Walking and finger tapping can be done with independent rhythms.
Rhythmic movements occur in many aspects of daily life. Examples include clapping the hands and walking. The production of two independent rhythms with multiple limbs is considered to be extremely difficult. In the present study we evaluated whether two different, independent rhythms that involved finger tapping and walking could be produced. In Experiment I, twenty subjects that had no experience of musical instrument training performed rhythmic finger tapping with the right index finger and one of four different lower limb movements; (1) self-paced walking, (2) given-paced walking, (3) alternative bilateral heel tapping from a sitting position, and (4) unilateral heel tapping with the leg ipsilateral to the tapping finger from a sitting position. The target intervals of finger tapping and heel strikes for walking step/heel tapping were set at 375 ms and 600 ms, respectively. The even distribution of relative phases between instantaneous finger tapping and heel strike was taken as the criteria of independency for the two rhythms. In the self-paced walking and given-paced walking tasks, 16 out of 20 subjects successfully performed finger tapping and walking with independent rhythms without any special practice. On the other hand, in the bipedal heels striking and unipedal heel striking tasks 19 subjects failed to perform the two movements independently, falling into interrelated rhythms with the ratio mostly being 2:1. In Experiment II, a similar independency of finger tapping and walking at a given pace was observed for heel strike intervals of 400, 600, and 800 ms, as well as at the constant 375 ms for finger tapping. These results suggest that finger tapping and walking are controlled by separate neural control mechanisms, presumably with a supra-spinal locus for finger tapping, and a spinal location for walking.


Risk factors for specific upper limb disorders as compared with non-specific upper limb pain: assessing the utility of a structured examination schedule.
Few community-based epidemiological investigations of upper limb disorders (ULDs) have classified cases by validated procedures involving a structured clinical examination. To compare risk factor profiles for different diagnostic categories of ULD using one such examination scheme. A questionnaire about upper limb pain and demographic, occupational and psychosocial risk factors was mailed to 10,264 adults from two English general practices, followed by standardized physical examination in those with arm or neck pain. Logistic regression was used to compare those with specific ULDs and non-specific arm pain with those who had no neck or arm symptoms. There was a 59% response rate. A total of 1,197 subjects with arm or neck pain underwent standardized physical examination and were classified as having one or more of 11 specific ULDs or non-specific regional pain. Among these, 250 subjects with specific ULDs and 176 with only non-specific arm pain were compared with 2,248 subjects who had no neck or arm symptoms. Certain physical risk factors were more strongly associated with specific disorders than with non-specific pain. In comparison with pain-free subjects, the odds ratios (ORs) in keyboard users (>or=1 h versus <1 h/day) were 3.1 (95% CI 1.3, 7.8) for hand-wrist tendonitis but 1.3 (0.8, 2.1) for non-specific hand-wrist pain. Other differential associations were found with age, sex, manual versus non-manual employment and smoking. Unexpectedly, low vitality was similarly associated with both specific disorders and non-specific pain. These findings suggest that the schedule may usefully distinguish disorders that differ in their association with physical risk factors.


Planning a future randomized clinical trial based on a network of relevant past trials.
The important role of network meta-analysis of randomized clinical trials in health technology assessment and guideline development is increasingly recognized. This approach has the potential to obtain conclusive results earlier than with new standalone trials or conventional, pairwise meta-analyses. Network meta-analyses can also be used to plan future trials. We introduce a four-step framework that aims to identify the optimal design for a new trial that will update the existing evidence while minimizing the required sample size. The new trial designed within this framework does not need to include all competing interventions and comparisons of interest and can contribute direct and indirect evidence to the updated network meta-analysis. We present the method by virtually planning a new trial to compare biologics in rheumatoid arthritis and a new trial to compare two drugs for relapsing-remitting multiple sclerosis. A trial design based on updating the evidence from a network meta-analysis of relevant previous trials may require a considerably smaller sample size to reach the same conclusion compared with a trial designed and analyzed in isolation. Challenges of the approach include the complexity of the methodology and the need for a coherent network meta-analysis of previous trials with little heterogeneity. When used judiciously, conditional trial design could significantly reduce the required resources for a new study and prevent experimentation with an unnecessarily large number of participants.


Editor's Choice-Medically managed patients with non-ST-elevation acute myocardial infarction have heterogeneous outcomes, based on performance of angiography and extent of coronary artery disease.
Medically managed individuals represent a high-risk group among patients with non-ST-elevation acute myocardial infarction (NSTE-AMI). We hypothesized that prognosis in this group is heterogeneous, depending on whether medical management was decided with or without coronary angiography (CAG). Using data from the French Registry of Acute ST-Elevation or Non-ST-Elevation Myocardial Infarction (FAST-MI), we analysed data from 798 patients with NSTE-AMI who were medically managed (i.e. without revascularization during the index hospitalization). Patients were categorized according to the performance of CAG and, if performed, to the extent of coronary artery disease (CAD). There were marked differences in baseline demographics, according to whether CAG was performed and to the extent of CAD. While the overall mortality rate at five years was high (56.2%), it differed greatly between groups, with patients who did not undergo CAG having a higher mortality rate (77.4%) than patients who underwent CAG (36.7%, p<0.001), and a higher mortality rate even than patients with multivessel CAD (54.2%, p<0.001). By multivariable analysis, non-performance of CAG was an independent predictor of all-cause mortality among medically managed NSTE-AMI patients (adjusted hazard ratios (95% confidence intervals) 3.19 (1.79-5.67) at 30 days, 2.28 (1.60-3.26) at one year, and 1.63 (1.28-2.07) at five years; all p<0.001). Medically managed patients with NSTE-AMI are a heterogeneous group in terms of baseline characteristics and outcomes. The highest risk patients are those who do not undergo CAG. Non-performance of CAG is a strong predictor of death. (FAST-MI, NCT00673036).


EPySeg: a coding-free solution for automated segmentation of epithelia using deep learning.
Epithelia are dynamic tissues that self-remodel during their development. During morphogenesis, the tissue-scale organization of epithelia is obtained through a sum of individual contributions of the cells constituting the tissue. Therefore, understanding any morphogenetic event first requires a thorough segmentation of its constituent cells. This task, however, usually involves extensive manual correction, even with semi-automated tools. Here, we present EPySeg, an open-source, coding-free software that uses deep learning to segment membrane-stained epithelial tissues automatically and very efficiently. EPySeg, which comes with a straightforward graphical user interface, can be used as a Python package on a local computer, or on the cloud via Google Colab for users not equipped with deep-learning compatible hardware. By substantially reducing human input in image segmentation, EPySeg accelerates and improves the characterization of epithelial tissues for all developmental biologists.


Design, synthesis and evaluation of indole derivatives as multifunctional agents against Alzheimer's disease.
A series of indole derivatives was designed and synthesised to improve on activity and circumvent pharmacokinetic limitations experienced with the structurally related compound, ladostigil. The compounds consisted of a propargylamine moiety (a known MAO inhibitor and neuroprotector) at the N1 position and a ChE inhibiting diethyl-carbamate/urea moiety at the 5 or 6 position of the indole ring. In order to prevent or slow down the in vivo hydrolysis and deactivation associated with the carbamate function of ladostigil, a urea moeity was incorporated into selected compounds to obtain more metabolically stable structures. The majority of the synthesised compounds showed improved MAO-A inhibitory activity compared to ladostigil. The compounds possessing the propargylamine moiety showed good MAO-B inhibitory activity with 6 and 8 portraying IC50 values between 14-20 fold better than ladostigil. The ChE assay results indicated that the compounds have non-selective inhibitory activities on eeAChE and eqBuChE regardless of the type or position of substitution (IC50: 2-5 μM). MAO-A and MAO-B docking results showed that the propargylamine moiety was positioned in close proximity to the FAD cofactor suggesting that the good inhibitory activity may be attributed to the propargylamine moiety and irreversible inhibition as confirmed in the reversibility studies. Docking results also indicated that the compounds have interactions with important amino acids in the AChE and BuChE catalytic sites. Compound 6 was the most potent multifunctional agent showing better inhibitory activity than ladostigil in vitro on all enzymes tested (hMAO-A IC50 = 4.31 μM, hMAO-B IC50 = 2.62 μM, eeAChE IC50 = 3.70 μM, eqBuChE IC50 = 2.82 μM). Chemical stability tests confirmed the diethyl-urea containing compound 6 to be more stable than its diethyl-carbamate containing counterpart compound 8. Compound 6 also exerted significant neuroprotection (52.62% at 1 μM) against MPP+ insult to SH-SY5Y neural cells and has good in silico predicted ADMET properties. The favourable neuronal enzyme inhibitory activity, likely improved pharmacokinetic properties in vivo and the potent neuroprotective ability of compound 6 make it a promising compound for further development.


Spectral analysis using the electronic scanning spectrometer.
Spectral scanning is accomplished in an electronic scanning spectrometer by means of a television-type camera tube called an image dissector. Since the scanning is done electronically, extremely rapid spectral scanning can be performed without any mechanical movement. The standard instrument has selectable scan rates of 100 or 1000 spectral scans per second, although faster and slower scan rates are possible. The sensitivity of the spectrometer is the same as a conventional mechanical scanning spectrometer using a photomultiplier detector if it were possible to scan the latter at the same high rate. The instrument is being used to investigate the time variation in spectral output of light sources, but should also be useful in other studies such as explosions, shock tubes, lightning, plasmas, missile launch and reentry, and other sources of intense transitory radiation phenomena.


Soy-protein consumption and kidney-related biomarkers among type 2 diabetics: a crossover, randomized clinical trial.
Renal disease is a major problem among diabetic patients. The type of protein consumed may affect alterations in kidney-related biomarkers in these patients. This study sought to assess the effects of soy-protein consumption on renal-related markers among type 2 diabetic patients with nephropathy. A crossover, randomized clinical trial was conducted among 14 patients (10 men and 4 women). One diet contained 0.8 g/kg protein (70% animal and 30% vegetable proteins), and a similar diet contained the same amount of protein with 35% animal protein, 35% soy protein, and 30% other vegetable proteins. These two diets were prescribed in each phase of the trial for 7 weeks. There was a 4-week washout between the two phases of the study. Consumption of soy protein reduced urinary urea nitrogen (-0.9 +/- 0.8 vs. 0.2 +/- 0.6 mg/dL, respectively, SD; P < .001), proteinuria (-78 +/- 37 vs. 42 +/- 39 mg/day, respectively, SD; P < .001), blood sodium (-2 +/- 0.04 vs. 2.0 +/- 0.06 mg/dL, respectively, SD; P < .01), and serum phosphorus (-0.03 +/- 0.2 vs. 0.2 +/- 0.3 mg/dL, respectively, SD; P < .01) compared with animal protein. Serum and urinary creatinine, blood urea nitrogen, serum calcium, and potassium levels were not significantly changed in soy-protein versus anima-protein consumption. Soy-protein consumption reduces proteinuria in type 2 diabetes with nephropathy.


Three-dimensional single-pixel imaging of incoherent light with spatiotemporally modulated illumination.
We derive analytic expressions for the three-dimensional coherent transfer function (CTF) and coherent spread function (CSF) for coherent holographic image reconstruction by phase transfer (CHIRPT) microscopy with monochromatic and broadband illumination sources. The 3D CSF and CTF were used to simulate CHIRPT images, and the results show excellent agreement with experimental data. Finally, we show that the formalism presented here for computing the CSF/CTF pair in CHIRPT microscopy can be readily extended to other forms of single-pixel imaging, such as spatial-frequency-modulated imaging.


Effect of genome-wide simultaneous hypotheses tests on the discovery rate.
An increasing number of genome-wide association studies are being performed in hundreds of thousands of single nucleotide polymorphisms (SNPs). Many of such studies carry on a second stage in which a selected number of SNPs are genotyped in new individuals in order to validate genome-wide findings. Unfortunately, a large proportion of such studies have been unable to validate the genome-wide findings. In this study we aim to better understand how to distinguish the truly associated features from the false positives in genome-wide scans. In order to achieve this goal we use empirical data to look at three aspects that may play a key role in determining which features are called to be associated with the phenotype. First, we examine the usual assumption of a uniform distribution on null p-values and assess whether or not it affects which features are called significant and the number of significant features. Second, we compare the global behavior of the p-value distribution genome-wide with the local behavior at regions such as chromosomes. Third, we look at the effect of minor allele frequency in the p-value distribution. We show empirically that the uniform distribution is not a generally valid assumption and we find that as a consequence strikingly different conclusions can be drawn regarding what we call significant associations and the number of significant findings. We propose that in order to better assign significance to potential associations one needs to estimate the true distribution of null and non-null p-values.


Liver fat quantification by dual-echo MR imaging outperforms traditional histopathological analysis.
The aim of this study was to evaluate the accuracy of dual-echo (DE) magnetic resonance imaging (MRI) with and without fat and water separation for the quantification of liver fat content (LFC) in vitro and in patients undergoing liver surgery, with comparison to histopathologic analysis. MRI was performed on a 1.5-T scanner using a three-dimensional DE MRI sequence with automated reconstruction of in-phase (IP) and out-of-phase (OP) and fat-signal-only and water-signal-only images. LFC was estimated by fat fractions from IP and OP images (MRI(IP/OP)) and from Dixon-based fat-only and water-only images (MRI(DIxON)). Seven phantoms containing a titrated mixture of liver and fat from 0% to 50% were examined. Forty-three biopsies in 22 patients undergoing liver surgery were prospectively evaluated by a pathologist by traditional determination of the cell-count fraction and by a computer-based algorithm, the latter serving as the reference standard. In vitro, both MRI(IP/OP) and MRI(DIxON) were significantly correlated with titrated LFC (r = 0.993, P < .001), with a smaller measurement bias for MRI(IP/OP) (+2.6%) than for MRI(DIxON) (+4.5%). In vivo, both MRI(IP/OP) and MRI(DIxON) from DE MRI were correlated significantly better with computer-based histologic results (P < .001) and showed significantly smaller measurement bias (4.8% vs 21.1%) compared to histologic cell-count fraction (P < .001). Measurement bias was significantly smaller for MRI(IP/OP) than for MRI(DIxON) (P < .001). DE MRI allows the accurate quantification of LFC in a surgical population, outperforming traditional histopathologic analysis. DE MRI without fat and water separation shows the highest accuracy and smallest measurement bias for the quantification of LFC.


Adenoviral transfer of the viral IL-10 gene periarticularly to mouse paws suppresses development of collagen-induced arthritis in both injected and uninjected paws.
Gene therapy is a promising new approach in the treatment of rheumatoid arthritis. Gene delivery to diseased joints offers the prospect of achieving high, local concentrations of a therapeutic gene product in a sustained manner, while minimizing exposure of nontarget organs. We report that a single administration of a modified adenovirus encoding the Epstein-Barr-derived homologue of IL-10 can suppress the development of disease for extended periods of time when injected locally within the periarticular tissue surrounding the ankle joints of mice with collagen type II-induced arthritis. Furthermore, we show that injection of an adenoviral vector carrying the IL-10 gene into a single paw can suppress development of arthritis in other, noninjected paws of the same individual. The systemic protection resulting from local gene therapy occurred in the absence of detectable levels of viral IL-10 in the serum. Circulating Ab levels to heterologous collagen were unaffected; however, treatment with viral IL-10 significantly suppressed the development of Abs to autologous mouse type II collagen. Thus, the treatment of a single joint by local delivery of the vIL-10 gene may protect multiple joints of the same individual while avoiding deleterious side effects often associated with systemic therapy.


Birth outcomes after inadvertent use of category X drugs contraindicated in pregnancy: Where is the real risk?
Öztürk Z, Ölmez E, Gürpınar T, Vural K. Birth outcomes after inadvertent use of category X drugs contraindicated in pregnancy: Where is the real risk? Turk J Pediatr 2018; 60: 298-305. Drugs contraindicated in pregnancy are medicines that should be avoided by pregnant women, since they carry a concern for teratogenicity or there is no indication for their use during pregnancy. It does not mean that exposures to these drugs always cause harm. The aim of the present study was to investigate the risk of adverse outcomes following maternal exposure to the drugs contraindicated in pregnancy. We retrospectively analyzed prenatal drug exposure records of the pregnant patients referred to the clinical pharmacology consultation service in a tertiary-level university hospital from January 2007 until December 2012. Exposures to category X drugs (CXD) contraindicated in pregnancy were evaluated. After the expected date of delivery, we collected data about pregnancy complications and the outcomes. For comparison the women in the exposed group (N=52) were matched with a control group (N=162) of pregnant women without teratogenic exposure. We observed only one baby born with a birth defect (congenital cryptorchidism) in CXD group (2.6%) and four in control group (RR 0.91; 95% CI 0.10- 7.94). The rates of adverse pregnancy outcomes including miscarriage, preterm birth and congenital abnormality were not significantly different from controls. However, the rate of elective termination of pregnancy was higher in women exposed to CXD while pregnant (RR 2.54; 95% CI 1.11- 5.80, p = 0.027). Contraceptive failure and unintended pregnancy are the reasons for inadvertent drug exposure and choosing abortion. The high perception of teratogenic risk among pregnant women may cause terminations of pregnancies. Individual risk assessment and avoiding the phrase `CXD` or `contraindicated in pregnancy` in counseling may help to reduce maternal concerns about medication use in pregnancy.


Magnetic Resonance Imaging Assessment of Kidney Oxygenation and Perfusion During Sickle Cell Vaso-occlusive Crises.
Our understanding of the pathophysiologic processes underlying sickle cell nephropathy remains incomplete. We performed a pilot study to investigate the potential value of magnetic resonance imaging (MRI) for the assessment of kidney oxygenation and detection of potential changes to tissue perfusion and cellular integrity during a vaso-occlusive crisis. A case-control study. 10 homozygous patients with sickle cell disease (SCD), without kidney disease (based on estimated glomerular filtration rate and albuminuria), underwent renal MRI during a vaso-occlusive crisis episode. The imaging data obtained were compared with those for a second MRI performed at steady state (median, 56 [IQR, 37-72] days after the vaso-occlusive crisis MRI). The control group consisted of 10 apparently healthy individuals. Deoxyhemoglobin level assessed by R2* value was calculated using the blood oxygen level-dependent technique. The intravoxel incoherent motion diffusion-weighted imaging technique was used to calculate D, D*, and F parameters. Median medullary R2* values on steady-state MRI were significantly higher for patients with SCD than for controls (P=0.01) and did not change significantly during the vaso-occlusive crisis. No significant differences in median cortical R2* values were observed. Both cellular integrity (D) and local perfusion (D* and F) were significantly altered in medullary and cortical areas during vaso-occlusive crises in comparison to steady state in patients with SCD. These parameters did not differ significantly between patients with SCD assessed at steady state and the control group. Small sample size, estimation of glomerular filtration rate according to CKD-EPI creatinine equation without adjustment for race. Deoxyhemoglobin levels in the medullary area are higher in patients with SCD, during vaso-occlusive crises and at steady state, than in controls. Alterations to the tissue perfusion and cellular integrity of renal parenchyma are a common finding during vaso-occlusive crises that provide additional evidence that a vaso-occlusive crisis may be associated with subclinical kidney injury detectable on MRI.


Covariation Is a Poor Measure of Molecular Coevolution.
Recent developments in the analysis of amino acid covariation are leading to breakthroughs in protein structure prediction, protein design, and prediction of the interactome. It is assumed that observed patterns of covariation are caused by molecular coevolution, where substitutions at one site affect the evolutionary forces acting at neighboring sites. Our theoretical and empirical results cast doubt on this assumption. We demonstrate that the strongest coevolutionary signal is a decrease in evolutionary rate and that unfeasibly long times are required to produce coordinated substitutions. We find that covarying substitutions are mostly found on different branches of the phylogenetic tree, indicating that they are independent events that may or may not be attributable to coevolution. These observations undermine the hypothesis that molecular coevolution is the primary cause of the covariation signal. In contrast, we find that the pairs of residues with the strongest covariation signal tend to have low evolutionary rates, and that it is this low rate that gives rise to the covariation signal. Slowly evolving residue pairs are disproportionately located in the protein's core, which explains covariation methods' ability to detect pairs of residues that are close in three dimensions. These observations lead us to propose the "coevolution paradox": The strength of coevolution required to cause coordinated changes means the evolutionary rate is so low that such changes are highly unlikely to occur. As modern covariation methods may lead to breakthroughs in structural genomics, it is critical to recognize their biases and limitations.


Inhibition of protein kinase CK2 reduces Cyp24a1 expression and enhances 1,25-dihydroxyvitamin D(3) antitumor activity in human prostate cancer cells.
Vitamin D has broad range of physiological functions and antitumor effects. 24-Hydroxylase, encoded by the CYP24A1 gene, is the key enzyme for degrading many forms of vitamin D including the most active form, 1,25D(3). Inhibition of CYP24A1 enhances 1,25D(3) antitumor activity. To isolate regulators of CYP24A1 expression in prostate cancer cells, we established a stable prostate cancer cell line PC3 with CYP24A1 promoter driving luciferase expression to screen a small molecular library for compounds that inhibit CYP24A1 promoter activity. From this screening, we identified, 4,5,6,7-tetrabromobenzimidazole (TBBz), a protein kinase CK2 selective inhibitor as a disruptor of CYP24A1 promoter activity. We show that TBBz inhibits CYP24A1 promoter activity induced by 1,25D(3) in prostate cancer cells. In addition, TBBz downregulates endogenous CYP24A1 mRNA level in TBBz-treated PC3 cells. Furthermore, siRNA-mediated CK2 knockdown reduces 1,25D(3)-induced CYP24A1 mRNA expression in PC3 cells. These results suggest that CK2 contributes to 1,25D(3)-mediated target gene expression. Finally, inhibition of CK2 by TBBz or CK2 siRNA significantly enhances 1,25D(3)-mediated antiproliferative effect in vitro and in vivo in a xenograft model. In summary, our findings reveal that protein kinase CK2 is involved in the regulation of CYP24A1 expression by 1,25D(3) and CK2 inhibitor enhances 1,25D(3)-mediated antitumor effect.


Motion detection in the presence of local orientation changes.
To investigate the orientation selectivity of motion detectors, we measured the perception of horizontal apparent motion of dense patterns of line elements with randomized orientation. Horizontal motion of these displays became invisible when the simultaneous rotation of the line elements exceeded a critical rate (pc). The value of pc increased for higher horizontal velocities, approximately according to a square-root relation. In a direct test of orientation selectivity, the discrimination of horizontal motion direction disappeared when the orientation change per horizontal jump exceeded 30 deg. Thus, for the perception of the global flow the orientation change should not exceed a critical angle during the traverse of a critical distance. The critical distance increases according to a square-root relation as a function of horizontal velocity. These results strongly suggest that bilocal motion detectors are involved in horizontal motion detection and that these detectors are selective for orientation. The properties of these detectors, such as the orientation sensitivity that is reported in this paper, seem highly relevant to the perception of coherent motion.


Serum C-reactive protein and neopterin concentrations in patients with viral or bacterial infection.
Serum C-reactive protein and neopterin concentrations were measured in samples taken at an early stage in different types of infection to see whether the combination of markers could contribute to the diagnosis of infection and help distinguish between bacterial and viral infections, tuberculosis, and infections due to "other" pathogens. Both markers were significantly raised in all categories of infection compared with controls, and there were significant differences between the means of both markers when comparing several of the categories of infection. Only C-reactive protein concentrations in bacteraemic patients, however, were both sensitive and specific at distinguishing the type of infection. The additional use of neopterin estimation played only a minor part in increasing the specificity of diagnosis in tuberculosis and in viral infections. On the basis of this study it was not considered worth the time and expense of performing neopterin assays in addition to C-reactive protein estimations to differentiate viral from bacterial infection.


Reliability of ambulatory walking activity in patients with hematologic malignancies.
To determine the relative and absolute reliability of the assessment of ambulatory walking activity during 2 consecutive weeks in patients with hematologic malignancies recovering at home from their medical treatment and to compare the physical activity level of hematologic cancer patients after high-dose chemotherapy with healthy subjects. Test-retest study of 2 consecutive 7-day recordings using the microprocessor-based step accelerometer 3 (SAM3). Home and community. Patients (n=23) with hematologic malignancies recovering from high-dose chemotherapy and healthy controls (n=30). Not applicable. The intraclass correlation coefficient (ICC(3,1)) and its 95% confidence interval (CI), SE of measurement procedure and its 95% CI, the smallest detectable difference (SDD), the coefficient of variation (CV), and t tests for the variables total steps and peak activity. The day-to-day and week-to-week CVs for walking activity and peak activity were 35.17% and 13.17% and 18.61% and 6.90%, respectively. For relative reliability, the ICCs for 2 consecutive 7-day recordings including the 95% CI for total steps and peak activity were 0.90 (95% CI, 0.75-0.98) and 0.85 (95% CI, 0.66-0.94), respectively. The absolute reliability for total steps and peak activity including the SE of measurement procedure and the 95% CI were 564 (95% CI, +/-1106) and 2.42 steps (95% CI, +/-4.74), respectively, for 2 consecutive 7-day recordings. The week-to-week SDD was 1564 for total steps and 6.70 for peak activity. The 7-day mean for total step activity was 5355 for the patients with hematologic malignancies and 6364 for healthy subjects (P<0.05). The results of this study indicate that there is good relative reliability for the assessment of 2 consecutive 7-day recordings of ambulatory walking activity, and it showed that the SDD derived from this sample may be useful in detecting changes in daily walking activity in hematologic cancer patients who are recovering from intensive medical treatment. The study also documented compromised levels of ambulatory walking activity among hematologic cancer patients recovering from high-dose chemotherapy as compared with healthy controls.


Entangling COVID-19 associated thrombosis into a secondary antiphospholipid antibody syndrome: Diagnostic and therapeutic perspectives (Review).
The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a novel β coronavirus that is the etiological agent of the pandemic coronavirus disease 2019 (COVID‑19) that at the time of writing (June 16, 2020) has infected almost 6 million people with some 450,000 deaths. These numbers are still rising daily. Most (some 80%) cases of COVID‑19 infection are asymptomatic, a substantial number of cases (15%) require hospitalization and an additional fraction of patients (5%) need recovery in intensive care units. Mortality for COVID‑19 infection appears to occur globally between 0.1 and 0.5% of infected patients although the frequency of lethality is significantly augmented in the elderly and in patients with other comorbidities. The development of acute respiratory distress syndrome and episodes of thromboembolism that may lead to disseminated intravascular coagulation (DIC) represent the primary causes of lethality during COVID‑19 infection. Increasing evidence suggests that thrombotic diathesis is due to multiple derangements of the coagulation system including marked elevation of D‑dimer that correlate negatively with survival. We propose here that the thromboembolic events and eventually the development of DIC provoked by SARS‑CoV‑2 infection may represent a secondary anti‑phospholipid antibody syndrome (APS). We will apply both Baconian inductivism and Cartesian deductivism to prove that secondary APS is likely responsible for coagulopathy during the course of COVID‑19 infection. Diagnostic and therapeutic implications of this are also discussed.


Enzymatically and electrocardiographically estimated infarct size in relation to pain in acute myocardial infarction.
In 563 patients with acute myocardial infarction and no previous myocardial infarction, the estimated infarct size was related to the estimated duration of pain and the amount of analgesics given. The size of infarction estimated from analyses of heat-stable lactate dehydrogenase (EC 22.214.171.124) at 12-hour intervals for 48-108 h and from Q- and R-wave changes in the ECG correlated positively, although weakly with duration of the pain and the amount of analgesics given. These data support the hypothesis that larger infarcts, as a group, evolve over a longer time period than smaller infarcts and that the duration of pain in many patients might be an indicator of the infarct size. In the individual patient, however, one cannot predict the size of the infarction from the severity of pain.


Integrating Image-Based High-Content Screening with Mouse Models Identifies 5-Hydroxydecanoate as a Neuroprotective Drug for Paclitaxel-Induced Neuropathy.
Chemotherapy-induced neurotoxicity is a common adverse effect of cancer treatment. No medication has been shown to be effective in the prevention or treatment of chemotherapy-induced neurotoxicity. This study aimed to discover potential neuroprotective drugs for paclitaxel-induced neurotoxicity. An image-based high-content platform was first developed to screen for potential neuroprotective drugs. The screening system comprised of automated image acquisition and multiparameter analysis, including neuronal viability, neurite outgrowth, and synaptogenesis. By this platform, we obtained a candidate list from compound libraries. In the drug screening from compound libraries of ion channel ligands, REDOX and GABAergic ligands, 5-hydroxydecanoate (5-HD) exhibited the most significant neuroprotective effects against paclitaxel-induced neurotoxicity in both cortical and dorsal root ganglion (DRG) neurons. In mouse behavioral tests, 5-HD restored the thermal sensitivity and alleviated mechanical allodynia induced by paclitaxel. Electron micrographs of sciatic nerve revealed that 5-HD reduced the damages caused by paclitaxel in the nonmyelinated and smaller myelinated fibers. The mechanistic study on DRG neurons suggested that 5-HD rescued the dysregulation of intracellular calcium homeostasis provoked by paclitaxel. Importantly, 5-HD did not jeopardize the antitumor effect of paclitaxel in tumor xenograft models. In conclusion, we established an imaged-based high-content screening platform and a protocol for verifying the neuroprotective effect in vivo, by which 5-HD was identified and validated as a potential neuroprotective drug for paclitaxel-induced neuropathy.


New allelic variants found in key rice salt-tolerance genes: an association study.
Salt stress is a complex physiological trait affecting plants by limiting growth and productivity. Rice, one of the most important food crops, is rated as salt-sensitive. High-throughput screening methods are required to exploit novel sources of genetic variation in rice and further improve salinity tolerance in breeding programmes. To search for genotypic differences related to salt stress, we genotyped 392 rice accessions by EcoTILLING. We targeted five key salt-related genes involved in mechanisms such as Na(+) /K(+) ratio equilibrium, signalling cascade and stress protection, and we found 40 new allelic variants in coding sequences. By performing association analyses using both general and mixed linear models, we identified 11 significant SNPs related to salinity. We further evaluated the putative consequences of these SNPs at the protein level using bioinformatic tools. Amongst the five nonsynonymous SNPs significantly associated with salt-stress traits, we found a T67K mutation that may cause the destabilization of one transmembrane domain in OsHKT1;5, and a P140A alteration that significantly increases the probability of OsHKT1;5 phosphorylation. The K24E mutation can putatively affect SalT interaction with other proteins thus impacting its function. Our results have uncovered allelic variants affecting salinity tolerance that may be important in breeding.


Vascularity of proliferative breast disease and carcinoma in situ correlates with histological features.
The level of vascularity within an invasive breast carcinoma is a predictor of metastatic potential and survival. However, little is known about the vascular potential and prognostic value of angiogenesis in preinvasive breast pathology. Women with proliferative breast disease or carcinoma in situ are at increased risk of developing invasive breast cancer. This relative risk increases in correlation with defined histopathological features. We asked whether these early proliferative lesions and carcinoma in situ were capable of inducing a vascular supply. Vascularity in preinvasive archival paraffin-embedded breast tissue from 90 patients was quantified by immunohistochemical identification of vessels using anti-von Willebrand factor. Vascular scores were analyzed with respect to histopathological diagnosis, age at diagnosis, and presence of coincident invasive disease. These data indicate that: (a) the vascularity of histopathologically normal epithelium is greater in breasts containing invasive disease than in breasts lacking invasive disease; (b) simple proliferative breast disease induces a vascular supply greater than that of normal breast epithelium; and (c) vascularity increases in proportion to epithelial lesion progression and relative risk of invasion. These studies indicate that the vascularity of preinvasive breast pathology may be a clinically useful predictor of invasive breast cancer.


Development of a computerized adaptive test for assessing balance function in patients with stroke.
An efficient and precise measure of balance is needed to improve administration efficiency and to reduce the assessment burden for patients. The purpose of this study was to develop a computerized adaptive testing (CAT) system for assessing balance function in an efficient, reliable, and valid fashion in patients with stroke. Two cross-sectional prospective studies were conducted. This study was conducted in the departments of physical medicine and rehabilitation in 6 hospitals. The participants were inpatients and outpatients who were receiving rehabilitation. A balance item pool (41 items) was developed on the basis of predefined balance concepts, expert opinions, and field testing. The items were administered by 5 raters to 764 patients. An item response theory model was fit to the data, and the item parameters were estimated. A simulation study was used to determine the performance (eg, reliability, efficiency) of the Balance CAT. The Balance CAT and the Berg Balance Scale (BBS) then were tested on another independent sample of 56 patients to determine the concurrent validity and time needed for administration. Seven items did not meet the model's expectations and were excluded from further analysis. The remaining 34 items formed the item bank of the Balance CAT. Two stopping rules (ie, reliability coefficient > 0.9 or < or = 6 items) were set for the CAT. The simulation study showed that the patients' balance scores estimated by the CAT had an average reliability value of .94. The scores obtained from the CAT were closely associated with those of the full item set (Pearson r=.98). The scores of the Balance CAT were highly correlated with those of the BBS (Pearson r=.88). The average time needed to administer the Balance CAT (83 seconds) was only 18% of that of the BBS. The convenience sampling of both samples may limit the generalization of the results. Further psychometric investigation of the Balance CAT is needed. The results provide strong evidence that the Balance CAT is efficient and has reliability and validity for patients with stroke.


Beyond clinical food prescriptions and mobile markets: parent views on the role of a healthcare institution in increasing healthy eating in food insecure families.
Children in food-insecure families face increased barriers to meeting recommendations for fruit and vegetable consumption. Hospitals and pediatric healthcare institutions have attempted to alleviate food-insecurity through various internal programs like food prescriptions, yet little evidence for these programs exist. Consistent with a patient-centered perspective, we sought to develop a comprehensive understanding of barriers to fruit and vegetable consumption and a parent-driven agenda for healthcare system action. We conducted six qualitative focus group discussions (four in English, two in Spanish) with 29 parents and caregivers of patients who had screened positive for food-insecurity during visits to a large pediatric healthcare system in a midwestern U.S. city. Our iterative analysis process consisted of audio-recording, transcribing and coding discussions, aiming to produce a) a conceptual framework of barriers to fruit and vegetable consumption and b) a synthesis of participant programmatic suggestions for their healthcare system. Participants were 90% female, 38% Black/African American and 41% Hispanic/Latino. Barriers to fruit and vegetable consumption in their families fell into three intersecting themes: affordability, accessibility and desirability. Participant-generated intervention recommendations were multilevel, suggesting healthcare systems focus not only on clinic and community-based action, but also advocacy for broader policies that alleviate barriers to acquiring healthy foods. Parents envision an expanded role for healthcare systems in ensuring their children benefit from a healthy diet. Findings offer critical insight on why clinic-driven programs aimed to address healthy eating may have failed and healthcare organizations may more effectively intervene by adopting a multilevel strategy.


Fibrosis of the lung and pleura and long-term exposure to wollastonite.
The purpose of this study was to determine whether long-term exposure to wollastonite causes fibrosis of the lung and pleura in humans. Forty-nine workers (mean exposure 25 years) in a Finnish limestone-wollastonite mine and mill were examined. Their work histories and symptoms of chronic bronchitis were recorded. The chest radiographs were classified according to the classification of the International Labour Office (1980); a radiographic follow-up from 1981 to 1990 was included. Spirometry and diffusion capacity were measured. Four workers underwent high-resolution computed tomography (HRCT) and bronchoalveolar lavage (BAL). Lung tissue specimens were available for 2 workers. Mineral fibers and asbestos bodies were analyzed from the BAL fluid and lung tissue specimens, which were also analyzed for lung fibrosis. Two workers (4%) had small irregular lung opacities (ILO 1/0), 1 worker (2%) ILO 0/1 of the s/t type. HRCT revealed no parenchymal fibrosis in the 2 workers with the ILO 1/0 classification. Of the 9 workers (18%) with pleural plaques, 5 had been exposed to asbestos. Multivariate logistic regression analyses revealed no association of plaques with the duration of wollastonite or asbestos exposure. Wollastonite fibers or bodies were not found in any of the 4 workers who underwent BAL, nor in either of the workers whose lung tissue specimens were available. No evidence was found that long-term exposure to wollastonite causes parenchymal fibrosis of the lung and pleura. Furthermore, the findings indicate that wollastonite fibers are poorly retained in human lungs.


Taxonomic and Phylogenetic Determinants of Functional Composition of Bolivian Bat Assemblages.
Understanding diversity patterns and the potential mechanisms driving them is a fundamental goal in ecology. Examination of different dimensions of biodiversity can provide insights into the relative importance of different processes acting upon biotas to shape communities. Unfortunately, patterns of diversity are still poorly understood in hyper-diverse tropical countries. Here, we assess spatial variation of taxonomic, functional and phylogenetic diversity of bat assemblages in one of the least studied Neotropical countries, Bolivia, and determine whether changes in biodiversity are explained by the replacement of species or functional groups, or by differences in richness (i.e., gain or loss of species or functional groups). Further, we evaluate the contribution of phylogenetic and taxonomic changes in the resulting patterns of functional diversity of bats. Using well-sampled assemblages from published studies we examine noctilionoid bats at ten study sites across five ecoregions in Bolivia. Bat assemblages differed from each other in all dimensions of biodiversity considered; however, diversity patterns for each dimension were likely structured by different mechanisms. Within ecoregions, differences were largely explained by species richness, suggesting that the gain or loss of species or functional groups (as opposed to replacement) was driving dissimilarity patterns. Overall, our results suggest that whereas evolutionary processes (i.e., historical connection and dispersal routes across Bolivia) create a template of diversity patterns across the country, ecological mechanisms modify these templates, decoupling the observed patterns of functional, taxonomic and phylogenetic diversity in Bolivian bats. Our results suggests that elevation represents an important source of variability among diversity patterns for each dimension of diversity considered. Further, we found that neither phylogenetic nor taxonomic diversity can fully account for patterns of functional diversity, highlighting the need for examining different dimensions of biodiversity of bats in hyperdiverse ecosystems.


Synthesis of high quality zinc blende CdSe nanocrystals.
Highly homogeneous and luminescent CdSe colloidal nanocrystals in the less common zinc blende crystal structure have been obtained at high temperature in a noncoordinating organic solvent. The key parameter appears to be the addition of a phosphonic acid to the trioctylphosphine-selenium complex before its injection into the hot cadmium mixture, while the role of temperature is less relevant. Compared to standard (wurtzite) colloidal CdSe preparations, we find that the growth rate is considerably reduced, and the energy gap between the first two absorption bands becomes larger.


Focusing of mammalian cells under an ultrahigh pH gradient created by unidirectional electropulsation in a confined microchamber†Electronic supplementary information (ESI) available: Figures S1-S5 and videos S1-S2. See DOI: 10.1039/c4sc00319eClick here for additional data file.Click here for additional data file.Click here for additional data file.
The transport and manipulation of cells in microfluidic structures are often critically required in cellular analysis. Cells typically make consistent movement in a dc electric field in a single direction, due to their electrophoretic mobility or electroosmotic flow or the combination of the two. Here we demonstrate that mammalian cells focus to the middle of a closed microfluidic chamber under the application of unidirectional direct current pulses. With experimental and computational data, we show that under the pulses electrochemical reactions take place in the confined microscale space and create an ultrahigh and nonlinear pH gradient (∼2 orders of magnitude higher than the ones in protein isoelectric focusing) at the middle of the chamber. The varying local pH affects the cell surface charge and the electrophoretic mobility, leading to focusing in free solution. Our approach provides a new and simple method for focusing and concentrating mammalian cells at the microscale.


Physical and functional interactions of human DNA polymerase eta with PCNA.
Human DNA polymerase eta (hPoleta) functions in the error-free replication of UV-damaged DNA, and mutations in hPoleta cause cancer-prone syndrome, the variant form of xeroderma pigmentosum. However, in spite of its key role in promoting replication through a variety of distorting DNA lesions, the manner by which hPoleta is targeted to the replication machinery stalled at a lesion site remains unknown. Here, we provide evidence for the physical interaction of hPoleta with proliferating cell nuclear antigen (PCNA) and show that mutations in the PCNA binding motif of hPoleta inactivate this interaction. PCNA, together with replication factor C and replication protein A, stimulates the DNA synthetic activity of hPoleta, and steady-state kinetic studies indicate that this stimulation accrues from an increase in the efficiency of nucleotide insertion resulting from a reduction in the apparent K(m) for the incoming nucleotide.


Intense electroacupuncture normalizes insulin sensitivity, increases muscle GLUT4 content, and improves lipid profile in a rat model of polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and insulin resistance, possibly reflecting defects in skeletal muscle and adipocyte insulin signaling. Low-frequency (2 Hz) electroacupuncture (EA) increases insulin sensitivity in female rats with dihydrotestosterone (DHT)-induced PCOS, but the mechanism is unclear. We hypothesized that low-frequency EA regulates mediators involved in skeletal muscle glucose uptake and metabolism and alters the lipid profile in rats with DHT-induced PCOS. To test this hypothesis, we implanted in prepubescent female rats 90-day continuous-release pellets containing DHT (PCOS). At 70 days of age, the rats were randomly subdivided into two groups: one received low-frequency EA (evoking muscle twitches) for 20-25 min five times/wk for 4-5 wk; the other did not. Controls were implanted with pellets containing vehicle only. All three groups were otherwise handled similarly. Lipid profile was measured in fasting blood samples. Insulin sensitivity was determined by euglycemic hyperinsulinemic clamp, soleus muscle protein expression of glucose transporter 4 (GLUT4), and phosphorylated and nonphosphorylated Akt, and Akt substrate of 160 kDa was determined by Western blot analysis and GLUT4 location by immunofluorescence staining. PCOS EA rats had normalized insulin sensitivity, lower levels of total high-density lipoprotein and low-density lipoprotein cholesterol, and increased expression of GLUT4 in different compartments of skeletal muscle compared with PCOS rats. Total weight and body composition did not differ in the groups. Thus, in rats with DHT-induced PCOS, low-frequency EA has systemic and local effects involving intracellular signaling pathways in muscle that may, at least in part, account for the marked improved insulin sensitivity.


At risk for schizophrenic or affective psychoses? A meta-analysis of DSM/ICD diagnostic outcomes in individuals at high clinical risk.
The clinical high-risk state for psychosis (HRP) is associated with an enhanced probability of developing a psychotic episode over a relatively short period of time. However, the extent to which different diagnostic types of illness develop remains unclear. A systematic review was performed to identify studies of HRP participants reporting International Classfication of Diseases/Diagnostic and Statistical Manual of Mental Disorders diagnostic outcomes at follow-up. Demographic, clinical, and methodological variables were extracted from each publication or obtained directly from its authors. A meta-analysis was performed of transition to schizophrenic (SP) or affective psychoses (AP) and to specific diagnostic categories. Statistical heterogeneity and small study bias were assessed, and meta-regressions were performed. Twenty-three studies were retrieved, including a total of 2182 HRP participants, 560 (26%) of them developed a frank psychotic disorder over the follow-up time (mean = 2.35 y). Among HRP participants who developed psychosis, 73% were diagnosed with SP and only 11% with AP (Risk Ratio, RR = 5.43, 95% CI from 3.35 to 8.83). The specific transition risk to ICD/DSM schizophrenia was of 15.7% (over 2.35y). Heterogeneity was statistically significant and moderate in magnitude. Use of basic symptoms criteria in the baseline clinical assessment was associated with a further increase in the proportion progressing to SP vs AP (RR = 17.1). There was no evidence of publication bias and the sensitivity analysis confirmed robustness of the above results. The HRP state is heterogeneous in term of longitudinal diagnoses; however, the current HRP diagnostic criteria appear strongly biased toward an identification of early phases of SP rather than AP.


The Rat Genome Database, update 2007--easing the path from disease to data and back again.
The Rat Genome Database (RGD, http://rgd.mcw.edu) is one of the core resources for rat genomics and recent developments have focused on providing support for disease-based research using the rat model. Recognizing the importance of the rat as a disease model we have employed targeted curation strategies to curate genes, QTL and strain data for neurological and cardiovascular disease areas. This work has centered on rat but also includes data for mouse and human to create 'disease portals' that provide a unified view of the genes, QTL and strain models for these diseases across the three species. The disease curation efforts combined with normal curation activities have served to greatly increase the content of the database, particularly for biological information, including gene ontology, disease, pathway and phenotype ontology annotations. In addition to improving the features and database content, community outreach has been expanded to demonstrate how investigators can leverage the resources at RGD to facilitate their research and to elicit suggestions and needs for future developments. We have published a number of papers that provide additional information on the ontology annotations and the tools at RGD for data mining and analysis to better enable researchers to fully utilize the database.


Hybrid correlation models based on active-space partitioning: correcting second-order Moller-Plesset perturbation theory for bond-breaking reactions.
Moller-Plesset second-order (MP2) perturbation theory breaks down at molecular geometries which are far away from equilibrium. We decompose the MP2 energy into contributions from different orbital subspaces and show that the divergent behavior of the MP2 energy comes from the excitations located within a small (or sometimes even the minimal) active space. The divergent behavior of the MP2 energy at large interfragment distances may be corrected by replacing a small number of terms by their more robust counterparts from coupled-cluster (CCSD) theory. We investigated several schemes of such a substitution, and we find that a coupling between the active-space CCSD and the remaining MP2 amplitudes is necessary to obtain the best results. This naturally leads us to an approach which has previously been examined in the context of cost-saving approximations to CCSD for equilibrium properties by Nooijen [J. Chem. Phys. 111, 10815 (1999)]. The hybrid MP2-CCSD approach, which has the same formal scaling as conventional MP2 theory, provides potential curves with a correct shape for bond-breaking reactions of BH, CH(4), and HF. The error of the MP2-CCSD method (measured against full configuration-interaction data) is smaller than that of MP2 at all interfragment separations and is qualitatively similar to that of full CCSD.


Duplex ultrasound criteria for defining the severity of carotid stenosis.
Duplex ultrasound scan (DUS) criteria for grading >50% carotid artery stenosis is typically divided into broad categories such as 50-79% stenosis, 80-99% stenosis, and occlusion. The purpose of this study is to validate DUS criteria for stratifying 50 to 100% carotid stenosis into 10% intervals using digital substraction cerebral angiography (DSCA) as the standard of comparison. Between 1996 and 2001, 163 patients were evaluated with duplex ultrasound and angiography. A total of 326 carotid arteries were studied using DUS in an accredited ICAVL vascular laboratory. Threshold velocity criteria for determining the degree of carotid stenosis was defined according to seven categories: <50%, 50-59%, 60-69%, 70-79%, 80-89%, 90-99%, and occlusion. Treatment decisions were based on the angiographic findings. In cases where the degree of stenosis as defined by duplex velocity criteria did not correlate with angiographically defined stenosis, each record was reviewed to determine whether the angiographic findings altered the surgeon's treatment decision. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for DUS-defined degree of stenosis as compared to angiographically defined stenosis were determined. There was a high correlation (R = 0.96) between duplex scan and angiography in 93% (302/326) of the cases. Clinical management was altered in only 3% (10/326) of the cases because of the results of angiography. The DUS velocity criteria to grade the severity of carotid disease in 10% intervals is reliable and accurate. Clinical management of patients with carotid stenosis can be based solely on carotid DUS in 97% of patients considered for treatment of carotid artery disease.


The prevalence of overweight and obesity in veterans with multiple sclerosis.
To estimate the prevalence and factors associated with overweight and obesity in veterans with multiple sclerosis (MS) enrolled in the Veterans Health Administration (VA) and to compare the prevalence in this group with gender-specific published rates for the general population of veterans receiving outpatient care at VA medical facilities. Cross-sectional cohort study linking electronic medical record information to mailed survey from 1999 to 2004. A total of 4703 veterans with MS enrolled in VA who returned questionnaires as part of two cross-sectional studies. Main outcome measures included body mass index, demographic information, Veteran RAND 36-item Health Survey, frequency of physical exercise, and other health conditions. Overall, 28% of female and 42.8% of male veterans with MS were overweight. Another 25% of women and 21.2% of male veterans met the criteria for obesity. Compared with a historical cohort of veterans enrolled in the VA, veterans with MS had a slightly higher adjusted prevalence of overweight than did veterans in general (42.3% vs. 39.6%, respectively) but a lower adjusted prevalence of obesity (20.1% vs. 33.1%). In adjusted logistic regression, age, smoking, and lower levels of pain were associated with a lower likelihood of overweight or obesity. Being male, married, employed and having arthritis and diabetes were associated with a greater likelihood of overweight or obesity. Overweight and obesity are a problem for more than 60% of veterans with MS in the VA. Screening for overweight and obesity should be done routinely. Interventions to prevent and manage excessive weight in individuals with MS should be developed and evaluated.


Developmental pathways to amygdala-prefrontal function and internalizing symptoms in adolescence.
Early life stress (ELS) and function of the hypothalamic-pituitary-adrenal axis predict later psychopathology. Animal studies and cross-sectional human studies suggest that this process might operate through amygdala-ventromedial prefrontal cortex (vmPFC) circuitry implicated in the regulation of emotion. Here we prospectively investigated the roles of ELS and childhood basal cortisol amounts in the development of adolescent resting-state functional connectivity (rs-FC), assessed by functional connectivity magnetic resonance imaging (fcMRI), in the amygdala-PFC circuit. In females only, greater ELS predicted increased childhood cortisol levels, which predicted decreased amygdala-vmPFC rs-FC 14 years later. For females, adolescent amygdala-vmPFC functional connectivity was inversely correlated with concurrent anxiety symptoms but positively associated with depressive symptoms, suggesting differing pathways from childhood cortisol levels function through adolescent amygdala-vmPFC functional connectivity to anxiety and depression. These data highlight that, for females, the effects of ELS and early HPA-axis function may be detected much later in the intrinsic processing of emotion-related brain circuits.


Iso-Seq analysis of the Taxus cuspidata transcriptome reveals the complexity of Taxol biosynthesis.
Taxus cuspidata is well known worldwide for its ability to produce Taxol, one of the top-selling natural anticancer drugs. However, current Taxol production cannot match the increasing needs of the market, and novel strategies should be considered to increase the supply of Taxol. Since the biosynthetic mechanism of Taxol remains largely unknown, elucidating this pathway in detail will be very helpful in exploring alternative methods for Taxol production. Here, we sequenced Taxus cuspidata transcriptomes with next-generation sequencing (NGS) and third-generation sequencing (TGS) platforms. After correction with Illumina reads and removal of redundant reads, more than 180,000 nonredundant transcripts were generated from the raw Iso-Seq data. Using Cogent software and an alignment-based method, we identified a total of 139 cytochrome P450s (CYP450s), 31 BAHD acyltransferases (ACTs) and 1940 transcription factors (TFs). Based on phylogenetic and coexpression analysis, we identified 9 CYP450s and 7 BAHD ACTs as potential lead candidates for Taxol biosynthesis and 6 TFs that are possibly involved in the regulation of this process. Using coexpression analysis of genes known to be involved in Taxol biosynthesis, we elucidated the stem biosynthetic pathway. In addition, we analyzed the expression patterns of 12 characterized genes in the Taxol pathway and speculated that the isoprene precursors for Taxol biosynthesis were mainly synthesized via the MEP pathway. In addition, we found and confirmed that the alternative splicing patterns of some genes varied in different tissues, which may be an important tissue-specific method of posttranscriptional regulation. A strategy was developed to generate corrected full-length or nearly full-length transcripts without assembly to ensure sequence accuracy, thus greatly improving the reliability of coexpression and phylogenetic analysis and greatly facilitating gene cloning and characterization. This strategy was successfully utilized to elucidate the Taxol biosynthetic pathway, which will greatly contribute to the goals of improving the Taxol content in Taxus spp. using molecular breeding or plant management strategies and synthesizing Taxol in microorganisms using synthetic biological technology.


Ge1-xSnx alloy quantum dots with composition-tunable energy gaps and near-infrared photoluminescence.
Low-cost, less-toxic, and abundantly-produced Ge1-xSnx alloys are an interesting class of narrow energy-gap semiconductors that received noteworthy interest in optical technologies. Incorporation of α-Sn into Ge results in an indirect-to-direct bandgap crossover significantly improving light absorption and emission relative to indirect-gap Ge. However, the narrow energy-gaps reported for bulk Ge1-xSnx alloys have become a major impediment for their widespread application in optoelectronics. Herein, we report the first colloidal synthesis of Ge1-xSnx alloy quantum dots (QDs) with a narrow size dispersity (3.3 ± 0.5-5.9 ± 0.8 nm), a wide range of Sn compositions (0-20.6%), and composition-tunable energy-gaps and near-infrared (IR) photoluminescence (PL). The structural analysis of the alloy QDs indicates linear expansion of the cubic Ge lattice with increasing Sn, suggesting the formation of strain-free nanoalloys. The successful incorporation of α-Sn into crystalline Ge has been confirmed by electron microscopy, which suggests the homogeneous solid solution behavior of QDs. The quantum confinement effects have resulted in energy gaps that are significantly blue-shifted from bulk Ge for the Ge1-xSnx alloy QDs with composition-tunable absorption onsets (1.72-0.84 eV for x = 1.5-20.6%) and PL peaks (1.62-1.31 eV for x = 1.5-5.6%). Time-resolved PL (TRPL) spectroscopy revealed microsecond and nanosecond timescale decays at 15 K and 295 K, respectively, owing to the radiative recombination of dark and bright excitons as well as the interplay of surface traps and core electronic states. Realization of low-to-non-toxic and silicon-compatible Ge1-xSnx QDs with composition-tunable near-IR PL allows the unprecedented expansion of direct-gap Group IV semiconductors to a wide range of biomedical and advanced technological studies.


Citizenship status and engagement in HIV care: an observational cohort study to assess the association between reporting a national ID number and retention in public-sector HIV care in Johannesburg, South Africa.
In many resource-limited settings, people from rural areas migrate to urban hubs in search of work. Thus, urban public-sector HIV clinics in South Africa (SA) often cater to both local residents and patients from other provinces and/or countries. The objective of this analysis was to compare programmatic treatment outcomes by citizenship status in an urban clinic in SA. An urban public-sector HIV treatment facility in Johannesburg, SA. We included all antiretroviral therapy (ART)-naïve, non-pregnant patients who initiated standard first-line treatment from January 2008 to December 2013. 12 219 patients were included and 59.5% were women. Patients were followed from ART initiation until death, transfer, loss to follow-up (LTF), or data set closure. We describe attrition (mortality and LTF) stratified by SA citizenship status (confirmed SA citizens (with national ID number), unconfirmed SA citizens (no ID), and foreign nationals) and model the risk of attrition using Cox proportional hazards regression. 70% of included patients were confirmed SA citizens, 19% were unconfirmed SA citizens, and 11% were foreign nationals. Unconfirmed SA citizens were far more likely to die or become LTF than other patients. A similar proportion of foreign nationals (18.2%) and confirmed SA citizens (17.7%) had left care at 1 year compared with 47.0% of unconfirmed SA citizens (adjusted hazard ratio (aHR) unconfirmed SA vs confirmed SA: 2.68; 95% CI 2.42 to 2.97). By the end of follow-up, 75.5% of unconfirmed SA citizens had left care, approximately twice that of any other group. Unconfirmed SA citizens were more likely to drop out of care after ART initiation than other patients. Further research is needed to determine whether this observed attrition is representative of migration and/or self-transfer to another HIV clinic as such high rates of attrition pose challenges for the success of the national ART programme.


NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer.
Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.


Intrathecal Transplantation of Embryonic Stem Cell-Derived Spinal GABAergic Neural Precursor Cells Attenuates Neuropathic Pain in a Spinal Cord Injury Rat Model.
Neuropathic pain following spinal cord injury (SCI) is a devastating disease characterized by spontaneous pain such as hyperalgesia and allodynia. In this study, we investigated the therapeutic potential of ESC-derived spinal GABAergic neurons to treat neuropathic pain in a SCI rat model. Mouse embryonic stem cell-derived neural precursor cells (mESC-NPCs) were cultured in media supplemented with sonic hedgehog (SHH) and retinoic acid (RA) and efficiently differentiated into GABAergic neurons. Interestingly, low doses of SHH and RA induced MGE-like progenitors, which expressed low levels of DARPP32 and Nkx2.1 and high levels of Irx3 and Pax6. These cells subsequently generated the majority of the DARPP32(-) GABAergic neurons after in vitro differentiation. The spinal mESC-NPCs were intrathecally transplanted into the lesion area of the spinal cord around T10-T11 at 21 days after SCI. The engrafted spinal GABAergic neurons remarkably increased both the paw withdrawal threshold (PWT) below the level of the lesion and the vocalization threshold (VT) to the level of the lesion (T12, T11, and T10 vertebrae), which indicates attenuation of chronic neuropathic pain by the spinal GABAergic neurons. The transplanted cells were positive for GABA antibody staining in the injured region, and cells migrated to the injured spinal site and survived for more than 7 weeks in L4-L5. The mESC-NPC-derived spinal GABAergic neurons dramatically attenuated the chronic neuropathic pain following SCI, suggesting that the spinal GABAergic mESC-NPCs cultured with low doses of SHH and RA could be alternative cell sources for treatment of SCI neuropathic pain by stem cell-based therapies.


Are molecular alphabets universal enabling factors for the evolution of complex life?
Terrestrial biosystems depend on macromolecules, and this feature is often considered as a likely universal aspect of life. While opinions differ regarding the importance of small-molecule systems in abiogenesis, escalating biological functional demands are linked with increasing complexity in key molecules participating in biosystem operations, and many such requirements cannot be efficiently mediated by relatively small compounds. It has long been recognized that known life is associated with the evolution of two distinct molecular alphabets (nucleic acid and protein), specific sequence combinations of which serve as informational and functional polymers. In contrast, much less detailed focus has been directed towards the potential universal need for molecular alphabets in constituting complex chemically-based life, and the implications of such a requirement. To analyze this, emphasis here is placed on the generalizable replicative and functional characteristics of molecular alphabets and their concatenates. A primary replicative alphabet based on the simplest possible molecular complementarity can potentially enable evolutionary processes to occur, including the encoding of secondarily functional alphabets. Very large uniquely specified ('non-alphabetic') molecules cannot feasibly underlie systems capable of the replicative and evolutionary properties which characterize complex biosystems. Transitions in the molecular evolution of alphabets can be related to progressive bridging of barriers which enable higher levels of biosystem organization. It is thus highly probable that molecular alphabets are an obligatory requirement for complex chemically-based life anywhere in the universe. In turn, reference to molecular alphabets should be usefully applied in current definitions of life.


Acute effect of fructose intake from sugar-sweetened beverages on plasma uric acid: a randomised controlled trial.
Excessive fructose intake has been linked to hyperuricaemia. Our aim was to test whether 355 and 600 ml of commercial sugar-sweetened soft drinks would acutely raise plasma uric acid. Forty-one participants were randomised to a control group or an intervention group. The control group consumed 600 ml of fructose and 600 ml of glucose beverages. The soft drink group consumed 355 and 600 ml of beverages in random order. The control beverages were matched for fructose content with 600 ml of soft drink (26.7 g). Blood samples were collected at baseline, 30 and 60 min and analysed for plasma uric acid. Plasma uric acid concentrations were 13 (95% confidence interval: (CI): 3, 23) and 17 μmol/l (95% CI: 6, 28) higher 30 and 60 min after consumption of 600 ml of soft drink compared with the glucose control. The corresponding values for the fructose beverage were 22 (95% CI: 16, 29) and 23 μmol/l (95% CI: 14, 33). There was no significant difference in the increase in uric acid following the 600-ml soft drink compared with the fructose control at 30 min (6 μmol/l; 95% CI: -4, 15) or 60 min (5 μmol/l; 95% CI: -7, 17). There was no difference in the uric-acid-raising effect between the 355 and 600 ml volumes at 30 min (-1 μmol/l; 95% CI: -9, 6) or 60 min (-5 μmol/l; 95% CI: -10, 1). Small and transient increases in plasma uric acid are likely after consumption of sucrose-sweetened commercially available single-serve soft drinks in volumes as small as 355 ml.


Mating system, mate choice and parental care in a bark beetle.
The cypress bark beetle, Phloeosinus armatus, is a common element of the dying cypress tree system in East-Mediterranean countries. Adult beetles congregate for breeding on this ephemeral resource. We studied three traits that characterize this beetle's sexual behavior and linked them to its reproductive success: mating system, mate choice, and parental care. We found that the females are the 'pioneering sex', excavating the mating chamber. The average female is slightly larger than the male, and female and male body size is correlated, demonstrating size-assortative mating. The time it takes for a male to enter the mating chamber is positively correlated with female size and negatively correlated with its own size, which is perhaps responsible for this assortative mating. Males remain in the gallery during the period of oviposition, gradually leaving soon after the eggs hatch. The number of eggs laid and tunnel length are positively correlated with male body size. Finally, in the presence of both parents, more eggs are laid than when the female alone is present, demonstrating the important contribution of biparental care for reproductive success. We suggest that the interaction between a monogamous mating system, assortative mating, and biparental care contributes to reproductive success.


BTB/POZ domain proteins are putative substrate adaptors for cullin 3 ubiquitin ligases.
Cullins (CULs) are subunits of a prominent class of RING ubiquitin ligases. Whereas the subunits and substrates of CUL1-associated SCF complexes and CUL2 ubiquitin ligases are well established, they are largely unknown for other cullin family members. We show here that S. pombe CUL3 (Pcu3p) forms a complex with the RING protein Pip1p and all three BTB/POZ domain proteins encoded in the fission yeast genome. The integrity of the BTB/POZ domain, which shows similarity to the cullin binding proteins SKP1 and elongin C, is required for this interaction. Whereas Btb1p and Btb2p are stable proteins, Btb3p is ubiquitylated and degraded in a Pcu3p-dependent manner. Btb3p degradation requires its binding to a conserved N-terminal region of Pcu3p that precisely maps to the equivalent SKP1/F box adaptor binding domain of CUL1. We propose that the BTB/POZ domain defines a recognition motif for the assembly of substrate-specific RING/cullin 3/BTB ubiquitin ligase complexes.


The experience of young adult cancer patients described through online narratives.
Young adults are often faced with challenges related to relationships, employment, housing, and emotional development. Experiencing cancer during this time complicates the developmental processes and creates a need for communicating concerns and discussing issues. The purpose of this study was to explore the experiences and gain a better understanding of young adults affected by cancer (YAACs) by examining their online narratives (also known as Web logs or blogs). Inclusion and exclusion criteria were used to identify eligible Web sites. The Web site that most corresponded to the selection criteria was chosen for analysis (Planet Cancer, http://www.planetcancer.org/). The blog content generated in July 2011 was collected. The blogs were written by a total of 34 female and 12 male writers and included 136 (by female) and 28 (by male) blog entries. Researchers conducted a descriptive qualitative examination of blogs to explore YAACs' experiences during/after cancer. At the end of the data analysis process, 10 main themes were identified: physical burdens, future prospects, isolation (physical and psychological), guilt, mortality, images of cancer, creating a positive attitude, healthcare, online social interaction, and cancer survivorship. The Internet provides young cancer patients with a space in which to express themselves and to share experiences with those who are of similar age and in similar situations. Blogs can be particularly helpful when patients are isolated or physically unable to interact with other people because of treatment requirements or physical deterioration.Future studies should investigate other types of Internet cancer communities and how they can benefit the development of Internet-based support networks for YAACs.


siRNA knockdown of GPR18 receptors in BV-2 microglia attenuates N-arachidonoyl glycine-induced cell migration.
Neurons are known to employ the endogenous cannabinoid system to communicate with other cells of the CNS. Endocannabioid signaling recruits microglia toward neurons by engaging cannabinoid CB2 and abnormal cannabidiol (Abn-CBD) receptors. The Abn-CBD receptor is a prominent atypical cannabinoid receptor that had been discriminated by means of various pharmacological and genetic tools but remained to be identified at the molecular level. We recently introduced N-arachidonoyl glycine (NAGly) signaling via GPR18 receptors as an important novel signaling mechanism in microglial-neuronal communication. NAGly is an endogenous, enzymatically oxygenated metabolite of the endocannabinoid N-arachidonoyl ethanolamide (AEA). Our recent studies support strongly two hypotheses; first that NAGly initiates directed microglial migration in the CNS through activation of GPR18, and second that GPR18 is the Abn-CBD receptor. Here we present siRNA knockdown data in further support of these hypotheses. A GPR18-targetting siRNA pSUPER G418 GFP cDNA plasmid was created and transfected into BV-2 microglia. Successfully transfected GFP+ GPR18 siRNA BV-2 microglia displayed reduced GPR18 mRNA levels and immunocytochemical staining. Cell migration induced by 1 μM concentrations of NAGly, O-1602 and Abn-CBD were significantly attenuated in GFP+ cells. Our data provide definitive evidence that these compounds, characteristic of Abn-CBD receptor pharmacology, are acting via GPR18 in BV-2 microglia. A fuller understanding of the hitherto unidentified cannabinoid receptors such as GPR18; their molecular interactions with endogenous ligands; and how phytocannabinoids influence their signaling is vital if we are to comprehensively assess the function of the endogenous cannabinoid signaling system in human health and disease.


Variable coordination geometries via an amine-tethered-enamidophosphinimine ligand on cobalt.
The synthesis of two new amine-tethered enamidophosphinimine donor sets is described and their coordination chemistry with cobalt(ii) detailed. Deprotonation of the enamine tautomers of each system generates the lithium derivatives that are used in metathesis reactions with either anhydrous CoCl2 or CoCl2(THF)1.5 to generate tetrahedral κ3-(NNpNR)CoCl (where R = DIPP, 2,6-diisopropylphenyl; R = TMS, trimethylsilyl) or tetrahedral κ2-(NNpNTMS)2Co, the latter likely due to the insolubility of the CoCl2. For the R = DIPP derivative, replacement of the chloride proceeds smoothly by methathesis with LiCH2SiMe3 and KBEt3H to generate the bulky alkyl derivative κ3-(NNpNDIPP)CoCH2SiMe3, and the dihydride-bridged dimer [κ2-(NNpNDIPP)Co]2(μ-H)2, respectively; interestingly, the hydride dimer has the diethylaminoethyl arms uncoordinated. Reduction of κ3-(NNpNDIPP)CoCl with KC8 under dinitrogen generates the π-arene complex, κ2:η6-(NNpNDIPP)Co, and not the expected N2 complex. In an attempt to generate a dinitrogen complex, we investigated the metathesis and reduction chemistry of the N-trimethylsilyl substituted phosphinimine cobalt derivative, κ3-(NNpNTMS)CoCl. Although reaction with LiCH2SiMe3 produced the anticipated tetrahedral Co(ii) alkyl complex κ3-(NNpNTMS)Co(CH2SiMe3), reaction with KBEt3H and KC8 did not give the analogous products to that of the DIPP derivative; instead, the reaction with hydride was complicated and the only product isolated was the bis(ligand) derivative, κ2-(NNpNTMS)2Co, while reaction with KC8 under N2 generated the C-H activated complex κ4-(NNpNSiMe2CH2)Co. Many of these complexes have been characterized by single-crystal X-ray analysis, elemental analysis and solution magnetic susceptibility measurements. In addition, a number of these derivatives were screened for their ability to act as catalyst precursors for the hydrosilylation of 1-hexene.


A phase II study of paclitaxel poliglumex in combination with transdermal estradiol for the treatment of metastatic castration-resistant prostate cancer after docetaxel chemotherapy.
Taxanes remain the only agents to extend survival in castration-resistant metastatic prostate cancer, but their impact on the natural history of this disease is modest. We sought to test the hypothesis that increased delivery of taxane chemotherapy to the tumor through the use of a macromolecular polymer-drug conjugate of paclitaxel modulated by estradiol could extend the utility of this class of drugs. Patients with metastatic adenocarcinoma of the prostate who progressed despite standard hormonal therapy and after docetaxel-containing chemotherapy were treated with transdermal estradiol (0.2 mg/24 h) for 4 weeks followed by the same dose of transdermal estradiol and paclitaxel poliglumex (PPX; 150 mg/m intravenous) every 28 days. The primary objective was to determine the level of activity of the regimen measured using a fraction of patients who experienced a confirmed decline in serum prostate-specific antigen (PSA) of 50% or more. A two-stage phase II study designed to identify a response rate of > or =25% required three responders among 21 patients in the first stage. Twenty-one patients who received a median of two earlier chemotherapy regimens were enrolled in the trial between March 2007 and May 2008. During the estradiol-only treatment phase, no patient had a PSA decline in excess of 50% and lesser PSA declines that ranged from 8.8 to 34.1% were seen in five patients. No patients achieved a > or =50% PSA decline following the addition of PPX and there were no responses in measurable disease. The median time to progression was 4 weeks. In conclusion, this regimen of low-dose transdermal estradiol induction followed by PPX does not have activity in taxane pretreated patients with castration-resistant prostate cancer.


Evaluation of BioCreAtIvE assessment of task 2.
Molecular Biology accumulated substantial amounts of data concerning functions of genes and proteins. Information relating to functional descriptions is generally extracted manually from textual data and stored in biological databases to build up annotations for large collections of gene products. Those annotation databases are crucial for the interpretation of large scale analysis approaches using bioinformatics or experimental techniques. Due to the growing accumulation of functional descriptions in biomedical literature the need for text mining tools to facilitate the extraction of such annotations is urgent. In order to make text mining tools useable in real world scenarios, for instance to assist database curators during annotation of protein function, comparisons and evaluations of different approaches on full text articles are needed. The Critical Assessment for Information Extraction in Biology (BioCreAtIvE) contest consists of a community wide competition aiming to evaluate different strategies for text mining tools, as applied to biomedical literature. We report on task two which addressed the automatic extraction and assignment of Gene Ontology (GO) annotations of human proteins, using full text articles. The predictions of task 2 are based on triplets of protein--GO term--article passage. The annotation-relevant text passages were returned by the participants and evaluated by expert curators of the GO annotation (GOA) team at the European Institute of Bioinformatics (EBI). Each participant could submit up to three results for each sub-task comprising task 2. In total more than 15,000 individual results were provided by the participants. The curators evaluated in addition to the annotation itself, whether the protein and the GO term were correctly predicted and traceable through the submitted text fragment. Concepts provided by GO are currently the most extended set of terms used for annotating gene products, thus they were explored to assess how effectively text mining tools are able to extract those annotations automatically. Although the obtained results are promising, they are still far from reaching the required performance demanded by real world applications. Among the principal difficulties encountered to address the proposed task, were the complex nature of the GO terms and protein names (the large range of variants which are used to express proteins and especially GO terms in free text), and the lack of a standard training set. A range of very different strategies were used to tackle this task. The dataset generated in line with the BioCreative challenge is publicly available and will allow new possibilities for training information extraction methods in the domain of molecular biology.


Rapid regulation of Na+ fluxes and ammonia excretion in response to acute environmental hypoxia in the Amazonian oscar, Astronotus ocellatus.
The Amazonian oscar is extremely resistant to hypoxia, and tolerance scales with size. Overall, ionoregulatory responses of small ( approximately 15 g) and large oscars ( approximately 200 g) to hypoxia were qualitatively similar, but the latter were more effective. Large oscars exhibited a rapid reduction in unidirectional Na(+) uptake rate at the gills during acute hypoxia (Po(2) approximately 10 mmHg), which intensified with time (7 or 8 h); Na(+) efflux rates were also reduced, so net balance was little affected. The inhibitions were virtually immediate (1st h) and preceded a later 60% reduction (at 3 h) in gill Na(+)-K(+)-ATPase activity, reflected in a 60% reduction in maximum Na(+) uptake capacity without change in affinity (Km) for Na(+). Upon acute restoration of normoxia, recovery of Na(+) uptake was delayed for 1 h. These data suggest that dual mechanisms may be involved (e.g., immediate effects of O(2) availability on transporters, channels, or permeability, slower effects of Na(+)-K(+)-ATPase regulation). Ammonia excretion appeared to be linked indirectly to Na(+) uptake, exhibiting a Michaelis-Menten relationship with external [Na(+)], but the Km was less than for Na(+) uptake. During hypoxia, ammonia excretion fell in a similar manner to Na(+) fluxes, with a delayed recovery upon normoxia restoration, but the relationship with [Na(+)] was blocked. Reductions in ammonia excretion were greater than in urea excretion. Plasma ammonia rose moderately over 3 h hypoxia, suggesting that inhibition of excretion was greater than inhibition of ammonia production. Overall, the oscar maintains excellent homeostasis of ionoregulation and N-balance during severe hypoxia.


Circulating Tumor Necrosis Factor Alpha May Modulate the Short-Term Detraining Induced Muscle Mass Loss Following Prolonged Resistance Training.
Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine that has been shown to modulate muscle mass, and is responsive to exercise training. The effects of resistance training (RT) followed by a short period of detraining on muscle size, architecture and function in combination with circulating TNFα levels have not been previously investigated in a young, healthy population. Sixteen participants (8 males and 8 females) were randomly assigned to a training group (TRA; age 20 ± 3 years, mass 76 ± 7 kg), whilst fourteen participants (7 males and 7 females) age 22 ± 2 years, mass 77 ± 6 kg were assigned to a control group (CON). Measures of vastus lateralis (VL) muscle size (normalized physiological cross-sectional area allometrically scaled to body mass; npCSA), architecture (fascicle length; LF, pennation angle Pθ), strength (knee extensor maximal voluntary contraction; KE MVC), specific force, subcutaneous fat (SF) and circulating TNFα were assessed at baseline (BL), post 8 weeks RT (PT), and at two (DT1) and four (DT2) weeks of detraining. Pooled BL TNFα was 0.87 ± 0.28 pg/mL with no differences between groups. BL TNFα tended to be correlated with npCSA (p = 0.055) and KEMVC (p = 0.085) but not specific force (p = 0.671) or SF (p = 0.995). There were significant (p < 0.05) increases in npCSA compared to BL and CON in TRA at PT, DT1, and DT2, despite significant (p < 0.05) decreases in npCSA compared to PT at DT1 and DT2. There were significant (p < 0.05) increases in LF, Pθ and KE MVC at PT but only LF and torque at DT1. There were no significant (p > 0.05) changes in SF, specific force or TNFα at any time points. There was a significant correlation (p = 0.022, r = 0.57) between the relative changes in TNFα and npCSA at DT2 compared to PT. Neither RT nor a period of short term detraining altered the quality of muscle (i.e., specific force) despite changes in morphology and function. TNFα does not appear to have any impact on RT-induced gains in muscle size or function, however, TNFα may play a role in inflammatory-status mediated muscle mass loss during subsequent detraining in healthy adults.


Pills and pints: risky drinking and alcohol-related harms among regular ecstasy users in Australia.
A significant proportion of young Australians engage in risky alcohol consumption, and an increasing minority are regular ecstasy (3,4-methylenedioxymethamphetamine) users. Risky alcohol use, alone or in combination with ecstasy, is associated with a range of acute and chronic health risks. The aim of this study was to document the incidence and some health-related correlates of alcohol use, and concurrent alcohol and ecstasy use, among a large, national sample of regular ecstasy users (REU) in Australia. National, cross-sectional surveys of REU in Australia 2003-2008. Among REU in 2008 (n=678) usual alcohol use, psychological distress and health-related quality of life were measured using the Alcohol Use Disorders Identification Test, Kessler Psychological Distress Scale and Short Form-8 Survey respectively. Among REU in 2008, 36% reported high-risk patterns of usual alcohol consumption, 62% reported usually consuming more than five standard drinks with ecstasy, and 24% reported currently experiencing high or very high levels of psychological distress. Controlling for age and education, high-risk drinking among REU was associated with higher levels of psychological distress and poorer health-related functioning; however, the associations between concurrent alcohol and ecstasy use, and health outcomes, were not significant (P>0.05). A large and increasing proportion of REU in Australia engage in high-risk patterns of alcohol consumption, including in combination with ecstasy. High-risk alcohol consumption among this group is associated with adverse health-related outcomes. Prevention and harm reduction interventions for REU should incorporate messages about the risks associated with alcohol use. There is an ongoing need for youth-specific, coordinated alcohol and other drug and mental health services.


High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study.
Half the patients with acute myeloid leukemia (AML) who achieve complete remission (CR), ultimately relapse. Residual treatment-surviving leukemia is considered responsible for the outgrowth of AML. In many retrospective studies, detection of minimal residual disease (MRD) has been shown to enable identification of these poor-outcome patients by showing its independent prognostic impact. Most studies focus on molecular markers or analyze data in retrospect. This study establishes the value of immunophenotypically assessed MRD in the context of a multicenter clinical trial in adult AML with sample collection and analysis performed in a few specialized centers. In adults (younger than age 60 years) with AML enrolled onto the Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research Acute Myeloid Leukemia 42A study, MRD was evaluated in bone marrow samples in CR (164 after induction cycle 1, 183 after cycle 2, 124 after consolidation therapy). After all courses of therapy, low MRD values distinguished patients with relatively favorable outcome from those with high relapse rate and adverse relapse-free and overall survival. In the whole patient group and in the subgroup with intermediate-risk cytogenetics, MRD was an independent prognostic factor. Multivariate analysis after cycle 2, when decisions about consolidation treatment have to be made, confirmed that high MRD values (> 0.1% of WBC) were associated with a higher risk of relapse after adjustment for consolidation treatment time-dependent covariate risk score and early or later CR. In future treatment studies, risk stratification should be based not only on risk estimation assessed at diagnosis but also on MRD as a therapy-dependent prognostic factor.


Sexually dimorphic adaptations in basal maternal stress physiology during pregnancy and implications for fetal development.
There is clear evidence of reciprocal exchange of information between the mother and fetus during pregnancy but the majority of research in this area has focussed on the fetus as a recipient of signals from the mother. Specifically, physiological signals produced by the maternal stress systems in response to the environment may carry valuable information about the state of the external world. Prenatal stress produces sex-specific adaptations within fetal physiology that have pervasive and long-lasting effects on development. Little is known, however, about the effects of sex-specific fetal signals on maternal adaptations to pregnancy. The current prospective study examined sexually dimorphic adaptations within maternal stress physiology, including the hypothalamic-adrenal-pituitary (HPA) axis and the autonomic nervous system (ANS) and associations with fetal growth. Using diurnal suites of saliva collected in early and late pregnancy, we demonstrate that basal cortisol and salivary alpha-amylase (sAA) differ by fetal sex. Women carrying female fetuses displayed greater autonomic arousal and flatter (but more elevated) diurnal cortisol patterns compared to women carrying males. Women with flatter daytime cortisol trajectories and more blunted sAA awakening responses also had infants with lower birth weight. These maternal adaptations are consistent with sexually dimorphic fetal developmental/evolutionary adaptation strategies that favor growth for males and conservation of resources for females. The findings provide new evidence to suggest that the fetus contributes to maternal HPA axis and ANS regulation during pregnancy and that these systems also contribute to the regulation of fetal growth.


Having Difficult Conversations: The Advanced Practitioner's Role.
Throughout the course of their disease, patients with cancer and their families look to the oncology advanced practitioner (AP) for support and guidance as they struggle with the emotional impact of a life-limiting illness, complex treatment decisions, and the challenge of sustaining hope while maintaining realistic goals. At various points along the disease trajectory, difficult conversations between the AP and the patient are essential. In this case report of a 43-year-old woman with metastatic breast cancer, we model the use of various strategies available for the AP to help make these difficult conversations as productive, relevant, and emotionally safe for the patient as possible.


To treat or not to treat: maternal depression, SSRI use in pregnancy and adverse neonatal effects.
Recent pharmaceutical company and regulatory body circulars warning against the use of selective serotonin reuptake inhibitors (SSRIs) in late pregnancy have left clinicians in somewhat of a quandary as to how to manage their more severely depressed patients in pregnancy. Conversely, up to 75% of depressed women ceasing their antidepressants periconceptually will relapse. Studies reporting on adverse neonatal outcomes following exposure to SSRIs in the latter half of pregnancy suggest that the fetus is exposed to significant concentrations of these medications during this time. Adverse neonatal effects affecting the respiratory, gastrointestinal and neurological systems are, however, predominantly mild and self-limiting. One small retrospective case study suggests that SSRI exposure in the latter half of pregnancy may be associated with an increased risk of persistent pulmonary hypertension of the neonate (PPHN), however, the absolute risk of developing PPHN remains very small and these findings will require replication with a prospective study. While the studies to date suggest the need to closely monitor SSRI-exposed neonates in the immediate postnatal period, preferably with a neonatal withdrawal scale and access to neonatology services, there is currently no clear argument for women to be weaned off their SSRI in late pregnancy. The decision to use SSRIs at this time will have to be made on a case-by-case basis in close consultation with the mother and her partner.