Incidence and risk of heart failure in systemic lupus erythematosus.
Although case series suggest a higher burden of cardiovascular risk factors in patients with systemic lupus erythematosus (SLE) compared with the general population, the association between SLE and heart failure (HF) remains undefined. We sought to investigate the incidence and risk of HF in patients with SLE. In April 2016, we performed a retrospective cohort analysis using the Explorys platform, which provides aggregated electronic medical record data from 26 major integrated healthcare systems across the USA from 1999 to present. Demographic and regression analyses were performed to assess the impact of SLE on HF incidence. Among 45 284 540 individuals in the database, we identified 95 400 (0.21%) with SLE and 98 900 (0.22%) with a new diagnosis of HF between May 2015 and April 2016. HF incidence was markedly higher in the SLE group compared with controls (0.97% vs 0.22%, relative risk (RR): 4.6 (95% CI 4.3 to 4.9)), as were other cardiovascular risk factors. In regression analysis, SLE was an independent predictor of HF (adjusted OR: 3.17 (2.63 to 3.83), p<0.0001). RR of HF was highest in young males with SLE (65.2 (35.3 to 120.5) for age 20-24), with an overall trend of increasing absolute risk but decreasing RR with advancing age in both sexes. Renal involvement in SLE correlated with earlier and higher incidence of HF. The findings of this study suggest that patients with SLE have significantly higher risk of developing HF and a worse cardiovascular risk profile compared with the general population. These results need to be confirmed by prospective studies.


Improved guinea pig model of cardiac tachyarrhythmias.
Guinea pigs are frequently used as models for ventricular tachyarrhythmias, including polymorphic ventricular tachycardia (VT) and ventricular fibrillation. However, applications of the model for short-term therapies are limited because the arrhythmias are transient, typically lasting <5 sec. Thus, spontaneous termination cannot be easily distinguished from effective short-term therapy in standard models. Results of this study confirmed an improved induction method that consistently extends the arrhythmias to 30 sec or longer. In 10 (400- to 1200-g) male guinea pigs, a pacing electrode was advanced in the esophagus. The anode for pacing was a wire advanced through a 20-gauge needle across the diaphragm toward the ventricular apex. Two 12-mm-diameter electrodes were placed on the skin on opposing aspects of the thorax for T-wave stimulation. The blood pressure in the carotid artery was continuously monitored. Two traditional methods were used to induce VT: 2 sec of a 50-Hz square wave, and a single 200 V/5 ms transthoracic stimulus at the peak of the T-wave after pacing at 80% of the intrinsic R-R interval. A third novel method also was used: a single 200 V/5 ms transthoracic stimulus at the peak of the T-wave after a rapid pacing sequence. The rapid pacing sequence was a 25-stimulus sequence, which accelerated to end with 15 beats at the shortest pacing interval for which all pacing stimuli captured. A tachyarrhythmia was defined as any abnormally rapid surface electrocardiographic waveform lasting at least 2 sec after termination of the initiating stimulus. Between 5 and 23 attempts were made to induce tachyarrhythmias in each animal. In four additional animals (>800 g), the efficacy of an established short-term therapy for tachyarrhythmias was measured, using the proposed rapid pacing model. All arrhythmias induced by use of the three induction methods were polymorphic VT accompanied by complete hemodynamic collapse. In hearts weighing >2.5 g (body mass >800 g), 100% of arrhythmia episodes were sustained for 30 sec or longer when initiated after rapid pacing, as opposed to only 55% sustained by use of other induction methods (P < 0.01). The efficacy results for the established short-term therapy matched those previously reported for 100-kg calves. A brief period of rapid pacing facilitates initiation of consistent, sustained ventricular tachyarrhythmias in large guinea pigs, eliminating spontaneous termination as a confounding factor in the study of short-term therapies.


Toward an absolute NMR shielding scale using the spin-rotation tensor within a relativistic framework.
One of the most influential articles showing the best way to get the absolute values of NMR magnetic shieldings, σ (non-measurables) from both accurate measurements and theoretical calculations, was published a long time ago by Flygare. His model was shown to break down when heavy atoms are involved. This fact motivated the development of new theories of nuclear spin-rotation (SR) tensors, which consider electronic relativistic effects. One was published recently by some of us. In this article we take another step further and propose three different models that generalize Flygare's model. All of them are written using four-component relativistic expressions, though the two-component relativistic SO-S term also appears in one. The first clues for these developments were built from the relationship among σ and the SR tensors within the two-component relativistic LRESC model. Besides, we had to introduce a few other well defined assumptions: (i) relativistic corrections must be included in a way to best reproduce the relationship among the (e-e) term (called "paramagnetic" within the non-relativistic domain) of σ and its equivalent part of the SR tensor, (ii) as happens in Flygare's rule, the shielding of free atoms shall be included to improve accuracy. In the highest accurate model, a new term known as Spin-orbit due to spin, SO-S (in this mechanism the spin-Zeeman Hamiltonian replaces the orbital-Zeeman Hamiltonian), is included. We show the results of the application of those models to halogen containing linear molecules.


A randomized controlled trial of acupuncture for initiation of labor in nulliparous women.
To evaluate the utility of outpatient acupuncture for labor stimulation. Nulliparous women at 39 4/7 weeks or greater with a singleton gestation and Bishop score of less than 7 were randomized to usual medical care (control group) versus usual care and three outpatient acupuncture treatments (acupuncture group). Each treatment consisted of eight needles applied to bilateral points LI4, SP6, UB31, and UB32. The primary outcome was time elapsed from the time of randomization to delivery. Secondary outcomes included rates of cesarean section and induction of labor. Medical records were abstracted for maternal demographic, medical, and delivery outcome data. A priori sample size calculation revealed that 56 women were required to detect a 72-hour difference in delivery time with a power of 83% and an alpha of 0.05. Student's t-test, Chi-square, and Kaplan-Meier statistics were used to compare groups. Fifty-six women were randomized and completed the study procedures. Race, age, gestational age, and cervical Bishop score were similar in both groups. Mean time to delivery occurred 21 hours sooner in the acupuncture group, but this difference did not reach statistical significance (p = 0.36). Compared to controls, women in the acupuncture group tended to be more likely to labor spontaneously (70% vs. 50%, p = 0.12) and less likely to deliver by cesarean section (39% vs. 17%, p = 0.07). Of women who were not induced, those in the acupuncture group were more likely to be delivered than the controls at any point after enrollment (p = 0.05). Acupuncture is well tolerated among term nulliparous women and holds promise in reducing interventions that occur in post-term pregnancies.


Comparison of captopril and ibopamine in mild to moderate heart failure.
To determine the effects of ibopamine 100 mg three times daily compared with captopril 25 mg three times daily on exercise capacity in patients with chronic heart failure. A randomised, double blind, parallel group comparison of the addition of ibopamine versus captopril during a period of 24 weeks. 26 outpatient cardiology clinics in seven European countries. 266 patients, with mild to moderate chronic heart failure (New York Heart Association (NYHA) functional class II, 81% and III, 19%) and evidence of an enlarged left ventricle. Patients received concomitant treatment with diuretics and/or digitalis. Exercise duration after 24 weeks of treatment, compared with baseline. Mean (SD) ejection fraction was 29 (8)% and the baseline exercise duration in the captopril and ibopamine groups 665 (160) and 675 (174) seconds, respectively. At the end of the study, exercise duration had improved in both groups, by 29 seconds in the ibopamine group (P < 0.01), and by 24 seconds in the captopril group (P < 0.05). There was no difference between groups (P = 0.69, 95% confidence interval -22 to 33). NYHA class, signs and symptoms score, and dyspnoea and fatigue index improved equally in both groups. The total number of adverse events was the same in both treatment groups, but gastrointestinal complaints occurred more often in the ibopamine group. The number of patients with premature withdrawals was no different. No difference was detected between the effect of captopril and ibopamine on exercise time in patients with mild to moderate heart failure during a treatment period of 24 weeks.


Inequities in access to primary care among opioid recipients in Ontario, Canada: A population-based cohort study.
Stigma and high-care needs can present barriers to the provision of high-quality primary care for people with opioid use disorder (OUD) and those prescribed opioids for chronic pain. We explored the likelihood of securing a new primary care provider (PCP) among people with varying histories of opioid use who had recently lost access to their PCP. We conducted a retrospective cohort study using linked administrative data among residents of Ontario, Canada whose enrolment with a physician practicing in a primary care enrolment model (PEM) was terminated between January 2016 and December 2017. We assigned individuals to 3 groups based upon their opioid use on the date enrolment ended: long-term opioid pain therapy (OPT), opioid agonist therapy (OAT), or no opioid. We fit multivariable models assessing the primary outcome of primary care reattachment within 1 year, adjusting for demographic characteristics, clinical comorbidities, and health services utilization. Secondary outcomes included rates of emergency department (ED) visits and opioid toxicity events. Among 154,970 Ontarians who lost their PCP, 1,727 (1.1%) were OAT recipients, 3,644 (2.4%) were receiving long-term OPT, and 149,599 (96.5%) had no recent prescription opioid exposure. In general, OAT recipients were younger (median age 36) than those receiving long-term OPT (59 years) and those with no recent prescription opioid exposure (44 years). In all exposure groups, the majority of individuals had their enrolment terminated by their physician (range 78.1% to 88.8%). In the primary analysis, as compared to those not receiving opioids, OAT recipients were significantly less likely to find a PCP within 1 year (adjusted hazard ratio [aHR] 0.55, 95% confidence interval [CI] 0.50 to 0.61, p < 0.0001). We observed no significant difference between long-term OPT and opioid unexposed individuals (aHR 0.96; 95% CI 0.92 to 1.01, p = 0.12). In our secondary analysis comparing the period of PCP loss to the year prior, we found that rates of ED visits were elevated among people not receiving opioids (adjusted rate ratio (aRR) 1.20, 95% CI 1.18 to 1.22, p < 0.0001) and people receiving long-term OPT (aRR 1.37, 95% CI 1.28 to 1.48, p < 0.0001). We found no such increase among OAT recipients, and no significant increase in opioid toxicity events in the period following provider loss for any exposure group. The main limitation of our findings relates to their generalizability outside of PEMs and in jurisdictions with different financial incentives incorporated into primary care provision. In this study, we observed gaps in access to primary care among people who receive prescription opioids, particularly among OAT recipients. Ongoing efforts are needed to address the stigma, discrimination, and financial disincentives that may introduce barriers to the healthcare system, and to facilitate access to high-quality, consistent primary care services for chronic pain patients and those with OUD.


Endemic kala-azar in eastern Sudan: a longitudinal study on the incidence of clinical and subclinical infection and post-kala-azar dermal leishmaniasis.
Between April 1991 and April 1993, a longitudinal study was performed in the village of Um-Salala (1,430 inhabitants) in the endemic area of kala-azar (visceral leishmaniasis) in eastern Sudan. During the two years, a total of 92 kala-azar cases were diagnosed (male:female ratio = 1.8:1, mean age 6.6 years). The annual incidence rates were 38.4/1,000 and 38.5/1,000 person-years, respectively. The ratio of clinical to subclinical cases was 1.6:1 in the first year and 2.4:1 in the second year. Post-kala-azar dermal leishmaniasis occurred in 48 (56%) of 85 kala-azar cases that were followed-up for at least six months. Kala-azar occurred only in previously leishmanin-negative individuals. The majority of the population had a positive leishmanin skin test result, probably due to previous exposure to Leishmania major causing cutaneous leishmaniasis in their homeland in western Sudan from which they had migrated in the 1980s. It was thus postulated that previous cutaneous leishmaniasis might protect against kala-azar but this could not be proved.


A novel core-shell magnetic nano-sorbent with surface molecularly imprinted polymer coating for the selective solid phase extraction of dimetridazole.
A novel core-shell magnetic nano-sorbent with surface molecularly-imprinted polymer coating was prepared via a sol-gel process. Methyltrimethoxysilane and 3-aminopropyltriethoxysilane were used as functional monomers, tetraethyl orthosilicate as cross-linker, and Al(3+) as dopant to generate Lewis acid sites in the silica matrix for the metal coordinate interactions with the template dimetridazole (DMZ). The ratios of the monomers, the dopant, and the cross-linker, were optimised by a OA9 (3(4)) orthogonal array design. The resultant sorbent was characterised by scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, powder X-ray diffraction, and magnetometry. The binding performances of the sorbent were evaluated by static, kinetic and selective adsorption experiments. The nano-sorbent was successfully applied to solid phase extraction followed by spectrophotometric determination of DMZ in real samples. Spiked recoveries ranged from 90.33% to 106.20% for egg, milk powder, and pig feed samples, with relative standard deviations of less than 4.54%.


The responses of multiple cytokines following incubation of whole blood from TB patients, latently infected individuals and controls with the TB antigens ESAT-6, CFP-10 and TB7.7.
The development of clinically relevant biomarkers is important for diagnosing latent tuberculosis infection (LTBI) and active tuberculosis (TB) and predicting their prognoses. This study examined whether the responses of multiple cytokines can be used as a biomarker to distinguish the TB infection status and mycobacterial load. We analysed the responses of multiple cytokines (IFN-γ, IL-2, IL-10, IL-13, IL-17 and TNF-α) in the supernatant from the QuantiFERON-TB Gold In-Tube assay following stimulation of whole blood from the TB group (n = 32), LTBI group (n = 19) and healthy controls (n = 30) with TB antigens (ESAT-6, CFP-10 and TB7.7). The median responses of IFN-γ, IL-2, IL-10 and IL-13 were higher in the LTBI and active TB groups than in the non-TB control group (IFN-γ, P < 0.001; IL-2, P < 0.001; IL-10, P = 0.012; IL-13, P < 0.001). The median IL-2/IFN-γ ratio of the LTBI group was higher than that of the active TB group (P = 0.014) and differed significantly between patients with LTBI, patients with smear-negative TB and patients with smear-positive TB (P = 0.027). This difference was especially evident between the patients with LTBI and patients with smear-positive TB (P = 0.047). In conclusion, IFN-γ, IL-2, IL-10 and IL-13 can serve as biomarkers for distinguishing TB infection. In addition, the IL-2/IFN-γ ratio appears to be a biomarker for diagnosing LTBI and may be useful as a prognostic factor and for evaluating treatment responses.


Assessing the repeatability of absolute CMRO2, OEF and haemodynamic measurements from calibrated fMRI.
As energy metabolism in the brain is largely oxidative, the measurement of cerebral metabolic rate of oxygen consumption (CMRO2) is a desirable biomarker for quantifying brain activity and tissue viability. Currently, PET techniques based on oxygen isotopes are the gold standard for obtaining whole brain CMRO2 maps. Among MRI techniques that have been developed as an alternative are dual calibrated fMRI (dcFMRI) methods, which exploit simultaneous measurements of BOLD and ASL signals during a hypercapnic-hyperoxic experiment to modulate brain blood flow and oxygenation. In this study we quantified the repeatability of a dcFMRI approach developed in our lab, evaluating its limits and informing its application in studies aimed at characterising the metabolic state of human brain tissue over time. Our analysis focussed on the estimates of oxygen extraction fraction (OEF), cerebral blood flow (CBF), CBF-related cerebrovascular reactivity (CVR) and CMRO2 based on a forward model that describes analytically the acquired dual echo GRE signal. Indices of within- and between-session repeatability are calculated from two different datasets both at a bulk grey matter and at a voxel-wise resolution and finally compared with similar indices obtained from previous MRI and PET measurements. Within- and between-session values of intra-subject coefficient of variation (CVintra) calculated from bulk grey matter estimates 6.7 ± 6.6% (mean ± std.) and 10.5 ± 9.7% for OEF, 6.9 ± 6% and 5.5 ± 4.7% for CBF, 12 ± 9.7% and 12.3 ± 10% for CMRO2. Coefficient of variation (CV) and intraclass correlation coefficient (ICC) maps showed the spatial distribution of the repeatability metrics, informing on the feasibility limits of the method. In conclusion, results show an overall consistency of the estimated physiological parameters with literature reports and a satisfactory level of repeatability considering the higher spatial sensitivity compared to other MRI methods, with varied performance depending on the specific parameter under analysis, on the spatial resolution considered and on the study design.


Tetramethylpyrazine suppresses HIF-1alpha, TNF-alpha, and activated caspase-3 expression in middle cerebral artery occlusion-induced brain ischemia in rats.
To examine the detailed mechanisms underlying the inhibitory effect of tetramethylpyrazine (TMPZ) in inflammatory and apoptotic responses induced by middle cerebral artery occlusion (MCAO) in rats. MCAO-induced focal cerebral ischemia in rats was used in this study. The hypoxia-inducible factor-1alpha(HIF-1alpha), activation of caspase-3, and TNF-alpha mRNA transcription in ischemic regions were detected by immunoblotting and RT-PCR, respectively. Anti-oxidative activity was investigated using a thiobarbituric acid-reactive substance (TBARS) test in rat brain homogenate preparations. We showed the statistical results of the infarct areas of solvent- and TMPZ (20 mg/kg)-treated groups at various distances from the frontal pole in MCAO-induced focal cerebral ischemia in rats. Treatment with TMPZ (20 mg/kg) markedly reduced the infarct area in all regions, especially in the third to fifth sections. MCAO-induced focal cerebral ischemia was associated with increases in HIF-1alpha and the activation of caspase-3, as well as TNF-alpha transcription in ischemic regions. These expressions were markedly inhibited by treatment with TMPZ (20 mg/kg). However, TMPZ (0.5-5 mmol/L) did not significantly inhibit TBARS reaction in rat brain homogenates. The neuroprotective effect of TMPZ may be mediated at least by a portion of the inhibition of HIF-1alpha and TNF-alpha activations, followed by the inhibition of apoptosis formation (active caspase-3), resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. Thus, TMPZ treatment may represent an ideal approach to lowering the risk of or improving function in ischemia- reperfusion brain injury-related disorders.


Polyploid evolution and Pleistocene glacial cycles: A case study from the alpine primrose Primula marginata (Primulaceae).
Recent studies highlighted the role of Pleistocene climatic cycles in polyploid speciation and of southern Alpine refugia as reservoirs of diversity during glacial maxima. The polyploid Primula marginata, endemic to the southwestern Alps, includes both hexaploid and dodecaploid cytotypes that show no ecological or morphological differences. We used flow cytometry to determine variation and geographic distribution of cytotypes within and between populations and analyses of chloroplast (cp) and nuclear ribosomal (nr) DNA sequences from the Internal Transcribed Spacer (ITS) region to infer the evolutionary history of the two cytotypes and the auto- vs. allopolyploid origin of dodecaploid populations. We did not detect any intermediate cytotypes or variation of ploidy levels within populations. Hexaploids occur in the western and dodecaploids in the eastern part of the distributional range, respectively. The cpDNA and nrDNA topologies are in conflict, for the former supports shared ancestry between P. marginata and P. latifolia, while the latter implies common origins between at least some ITS clones of P. marginata and P. allionii. Our results suggest an initial episode of chloroplast capture involving ancestral lineages of P. latifolia and P. marginata, followed by polyploidization between P. marginata-like and P. allionii-like lineages in a southern refugium of the Maritime Alps. The higher proportion of ITS polymorphisms in dodecaploid than in hexaploid accessions of P. marginata and higher total nucleotide diversity of ITS clones in dodecaploid vs. hexaploid individuals sequences are congruent with the allopolyploid hypothesis of dodecaploid origin.


Antibacterial activity of cefpodoxime in vitro.
Cefpodoxime proxetil is a new orally administered prodrug which is absorbed and de-esterified by the intestinal mucosa to release the third-generation cephalosporin, cefpodoxime, and which is undergoing in vitro and in vivo evaluations. Using the standard agar dilution method, we compared the in vitro activity of this drug with other oral cephalosporins and quinolones against 637 recent clinical isolates from Kaohsiung Veterans General Hospital in Taiwan. Against Escherichia coli and Klebsiella pneumoniae, cefpodoxime showed excellent activity, inhibiting over 90% of these isolates at 1 mg/l. Like other oral drugs of its class, it had little activity against Pseudomonas aeruginosa and Acinetobacter spp. Against Haemophilus influenzae, irrespective of beta-lactamase production, its activity was similar to comparative drugs. Against methicillin-susceptible Staphylococcus aureus, cefpodoxime showed moderate activity, inhibiting 90% of these isolates at 4 mg/l, whereas it was inactive against methicillin-resistant S. aureus. However, all cephalosporins have shown little in vivo activity against methicillin-resistant S. aureus regardless of in vitro results. Cefpodoxime was inactive against Enterococcus spp. Against other streptococci, its activity was similar to other oral cephalosporins and quinolones tested. The results of this in vitro study indicated that oral administration of cefpodoxime should be an ideal agent in the empirical outpatient treatment for community-acquired cutaneous, respiratory and urinary tract infections.


How nursing students' placement preferences and perceptions of community care develop in a more 'community-oriented' curriculum: a longitudinal cohort study.
Extramuralisation in healthcare has influenced medical and nursing curricula internationally with the incorporation of themes related to primary/ community care. Despite this, students do not easily change their career preferences. The hospital is still favourite, leading to labour market shortages in extramural care. This study investigates how baccalaureate nursing students' perceptions of community care and placement preferences develop over time in a more 'community-care-oriented' curriculum, to gain insights on which curriculum elements potentially influence career choices. A nursing student cohort of a University of Applied Sciences in the Netherlands (n = 273) underwent a new four-year curriculum containing extended elements of community care. The primary outcome was assessed with the Scale on Community Care Perceptions (SCOPE). Data were collected each year of study. Descriptive statistics were used to investigate students' placement preferences and perceptions, and linear mixed model techniques (LMMs) for measuring how students' perceptions develop over time. Patterns of placement preferences at individual level were visualised. Students' perceptions of community care, as measured with SCOPE, show a slight decrease between year 1 and 4, while items mutually differ substantially. In contrast, the preference of community care for a placement increases from 2.6% in year 1 tot 8.2% in year 4. The hospital is favourite in year 1 (79.8%), and remains most popular. At individual level, students often change placement preferences, although a preference for the hospital is more consistent. The LMMs indicates that, at the four time-points, the estimated marginal means of students' perceptions fluctuate between 6 and 7 (range 1-10). A placement in community care did not positively influence students' perceptions, and an intensive 1 week theoretical programme was only temporarily influential. Although interest for placement in community care increased substantially, it was not clear which curriculum elements stimulated this, nor did the curriculum positively influence students' perceptions. As most students do not look forward to the high responsibility of the field, other curricula with educational tracks for more mature students/ nurses with a vocational training may be an alternative contribution to solving the labour market problems in community care.


Thermal luminescence water monitor.
A thermal luminescence (TL) spectroscopy method for detecting organic impurities in water solution is presented. Infrared emissions by the dissolved organic matter are measurable, once a thermal gradient between it and the water medium is established, at those TL frequencies that are absorbed by the contaminant, following irradiation by a pulsed microwave beam. This detection window of opportunity closes as the liquid reaches thermal equilibrium at elevated temperatures and on collapse of the gradient. TL radiance liberated by a suspected contaminated water sample is scanned interferometrically about the maximum thermal gradient event, where N interferograms are acquired and grouped into contiguous sets of two, with N/2 interferogram elements per set. The coadded averages of these sets enhance the sensitivity of measurement to a small variance in emissivity and are Fourier transformed, and the adjacent spectra are subtracted. The difference spectrum is preprocessed with linear baseline, noise filtration, scaling, and parity operators to reveal a clear emissions band signature of the solute of dimethylmethylphosphonate to concentrations of parts per 10(3) and less. An artificial neural network facilitates detection of the contaminant by pattern recognition of the contaminant's infrared band signature.


Improving the school food environment: results from a pilot study in middle schools.
Our objective for this study was to examine the feasibility of instituting environmental changes during a 6-week pilot in school foodservice programs, with long-term goals of improving dietary quality and preventing obesity and type 2 diabetes in youth. Participants included students and staff from six middle schools in three states. Formative assessment with students and school staff was conducted in the spring of 2003 to inform the development of school foodservice policy changes. Thirteen potential policy goals were delineated. These formed the basis for the environmental change pilot intervention implemented during the winter/spring of 2004. Questionnaires were used to assess the extent to which the 13 foodservice goals were achieved. Success was defined as achieving 75% of goals not met at baseline. Daily data were collected on goal achievement using the schools' daily food production and sales records. Qualitative data were also collected after the pilot study to obtain feedback from students and staff. Formative research with staff and students identified potential environmental changes. Most schools made substantial changes in the National School Lunch Program meal and snack bar/a la carte offerings. Vending goals were least likely to be achieved. Only one school did not meet the 75% goal achievement objective. Based on the objective data as well as qualitative feedback from student focus groups and interviews with students and school staff, healthful school foodservice changes in the cafeteria and snack bar can be implemented and were acceptable to the staff and students. Implementing longer-term and more ambitious changes and assessing cost issues and the potential enduring impact of these changes on student dietary change and disease risk reduction merits investigation.


Epidemiological surveillance of Schmallenberg virus in small ruminants in southern Spain.
Schmallenberg virus (SBV) is an emerging Culicoides-borne Orthobunyavirus that affects ruminant species. Between 2011 and 2013, it was responsible for a large-scale epidemic in Europe. In the present study, we aimed to determine the seroprevalence, spatial distribution and risk factors associated with SBV exposure in sheep and goats in the region where the first Schmallenberg disease outbreak in Spain was reported. Blood samples from 1,796 small ruminants from 120 farms were collected in Andalusia (southern Spain) between 2015 and 2017. Antibodies against SBV were detected in 536 of 1,796 animals (29.8%; 95%CI: 27.7-32.0) using a commercial blocking ELISA. The individual seroprevalence according to species was 31.1% (280/900; 95%CI: 28.1-34.1) in sheep and 28.6% (256/896; 95%CI: 25.6-31.5) in goats. The farm prevalence was 76.7% (95%CI: 69.1-84.2). Seropositivity to SBV was confirmed in both sheep and goats in all provinces by virus neutralization test. Two significant (p < .001) spatial clusters of high seroprevalence were identified. The generalized estimating equation analysis showed that management system (extensive), temperature (>14ºC) and altitude (<400 metres above sea level) were risk factors associated with SBV exposure in small ruminants. Our results highlight widespread but not homogeneous circulation of SBV in small ruminant populations in Spain.


Uptake and intracytoplasmic storage of pigmented particles by human CD34+ stromal cells/telocytes: endocytic property of telocytes.
We studied the phagocytic-like capacity of human CD34+ stromal cells/telocytes (TCs). For this, we examined segments of the colon after injection of India ink to help surgeons localize lesions identified at endoscopy. Our results demonstrate that CD34+ TCs have endocytic properties (phagocytic-like TCs: phTCs), with the capacity to uptake and store India ink particles. phTCs conserve the characteristics of TCs (long, thin, bipolar or multipolar, moniliform cytoplasmic processes/telopodes, with linear distribution of the pigment) and maintain their typical distribution. Likewise, they are easily distinguished from pigment-loaded macrophages (CD68+ macrophages, with oval morphology and coarse granules of pigment clustered in their cytoplasm). A few c-kit/CD117+ interstitial cells of Cajal also incorporate pigment and may conserve the phagocytic-like property of their probable TC precursors. CD34+ stromal cells in other locations (skin and periodontal tissues) also have the phagocytic-like capacity to uptake and store pigments (hemosiderin, some components of dental amalgam and melanin). This suggests a function of TCs in general, which may be related to the transfer of macromolecules in these cells. Our ultrastructural observation of melanin-storing stromal cells with characteristics of TCs (telopodes with dichotomous branching pattern) favours this possibility. In conclusion, intestinal TCs have a phagocytic-like property, a function that may be generalized to TCs in other locations. This function (the ability to internalize small particles), together with the capacity of these cells to release extracellular vesicles with macromolecules, could close the cellular bidirectional cooperative circle of informative exchange and intercellular interactions.


Selenium- or Vitamin E-Related Gene Variants, Interaction with Supplementation, and Risk of High-Grade Prostate Cancer in SELECT.
Epidemiologic studies and secondary analyses of randomized trials supported the hypothesis that selenium and vitamin E lower prostate cancer risk. However, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed no benefit of either supplement. Genetic variants involved in selenium or vitamin E metabolism or transport may underlie the complex associations of selenium and vitamin E. We undertook a case-cohort study of SELECT participants randomized to placebo, selenium, or vitamin E. The subcohort included 1,434 men; our primary outcome was high-grade prostate cancer (N = 278 cases, Gleason 7 or higher cancer). We used weighted Cox regression to examine the association between SNPs and high-grade prostate cancer risk. To assess effect modification, we created interaction terms between randomization arm and genotype and calculated log likelihood statistics. We noted statistically significant (P < 0.05) interactions between selenium assignment, SNPs in CAT, SOD2, PRDX6, SOD3, and TXNRD2, and high-grade prostate cancer risk. Statistically significant SNPs that modified the association of vitamin E assignment and high-grade prostate cancer included SEC14L2, SOD1, and TTPA In the placebo arm, several SNPs, hypothesized to interact with supplement assignment and risk of high-grade prostate cancer, were also directly associated with outcome. Variants in selenium and vitamin E metabolism/transport genes may influence risk of overall and high-grade prostate cancer, and may modify an individual man's response to vitamin E or selenium supplementation with regards to these risks. The effect of selenium or vitamin E supplementation on high-grade prostate cancer risk may vary by genotype. Cancer Epidemiol Biomarkers Prev; 25(7); 1050-8. ©2016 AACR.


Cognition and learning in horses (Equus caballus): What we know and why we should ask more.
Horses (Equus caballus) have a rich history in their relationship with humans. Across different cultures and eras they have been utilized for work, show, cultural rituals, consumption, therapy, and companionship and continue to serve in many of these roles today. As one of the most commonly trained domestic animals, understanding how horses learn and how their relationship with humans and other horses impacts their ability to learn has implications for horse welfare, training, husbandry and management. Given that unlike dogs and cats, domesticated horses have evolved from prey animals, the horse-human relationship poses interesting and unique scientific questions of theoretical value. There is still much to be learned about the cognition and behaviour of horses from a scientific perspective. This review explores current research within three related areas of horse cognition: human-horse interactions, social learning and independent learning in horses. Research on these topics is summarized and suggestions for future research are provided.


The influence of cement viscosity on the early migration of a tapered polished femoral stem.
It is unclear whether it is best to use high-viscosity or low-viscosity cement for fixation of total hip replacement (THR) femoral components. This study examines the influence of cement viscosity on the migration of the Exeter femoral component using roentgen stereophotogrammetric analysis (RSA). Simplex, CMW1 and CMW3 G cements were examined in a total of 46 patients over a 12-month period. The overall pattern of migration for all cohorts was one of subsidence and rotation into valgus. There was no significant difference in any aspect of migration between the groups. In vitro studies demonstrate that low-viscosity cement forms a more stable bone-cement interface. Several groups have examined the in vivo effect of cement viscosity on stem longevity with conflicting results. For a polished, tapered implant that is designed to subside, cement viscosity does not influence the 1-year migration, and it is therefore unlikely to affect long-term outcome.


Hacking Aging: A Strategy to Use Big Data From Medical Studies to Extend Human Life.
Age is the most important single factor associated with chronic diseases and ultimately, death. The mortality rate in humans doubles approximately every eight years, as described by the Gompertz law of mortality. The incidence of specific diseases, such as cancer or stroke, also accelerates after the age of about 40 and doubles at a rate that mirrors the mortality-rate doubling time. It is therefore, entirely plausible to think that there is a single underlying process, the driving force behind the progressive reduction of the organism's health leading to the increased susceptibility to diseases and death; aging. There is, however, no fundamental law of nature requiring exponential morbidity and mortality risk trajectories. The acceleration of mortality is thus the most important characteristics of the aging process. It varies dramatically even among closely related mammalian species and hence appears to be a tunable phenotype. Here, we follow how big data from large human medical studies, and analytical approaches borrowed from physics of complex dynamic systems can help to reverse engineer the underlying biology behind Gompertz mortality law. With such an approach we hope to generate predictive models of aging for systematic discovery of biomarkers of aging followed by identification of novel therapeutic targets for future anti-aging interventions.


Lactobacillus plantarum and Bifidobacterium bifidum alleviate dry eye in mice with exorbital lacrimal gland excision by modulating gut inflammation and microbiota.
In order to understand the efficacy of probiotics against dry eye syndrome, we selected anti-inflammatory probiotics Lactobacillus plantarum NK151 and Bifidobacterium bifidum NK175, which increased the ratio of IL-10 to TNF-α expression, from the human gut bacteria collection and examined their effects on tear secretion and cornea/conjunctiva inflammation in mice with excision of the unilateral exorbital lacrimal gland and 1% atropine and 0.1% benzalkonium chloride solution (ELA)-induced dry eye. Exposure to ELA significantly reduced tear secretion in mice, assessed by the phenol red thread tear test. However, oral gavage of NK151 and/or NK175 significantly increased ELA-suppressed tear secretion, IL-10 expression, and goblet cell population and decreased the ELA-induced corneal fluorescein-staining score, IL-1β and TNF-α expression in the conjunctiva. They also suppressed ELA-induced myeloperoxidase, IL-1β, and TNF-α expression. In particular, they increased the ratio of IL-10 to TNF-α expression in the colon. Their treatments increased ELA-induced α-diversity reduction to that of the control group and partially restored ELA-shifted β-diversity to that of the control group. Oral gavage of NK151 and/or NK175 reduced ELA-induced Verrucomicrobia and Actinobacteria populations at the phylum level. Furthermore, they reduced ELA-induced Bacteroidaceae, Akkemansiaceae, and AC160630_f populations and increased ELA-suppressed Lactobacillaceae and Muribaculaceae populations at the family level. These gut bacteria populations exhibited significant correlation with the tear secretion volume. In conclusion, NK151 and/or NK175 alleviated dry eye by modulating the expression ratio of pro-inflammatory cytokines such as TNF-α and anti-inflammatory cytokines such as IL-10 and gut microbiota composition.


Selective upregulation of platelet-derived growth factor alpha receptors by transforming growth factor beta in scleroderma fibroblasts.
Transforming growth factor beta (TGF-beta), a multifunctional cytokine, is an indirect mitogen for human fibroblasts through platelet-derived growth factor (PDGF), particularly the A ligand-alpha receptor arm of that system. TGF-beta effects on PDGF alpha receptor expression were studied in vitro using ligand binding techniques in three human dermal fibroblast strains: newborn foreskin, adult skin, and scleroderma (systemic sclerosis, SSc). Each cell strain responded differently to TGF-beta. In newborn foreskin fibroblasts, PDGF alpha receptor number decreased in a dose-dependent manner after exposure to low concentrations of TGF-beta (0.1-1 ng/ml). Responses of normal skin fibroblasts were varied, and mean net receptor number was unchanged. Increases in PDGF alpha receptor number by TGF-beta occurred consistently with SSc fibroblasts and low concentrations of TGF-beta (0.1-1 ng/ml) were particularly stimulatory. Increased surface expression of alpha receptor subunit by TGF-beta in SSc fibroblasts correlated with increased new PDGF alpha receptor synthesis as demonstrated by radioimmunoprecipitation analysis of metabolically labeled cells and with increased steady-state levels of corresponding mRNAs. In normal adult skin fibroblasts, TGF-beta had no effect on either synthesis or mRNA expression of alpha receptor subunits. Proliferative responses to PDGF-AA after pretreatment with TGF-beta correlated positively with effects of TGF-beta on expression of alpha receptor subunit. Decreased mitogenic responses to PDGF-AA were observed in foreskin fibroblasts, small changes in responses in adult fibroblasts, and significant increases in SSc fibroblasts. Thus, costimulation with PDGF-AA and TGF-beta selectively enhanced proliferation of fibroblasts with the SSc phenotype. Immunohistochemical examination of SSc and control skin biopsies revealed the presence of PDGF-AA in SSc skin. Data obtained by ligand binding, immunoprecipitation, mRNA, and mitogenic techniques are consistent with the hypothesis that activation of the PDGF-AA ligand/alpha receptor pathway is a characteristic of the SSc fibroblast and may contribute to the expansion of fibroblasts in SSc.


Joint inflammation related citrullination of functional arginines in extracellular proteins.
We report the extent, specific sites and structural requirements of joint inflammation related citrullination in extracellular proteins. A total of 40 synovial fluid samples derived from chronically inflamed human joints were analysed by heparin-agarose fractionation and LC-MS/MS. Citrullination of 55 arginines in extracellular proteins was detected. Importantly, 20% of the sites have a characterized function related to the hallmarks of destructive joint inflammation. E.g. four arginine residues, shown here to be citrullinated, are also affected by mutations in inherited diseases causing haemolysis or blood clotting dysfunction. Citrullination of integrin ligands was selected for further studies since fibronectin R234 in isoDGR was among the most frequently citrullinated arginines in synovial fluid. Assays with synovial fibroblasts and integrin αVβ3 indicated decreased affinity to the enzymatically citrullinated integrin binding sites. To conclude, our data indicate that in inflamed joints extensive citrullination affects the functional arginine residues in extracellular proteins.


Health "Brexternalities": The Brexit Effect on Health and Health Care outside the United Kingdom.
The principal effects of Brexit on health and health care will fall within the United Kingdom, and all forms of Brexit have overwhelmingly negative implications for health care and health within the UK. This article focuses on the external effects of Brexit ("Brexternalities") for health and health care. The EU is a particularly powerful institutional and legal arrangement for managing economic and political externalities in health policy as in any other policy. Equally, when a state leaves the EU, the manner of leaving will result in better or worse management of relevant externalities. Brexternalities thus involve questions about policy legitimacy and accountability. Health Brexternalities do not fall equally in all EU countries. They are felt more distinctly in the context of those elements of health policy that are most closely entwined with the UK's health policy (e.g., on the island of Ireland, certain areas of Spain, and other parts of southern Europe). Some health Brexternalities, such as in medicine safety, will be imposed on the whole population of the EU. And some health Brexternalities, such as communicable disease control, will be felt globally.


Genetic Determinants of 1,3-Butadiene Metabolism and Detoxification in Three Populations of Smokers with Different Risks of Lung Cancer.
Background: 1,3-Butadiene (BD) is an important carcinogen in tobacco smoke that undergoes metabolic activation to DNA-reactive epoxides. These species can be detoxified via glutathione conjugation and excreted in urine as the corresponding N-acetylcysteine conjugates. We hypothesize that single nucleotide polymorphisms (SNPs) in BD-metabolizing genes may change the balance of BD bioactivation and detoxification in White, Japanese American, and African American smokers, potentially contributing to ethnic differences in lung cancer risk.Methods: We measured the levels of BD metabolites, 1- and 2-(N-acetyl-L-cysteine-S-yl)-1-hydroxybut-3-ene (MHBMA) and N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (DHBMA), in urine samples from a total of 1,072 White, Japanese American, and African American smokers and adjusted these values for body mass index, age, batch, and total nicotine equivalents. We also conducted a genome-wide association study to identify genetic determinants of BD metabolism.Results: We found that mean urinary MHBMA concentrations differed significantly by ethnicity (P = 4.0 × 10-25). African Americans excreted the highest levels of MHBMA followed by Whites and Japanese Americans. MHBMA levels were affected by GSTT1 gene copy number (P < 0.0001); conditional on GSTT1, no other polymorphisms showed a significant association. Urinary DHBMA levels also differed between ethnic groups (P = 3.3 × 10-4), but were not affected by GSTT1 copy number (P = 0.226).Conclusions:GSTT1 gene deletion has a strong effect on urinary MHBMA levels, and therefore BD metabolism, in smokers.Impact: Our results show that the order of MHBMA levels among ethnic groups is consistent with their respective lung cancer risk and can be partially explained by GSTT1 genotype. Cancer Epidemiol Biomarkers Prev; 26(7); 1034-42. ©2017 AACR.


Evaluation of the antitumor activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine).
A new pyrimidine antimetabolite, 2',2'-difluorodeoxycytidine, Gemcitabine (LY188011, dFdCyd) has been synthesized and evaluated in experimental tumor models. dFdCyd is a very potent and specific deoxycytidine analogue. The concentration required for 50% inhibition of growth is 1 ng/ml in the CCRF-CEM human leukemia cell culture assay. Concurrent addition of deoxycytidine to the cell culture system provides about a 1000-fold decrease in biological activity. The inhibition of growth of human leukemia cells in culture led to the in vivo evaluation of this compound as a potential oncolytic agent. Maximal activity in vivo was seen with dFdCyd when administered on an every third day schedule. 1-beta-D-Arabinofuranosylcytosine, administered on a daily for 10-day schedule, was directly compared to dFdCyd in this evaluation. dFdCyd demonstrated good to excellent antitumor activity in eight of the eight murine tumor models evaluated. 1-beta-D-Arabinofuranosylcytosine was substantially less active or had no activity in these same tumor models. This in vivo activity against murine solid tumors supports the conclusion that dFdCyd is an excellent candidate for clinical trials in the treatment of cancer.


Leptospirosis prevalence in a population of yucatan, Mexico.
Objective. To measure the prevalence of leptospirosis with two techniques in inhabitants of Izamal, Yucatan and to determine its relation with some exposure factors. Material and Methods. Transversal study in populations belonging to the HR62-IMSS-Opportunities working force in Izamal, Yucatan. Population, including 6 years of age or more, was randomly selected to participate in the study. A questionnaire was applied for personal ID and exposure factors; blood samples were taken for leptospirosis diagnosis. Simple frequencies, proportions, tendency and dispersion measures, prevalence and odd ratios and confidence intervals (CI) of 95%, and logistic regression model were obtained. Results. 204 patients, between 9 and 80 years old were included; 180 were positive (88.2%) with the dark-field technique; using MAT cutoff at 1 : 40, 178 patients (87.3%) were positive, while at 1 : 80 there were 103 positive (50.5%). The predominant serovar was Hardjo (94%). The highest prevalence was in women (96.3%) and in the >45-year-old group (95.7%); feminine gender (RM = 2.31 IC 95% 3.59-28.6), housewife (RM = 22.8 IC 95% 4.9-106.1), being in contact with stagnant water (RM = 5.2 IC 95% 1.7-15.9), and being in contact with domestic animal feces (RM = 5.1 IC 95% 1.9-13.1), these being the most significant variables in the final logistic regression model. Conclusions. The prevalence found was higher than the one nationally and internationally reported, representing an important finding, being in turn a local public health, maybe nationally. It is urgent to reinforce this research as well as to establish preventive and control measure to avoid exposure and health damages.


High-speed volumetric imaging of cone photoreceptors with adaptive optics spectral-domain optical coherence tomography.
We report the first observations of the three-dimensional morphology of cone photoreceptors in the living human retina. Images were acquired with a high-speed adaptive optics (AO) spectral-domain optical coherence tomography (SD-OCT) camera. The AO system consisted of a Shack-Hartmann wavefront sensor and bimorph mirror (AOptix) that measured and corrected the ocular and system aberrations at a closed-loop rate of 12 Hz. The bimorph mirror was positioned between the XY mechanical scanners and the subject's eye. The SD-OCT system consisted of a superluminescent diode and a 512 pixel line scan charge-coupled device (CCD) that acquired 75,000 A-scans/s. This rate is more than two times faster than that previously reported. Retinal motion artifacts were minimized by quickly acquiring small volume images of the retina with and without AO compensation. Camera sensitivity was sufficient to detect reflections from all major retinal layers. The regular distribution of bright spots observed within C-scans at the inner segment / outer segment (IS/OS) junctions and at the posterior tips of the OS were found to be highly correlated with one another and with the expected cone spacing. No correlation was found between the posterior tips of the OS and the other retinal layers examined, including the retinal pigment epithelium.


Spontaneous resolution and complete recovery of spontaneous cervical epidural hematoma: Report of two cases and literature review.
To present the natural course and treatment modalities of spontaneous cervical epidural hematoma (SCEH), by reporting two rare cases with spontaneous resolution in both clinical and radiologic findings without surgery. One patient presenting with acute right side hemiparesis and another showing pure cervical radiculopathy were diagnosed with SCEH on magnetic resonance imaging (MRI). Both were both treated non-operatively. We also conducted a literature review of 19 cases of spontaneous spinal epidural hematoma (SSEH). These two patients achieved complete resolution in terms of both neurologic function and radiologic findings within 21 days after onset. In the literature review, 63.2% of cases experienced neurologic improvement in the first 24h, 78.9% achieved complete neurologic recovery within 1 month, and radiological images showed complete resolution of hematoma in the first month for 73.7% of patients. Atypical cervical SSEH can mimic cerebral stroke or a ruptured cervical disc. A high index of clinical suspicion followed by MRI examination is critical for diagnosis. Prompt surgical decompression and evacuation of the hematoma is generally regarded as first-line treatment. However, for patients without or with only slight neurologic symptoms, or showing early and sustained neurologic improvement, non-surgical therapy with close observation is a viable alternative. Both neurologic and radiologic resolution can be expected within the first month following onset in most cases of spontaneous resolution of SSEH.


Thyroid medication use and subsequent development of dementia of the Alzheimer type.
Associations between medication use and the development of Alzheimer disease have been investigated since the late 1900s. Thyroid hormone supplementation is rarely a studied medication class in this area of research. We examined data from participants enrolled in longitudinal studies at the Washington University Alzheimer's Disease Research Center for associations between thyroid disease, thyroid hormone supplementation therapy, and subsequent development of dementia of the Alzheimer type (DAT). Data collected between April 1992 and June 2008 from 499 participants, 184 men and 315 women, were analyzed. Mean age was 76.9 years (SD = 9.2). At baseline, 61 participants reported thyroid medication use and 87 were identified as having a history of thyroid dysfunction. These participants progressed to a DAT diagnosis more rapidly than individuals not taking thyroid medication (hazard ratios [HR]: 1.67, 95% CI: 0.99-2.78, P = .054). Although an interesting trend was seen, baseline thyroid disease was not significantly (P = .093) associated with time to DAT diagnosis. Our findings suggest that utilization of thyroid medication may be associated with the development of DAT.


Aortic intima-media thickness and lipid profile in macrosomic newborns.
Macrosomia is associated with alterations in lipoprotein composition and concentration at birth. Exposure to diabetes in utero has been established as a significant risk factor for some of the components of metabolic syndrome. The aim of this study was to investigate the effect of macrosomia on lipid metabolism, aortic intima-media thickness (aIMT) and subsequent atherogenic risk in newborn infants. Aortic intima-media thickness was measured in 40 macrosomic neonates of diabetic mothers (group A), 30 macrosomic neonates of healthy mothers (group B) and 30 healthy neonates (group C). Lipid profile was determined in all infants and their mothers. Mean aIMT was significantly higher in macrosomic neonates of diabetic and healthy mothers (0.56+/-0.06 and 0.49+/-0.03 mm respectively) than in controls (0.39+/-0.03 mm). Weight-adjusted aIMT in macrosomic neonates of diabetic mothers (0.129+/-0.013 mm/kg) was significantly higher than in groups B and C (0.114+/-0.008 and 0.113+/-0.011 mm/kg respectively). There were significant alterations of total serum, high-density lipoprotein (HDL), very low-density lipoprotein (VLDL) cholesterols and triglyceride levels in the macrosomic neonates of diabetic mothers compared with controls. Macrosomia was associated with increased lipid concentrations. Macrosomic neonates of diabetic mothers have significantly higher aIMT with lipid alterations. This may play a role in the pathogenesis of atherosclerosis in adult life.


Add-on azithromycin reduces sputum cytokines in non-eosinophilic asthma: an AMAZES substudy.
Add-on azithromycin (AZM) significantly reduces exacerbations in poorly controlled asthma irrespective of disease phenotype. In a predefined substudy of the original AMAZES protocol (500 mg, three times a week for 48 weeks), we report that AZM treatment reduces key sputum inflammatory proteins (interleukin (IL)-6, IL-1β and extracellular DNA), which is more evident in non-eosinophilic asthma (NEA). Moreover, AZM reduced Haemophilus influenzae load only in NEA. Our data support the anti-inflammatory effects of AZM in poorly controlled asthma. Prospective studies are required to identify patients that derive greatest benefit from AZM add-on therapy.


Promising outcomes in teen mothers enrolled in a school-based parent support program and child care center.
This study described a cohort of teen mothers and their children attending an urban high school with a parent support program and school-based child care center. Specific aims of the study were to describe maternal characteristics and outcomes, and child developmental and health outcomes. A volunteer sample of 65 adolescent mothers enrolled in the parent support program and their children were interviewed, surveyed, and assessed. Fifty-three mothers had children enrolled in the school-based child care center and 12 mothers had their children cared for by family members. Maternal characteristics assessed included self-esteem and depressive symptoms, social stressors and support, self-perceived parental competence, parent-child teaching interactions, and subsequent childbearing and maternal educational outcomes. Child outcomes included child developmental assessments and health outcomes. About 33% of teen mothers were mildly to moderately depressed and 39% of the sample had experienced transitional homelessness. Social support networks were small; in the past 12 months, mothers experienced a mean number of 13.2 +/- 11.9 negative life events. Maternal self-report measures and mother-child observation measures indicated positive levels of parental competence. Maternal educational outcomes were positive, and only 6% of mothers had subsequent childbirths within 2 years. The mean scores on developmental assessments of children fell within the normal range, although there were 7 children identified with developmental delays. For at-risk teen mothers, this parent support program and school-based child care setting appears to offer promising opportunities to help young mothers with parenting, avoid rapid subsequent pregnancies, and stay engaged with school, while their children are cared for in a close and safe environment.


Influence of the history on physicians' interpretations of girls' genital findings.
Because physicians customarily obtain histories before examining children in cases of possible sexual abuse, and because the resulting diagnostic opinions can influence important social and legal decisions, we investigated whether clinical histories influence physicians' interpretations of girls' genital findings. In mailed questionnaires, 1387 randomly selected Fellows of the American Academy of Pediatrics and all 802 members of four professional groups concerned with child abuse or pediatric gynecology were asked to interpret seven simulated cases. Respondents were asked to interpret seven additional cases in separate questionnaires mailed 4 months later. Both sets of cases involved the same seven photographs of girls' external genitalia. However, in six of the seven case pairs, the histories in the two questionnaires differed in the extent to which they suggested sexual abuse. In the remaining (control) pair, the same history was presented in both questionnaires. Of 2189 physicians, 1114 (50.9%) responded. Responses from 604 physicians (54.2%) were eligible for analysis. Overall, the genital findings were interpreted most consistently by the most experienced physicians and least consistently by the least experienced physicians. The proportion of physicians whose interpretations of a photograph reversed in the direction suggested by the change in the associated history from "no indication of abuse" to "probable abuse," or vice versa, ranged for experienced physicians from none to 5.6%; for moderately experienced physicians from 1.6% to 19.8%; and for inexperienced physicians from 3.6% to 27.2%. This difference between the experience groups was statistically significant in four case pairs. Mean interpretation scores for genital findings changed significantly when the histories changed in two case pairs for the experienced physicians, in five pairs for the moderately experienced physicians, and in all six pairs for the inexperienced physicians. In some cases and especially for less experienced physicians, diagnostic expectation appears likely to influence physicians' interpretations of girls' genital findings. Physicians should be alert to the possibility of diagnostic expectation bias and its potentially serious social and legal consequences.


Review of forensically important entomological specimens collected from human cadavers in Malaysia (2005-2010).
Forensic entomological specimens collected from human decedents during crime scene investigations in Malaysia in the past 6 years (2005-2010) are reviewed. A total of 80 cases were recorded and 93 specimens were collected. From these specimens, 10 species of cyclorrphagic flies were identified, consisting of Chrysomya rufifacies (Macquart) -38 specimens (40.86%), Chrysomya megacephala (Fabricius) -36 specimens (38.70%), Chrysomya villeneuvi (Patton) -2 specimens (2.15%), Chrysomya nigripes (Aubertin) -2 specimens (2.15%), Chrysomya pinguis (Walker) -1 specimen (1.08%), Hermetia illucens (Linnaeus) -1 specimen (1.08%), Hemipyrellia liguriens (Wiedemann) -5 specimens (5.37%), Synthesiomyia nudiseta (Wulp) -1 specimen (1.08%), Megaselia scalaris (Loew)-1 specimen (1.08%) and Sarcophaga ruficornis (Fabricius) -4 specimens (4.30%). In two specimens (2.15%), the maggots were not identifiable. Ch. megacephala and Ch. rufifacies were the commonest species found in human decedents from three different ecological habitats. S. nudiseta is an uncommon species found only on human cadavers from indoors. A total of 75 cases (93.75%) had a single fly infestation and 5 cases (6.25%) had double fly infestation. In conclusion, although large numbers of fly species were found on human decedents, the predominant species are still those of Chrysomya.


Plasma beta carotene in Alzheimer's disease. Association with cerebrospinal fluid beta-amyloid 1-40, (Abeta40), beta-amyloid 1-42 (Abeta42) and total Tau.
We studied the plasma beta carotene concentrations in 40 Alzheimer's disease patients and the association with cerebrospinal fluid beta-amyloid 1-40, (Abeta40), cerebrospinal fluid beta-amyloid 1-42 (Abeta42) and cerebrospinal fluid total Tau. We found that patients with plasma beta carotene levels below the 25th percentile had 55% reduced ratios of Abeta40/Tau and 51% reduced ratios of Abeta 40/Abeta 42 compared with patients in the highest quartile. Mean Tau concentrations in the lowest quartile of plasma beta-carotene levels were 74% higher compared with the highest quartile of plasma beta-carotene levels. Thus, we could demonstrate an statistically significant association between beta carotene levels in plasma and neurochemical markers in the cerebrospinal fluid of Alzheimer's disease patients.


Discovery of T cell antigens by high-throughput screening of synthetic minigene libraries.
The identification of novel T cell antigens is central to basic and translational research in autoimmunity, tumor immunology, transplant immunology, and vaccine design for infectious disease. However, current methods for T cell antigen discovery are low throughput, and fail to explore a wide range of potential antigen-receptor interactions. To overcome these limitations, we developed a method in which programmable microarrays are used to cost-effectively synthesize complex libraries of thousands of minigenes that collectively encode the content of hundreds of candidate protein targets. Minigene-derived mRNA are transfected into autologous antigen presenting cells and used to challenge complex populations of purified peripheral blood CD8+ T cells in multiplex, parallel ELISPOT assays. In this proof-of-concept study, we apply synthetic minigene screening to identify two novel pancreatic islet autoantigens targeted in a patient with Type I Diabetes. To our knowledge, this is the first successful screen of a highly complex, synthetic minigene library for identification of a T cell antigen. In principle, responses against the full protein complement of any tissue or pathogen can be assayed by this approach, suggesting that further optimization of synthetic libraries holds promise for high throughput antigen discovery.


Filtering of acoustic signals within the hearing organ.
The detection of sound by the mammalian hearing organ involves a complex mechanical interplay among different cell types. The inner hair cells, which are the primary sensory receptors, are stimulated by the structural vibrations of the entire organ of Corti. The outer hair cells are thought to modulate these sound-evoked vibrations to enhance hearing sensitivity and frequency resolution, but it remains unclear whether other structures also contribute to frequency tuning. In the current study, sound-evoked vibrations were measured at the stereociliary side of inner and outer hair cells and their surrounding supporting cells, using optical coherence tomography interferometry in living anesthetized guinea pigs. Our measurements demonstrate the presence of multiple vibration modes as well as significant differences in frequency tuning and response phase among different cell types. In particular, the frequency tuning at the inner hair cells differs from other cell types, causing the locus of maximum inner hair cell activation to be shifted toward the apex of the cochlea compared with the outer hair cells. These observations show that additional processing and filtering of acoustic signals occur within the organ of Corti before inner hair cell excitation, representing a departure from established theories.


Phenotypic differences between pregnancy-onset and postpartum-onset major depressive disorder.
To compare clinical features of major depression that begins during pregnancy to clinical features of postpartum-onset depression. The hormonal environments of pregnancy and postpartum periods are quite different and therefore may promote distinct subtypes of major depression. Data were collected from medical records of 229 women who were evaluated in an academic medical center reproductive psychiatry clinic. All patients evaluated between 2005 and 2010 who were pregnant or in the first year postpartum and received a DSM-IV diagnosis of major depressive disorder were included. Comparisons between the pregnancy-onset and postpartum-onset subjects included demographics, psychiatric diagnostic history, psychosocial stressors, reproductive history, and current episode symptoms. Time of onset within trimesters of pregnancy and within the postpartum year as well as the effects of discontinuation of antidepressant medication were also examined. Women with major depressive episodes that began during pregnancy had higher rates of prior episodes of postpartum and nonperinatal major depression (both P values < .001). Major depression that began during pregnancy was also more commonly associated with psychosocial stressors. Obsessive-compulsive symptoms and psychotic symptoms were more common in postpartum-onset depression. These findings were also evident in the subgroup of 176 subjects who did not discontinue antidepressant medication during the year prior to development of perinatal depression. The onset of 94% of postpartum major depressive episodes occured within the first 4 months postpartum. Episodes of major depression during pregnancy were more likely to develop in the first trimester for women who discontinued antidepressant medication within the past year; otherwise, depression onset was more evenly distributed across trimesters. Women with a history of perinatal and nonperinatal major depression are more likely to relapse during pregnancy than postpartum, a finding that points to the need for closely monitoring these women for depression during pregnancy. In addition, these findings of differences in risk factors and clinical features suggest that postpartum-onset major depression may have a pathophysiology distinct from major depression that begins during pregnancy. Time of onset of perinatal depression should be considered in the design of genetic and treatment studies.


A comparison of troglitazone and metformin on insulin requirements in euglycemic intensively insulin-treated type 2 diabetic patients.
Troglitazone and metformin lower glucose levels in diabetic patients without increasing plasma insulin levels. We compared the insulin sparing actions of these two agents and their effects on insulin sensitivity and insulin secretion in 20 type 2 diabetic patients. To avoid the confounding effect of improved glycemic control on insulin action and secretion, patients were first rendered euglycemic with 4 weeks of continuous subcutaneous insulin infusion (CSII) before randomization to CSII plus troglitazone (n = 10) or CSII plus metformin (n = 10); euglycemia was maintained for another 6-7 weeks. Insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp 1) at baseline, 2) after 4 weeks of CSII, and 3) after CSII plus either troglitazone or metformin. The 24-h glucose, insulin, and C-peptide profiles were performed on the day before the second and third glucose clamps. Good glycemic control was achieved with CSII alone and was maintained with CSII plus an oral agent (mean 24-h glucose: troglitazone, 6.2+/-0.6 mmol/l; metformin, 6.2 +/-0.3 mmol/l). Insulin requirements decreased 53% with troglitazone compared with CSII alone (48+/-4 vs. 102+/-13 U/day, P < 0.001), but only 31% with metformin (76+/-13 vs. 110+/-18 U/day, P < 0.005). The 24-h C-peptide profiles were similar. Normal fasting hepatic glucose output was maintained with both agents despite lower insulin levels than on CSII alone. Insulin sensitivity did not change significantly with CSII alone or with CSII plus metformin, but improved 29% with CSII plus troglitazone (P < 0.005 vs. CSII alone) and was then 45% higher than in the CSII plus metformin patients (P < 0.005). In conclusion, metformin has no effect on insulin-stimulated glucose disposal independent of glycemic control in type 2 diabetes. Troglitazone (600 mg/day) has greater insulin-sparing effects than metformin (1,700 mg/day) in CSII-treated euglycemic patients. This is probably explained by the peripheral tissue insulin-sensitizing effects of troglitazone.


Kinetics of Surface-Driven Self-Assembly and Fatigue-Induced Disassembly of a Virus-Based Nanocoating.
Self-assembling protein layers provide a "bottom-up" approach for precisely organizing functional elements at the nanoscale over a large solid surface area. The design of protein sheets with architecture and physical properties suitable for nanotechnological applications may be greatly facilitated by a thorough understanding of the principles that underlie their self-assembly and disassembly. In a previous study, the hexagonal lattice formed by the capsid protein (CA) of human immunodeficiency virus (HIV) was self-assembled as a monomolecular layer directly onto a solid substrate, and its mechanical properties and dynamics at equilibrium were analyzed by atomic force microscopy. Here, we use atomic force microscopy to analyze the kinetics of self-assembly of the planar CA lattice on a substrate and of its disassembly, either spontaneous or induced by materials fatigue. Both self-assembly and disassembly of the CA layer are cooperative reactions that proceed until a phase equilibrium is reached. Self-assembly requires a critical protein concentration and is initiated by formation of nucleation points on the substrate, followed by lattice growth and eventual merging of CA patches into a continuous monolayer. Disassembly of the CA layer showed hysteresis and appears to proceed only after large enough defects (nucleation points) are formed in the lattice, whose number is largely increased by inducing materials fatigue that depends on mechanical load and its frequency. Implications of the kinetic results obtained for a better understanding of self-assembly and disassembly of the HIV capsid and protein-based two-dimensional nanomaterials and the design of anti-HIV drugs targeting (dis)assembly and biocompatible nanocoatings are discussed.


The persistence of stuttering behaviours in older people.
To measure and describe the speech characteristics of a group of 16 people over the age of 55 years who self-reported stuttering into adulthood. A cross-sectional, descriptive design was used. Sixteen participants were divided into two groups: a group of 12, (mean age 68.8) who self-reported that they continued to stutter in older age, and a group of four who self-reported recovery from stuttering in adulthood (mean age 75.5). Speech samples during face-to-face and telephone conversations were analysed for stuttering frequency (%SS) and stuttering behaviours using the Lidcombe Behavioural Data Language. Descriptive statistics showed that all participants in the persistent stuttering group evidenced stuttering with varying severity. In the group of four who reported recovery, one participant presented with measurable stuttering behaviours in the conversational and telephone sample. Participants, in the group who reported persistence of stuttering evidenced the full range of stuttering behaviours seen in younger adults. Stuttering is a disorder that may persist for some beyond 55 years of age. This result compels investigation to explore how stuttering impacts on activity and participation for this older group.


Multiplexed Nanopore Sequencing of HLA-B Locus in Māori and Pacific Island Samples.
The human leukocyte antigen (HLA) system encodes the human major histocompatibility complex (MHC). HLA-B is the most polymorphic gene in the MHC class I region and many HLA-B alleles have been associated with adverse drug reactions (ADRs) and disease susceptibility. The frequency of such HLA-B alleles varies by ethnicity, and therefore it is important to understand the prevalence of such alleles in different population groups. Research into HLA involvement in ADRs would be facilitated by improved methods for genotyping key HLA-B alleles. Here, we describe an approach to HLA-B typing using next generation sequencing (NGS) on the MinION™ nanopore sequencer, combined with data analysis with the SeqNext-HLA software package. The nanopore sequencer offers the advantages of long-read capability and single molecule reads, which can facilitate effective haplotyping. We developed this method using reference samples as well as individuals of New Zealand Māori or Pacific Island descent, because HLA-B diversity in these populations is not well understood. We demonstrate here that nanopore sequencing of barcoded, pooled, 943 bp polymerase chain reaction (PCR) amplicons of 49 DNA samples generated ample read depth for all samples. HLA-B alleles were assigned to all samples at high-resolution with very little ambiguity. Our method is a scaleable and efficient approach for genotyping HLA-B and potentially any other HLA locus. Finally, we report our findings on HLA-B genotypes of this cohort, which adds to our understanding of HLA-B allele frequencies among Māori and Pacific Island people.


Systematic review and meta-analysis of the efficacy of tuina for cervical spondylosis.
This study performed a meta-analysis of seven parallel-group comparison studies evaluating the efficacy of tuina in treating cervical spondylosis. Tuina is a form of Chinese manipulative therapy. It has been used as a modality for the treatment of symptoms associated with such a musculoskeletal condition as cervical spondylosis. However, evidence regarding the efficacy of tuina for cervical spondylosis has yet to be determined. Systematic review. Cochrane library, Pubmed, MEDLINE, EBM review, ProQuest Medical Bundle and SCOPUS databases were searched using the following medical subject headings or key words: tuina, tuinaology, manual medicine, massotherapy, cervical spondylopathy, cervical spondylosis and cervical vertebrae. Chinese research papers were searched through the Chinese electronic periodical services and Wangfane database. The publication date was limited from 1996-2007. Studies were selected if they were written in English or Chinese, used tuina as a stand-alone modality, used a parallel-group comparison design and explicated raw data regarding symptoms relief. Two independent reviewers reviewed the selected studies based on the evidence rating system of the US Preventive Services Task Force. Studies with an evidence rating of II-2 fair or above were included in this review. The direction of the effect size for the improvement of blood flow velocity of vertebral artery and basilar artery was not consistent across studies. Moreover, the pooled effect size was negligible. No evidence supported that tuina could improve headache and vertigo. A small effect of tuina on the viscosity of blood and plasma was found. Based on the results of this systematic review, a definitive conclusion regarding the effects of tuina on cervical spondylosis remains to be determined. The efficacy of tuina is not supported by parallel-group comparison studies.


Microbiological and molecular characterization of Staphylococcus hominis isolates from blood.
Among Coagulase-Negative Staphylococci (CoNS), Staphylococcus hominis represents the third most common organism recoverable from the blood of immunocompromised patients. The aim of this study was to characterize biofilm formation, antibiotic resistance, define the SCCmec (Staphylococcal Chromosomal Cassette mec) type, and genetic relatedness of clinical S. hominis isolates. S. hominis blood isolates (n = 21) were screened for biofilm formation using crystal violet staining. Methicillin resistance was evaluated using the cefoxitin disk test and the mecA gene was detected by PCR. Antibiotic resistance was determined by the broth microdilution method. Genetic relatedness was determined by pulsed-field gel electrophoresis (PFGE) and SCCmec typed by multiplex PCR using two different methodologies described for Staphylococcus aureus. Of the S. hominis isolates screened, 47.6% (10/21) were categorized as strong biofilm producers and 23.8% (5/21) as weak producers. Furthermore, 81% (17/21) of the isolates were methicillin resistant and mecA gene carriers. Resistance to ampicillin, erythromycin, and trimethoprim was observed in >70% of isolates screened. Each isolate showed a different PFGE macrorestriction pattern with similarity ranging between 0-95%. Among mecA-positive isolates, 14 (82%) harbored a non-typeable SCCmec type: eight isolates were not positive for any ccr complex; four contained the mec complex A ccrAB1 and ccrC, one isolate contained mec complex A, ccrAB4 and ccrC, and one isolate contained the mec complex A, ccrAB1, ccrAB4, and ccrC. Two isolates harbored the association: mec complex A and ccrAB1. Only one strain was typeable as SCCmec III. The S. hominis isolates analyzed were variable biofilm producers had a high prevalence of methicillin resistance and resistance to other antibiotics, and high genetic diversity. The results of this study strongly suggested that S. hominis isolates harbor new SCCmec structural elements and might be reservoirs of ccrC1 in addition to ccrAB1 and mec complex A.


Higher-level pattern features provide additional information to birds when recognizing and rejecting parasitic eggs.
Despite a recent explosion of research on pattern recognition, in both neuroscience and computer vision, we lack a basic understanding of how most animals perceive and respond to patterns in the wild. Avian brood parasites and their hosts provide an ideal study system for investigating the mechanisms of pattern recognition. The cuckoo finch, Anomalospiza imberbis, and its host the tawny-flanked prinia, Prinia subflava, lay highly polymorphic eggs with a great deal of variation in colour and patterning, with the cuckoo finch capable of close egg mimicry. Behavioural experiments in Zambia have previously shown that prinias use colour and multiple 'low-level' (occurring in early stages of visual processing) pattern attributes, derived from spatial frequency analysis, when rejecting foreign eggs. Here, we explore the extent to which host birds might also use 'higher-level' pattern attributes, derived from a feature detection algorithm, to make rejection decisions. Using a SIFT-based pattern recognition algorithm, NaturePatternMatch, we show that hosts are more likely to reject a foreign egg if its higher-level pattern features-which capture information about the shape and orientation of markings-differ from those of the host eggs. A revised statistical model explains about 37% variance in egg rejection behaviour, and differences in colour, low-level and higher-level pattern features all predict rejection, accounting for 42, 44 and 14% of the explained variance, respectively. Thus, higher-level pattern features provide a small but measurable improvement to the original model and may be especially useful when colour and low-level pattern features provide hosts with little information. Understanding the relative importance of low- and higher-level pattern features is a valuable goal for future work on animal coloration, especially in the contexts of mimicry, camouflage and individual recognition. This article is part of the theme issue 'The coevolutionary biology of brood parasitism: from mechanism to pattern'.


An automated system for quantitative analysis of Drosophila larval locomotion.
Drosophila larvae have been used as a model to study to genetic and cellular circuitries modulating behaviors. One of the challenges in behavioral study is the quantification of complex phenotypes such as locomotive behaviors. Experimental capability can be greatly enhanced by an automatic single-animal tracker that records an animal at a high resolution for an extended period, and analyzes multiple behavioral parameters. Here we present MaggotTracker, a single-animal tracking system for Drosophila larval locomotion analysis. This system controls the motorized microscope stage while taking a video, so that the animal remains in the viewing center. It then reduces the animal to 13 evenly distributed points along the midline, and computes over 20 parameters evaluating the shape, peristalsis movement, stamina, and track of the animal. To demonstrate its utility, we applied MaggotTracker to analyze both wild-type and mutant animals to identify factors affecting locomotive behaviors. Each animal was tracked for four minutes. Our analysis on Canton-S third-instar larvae revealed that the distance an animal travelled was correlated to its striding speed rather than the percentage of time the animal spent striding, and that the striding speed was correlated to both the distance and the duration of one stride. Sexual dimorphism was observed in body length but not in locomotive parameters such as speed. Locomotive parameters were affected by animal developmental stage and the crawling surface. No significant changes in movement speed were detected in mutants of circadian genes such as period (per), timeout, and timeless (tim). The MaggotTracker analysis showed that ether a go-go (eag), Shaker (Sh), slowpoke (slo), and dunce (dnc) mutant larvae had severe phenotypes in multiple locomotive parameters such as stride distance and speed, consistent with their function in neuromuscular junctions. Further, the phenotypic patterns of the K(+) channel genes eag, Sh and slo are highly similar. These results showed that MaggotTracker is an efficient tool for automatic phenotyping. The MaggotTracker software as well as the data presented here can be downloaded from our open-access site www.WormLoco.org/Mag.


5-Fluorouracil with folinic acid is not effective against metastatic adenocarcinoma of the lung.
Thirty patients with a diagnosis of metastatic adenocarcinoma of the lung were entered on a trial to evaluate the antitumor efficacy of 5-fluorouracil 370 mg/m2 daily for 5 days every four weeks in combination with folinic acid 200 mg/m2, 60 min prior to 5FU. All patients had a good performance status, bidimensionally measurable disease, and weight loss less than or equal to 5% of preillness weight. Of the 29 evaluable patients, only two (7%) had partial responses (95% confidence limits 1-24%). Eleven (38%) had stable disease and 16 (55%) progressed. The two responding patients survived 12 and 60+ weeks. The median survival of all evaluable patients was 25 weeks (range 7-60+) and that of the stable patients was 26 weeks. The principal toxicities observed were diarrhea and stomatitis. Myelosuppression was rarely dose limiting. In contrast to the results of treatment with 5FU and folinic acid in metastatic colorectal cancer and breast cancer, the results of treatment with this combination of agents have been much less encouraging in adenocarcinoma of the lung.


Uncertainty in science and its role in climate policy.
Policy-making is usually about risk management. Thus, the handling of uncertainty in science is central to its support of sound policy-making. There is value in scientists engaging in a deep conversation with policy-makers and others, not merely 'delivering' results or analyses and then playing no further role. Communicating the policy relevance of different varieties of uncertainty, including imprecision, ambiguity, intractability and indeterminism, is an important part of this conversation. Uncertainty is handled better when scientists engage with policy-makers. Climate policy aims both to alter future risks (particularly via mitigation) and to take account of and respond to relevant remaining risks (via adaptation) in the complex causal chain that begins and ends with individuals. Policy-making profits from learning how to shift the distribution of risks towards less dangerous impacts, even if the probability of events remains uncertain. Immediate value lies not only in communicating how risks may change with time and how those risks may be changed by action, but also in projecting how our understanding of those risks may improve with time (via science) and how our ability to influence them may advance (via technology and policy design). Guidance on the most urgent places to gather information and realistic estimates of when to expect more informative answers is of immediate value, as are plausible estimates of the risk of delaying action. Risk assessment requires grappling with probability and ambiguity (uncertainty in the Knightian sense) and assessing the ethical, logical, philosophical and economic underpinnings of whether a target of '50 per cent chance of remaining under +2(°)C' is either 'right' or 'safe'. How do we better stimulate advances in the difficult analytical and philosophical questions while maintaining foundational scientific work advancing our understanding of the phenomena? And provide immediate help with decisions that must be made now?


Exploratory Investigation of a Brief Cognitive Behavioral Intervention and Transcranial Direct Current Stimulation on Odor Sensitivity.
Enhanced odor sensitivity is a phenomenon that potentially underlies conditions such as multiple chemical sensitivity (MCS). Currently, there are no treatments that have been shown to effectively decrease odor sensitivity. Given similarities of odor hypersensitivity/MCS to pain sensitization disorders such as fibromyalgia, there may be a potential for interventions that improve pain tolerance to modulate odor sensitivity. This exploratory study randomized 72 healthy community adult volunteers to receive one of six treatments in between two assessments of thermal pain tolerance and odor threshold. Participants were randomized to receive either cathodal, anodal, or sham transcranial direct current stimulation (tDCS) aimed at dorsolateral prefrontal cortex. In addition, participants were provided a brief cognitive behavioral intervention (CBI) for pain consisting of task framing, cognitive restructuring, and distraction technique training, or a control intervention consisting of information about pain. Persons who received a brief CBI showed significantly increased odor thresholds (reduced sensitivity) during intervention (F (1,62) = 7.29, p = .009, ηp = .11), whereas the control intervention was not associated with altered odor thresholds. Moreover, in those who received brief CBI, more severe anxiety associated with larger reductions in odor sensitivity (ρ = .364, p = .035). There was no effect of tDCS (F (2,62) = .11, p = .90) nor interaction between tDCS and CBI (F (2,62) = .32, p = .73). Given the connection between anxiety and MCS, results suggest that CBT techniques for somatic processes may show promise in treating conditions characterized by increased sensitivity to odors (e.g., MCS).


Changes in Visual Function in the Elderly Population in the United States: 1995-2010.
To document recent trends in visual function among the United States population aged 70+ years and investigate how the trends can be explained by inter-temporal changes in: (1) population sociodemographic characteristics, and chronic disease prevalence, including eye diseases (compositional changes); and (2) effects of the above factors on visual function (structural changes). Data from the 1995 Asset and Health Dynamics among the Oldest Old (AHEAD) and the 2010 Health and Retirement Study (HRS) were merged with Medicare Part B claims in the interview years and the 2 previous years. Decomposition analysis was performed. Respondents from both studies were aged 70+ years. The outcome measure was respondent self-reported visual function on a 6-point scale (from 6 = blind to 1 = excellent). Overall, visual function improved from slightly worse than good (3.14) in 1995 to slightly better than good (2.98) in 2010. A decline in adverse effects of aging on vision was found. Among the compositional changes were higher educational attainment leading to improved vision, and higher prevalence of such diseases as diabetes mellitus, which tended to lower visual function. However, compared to compositional changes, structural changes were far more important, including decreased adverse effects of aging, diabetes mellitus (when not controlling for eye diseases), and diagnosed glaucoma. Although the US population has aged and is expected to age further, visual function improved among elderly persons, especially among persons 80+ years, likely reflecting a favorable role of structural changes identified in this study in mitigating the adverse effect of ongoing aging on vision.


Effect of hydration state on resistance exercise-induced endocrine markers of anabolism, catabolism, and metabolism.
Hypohydration (decreased total body water) exacerbates the catabolic hormonal response to endurance exercise with unclear effects on anabolic hormones. Limited research exists that evaluates the effect of hypohydration on endocrine responses to resistance exercise; this work merits attention as the acute postexercise hormonal environment potently modulates resistance training adaptations. The purpose of this study was to examine the effect of hydration state on the endocrine and metabolic responses to resistance exercise. Seven healthy resistance-trained men (age = 23 +/- 4 yr, body mass = 87.8 +/- 6.8 kg, body fat = 11.5 +/- 5.2%) completed three identical resistance exercise bouts in different hydration states: euhydrated (EU), hypohydrated by approximately 2.5% body mass (HY25), and hypohydrated by approximately 5.0% body mass (HY50). Investigators manipulated hydration status via controlled water deprivation and exercise-heat stress. Cortisol, epinephrine, norepinephrine, testosterone, growth hormone, insulin-like growth factor-I, insulin, glucose, lactate, glycerol, and free fatty acids were measured during euhydrated rest, immediately preceding resistance exercise, immediately postexercise, and during 60 min of recovery. Body mass decreased 0.2 +/- 0.4, 2.4 +/- 0.4, and 4.8 +/- 0.4% during EU, HY25, and HY50, respectively, supported by humoral and urinary changes that clearly indicated subjects achieved three distinct hydration states. Hypohydration significantly 1) increased circulating concentrations of cortisol and norepinephrine, 2) attenuated the testosterone response to exercise, and 3) altered carbohydrate and lipid metabolism. These results suggest that hypohydration can modify the hormonal and metabolic response to resistance exercise, influencing the postexercise circulatory milieu.


Human USP3 is a chromatin modifier required for S phase progression and genome stability.
Protein ubiquitination is critical for numerous cellular functions, including DNA damage response pathways. Histones are the most abundant monoubiquitin conjugates in mammalian cells; however, the regulation and the function of monoubiquitinated H2A (uH2A) and H2B (uH2B) remain poorly understood. In particular, little is known about mammalian deubiquitinating enzymes (DUBs) that catalyze the removal of ubiquitin from uH2A/uH2B. Here we identify the ubiquitin-specific protease 3 USP3 as a deubiquitinating enzyme for uH2A and uH2B. USP3 dynamically associates with chromatin and deubiquitinates H2A/H2B in vivo. The ZnF-UBP domain of USP3 mediates uH2A-USP3 interaction. Functional ablation of USP3 by RNAi leads to delay of S phase progression and to accumulation of DNA breaks, with ensuing activation of DNA damage checkpoint pathways. In addition, we show that in response to ionizing radiation, (1) uH2A redistributes and colocalizes in gamma-H2AX DNA repair foci and (2) USP3 is required for full deubiquitination of ubiquitin-conjugates/uH2A and gamma-H2AX dephosphorylation. Our studies identify USP3 as a novel regulator of H2A and H2B ubiquitination, highlight its role in preventing replication stress, and suggest its involvement in the response to DNA double-strand breaks. Together, our results implicate USP3 as a novel chromatin modifier in the maintenance of genome integrity.


Predicting homophobic behavior among heterosexual youth: domain general and sexual orientation-specific factors at the individual and contextual level.
As a form of bias-based harassment, homophobic behavior remains prominent in schools. Yet, little attention has been given to factors that underlie it, aside from bullying and sexual prejudice. Thus, we examined multiple domain general (empathy, perspective-taking, classroom respect norms) and sexual orientation-specific factors (sexual orientation identity importance, number of sexual minority friends, parents' sexual minority attitudes, media messages). We documented support for a model in which these sets of factors converged to predict homophobic behavior, mediated through bullying and prejudice, among 581 students in grades 9-12 (55 % female). The structural equation model indicated that, with the exception of media messages, these additional factors predicted levels of prejudice and bullying, which in turn predicted the likelihood of students to engage in homophobic behavior. These findings highlight the importance of addressing multiple interrelated factors in efforts to reduce bullying, prejudice, and discrimination among youth.


Gender difference in HIV-1 RNA viral loads.
To test and characterize the dependence of viral load on gender in different countries and racial groups as a function of CD4 T-cell count. Plasma viral load data were analysed for > 30,000 HIV-infected patients attending clinics in the USA [HIV Insight (Cerner Corporation, Vienna, VA, USA) and Plum Data Mining LLC (East Meadow, NY, USA) databases] and the Netherlands (Athena database; HIV Monitoring Foundation, Amsterdam, Netherlands). Log-normal regression models were used to test for an effect of gender on viral load while adjusting for covariates and allowing the effect to depend on CD4 T-cell count. Sensitivity analyses were performed to test the robustness of conclusions to assumptions regarding viral loads below the lower limit of quantification (LLOQ). After adjusting for covariates, women had (nonsignificantly) lower viral loads than men (HIV Insight: -0.053 log(10) HIV-1 RNA copies/mL, P = 0.202; Athena: -0.005 log(10) copies/mL, P = 0.667; Plum: -0.072 log(10) copies/mL, P = 0.273). However, further investigation revealed that the gender effect depended on CD4 T-cell count. Women had consistently higher viral loads than men when CD4 T-cell counts were at most 50 cells/microL, and consistently lower viral loads than men when CD4 T-cell counts were greater than 350 cells/microL. These effects were remarkably consistent when estimated independently for the racial groups with sufficient data available in the HIV Insight and Plum databases. The consistent relationship between gender-related differences in viral load and CD4 T-cell count demonstrated here explains the diverse findings previously published.