micromol min(-1)) were both higher (each P < 0.05) in the subjects consuming the fat-rich diet. Whole-body plasma FA oxidation (determined by comparison of (13)CO(2) production and blood palmitate labelling) was 55-65 % of total lipid oxidation, and was higher after the fat-rich diet than after the carbohydrate-rich diet (13.5 +/- 1.2 vs. 8.9 +/- 1.1 micromol min(-1) kg(-1); P < 0.05). Muscle glycogen breakdown was significantly lower in the subjects taking the fat-rich diet than those taking the carbohydrate-rich diet (2.6 +/- 0.5 vs. 4.8 +/- 0.5 mmol (kg dry weight)(-1) min(-1), respectively; P < 0.05), whereas leg glucose uptake was similar (1.07 +/- 0.13 vs. 1.15 +/- 0.13 mmol min(-1)). 4. In conclusion, plasma VLDL-TG appears to be an important substrate source during aerobic exercise, and in combination with the higher plasma FA uptake it accounts for the increased fat oxidation observed during exercise after fat diet adaptation. The decreased carbohydrate oxidation was apparently due to muscle glycogen sparing and not to diminished plasma glucose uptake.


Inspectors' responses to adolescents' assessment of quality of care: a case study on involving adolescents in inspections.
Users of care services are increasingly participating in inspections of the quality of care. In practice, incorporating service users' views is difficult, as users may have other views on good care than inspectors and thus give information that does not fit the inspectors' assessment criteria. This study compared the views on good care of young care users (adolescents) and inspectors, seeking to understand what the differences and similarities mean to incorporating the users' views in inspections. We conducted a single-case study combining document analysis with a meeting with inspectors. The selected case came from a Dutch inspectorate and involved a thematic inspection of care for children growing up poor. Inspectors and adolescents agree on the importance of timely care, creating opportunities for personal development, and a respectful relationship. The views on quality of care differ with regard to sharing information, creating solutions, and the right moment to offer help. We identified three ways inspectors deal with the differences: 1) prioritize their own views, 2) pass the problem onto others to solve, and 3) separate the differing perspectives. With similar viewpoints, inspectors use the adolescents' views to support their assessments. When viewpoints conflict, information from adolescents does not affect the inspectors' judgments. Explanations are related to the vulnerability of the adolescents involved, the inspectorate's organizational rules and routines and the external regulatory context. Service user involvement in inspections potentially impacts the quality of care. Yet, conflicts between the views of service users and inspectors are not easily overcome in the regulatory context.


Muscle tenderness in tension headache treated with acupuncture or physiotherapy.
Sixty-two female patients with chronic tension headache were randomized into two treatment groups--acupuncture and physiotherapy. The intensity of headache, muscle tenderness and neck mobility was assessed before and after treatment. Thirty healthy women were used for comparison. Before treatment it was found that muscle tenderness was increased and neck rotation was reduced in the patient group compared with controls. There was a significant correlation between the intensity of headache and muscle tenderness. After treatment, the intensity of headache and muscle tenderness were reduced in both treatment groups. The headache was more improved in the physiotherapy group, and there was a marked reduction in the intake of analgesics. The tenderness was reduced in all muscles tested in the physiotherapy group but only in some of the muscles after acupuncture. The limitation of neck rotation was not influenced by either treatment.


The c-Met Tyrosine Kinase Inhibitor JNJ-38877605 Causes Renal Toxicity through Species-Specific Insoluble Metabolite Formation.
The receptor tyrosine kinase c-Met plays an important role in tumorigenesis and is a novel target for anticancer treatment. This phase I, first-in-human trial, explored safety, pharmacokinetics, pharmacodynamics, and initial antitumor activity of JNJ-38877605, a potent and selective c-Met inhibitor. We performed a phase I dose-escalation study according to the standard 3+3 design. Even at subtherapeutic doses, mild though recurrent renal toxicity was observed in virtually all patients. Renal toxicity had not been observed in preclinical studies in rats and dogs. Additional preclinical studies pointed toward the rabbit as a suitable toxicology model, as the formation of the M10 metabolite of JNJ-38877605 specifically occurred in rabbits and humans. Additional toxicology studies in rabbits clearly demonstrated that JNJ-38877605 induced species-specific renal toxicity. Histopathological evaluation in rabbits revealed renal crystal formation with degenerative and inflammatory changes. Identification of the components of these renal crystals revealed M1/3 and M5/6 metabolites. Accordingly, it was found that humans and rabbits showed significantly increased systemic exposure to these metabolites relative to other species. These main culprit insoluble metabolites were generated by aldehyde oxidase activity. Alternative dosing schedules of JNJ-3877605 and concomitant probenecid administration in rabbits failed to prevent renal toxicity at dose levels that could be pharmacologically active. Combined clinical and correlative preclinical studies suggest that renal toxicity of JNJ-38877605 is caused by the formation of species-specific insoluble metabolites. These observations preclude further clinical development of JNJ-38877605.


The International Society of Hypertension and World Hypertension League call on governments, nongovernmental organizations and the food industry to work to reduce dietary sodium.
The International Society of Hypertension and the World Hypertension League have developed a policy statement calling for reducing dietary salt. The policy supports the WHO and the United Nations recommendations, which are based on a comprehensive and up-to-date review of relevant research. The policy statement calls for broad societal action to reduce dietary salt, thus reducing blood pressure and preventing hypertension and its related burden of cardiovascular disease. The hypertension organizations and experts need to become more engaged in the efforts to prevent hypertension and to advocate strongly to have dietary salt reduction policies implemented. The statement is being circulated to national hypertension organizations and to international nongovernmental health organizations for consideration of endorsement. Member organizations of the International Society of Hypertension and the World Hypertension League are urged to support this effort.


Exposure to metalworking fluid aerosols and determinants of exposure.
Metalworking fluid (MWF) aerosols are associated with respiratory disorders including asthma and hypersensitivity pneumonitis. The aims of this study were to describe exposure to inhalable MWF aerosols and volatile compounds in machine shops, to estimate the influence of important determinants of exposure and to compare different sampling techniques for MWF aerosols. Personal full-shift air samples of inhalable aerosol (PAS-6 sampler) and total aerosol (open-faced sampler) were collected on operators in five medium to big-sized machine shops in three companies. The filters were analysed gravimetrically and extracted by supercritical fluid extraction for MWF aerosol and triethanolamine content. In addition, personal measurements were taken for formaldehyde and volatile compounds on adsorbent samplers. Continuous dust measurements were performed with a real-time instrument (DataRAM) during 2 h periods, using 1-min average values. In total, 95 measurements of inhalable aerosol and extracted MWF aerosols on 51 operators were conducted. Within the companies, the average exposure to inhalable aerosol ranged from 0.19 to 0.25 mg m(-3) with geometric standard deviations from 1.56 to 1.79. On average, the extracted fraction of MWF aerosol was 67% of the inhalable aerosol concentration. The exposure levels of triethanolamine, formaldehyde and volatile compounds were generally low. About 45% of the between-worker variance could be explained by use of compressed air, lack of complete enclosure of machines or grinding as cutting task. In 21 workers with continuous aerosol measurements, short-term peak exposures during 6% of the work time contributed to approximately 25% of the average concentration of inhalable MWF aerosol. Inhalable MWF aerosol concentration measured with the PAS-6 sampler was a factor 2 higher than the concentrations derived from the open-faced sampler. These findings suggest that control measures, such as full enclosure of machines and the elimination of the use of compressed air as cleaning technique, are required to reduce the exposure to MWF aerosols to levels below the expected threshold for adverse respiratory health effects.


ACR Appropriateness Criteria® Nontraumatic Aortic Disease.
Nontraumatic aortic disease can be caused by a wide variety of disorders including congenital, inflammatory, infectious, metabolic, neoplastic, and degenerative processes. Imaging examinations such as radiography, ultrasound, echocardiography, catheter-based angiography, CT, MRI, and nuclear medicine examinations are essential for diagnosis, treatment planning, and assessment of therapeutic response. Depending upon the clinical scenario, each of these modalities has strengths and weaknesses. Whenever possible, the selection of a diagnostic imaging examination should be based upon the best available evidence. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. The purpose of this document is to assist physicians select the most appropriate diagnostic imaging examination for nontraumatic aortic diseases.


Binary DNA nanostructures for data encryption.
We present a simple and secure system for encrypting and decrypting information using DNA self-assembly. Binary data is encoded in the geometry of DNA nanostructures with two distinct conformations. Removing or leaving out a single component reduces these structures to an encrypted solution of ssDNA, whereas adding back this missing "decryption key" causes the spontaneous formation of the message through self-assembly, enabling rapid read out via gel electrophoresis. Applications include authentication, secure messaging, and barcoding.


Serological signature of tick-borne pathogens in Scandinavian brown bears over two decades.
Anthropogenic disturbances are changing the geographic distribution of ticks and tick-borne diseases. Over the last few decades, the tick Ixodes ricinus has expanded its range and abundance considerably in northern Europe. Concurrently, the incidence of tick-borne diseases, such as Lyme borreliosis and tick-borne encephalitis, has increased in the human populations of the Scandinavian countries. Wildlife populations can serve as sentinels for changes in the distribution of tick-borne diseases. We used serum samples from a long-term study on the Scandinavian brown bear, Ursus arctos, and standard immunological methods to test whether exposure to Borrelia burgdorferi sensu lato, the causative agent of Lyme borreliosis, and tick-borne encephalitis virus (TBEV) had increased over time. Bears had been sampled over a period of 18 years (1995-2012) from a southern area, where Ixodes ricinus ticks are present, and a northern area where ticks are uncommon or absent. Bears had high levels of IgG antibodies against B. burgdorferi sensu lato but not TBEV. Bears at the southern area had higher values of anti-Borrelia IgG antibodies than bears at the northern area. Over the duration of the study, the value of anti-Borrelia IgG antibodies increased in the southern area but not the northern area. Anti-Borrelia IgG antibodies increased with the age of the bear but declined in the oldest age classes. Our study is consistent with the view that ticks and tick-borne pathogens are expanding their abundance and prevalence in Scandinavia. Long-term serological monitoring of large mammals can provide insight into how anthropogenic disturbances are changing the distribution of ticks and tick-borne diseases.


In vivo assessment of SMT19969 in a hamster model of clostridium difficile infection.
SMT19969 [2,2'-bis(4-pyridyl)3H,3'-H 5,5-bibenzimidazole] is a novel narrow-spectrum nonabsorbable antibiotic currently in development for the treatment of Clostridium difficile infection. The comparative activities of SMT19969 and vancomycin against nonepidemic and epidemic strains of C. difficile were studied in an established hamster model. Against nonepidemic (VA11) strains, the survival rates of SMT19969-treated animals ranged from 80% to 95%. Vancomycin exhibited 100% protection during treatment, with relapse observed starting on day 9 and 50% survival at day 20. At 50 mg/kg of body weight, SMT19969 administered orally once daily for 5 days provided full protection of treated animals on the dosing days and through day 12 against epidemic strains. Vancomycin also protected during the dosing interval, but apparent relapse occurred earlier, starting on day 11. SMT19969 exhibited excellent in vitro activity, with MICs of 0.25 μg/ml for all isolates. The MICs for vancomycin were 2- to 4-fold higher at ≤0.5 to 1 μg/ml. All plasma sample concentrations of SMT19969 were below the limit of quantification (25 ng/ml) at all time points, consistent with the reported lack of bioavailability of the compound. Cecal concentrations were significantly above the MIC (ranging from 96 μg/ml to 172 μg/ml).


db/db mice exhibit severe wound-healing impairments compared with other murine diabetic strains in a silicone-splinted excisional wound model.
The pathophysiology of diabetic wound healing and the identification of new agents to improve clinical outcomes continue to be areas of intense research. There currently exist more than 10 different murine models of diabetes. The degree to which wound healing is impaired in these different mouse models has never been directly compared. We determined whether differences in wound impairment exist between diabetic models in order to elucidate which model would be the best to evaluate new treatment strategies. Three well-accepted mouse models of diabetes were used in this study: db/db, Akita, and streptozocin (STZ)-induced C57BL/6J. Using an excisional model of wound healing, we demonstrated that db/db mice exhibit severe impairments in wound healing compared with STZ and Akita mice. Excisional wounds in db/db mice show a statistically significant delay in wound closure, decreased granulation tissue formation, decreased wound bed vascularity, and markedly diminished proliferation compared with STZ, Akita, and control mice. There was no difference in the rate of epithelialization of the full-thickness wounds between the diabetic or control mice. Our results suggest that splinted db/db mice may be the most appropriate model for studying diabetic wound-healing interventions as they demonstrate the most significant impairment in wound healing. This study utilized a novel model of wound healing developed in our laboratory that stents wounds open using silicone splints to minimize the effects of wound contraction. As such, it was not possible to directly compare the results of this study with other studies that did not use this wound model.


Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that destroys patient memory and cognition, communication ability with the social environment and the ability to carry out daily activities. Despite extensive research into the pathogenesis of AD, a neuroprotective treatment - particularly for the early stages of disease - remains unavailable for clinical use. In this review, we advance the suggestion that lipoic acid (LA) may fulfil this therapeutic need. A naturally occurring cofactor for the mitochondrial enzymes pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, LA has been shown to have a variety of properties which can interfere with the pathogenesis or progression of AD. For example, LA increases acetylcholine (ACh) production by activation of choline acetyltransferase and increases glucose uptake, thus supplying more acetyl-CoA for the production of ACh. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals and also scavenges reactive oxygen species (ROS), thereby increasing the levels of reduced glutathione. In addition, LA down-regulates the expression of redox-sensitive pro-inflammatory proteins including TNF and inducible nitric oxide synthase. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. In human plasma, LA exists in an equilibrium of free and plasma protein bound form. Up to 150 muM, it is bound completely, most likely binding to high affinity fatty acid sites on human serum albumin, suggesting that one large dose rather than continuous low doses (as provided by "slow release" LA) will be beneficial for delivery of LA to the brain. Evidence for a clinical benefit for LA in dementia is yet limited. There are only two published studies, in which 600 mg LA was given daily to 43 patients with AD (receiving a standard treatment with choline-esterase inhibitors) in an open-label study over an observation period of up to 48 months. Whereas the improvement in patients with moderate dementia was not significant, the disease progressed extremely slowly (change in ADAScog: 1.2 points=year, MMSE: -0.6 points=year) in patients with mild dementia (ADAScog<15). Data from cell culture and animal models suggest that LA could be combined with nutraceuticals such as curcumin, (-)-epigallocatechin gallate (from green tea) and docosahexaenoic acid (from fish oil) to synergistically decrease oxidative stress, inflammation, Abeta levels and Abeta plaque load and thus provide a combined benefit in the treatment of AD.


Molecular diversity of voltage-gated sodium channel alpha subunits expressed in neuronal and non-neuronal excitable cells.
In order to investigate the role of molecular diversity of voltage-activated sodium channel alpha-subunits in excitability of neuronal and non-neuronal cells, we carried out patch-clamp recordings and single-cell RT-PCR on two different types of mammalian excitable cells i.e. hippocampal neurons and non-neuronal utricular epithelial hair cells. In each cell type, multiple different combinations of sodium channel alpha-subunits exist from cell to cell despite similar sodium current properties. The mRNA isoforms, Nav1.2 and Nav1.6, are the most frequently detected by single cell analysis in the two cell types while Nav1.3 and Nav1.7 are also moderately expressed in embryonic hippocampal neurons and in neonatal utricular hair cells respectively. By investigating the particular alternate splice isoforms of Nav1.6 occurring at the exon 18 of the mouse orthologue SCN8A, we revealed that this subunit co-exist in the two cell types under different alternative spliced isoforms. The expression of non-functional isoforms of Nav1.6 in utricular epithelial hair cells excludes the involvement of this subunit in supporting their excitability. Thus, from a functional point of view, the present results suggest that, at the single cell level, both neuronal and non-neuronal excitable cells expressed different and complex patterns of sodium channel gene transcripts but this diversity alone cannot explain the sodium current properties of these cell types.


Occupational Exposure to Secondhand Cannabis Smoke Among Law Enforcement Officers Providing Security at Outdoor Concert Events.
Numerous states within the USA have legalized cannabis for medical or non-medical (adult/recreational) use. With the increased availability and use of cannabis, occupational and environmental exposures to secondhand cannabis smoke (SHCS) raise concerns over whether non-users may be at risk for a 'contact high', impaired neurocognitive function, harm from irritants and carcinogens in smoke, or potentially failing a cannabis screening test. The extent of health effects from potential occupational exposure to SHCS is unknown. This is a study of occupational exposures to SHCS among law enforcement officers (LEOs) providing security at outdoor concerts on a college campus in a state where adult use of cannabis is legal. Investigators evaluated a convenience sample of LEOs' potential exposure to SHCS and symptoms experienced while providing security during two open-air stadium rock-n-roll concerts on consecutive days in July 2018. During each event, full-shift area and LEO personal air samples were collected for Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of cannabis. Urine (pre- and postevent; n = 58) and blood (postevent; n = 29) were also collected and analyzed for Δ9-THC and two of its metabolites [11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) and 11-nor-hydroxy-delta-9-tetrahydrocannabinol (OH-THC)]. Urine samples were analyzed using ultrahigh performance liquid chromatography coupled with positive electrospray ionization tandem mass spectrometry and results were compared with the Department of Transportation guidelines for urine screening for cannabis. Blood (postevent) samples were also collected and the plasma fraction was tested for Δ9-THC, THC-COOH, and OH-THC using high-performance liquid chromatography coupled with mass spectrometry. LEOs also completed a medical questionnaire asking about symptoms experienced during the concerts. Twenty-nine LEOs participated in the evaluation. Measurable amounts of Δ9-THC were found in area (concentrations ranged from non-detectable to 330 ng m-3) and personal air samples (53-480 ng m-3). Small amounts (<1.0 ng ml-1) of a Δ9-THC metabolite (THC-COOH) were found in the postevent urine of 34% of LEOs. Neither Δ9-THC nor its metabolites were detected in any blood sample. LEOs reported experiencing non-specific symptoms during the concerts, such as burning, itchy, or red eyes (31%); dry mouth (21%); headache (21%); and coughing (21%). Identification of Δ9-THC in the breathing zone for some LEOs indicates the potential for airborne exposure to the psychoactive component of cannabis. However, the magnitude of these exposures was small compared with those that would result in a dose of Δ9-THC associated with psychotropic effects. Similarly, THC-COOH was found in the postevent urine of some LEOs at concentrations that were orders of magnitude below active use cut-points used during a cannabis screening test (50 ng ml-1). Exposure to SHCS was not high enough to detect concentrations of THC, THC-COOH, to OH-THC in the blood, which could be due to differences between the limits of detection for the tests employed. The ocular and respiratory symptoms reported by LEOs may be related to irritants in SHCS. However, the health effects of SHCS remain unclear, and further research concerning occupational and environmental exposures is warranted.


Learning to fear a second-order stimulus following vicarious learning.
Vicarious fear learning refers to the acquisition of fear via observation of the fearful responses of others. The present study aims to extend current knowledge by exploring whether second-order vicarious fear learning can be demonstrated in children. That is, whether vicariously learnt fear responses for one stimulus can be elicited in a second stimulus associated with that initial stimulus. Results demonstrated that children's (5-11 years) fear responses for marsupials and caterpillars increased when they were seen with fearful faces compared to no faces. Additionally, the results indicated a second-order effect in which fear-related learning occurred for other animals seen together with the fear-paired animal, even though the animals were never observed with fearful faces themselves. Overall, the findings indicate that for children in this age group vicariously learnt fear-related responses for one stimulus can subsequently be observed for a second stimulus without it being experienced in a fear-related vicarious learning event. These findings may help to explain why some individuals do not recall involvement of a traumatic learning episode in the development of their fear of a specific stimulus.


Characterization of P. falciparum dipeptidyl aminopeptidase 3 specificity identifies differences in amino acid preferences between peptide-based substrates and covalent inhibitors.
Malarial dipeptidyl aminopeptidases (DPAPs) are cysteine proteases important for parasite development thus making them attractive drug targets. In order to develop inhibitors specific to the parasite enzymes, it is necessary to map the determinants of substrate specificity of the parasite enzymes and its mammalian homologue cathepsin C (CatC). Here, we screened peptide-based libraries of substrates and covalent inhibitors to characterize the differences in specificity between parasite DPAPs and CatC, and used this information to develop highly selective DPAP1 and DPAP3 inhibitors. Interestingly, while the primary amino acid specificity of a protease is often used to develop potent inhibitors, we show that equally potent and highly specific inhibitors can be developed based on the sequences of nonoptimal peptide substrates. Finally, our homology modelling and docking studies provide potential structural explanations of the differences in specificity between DPAP1, DPAP3, and CatC, and between substrates and inhibitors in the case of DPAP3. Overall, this study illustrates that focusing the development of protease inhibitors solely on substrate specificity might overlook important structural features that can be exploited to develop highly potent and selective compounds.


Characteristics of burn patients developing pressure ulcers.
In 1997 a prospective study to identify pressure ulcer development and identify risk factors was conducted on 217 consecutive patients in the burn center. Weekly rounds were conducted, and the specifics of pressure ulcer development, demographics, concurrent injuries, comorbid conditions, risk factors, and patient outcomes were identified. An incidence of 4.1% was identified, with the most common locations being the sacrum, occipital area, and heel. All patients with pressure ulcers met criteria for a major burn injury. The patients had concurrent injuries or an infectious process, had more surgical procedures, and were older than the group that did not develop pressure ulcers. A lower Braden Scale for risk assessment and a later onset of ulceration was noted in this population compared with previous studies of nonburn patients. The results of this study have led to changes in our burn clinical pathways that target preventive strategies in high-risk patients.


Robot-Aided Systems for Improving the Assessment of Upper Limb Spasticity: A Systematic Review.
Spasticity is a motor disorder that causes stiffness or tightness of the muscles and can interfere with normal movement, speech, and gait. Traditionally, the spasticity assessment is carried out by clinicians using standardized procedures for objective evaluation. However, these procedures are manually performed and, thereby, they could be influenced by the clinician's subjectivity or expertise. The automation of such traditional methods for spasticity evaluation is an interesting and emerging field in neurorehabilitation. One of the most promising approaches is the use of robot-aided systems. In this paper, a systematic review of systems focused on the assessment of upper limb (UL) spasticity using robotic technology is presented. A systematic search and review of related articles in the literature were conducted. The chosen works were analyzed according to the morphology of devices, the data acquisition systems, the outcome generation method, and the focus of intervention (assessment and/or training). Finally, a series of guidelines and challenges that must be considered when designing and implementing fully-automated robot-aided systems for the assessment of UL spasticity are summarized.


Which preoperative factors, including bone bruise, are associated with knee pain/symptoms at index anterior cruciate ligament reconstruction (ACLR)? A Multicenter Orthopaedic Outcomes Network (MOON) ACLR Cohort Study.
Increased knee pain at the time of anterior cruciate ligament reconstruction may potentially predict more difficult rehabilitation, prolonged recovery, and/or be predictive of increased knee pain at 2 years. A bone bruise and/or other preoperative factors are associated with more knee pain/symptoms at the time of index anterior cruciate ligament reconstruction, and the presence of a bone bruise would be associated with specific demographic and injury-related factors. Cohort study (prevalence); Level of evidence, 2. In 2007, the Multicenter Orthopaedic Outcomes Network (MOON) database began to prospectively collect surgeon-reported magnetic resonance imaging bone bruise status. A multivariable analysis was performed to (1) determine if a bone bruise, among other preoperative factors, is associated with more knee symptoms/pain and (2) examine the association of factors related to bone bruise. To evaluate the association of a bone bruise with knee pain/symptoms, linear multiple regression models were fit using the continuous scores of the Knee injury and Osteoarthritis Outcome Score (KOOS) symptoms and pain subscales and the Short Form 36 (SF-36) bodily pain subscale as dependent variables. To examine the association between a bone bruise and risk factors, a logistic regression model was used, in which the dependent variable was the presence or absence of a bone bruise. Baseline data for 525 patients were used for analysis, and a bone bruise was present in 419 (80%). The cohort comprises 58% male patients, with a median age of 23 years. The median Marx activity level was 13. Factors associated with more pain were higher body mass index (P < .0001), female sex (P = .001), lateral collateral ligament injury (P = .012), and older age (P = .038). Factors associated with more symptoms were a concomitant lateral collateral ligament injury (P = .014), higher body mass index (P < .0001), and female sex (P < .0001). Bone bruise is not associated with symptoms/pain at the time of index anterior cruciate ligament reconstruction. None of the factors included in the SF-36 bodily pain model were found to be significant. After controlling for other baseline factors, the following factors were associated with a bone bruise: younger age (P = .034) and not jumping at the time of injury (P = .006). After anterior cruciate ligament injury, risk factors associated with a bone bruise are younger age and not jumping at the time of injury. Bone bruise is not associated with symptoms/pain at the time of index anterior cruciate ligament reconstruction.


Genetic risk score predicting accelerated progression from mild cognitive impairment to Alzheimer's disease.
Aside from APOE, the genetic factors that influence the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) remain largely unknown. We assessed whether a genetic risk score (GRS), based on eight non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD. Among 288 subjects with MCI, follow-up (mean 26.3 months) identified 118 MCI-converters to AD and 170 MCI-nonconverters. We genotyped ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179. For each subject we calculated a cumulative GRS, defined as the number of risk alleles (range 0-16) with each allele weighted by the AD risk odds ratio. GRS was not associated with risk of conversion from MCI to AD. However, MCI-converters to AD harboring six or more risk alleles (second and third GRS tertiles) progressed twofold more rapidly to AD when compared with those with less than six risk alleles (first GRS tertile). Our GRS is a first step toward development of prediction models for conversion from MCI to AD that incorporate aggregate genetic factors.


The complete unique long sequence and the overall genomic organization of the GA strain of Marek's disease virus.
We have determined the DNA sequence of the unique long (UL) region and the repeat long (RL) region in the genome of serotype 1 GA strain of Marek's disease virus (MDV), a member of the alpha-herpesvirus family. With this information, the complete nucleotide sequence of GA-MDV is now known. The entire GA-MDV genome is predicted to be about 174 kbp in size, with an organization of TRL-UL-IRL-IRS-US-TRS, typical of a alpha-herpesvirus. The UL sequence contains 113,508 bp and has a base composition of 41.7% G + C. A total of 67 ORFs were identified completely within the UL region, among which 55 are homologous to genes encoded by herpes simplex virus-1. Twelve of them are unique with presently unknown functions. The sequence of RL reported here together with those published earlier reveal the major structural features of the RL. Virtually all of the ORFs encoded by RL are specific to serotype I of MDV. These ORFs are likely to contribute to some of the unique biological properties of MDV. Among the proteins encoded by MDV-specific ORFs are Meq, a jun/fos family of transcriptional factor implicated in transformation and latency, virus-encoded interleukin-8, a CXC chemokine, and pp38 and pp24, two phosphoproteins with undefined functions. There is also a putative lipase gene (LORF2) that has homologies in HPRS-24 (serotype II) strain of MDV and in various avian adenoviruses. An additional unique feature of MDV is the presence of long terminal repeat remnant sequences of avian retrovirus reticuloendotheliosis virus. These remnant sequences are derived from the U3-enhancer region through ancestral insertions by reticuloendotheliosis virus proviruses.


Aging and the number sense: preserved basic non-symbolic numerical processing and enhanced basic symbolic processing.
Aging often leads to general cognitive decline in domains such as memory and attention. The effect of aging on numerical cognition, particularly on foundational numerical skills known as the number sense, is not well-known. Early research focused on the effect of aging on arithmetic. Recent studies have begun to investigate the impact of healthy aging on basic numerical skills, but focused on non-symbolic quantity discrimination alone. Moreover, contradictory findings have emerged. The current study aimed to further investigate the impact of aging on basic non-symbolic and symbolic numerical skills. A group of 25 younger (18-25) and 25 older adults (60-77) participated in non-symbolic and symbolic numerical comparison tasks. Mathematical and spelling abilities were also measured. Results showed that aging had no effect on foundational non-symbolic numerical skills, as both groups performed similarly [RTs, accuracy and Weber fractions (w)]. All participants showed decreased non-symbolic acuity (accuracy and w) in trials requiring inhibition. However, aging appears to be associated with a greater decline in discrimination speed in such trials. Furthermore, aging seems to have a positive impact on mathematical ability and basic symbolic numerical processing, as older participants attained significantly higher mathematical achievement scores, and performed significantly better on the symbolic comparison task than younger participants. The findings suggest that aging and its lifetime exposure to numbers may lead to better mathematical achievement and stronger basic symbolic numerical skills. Our results further support the observation that basic non-symbolic numerical skills are resilient to aging, but that aging may exacerbate poorer performance on trials requiring inhibitory processes. These findings lend further support to the notion that preserved basic numerical skills in aging may reflect the preservation of an innate, primitive, and embedded number sense.


Challenges in Developing a Controlled Human Tuberculosis Challenge Model.
Controlled human infection models (CHIMs) have provided pivotal scientific advancements, contributing to the licensure of new vaccines for many pathogens. Despite being one of the world's oldest known pathogens, there are still significant gaps in our knowledge surrounding the immunobiology of Mycobacterium tuberculosis (M. tb). Furthermore, the only licensed vaccine, BCG, is a century old and demonstrates limited efficacy in adults from endemic areas. Despite good global uptake of BCG, tuberculosis (TB) remains a silent epidemic killing 1.4 million in 2019 (WHO, Global tuberculosis report 2020). A mycobacterial CHIM could expedite the development pipeline of novel TB vaccines and provide critical understanding on the immune response to TB. However, developing a CHIM for such a complex organism is a challenging process. The first hurdle to address is which challenge agent to use, as it would not be ethical to use virulent M. tb. This chapter describes the current progress and outstanding issues in the development of a TB CHIM. Previous and current human studies include both aerosol and intradermal models using either BCG or purified protein derivative (PPD) as a surrogate agent. Future work investigating the use of attenuated M. tb is underway.


Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility.
The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates. We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies. After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P=0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P=0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P=0.15) or clomiphene alone (8 of 85, 9%; P=0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P=0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications. In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01044862.).


Anti-nucleic acid antibodies in systemic lupus erythematosus patients and their families. Incidence and correlation with lymphocytotoxic antibodies.
Anti-RNA antibodies were found in 82% of 28 systemic lupus erythematosus (SLE) probands and in 16% of 124 of their family members. The incidence in 76 control family members was only 5%. In the SLE family members, the antibodies were found exclusively in 21% of the 94 close household contacts of the probands. The incidence of anti-native DNA (nDNA) antibodies was 68% for the SLE probands. The incidence of anti-nDNA antibodies in close household contacts of the probands was 6%, which was not significantly different from the 1% incidence found in control families. Lymphocytotoxic antibodies occurred in 57% of the SLE family members as a whole and in 68% of the close household contacts. In the SLE probands, lymphocytotoxic antibodies correlated with anti-single-stranded RNA (poly A) and anti-nDNA but not with anti-double-stranded RNA (poly A-poly U). On the other hand, lymphocytotoxic antibodies in the household contacts correlated with anti-double-stranded RNA (poly A-poly U) but not with anti-poly A or anti-nDNA. The anti-RNA antibodies were present in consanguineous household contacts but not in nonconsanguineous household contacts. These findings strengthen the hypothesis that both an environmental agent, possibly a virus, as well as the genetic response are important in the pathogenesis of SLE. Family members may therefore be a logical population in whom to search for specific antibodies to a viral agent.


On the origin of the huge nonlinear response of dye-doped liquid crystals.
We report the results of an investigation carried on Methyl Red-doped nematic liquid crystals with the aim of studying the basic mechanism of the extraordinarily large nonlinear response recently reported. We show that the experimental data can be explained as due to light-induced modifications of the anchoring conditions leading to director reorientation on the irradiated surface, which in turn gives rise to a bulk reorientation through the cell. We have called this phenomenon SINE (Surface Induced Nonlinear Effect) to remind that it occurs "without" (= sine in latin language) a direct optical or electric torque on the director in the bulk.


pH and amine-induced various octamolybdate-based metal-organic complexes: assembly, structures and properties.
Three octamolybdate-based metal-organic complexes (MOCs), namely, [H2en]2[Cu(pzca)2(Mo8O26)]·4H2O (1), [Cu2(pzca)2(Mo8O26)0.5(H2O)4]·H2O (2) and [Cu(I)3Cu(II)4(pzca)7(Mo8O26)(H2O)2]·4H2O (3) (en = ethylenediamine, pzca = 2-pyrazinecarboxylic acid), have been successfully synthesized under hydrothermal conditions via adding different kinds of amine and adjusting the pH values. The single crystal X-ray diffraction, elemental analyses, IR spectra, and thermogravimetric analyses have been used to characterize the title complexes. In compound 1, the [Cu(pzca)2] units bridge the [β-Mo8O26](4-) clusters to generate a 1D chain, which is extended by hydrogen-bonding interactions to a 3D supramolecular structure. Compound 2 exhibits a 3D coordination framework based on the 1D infinite [Cu2(pzca)2]n(2n+) zigzag chains and β-Mo8O26(4-) anions, and shows a trinodal 3,3,4-connected {8(3)}4{8(6)} topology containing a dodecagonal channel with the dimension of 13.496 × 19.642 Å(2). Compound 3 is a 3D metal-organic network derived from the "λ"-like [Cu5(pzca)4] subunits and [β-Mo8O26](4-) anions, which represents a novel {4·6·8(3)·10}2{4·6·8}2{4(2)·10(4)}{4(2)·8(3)·10}{6·8(2)}2{6(2)·10(3)·12}{6(2)·8(2)·10(2)}{6(2)·8(3)·10}{6(3)}4 topology in octamolybdate-based MOCs. The structural diversities show that the different amines and pH value of the reaction system play key roles in the construction of high dimensional architectures. Moreover, the electrochemical behaviors and photocatalytic activity for compound 1 have been investigated in detail.


Transient Effects in Fluorescence Quenching Measured by 2-GHz Frequency-Domain Fluorometry.
We used harmonic-content frequency-domain fluorometry to investigate the quenching of indole fluorescence by iodide and acrylamide in aqueous solution. The time-resolved intensity decays were recovered from the frequency response of the fluorescence emission, measured over a frequency range from 10 to 2000 MHz. In the absence of collisional quenching the decay of indole in water is predominately a single exponential. The intensity decays became increasingly nonexponential when quenched by either iodide or acrylamide. We attribute the complex decays to transient effects, as predicted originally by Smoluchowski. At quencher concentrations below 0.1 M the decays are of the form exp(-t/τ - 2bt 1/2), which is known to be an approximate model. At quencher concentrations above 0.1 M this decay law does not account for the data. The data are in better agreement with the radiation model, and the diffusion coefficients and interaction radii are more reasonable. However, in aqueous solution above 0.5 M acrylamide there appear to be deviations from the radiation model. The deviations are less apparent at high iodide concentrations. For comparison with future theoretical developments, the intensity decay laws are reported up to 0.5 M iodide or 0.7 M acrylamide. Evidently, the resolution and sensitivity of the frequency-domain method are adequate to recover the complex subnanosecond decays found at high concentrations of quenchers.


Tree edit distance for leaf-labelled trees on free leafset and its comparison with frequent subsplit dissimilarity and popular distance measures.
This paper is devoted to distance measures for leaf-labelled trees on free leafset. A leaf-labelled tree is a data structure which is a special type of a tree where only leaves (terminal) nodes are labelled. This data structure is used in bioinformatics for modelling of evolution history of genes and species and also in linguistics for modelling of languages evolution history. Many domain specific problems occur and need to be solved with help of tree postprocessing techniques such as distance measures. Here we introduce the tree edit distance designed for leaf labelled trees on free leafset, which occurs to be a metric. It is presented together with tree edit consensus tree notion. We provide statistical evaluation of provided measure with respect to R-F, MAST and frequent subsplit based dissimilarity measures as the reference measures. The tree edit distance was proven to be a metric and has the advantage of using different costs for contraction and pruning, therefore their properties can be tuned depending on the needs of the user. Two of the presented methods carry the most interesting properties. E(3,1) is very discriminative (having a wide range of values) and has a very regular distance distribution which is similar to a normal distribution in its shape and is good both for similar and non-similar trees. NFC(2,1) on the other hand is proportional or nearly proportional to the number of mutation operations used, irrespective of their type.