Leucine-rich repeat-containing G protein-coupled receptor-4 (LGR4, Gpr48) is essential for renal development in mice.
Leucine-rich repeat-containing G protein-coupled receptor (LGR)-4 is a G protein-coupled receptor (GPCR) with a seven-transmembrane domain structure. LGRs are evolutionally and structurally phylogenetic, classified into three subgroups and are members of the so-called orphan receptors whose ligands have yet to be identified. We generated knockout mice lacking Lgr4(Gpr48) by targeted deletion of part of exon 18, which codes for the transmembrane and signal-transducing domains of the receptor. Lgr4 null mice were born at much less than the 25% expected frequency from crosses of Lgr4 heterozygous mice (Lgr4+/-). Lgr4 null mice that survived in utero died shortly after birth in almost all cases. We observed striking renal hypoplasia in the null mice, accompanied by elevated concentration of plasma creatinine. Histological analysis of the P0 null mouse kidney showed a notable decrease in the total number and density of the glomerulus. Thus, the function of Lgr4 is essential to regulate renal development in the mouse. This study suggests that the Lgr4 gene is a new and important member of LGRs involved in a group of genes responsible for hereditary disease in the kidney.


Social power and frontal alpha asymmetry.
Recent studies have shown that the states of high and low social power (the ability to control or influence another's thoughts, feelings, or behaviours) are related to left and right frontal hemisphere activity, respectively, suggesting a connection with two neurobiological motivational systems-the Behavioural Activation and Inhibition Systems. However, an important and outstanding question is which state of social power is associated with differences in hemispheric activity. In the current study, we addressed this outstanding issue by examining differences in frontal alpha asymmetry while participants engaged in an established episodic recall task, priming states of high, low, or neutral social power. Our results showed that it was the low social power state that was associated with hemispheric differences; that is, the low social power state was associated with significantly less left-frontal cortical activity relative to both the high and neutral social power states, while the latter two states did not differ. We discuss our results considering previous work on social power and the notion that different social power states are associated with different cognitive and behavioural tendencies.


Route visualization using detail lenses.
We present a method designed to address some limitations of typical route map displays of driving directions. The main goal of our system is to generate a printable version of a route map that shows the overview and detail views of the route within a single, consistent visual frame. Our proposed visualization provides a more intuitive spatial context than a simple list of turns. We present a novel multifocus technique to achieve this goal, where the foci are defined by points of interest (POI) along the route. A detail lens that encapsulates the POI at a finer geospatial scale is created for each focus. The lenses are laid out on the map to avoid occlusion with the route and each other, and to optimally utilize the free space around the route. We define a set of layout metrics to evaluate the quality of a lens layout for a given route map visualization. We compare standard lens layout methods to our proposed method and demonstrate the effectiveness of our method in generating aesthetically pleasing layouts. Finally, we perform a user study to evaluate the effectiveness of our layout choices.


A simple, sensitive high-performance liquid chromatography -ultraviolet method for the quantification of concentration and steady-state pharmacokinetics of itraconazole and hydroxyitraconazole.
A steady-state trough plasma itraconazole concentration greater than 500 ng/mL is a therapeutic target for itraconazole. A simple, rapid and sensitive high-performance liquid chromatography-based method was developed for quantitation of itraconazole and hydroxyitraconazole in human plasma. Itraconazole and hydroxyitraconazole were separated using a mobile phase of 0.5% KH2PO4 (pH 6.0)-acetonitrile (30:70, v/v) on a CAPCELLPAK C18 MGII column at a flow rate of 0.5 mL/min and ultraviolet absorbance at 260 nm. The analysis required 200 microL of plasma and involved a rapid, simple solid-phase extraction with an Oasis HLB cartridge, which resulted in recoveries of 87-92% for itraconazole and 91-94% for hydroxyitraconazole. The lower limit of quantification for itraconazole and hydroxyitraconazole was 5 ng/mL each. Intra- and interday coefficients of variation for itraconazole and hydroxyitraconazole were less than 11.3% and 12.2%, respectively, and accuracies were within 11.7% and 4.5% over the linear range, respectively. Although the steady-state plasma concentrations of itraconazole and hydroxyitraconazole ranged from 506 to 2482 ng/mL and from 766 to 2444 ng/mL, respectively, after a two-day loading dose of 400 mg/day intravenous itraconazole followed by the administration of 200 mg/day itraconazole oral solution, calibration curves of itraconazole and hydroxyitraconazole showed positive linearity in a concentration range of 5-2500 and 50-2500 ng/mL, respectively. Our results indicate that this method is applicable for the monitoring of plasma levels of itraconazole and hydroxyitraconazole in a clinical setting. Furthermore, the regimen presented here might also be effective in preventing infection, but further studies with large sample sizes are necessary to investigate this avenue.


Understanding needle-related distress in children with cystic fibrosis.
To explore the nature and management of needle-related distress in children and adolescents with cystic fibrosis (CF). Qualitative study using semi-structured interviews. Fourteen child-parent dyads took part. Children (5 male; 9 female) had a mean age of 12.4 years (range 7-17) and were mostly diagnosed with CF at birth (N= 11). Frequency of needle procedures ranged from once to six times a year. Parents (3 male; 11 female) had a mean age of 41.5 years and were from a variety of socio-economic backgrounds. Interviews were transcribed and analysed using thematic analysis. Most participants identified previous needle experiences and pain as related to their needle anxiety. Over half of parents and children considered 'taking control' to be the optimum coping strategy. The majority of parents and children thought inhaled nitrous oxide gas during needle procedures was helpful in managing needle-related distress. Parent and staff influences on needle-related distress are also examined. Needle-related distress in children with CF has a substantial impact on children and their parents, and may lead to management problems and treatment refusal. Psychological and pharmacological interventions could reduce distress and aid management.


SU2C phase Ib study of paclitaxel and MK-2206 in advanced solid tumors and metastatic breast cancer.
There is preclinical synergism between taxanes and MK-2206. We aim to determine the maximum tolerated dose, safety, and activity of combining MK-2206 and paclitaxel in metastatic cancer. Patients received weekly doses of paclitaxel at 80mg/m2 on day 1, followed by MK-2206 orally on day 2 escalated at 90mg, 135mg, and 200mg. Treatment continued until progression, excessive toxicity, or patient request. Blood and tissue were collected for pharmacokinetic and pharmacodynamics markers. A cycle consisted of three weeks of therapy. Dose-limiting toxicity (DLT) was defined as unacceptable toxicity during the first cycle. All statistical tests were two-sided. Twenty-two patients were treated, nine in dose escalation and 13 in dose expansion. Median age was 55 years. Median number of cycles was four. Dose escalation was completed with no DLT. CTCAE Grade 3 or higher adverse events were fatigue (n = 2), rash (n = 2), hyperglycemia (n = 1), and neutropenia (n = 7). Four patients in the expansion phase required MK-2206 dose reduction. Phase II recommended dose was established as paclitaxel 80mg/m2 weekly on day 1, and MK-2206 135mg weekly on day 2. Paclitaxel systemic exposure was similar in the presence or absence of MK-2206. Plasma MK-2206 concentrations were similar to data from previous phase I monotherapy. There was a statistically significant decrease in expression of pAKT S473 (P = .01) and pAKT T308 (P = .002) after therapy. PI3K/AKT/mTOR downregulation in tumor tissues and circulating markers did not correlate with tumor response or clinical benefit. There were five objective responses, and nine patients had stable disease. MK-2206 was well tolerated with paclitaxel. Preliminary antitumor activity was documented.


Marriage and Health: Selection, Protection, and Assortative Mating.
Using data from the Panel Study of Income Dynamics (PSID) and the Medical Expenditure Panel Survey (MEPS), we analyze the health gap between married and unmarried individuals of working-age. Controlling for observables, we find a gap that peaks at 10 percentage points at ages 55-59 years. The marriage health gap is similar for men and women. If we allow for unobserved heterogeneity in innate health (permanent and age-dependent), potentially correlated with timing and likelihood of marriage, we find that the effect of marriage on health disappears below age 40 years, while about 5 percentage points difference between married and unmarried individuals remains at older ages (55-59 years). This indicates that the observed gap is mainly driven by selection into marriage at younger ages, but there might be a protective effect of marriage at older ages. Exploring the mechanisms behind this result, we find that better innate health is associated with a higher probability of marriage and a lower probability of divorce, and there is strong assortative mating among couples by innate health. We also find that married individuals are more likely to have a healthier behavior compared to unmarried ones. Finally, we find that health insurance is critical for the beneficial effect of marriage.


Acupuncture for a first episode of acute ischaemic stroke: an observer-blinded randomised controlled pilot study.
To determine the required sample size for, and feasibility of, a RCT examining the effectiveness of early acupuncture for acute ischaemic stroke. Thirty-eight patients aged 40-85 years with a first episode of acute ischaemic stroke presenting within 72 h of stroke onset were randomly assigned to receive manual acupuncture (MA group; n=20) plus standard care or standard care only (control group, n=18). The acupuncture treatment was provided daily for 2 weeks. The primary outcome was the change in the National Institutes of Health Stroke Scale (NIHSS) score between baseline and 4 weeks. Secondary outcomes included changes in the Fugl-Meyer assessment (FMA) and the functional independence measure scores between baseline and 4 weeks, and changes in NIHSS, Barthel Index and modified Rankin Scale scores at 12 weeks. Thirty-one patients completed the study (dropout rate=18%) and adverse effects were minimal. No significant differences were seen between groups in the improvements in NIHSS scores, although there tended to be a greater reduction in NIHSS score after 1 week in the MA group relative to the control group (p=0.066). The post-stroke motor activity at 4 weeks was associated with a significantly increased FMA score in the acupuncture group compared with the control group (p<0.05), but not supported by intergroup analysis. This pilot study indicates that acupuncture appears to be safe for patients in the acute stage of ischaemic stroke. A subsequent trial with a larger sample size (estimated at n=122) is required to confirm whether early acupuncture intervention contributes to earlier functional improvement and to assess the longer-term clinical efficacy of acupuncture. NCT02210988; Results.


Costs of diabetes in Texas, 1992.
To estimate direct and indirect costs of diabetes in Texas in 1992. For most direct medical costs, we relied on third party and provider billing databases, including Medicare, Medicaid, VA facilities, public hospitals, and others. The researchers identified people with diabetes in the respective databases, located all records of their care, and sorted records as clearly, probably, or probably not attributable to diabetes on the basis of principal diagnoses. In most cases, costs were valued as allowable or paid charges. Some medical costs, such as private insurance, were estimated from national data and state surveys. Indirect costs included current short- and long-term disability costs and the discounted present value of future costs of mortality. Disability estimates relied on National Health Interview Survey (NHIS) data and U.S. Department of Labor wage data applied to Texas. Mortality estimates were based on death certificates. Total costs clearly or probably attributable to diabetes among Texans in 1992 were estimated at $4.0 billion. Direct medical costs were approximately $1.6 billion. Indirect costs were estimated at $2.4 billion. the largest direct costs were paid by Medicare. Most indirect costs were from long-term disability. This study demonstrates methods for conducting cost of illness studies at the state level. In a state like Texas, with a large and growing Mexican-American population, estimation of current and future economic costs of diabetes is vital for development of strategies to minimize social and economic consequences of diabetes.


Modulation of the Hypoxic Response.
Hypoxia stimulates a variety of adaptive responses, many mediated via the hypoxia inducible factors (HIF) family of transcriptional complexes. The balance of HIF-1, -2 and -3 controls a variety of genes, directly up-regulating transcription of genes involved in erythropoiesis, angiogenesis, vasomotor tone, metabolic pathways and processes related to cell multiplication and survival, and indirectly reducing the transcription of genes with other effects. HIF transcription factors are heterodimers consisting of an oxygen-regulated alpha chain bound to the constitutive aryl hydrocarbon receptor nuclear translocator. Under circumstances where oxygen is abundant the activity of the alpha chain is blocked by the actions of members of a family of oxygen-, iron- and oxoglutarate-dependent dioxygenase enzymes. Hydroxylation of two critical prolyl residues by the HIF prolyl hydroxylases (PHD1-3) leads to recognition by the von Hippel-Lindau E3 ubiquitin ligase complex, polyubiquitylation of the alpha chain and its consequent destruction by the proteasome. Hydroxylation of an asparaginyl residue by Factor Inhibiting HIF prevents any surviving HIF alpha chains from recruiting p300-CBP proteins, important for maximal transcriptional activation. Under conditions of acute hypoxia enzyme activity is suppressed, the HIF alpha chains are allowed to exist in their active form and target gene transcription is enhanced. In sustained hypoxia, adaptive responses mediated by the HIF pathway reduce oxygen demand and increase oxygen supply and thus ultimately down-regulate the pathway. However, a number of other processes also modulate HIF signalling and the balance between HIF-1 and HIF-2 actions. These include the generation of antisense HIF-1 and micro RNAs, up-regulation of HIF-3 alpha, antagonism of the HIF-p300 interaction by CITED2, increased PHD2 and PHD3 levels and effects on the pool of ankyrins within the cell which compete with HIF for the action of FIH. Additionally, effects on intermediary metabolism, reactive oxygen species, iron availability, nitric oxide levels and redox status within the cell may modulate HIF activity. Together, these effects lead to a reduction in the magnitude of the HIF response even if oxygenation is not restored and are predicted to alter the responsiveness of the system when oxygenation is restored.


Acetylation of tau inhibits its degradation and contributes to tauopathy.
Neurodegenerative tauopathies characterized by hyperphosphorylated tau include frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) and Alzheimer's disease (AD). Reducing tau levels improves cognitive function in mouse models of AD and FTDP-17, but the mechanisms regulating the turnover of pathogenic tau are unknown. We found that tau is acetylated and that tau acetylation prevents degradation of phosphorylated tau (p-tau). We generated two antibodies specific for acetylated tau and showed that tau acetylation is elevated in patients at early and moderate Braak stages of tauopathy. Histone acetyltransferase p300 was involved in tau acetylation and the class III protein deacetylase SIRT1 in deacetylation. Deleting SIRT1 enhanced levels of acetylated-tau and pathogenic forms of p-tau, probably by blocking proteasome-mediated degradation. Inhibiting p300 with a small molecule promoted tau deacetylation and eliminated p-tau associated with tauopathy. Modulating tau acetylation could be a new therapeutic strategy to reduce tau-mediated neurodegeneration.


Comparison of fixatives and fixation time for PCR detection of Mycobacterium in zebrafish Danio rerio .
Mycobacteriosis is a common disease of laboratory zebrafish Danio rerio. Different infection patterns occur in zebrafish depending on mycobacterial species. Mycobacterium marinum and M. haemophilum produce virulent infections associated with high mortality, whereas M. chelonae is more widespread and is not associated with high mortality. Identification of mycobacterial infections to the species level provides important information for making management decisions. Observation of acid-fast bacilli in histological sections or tissue imprints is the most common diagnostic method for mycobacteriosis in fish, but only allows for diagnosis to the genus level. Mycobacterial culture followed by molecular or biochemical identification is the traditional approach, but DNA of diagnostic value can also be retrieved from paraffin blocks. Here we investigated the type of fixative, time in fixative before processing, species of mycobacteria, and severity of infection as parameters to determine whether the hsp gene PCR assay (primer set HS5F/hsp667R) could detect and amplify mycobacterial DNA from paraffin-embedded zebrafish. Whole zebrafish were experimentally infected with either M. chelonae or M. marinum, and then preserved in 10% neutral buffered formalin or Dietrich's fixative for 3, 7, 21, and 45 d. Subsequently, fish were evaluated by hematoxylin and eosin and Fite's acid-fast stains to detect mycobacteria within granulomatous lesions. The PCR assay was quite effective and obtained PCR product from 75 and 88% of the M. chelonae- and M. marinum-infected fish, respectively. Fixative type, time in fixative, and mycobacterial species showed no statistical relationship with the efficacy of the PCR test.


A Note on the Risk of Infections Invading Unaffected Regions.
We present two probabilistic models to estimate the risk of introducing infectious diseases into previously unaffected countries/regions by infective travellers. We analyse two distinct situations, one dealing with a directly transmitted infection (measles in Italy in 2017) and one dealing with a vector-borne infection (Zika virus in Rio de Janeiro, which may happen in the future). To calculate the risk in the first scenario, we used a simple, nonhomogeneous birth process. The second model proposed in this paper provides a way to calculate the probability that local mosquitoes become infected by the arrival of a single infective traveller during his/her infectiousness period. The result of the risk of measles invasion of Italy was of 93% and the result of the risk of Zika virus invasion of Rio de Janeiro was of 22%.


In vivo imaging of inflammasome activation reveals a subcapsular macrophage burst response that mobilizes innate and adaptive immunity.
The inflammasome is activated in response to a variety of pathogens and has an important role in shaping adaptive immunity, yet the spatiotemporal orchestration of inflammasome activation in vivo and the mechanisms by which it promotes an effective immune response are not fully understood. Using an in vivo reporter to visualize inflammasome assembly, we establish the distribution, kinetics and propagation of the inflammasome response to a local viral infection. We show that modified vaccinia Ankara virus induces inflammasome activation in subcapsular sinus (SCS) macrophages, which is immediately followed by cell death and release of extracellular ASC specks. This transient inflammasome signaling in the lymph node generates a robust influx of inflammatory cells and mobilizes T cells from the circulation to increase the magnitude of T cell responses. We propose that after infection, SCS macrophages deliver a burst response of inflammasome activity and cell death that translates into the broadening of T cell responses, identifying an important aspect of inflammasome-driven vaccination strategies.


The Effect of Postexercise Milk Protein Intake on Rehydration of Children.
In adults, rehydration after exercise in the heat can be enhanced with a protein-containing beverage; however, whether this applies to children remains unknown. This study examined the effect of milk protein intake on postexercise rehydration in children. Fifteen children (10-12 years) performed three exercise trials in the heat (34.4 ± 0.2 °C, 47.9 ± 1.1% relative humidity). In a randomized, counterbalanced crossover design, participants consumed iso-caloric and electrolyte-matched beverages containing 0 g (CONT), 0.76 g (Lo-PRO) or 1.5 g (Hi-PRO) of milk protein/100 mL in a volume equal to 150% of their body mass (BM) loss during exercise. BM was then assessed over 4 h of recovery. Fluid balance demonstrated a significant condition × time interaction (p = .012) throughout recovery; Hi-PRO was less negative than CONT at 2 hr (p = .01) and tended to be less negative at 3 h (p = .07). Compared with CONT, beverage retention was enhanced by Hi-PRO at 2 h (p < .05). A postexercise beverage containing milk protein can favorably affect fluid retention in children. Further research is needed to determine the optimal volume and composition of a rehydration beverage for complete restoration of fluid balance.


Critical Time Intervention for Homeless People Making the Transition to Community Living: A Randomized Controlled Trial.
To help create an evidence base in Europe for effective interventions that improve the well-being of homeless people, we tested whether critical time intervention (CTI), a time-limited intervention developed to support vulnerable people during times of transition, is effective outside the United States. For this multicenter, parallel-group randomized controlled trial, 183 adults who were moving from shelters in the Netherlands to supported or independent housing were allocated to CTI or care-as-usual. The primary outcome was number of days rehoused, which was assessed by interviewing participants four times during a 9-month follow-up. Outcomes were analyzed with three-level mixed-effects models. The primary outcome did not differ between groups. CTI had a significant effect on family support and, for people experiencing less social support, psychological distress. Groups did not differ significantly on social support, fulfillment of care needs, quality of life, self-esteem, excessive alcohol use, or cannabis use. Because few participants were homeless at 9 months, more research is needed to establish whether CTI can prevent long-term recurrent homelessness. Given recent emphasis on informal support in public services and positive effects of CTI on family support and psychological distress, CTI is a fitting intervention for Dutch shelter services.


Drugs for the acute treatment of migraine in children and adolescents.
Numerous medications are available for the acute treatment of migraine in adults, and some have now been approved for use in children and adolescents in the ambulatory setting. A systematic review of acute treatment of migraine medication trials in children and adolescents will help clinicians make evidence-informed management choices. To assess the effects of pharmacological interventions by any route of administration versus placebo for migraine in children and adolescents 17 years of age or less. For the purposes of this review, children were defined as under 12 years of age and adolescents 12 to 17 years of age. We searched seven bibliographic databases and four clinical trial registers as well as gray literature for studies through February 2016. We included prospective randomized controlled clinical trials of children and adolescents with migraine, comparing acute symptom relieving migraine medications with placebo in the ambulatory setting. Two reviewers screened titles and abstracts and reviewed the full text of potentially eligible studies. Two independent reviewers extracted data for studies meeting inclusion criteria. We calculated the risk ratios (RRs) and number needed to treat for an additional beneficial outcome (NNTB) for dichotomous data. We calculated the risk difference (RD) and number needed to treat for an additional harmful outcome (NNTH) for proportions of adverse events. The percentage of pain-free patients at two hours was the primary efficacy outcome measure. We used adverse events to evaluate safety and tolerability. Secondary outcome measures included headache relief, use of rescue medication, headache recurrence, presence of nausea, and presence of vomiting. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created 'Summary of findings' tables. We identified a total of 27 randomized controlled trials (RCTs) of migraine symptom-relieving medications, in which 9158 children and adolescents were enrolled and 7630 (range of mean age between 8.2 and 14.7 years) received medication. Twenty-four studies focused on drugs in the triptan class, including almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan, sumatriptan + naproxen sodium, and zolmitriptan. Other medications studied included paracetamol (acetaminophen), ibuprofen, and dihydroergotamine (DHE). More than half of the studies evaluated sumatriptan. All but one study reported adverse event data. Most studies presented a low or unclear risk of bias, and the overall quality of evidence, according to GRADE criteria, was low to moderate, downgraded mostly due to imprecision and inconsistency. Ibuprofen was more effective than placebo for producing pain freedom at two hours in two small studies that included 162 children (RR 1.87, 95% confidence interval (CI) 1.15 to 3.04) with low quality evidence (due to imprecision). Paracetamol was not superior to placebo in one small study of 80 children. Triptans as a class of medication were superior to placebo in producing pain freedom in 3 studies involving 273 children (RR 1.67, 95% CI 1.06 to 2.62, NNTB 13) (moderate quality evidence) and 21 studies involving 7026 adolescents (RR 1.32, 95% CI 1.19 to 1.47, NNTB 6) (moderate quality evidence). There was no significant difference in the effect sizes between studies involving children versus adolescents. Triptans were associated with an increased risk of minor (non-serious) adverse events in adolescents (RD 0.13, 95% CI 0.08 to 0.18, NNTH 8), but studies did not report any serious adverse events. The risk of minor adverse events was not significant in children (RD 0.06, 95% CI - 0.04 to 0.17, NNTH 17). Sumatriptan plus naproxen sodium was superior to placebo in one study involving 490 adolescents (RR 3.25, 95% CI 1.78 to 5.94, NNTB 6) (moderate quality evidence). Oral dihydroergotamine was not superior to placebo in one small study involving 13 children. Low quality evidence from two small trials shows that ibuprofen appears to improve pain freedom for the acute treatment of children with migraine. We have only limited information on adverse events associated with ibuprofen in the trials included in this review. Triptans as a class are also effective at providing pain freedom in children and adolescents but are associated with higher rates of minor adverse events. Sumatriptan plus naproxen sodium is also effective in treating adolescents with migraine.


Inhibition of HIV-1 in cell culture by oligonucleotide-loaded nanoparticles.
To investigate the potential use of polymeric nanoparticles for the delivery of antisense oligonucleotides in HIV-1-infected cell cultures. Phosphorothioate oligonucleotides were encapsulated into poly (D,L-lactic acid) nanoparticles. Two models of infected cells were used to test the ability of nanoparticles to deliver them. HeLa P4-2 CD4+ cells, stably transfected with the beta-galactosidase reporter gene, were first used to evaluate the activity of the oligonucleotides on a single-round infection cycle. The acutely infected lymphoid CEM cells were then used to evaluate the inhibition of the viral production of HIV-1 by the oligonucleotides. The addition to infected CEM cells of nanoparticles containing gag antisense oligonucleotides in the nanomolar range led to strong inhibition of the viral production in a concentration-dependent manner. Similar results were previously observed in HeLa P4-2 CD4+ cells. Nanoparticle-entrapped random-order gag oligonucleotides had similar effects on reverse transcription. However, the reverse transcriptase activity of infected cells treated with nanomolar concentrations of free antisense and random oligonucleotides was not affected. These results suggest that poly (D,L-lactic acid) nanoparticles may have great potential as an efficient delivery system for oligonucleotides in HIV natural target cells, i.e., lymphocytic cells.


Good prognosis for survival to hospital discharge in a group of horses with uterine prolapse treated at a veterinary medical teaching hospital.
To describe uterine prolapse, predispositions, and outcomes in mares treated between 1988 and 2019. 24 mares with uterine prolapse. Clinical records were retrospectively reviewed, and follow-up information was gathered. The Mann-Whitney U test and Fisher exact test were used to analyze results for history and outcome variables for potential association with mare survival to hospital discharge. The χ2 test was used to compare breed distribution. Age was known in 23 mares (median, 11.1 years). For 15 mares with exact known parity, the median parity was 3 births (range, 1 to 13 births). For 22 mares, the maiden status was known (7 [32%] maiden; 15 [68%] multiparous). Breed distribution differed significantly between mares with uterine prolapse and all mares treated at the Veterinary Medical Teaching Hospital. Arabians were overrepresented in the uterine prolapse group (7/24 [29%]), compared with all mares treated (4,174/44,474 [9%]). Uterine prolapse occurred within 2 hours after parturition for 10 of 11 mares with known foaling times, after dystocia for 7 mares, and after abortion for 4 mares. Seventeen of 23 (74%) mares survived to hospital discharge. Acute hemorrhage was the most frequent cause of death. There were no correlations between mare survival to hospital discharge and mare parity or age, foal sex, retained fetal membranes, sepsis, or maiden status. Colts were overrepresented in foals with a known sex (12/17). Results indicated a breed predisposition to uterine prolapse, with Arabian mares overrepresented among affected mares. No characteristics correlated with mare survival to hospital discharge.


Production of H2-Rich Syngas From Lignocellulosic Biomass Using Microwave-Assisted Pyrolysis Coupled With Activated Carbon Enabled Reforming.
This study focuses on the use of a microwave reactor that combines biomass pyrolysis, at mild temperature, with catalytic reforming of the pyrolytic gas, using activated carbon, for generating hydrogen-rich synthesis gas. The traditional pyrolysis of biomass coupled with the reforming of its pyrolytic yields were also conducted using an electrically heated reactor. The bio-oil attained from conventional pyrolysis was higher in comparison to the yield from microwave pyrolysis. The reforming of the pyrolytic gas fraction led to reductions in bio-oil yield to <3.0 wt%, with a simultaneous increase in gaseous yields. An increase in the syngas and H2 selectivity was discovered with the reforming process such that the use of microwave pyrolysis with activated carbon reforming produced 85 vol% synthesis gas fraction containing 55 vol% H2 in comparison to the 74 vol% syngas fraction with 30 vol% H2 obtained without the reforming. Cracking reactions were improved with microwave heating, while deoxidation and dehydrogenation reactions were enhanced by activated carbon, which creates a reduction environment. Consequently, these reactions generated H2-rich syngas formation. The approach implemented in this study revealed higher H2, syngas yield and that the overall LHV of products has huge potential in the transformation of biomass into high-value synthesis gas.


The human visual system differentially represents subjectively and objectively invisible stimuli.
The study of unconscious processing requires a measure of conscious awareness. Awareness measures can be either subjective (based on participant's report) or objective (based on perceptual performance). The preferred awareness measure depends on the theoretical position about consciousness and may influence conclusions about the extent of unconscious processing and about the neural correlates of consciousness. We obtained functional magnetic resonance imaging (fMRI) measurements from 43 subjects while they viewed masked faces and houses that were either subjectively or objectively invisible. Even for objectively invisible (perceptually indiscriminable) stimuli, we found significant category information in both early, lower-level visual areas and in higher-level visual cortex, although representations in anterior, category-selective ventrotemporal areas were less robust. For subjectively invisible stimuli, similar to visible stimuli, there was a clear posterior-to-anterior gradient in visual cortex, with stronger category information in ventrotemporal cortex than in early visual cortex. For objectively invisible stimuli, however, category information remained virtually unchanged from early visual cortex to object- and category-selective visual areas. These results demonstrate that although both objectively and subjectively invisible stimuli are represented in visual cortex, the extent of unconscious information processing is influenced by the measurement approach. Furthermore, our data show that subjective and objective approaches are associated with different neural correlates of consciousness and thus have implications for neural theories of consciousness.


First Report of Coleus blumei viroid 5 from Coleus blumei in India and Indonesia.
Coleus blumei, which was found originally in Indonesia, is an ornamental plant grown worldwide. It can be infected by several viroids of the genus Coleviroid, family Pospiviroidae. Six main viroids that infect coleus have been reported: Coleus blumei viroid 1 through 6 (CbVd-1 ~ CbVd-6). Although CbVd-1 was first reported in a commercial coleus in Brazil in 1989 (1), and then in Germany, Japan, Canada, Korea, China, and India, CbVd-5 was reported only in China in 2009 (2). Symptoms caused by CbVd-5 varied depending on different cultivars, and in case of an unknown cultivar of "Red with dark green edge," are very clear albino symptoms. From 2010 to 2011, 60 and 3 leaf samples of coleus were collected from Hyderabad, India, and Java, Indonesia, respectively, and subjected to low molecular weight RNA extraction according to Li et al. (3). The results of dot-blot hybridization using CbVd-5 cRNA probes and RT-PCR using CbVd-5 specific primers (CbVd-5-PF: 5'-TGACTAGAACAGTAGTAAAG-3' / CbVd-5-PR: 5'-AATTGAGGTCAAACCTCTTT-3') demonstrated that 28 out of the 60 samples from India and all three samples from Indonesia were positive for CbVd-5. The resulting RT-PCR fragments from one sample selected randomly from each country were cloned into the pMD18-T vector (Takara) and transformed into E. coli DH5α competent cells. Five positive clones of each sample were sequenced. The result of sequence analysis revealed that the similarities of CbVd-5 between the sequences we obtained and the reference sequence (GenBank Accession No. NC003683) were 97.8 to 100%. Bioassay using nine viroid-free coleus plants from three cultivars (three from each cultivar), inoculated with CbVd-5 infectious clones by stem slashing, demonstrated that CbVd-5 could induce albino symptom on the leaves of the unknown cultivar "Red with dark green edge" 2 months after inoculation. To our knowledge, this is the first report of CbVd-5 from India and Indonesia, and the second report of CbVd-5 in the world. Considering the effect of CbVd-5 on the appearance of coleus and its recombination ability, a certification program may be needed to control the spread of this viroid. References: (1) M. E. N. Fonseca et al. Fitopatol. Bras. 14:94, 1989. (2) W. Y. Hou et al. Arch. Virol. 154:315, 2009. (3) S. F. Li et al. Ann. Phytopathol. Soc. Jpn. 61:381, 1995.


Harnessing Synthetic Ecology for commercial algae production.
Synthetic Ecology is a novel concept describing the design of de novo ecological communities for a designated purpose. This study is a proof of concept for harnessing Synthetic Ecology in expanding the scale of commercially relevant micro algae (Chlorella vulgaris) cultivation using stable Synthetic Ecologies in open environments as opposed to vulnerable monocultures. We focused on whether the grazing activity of zebra mussels (Dreissena polymorpha) would result in a consistent, and commercially favourable, dominance of Chlorella in cultures that were also inoculated with a competing and potentially invasive cyanobacteria (Synechocystis sp. PCC6803). The key result of this study was that in axenic mixed species co-cultures, zebra mussels had a significantly greater negative effect on Synechocystis cell numbers than Chlorella (P < 0.0001). The zebra mussels' putative preference for Synechocystis over Chlorella suggests they could be used to maintain the dominance of Chlorella in outdoor cultivation systems prone to contamination by invasive cyanobacteria.


Medical clearance in the psychiatric emergency setting: a call for more standardization.
Literature suggests little standardization in the practice of medical clearance of patients who present to emergency rooms in psychiatric crisis. The present quality improvement study examined current practice in a large psychiatric teaching hospital setting. Using chart review, the completeness of physical examination was examined for 10 body areas in a random sample of 20 psychiatric patients admitted via a psychiatric emergency department (ED) during a one-month period. Charts were examined for four professional groups - family physicians or nurse practitioners, psychiatry residents, medical students and general ED physicians. Results indicated a wide variation in documentation across the four groups and some body systems that were consistently never assessed. To improve standardization, a physical examination form is proposed that is user friendly and based on a review of current literature.


Interferon regulatory factor-1 regulates the autophagic response in LPS-stimulated macrophages through nitric oxide.
The pathogenesis of sepsis is complex and, unfortunately, poorly understood. The cellular process of autophagy is believed to play a protective role in sepsis; however, the mechanisms responsible for its regulation in this setting are ill defined. In the present study, interferon regulatory factor 1 (IRF-1) was found to regulate the autophagic response in lipopolysaccharide (LPS)-stimulated macrophages. In vivo, tissue macrophages obtained from LPS-stimulated IRF-1 knockout (KO) mice demonstrated increased autophagy and decreased apoptosis compared to those isolated from IRF-1 wild-type (WT) mice. In vitro, LPS-stimulated peritoneal macrophages obtained from IRF-1 KO mice experienced increased autophagy and decreased apoptosis. IRF-1 mediates the inhibition of autophagy by modulating the activation of the mammalian target of rapamycin (mTOR). LPS induced the activation of mTOR in WT peritoneal macrophages, but not in IRF-1 KO macrophages. In contrast, overexpression of IRF-1 alone increased the activation of mTOR and consequently decreased autophagic flux. Furthermore, the inhibitory effects of IRF-1 mTOR activity were mediated by nitric oxide (NO). Therefore, we propose a novel role for IRF-1 and NO in the regulation of macrophage autophagy during LPS stimulation in which IRF-1/NO inhibits autophagy through mTOR activation.


Identifying the needs of LGBTQ immigrants and refugees in Southern Arizona.
This article reports on the results of a needs assessment conducted for lesbian, gay, bisexual, transgender, and queer (LGBTQ) immigrants, asylees, refugees, and their allies in Southern Arizona, and it is the first study of its kind in the United States. Utilizing interview data collected with migrants, allies, and service providers in Tucson, Arizona, this article presents findings on the quality of service provision provided to this very underserved community pertaining to health care, housing, and legal services. The assessment shows that no services are provided specifically for LGBTQ migrants, and most LGBTQ migrants turn to family and friends when they have needs. The most significant result of this study pertains to the lack of cultural competence and an overall deficiency in terms of cultural awareness when it comes to the specific needs of LGBTQ migrants.


Allium hookeri Root Extract Inhibits Adipogenesis by Promoting Lipolysis in High Fat Diet-Induced Obese Mice.
Allium hookeri (AH) is widely consumed as a herbal medicine. It possesses biological activity against metabolic diseases. The objective of this study was to investigate effects of AH root water extract (AHR) on adipogenesis in 3T3-L1 cells and in high-fat diet (HFD)-induced obese mice. AHR inhibited lipid accumulation during adipocyte differentiation by downregulation of gene expression, such as hormone sensitive lipase (HSL), lipoprotein lipase (LPL) and an adipogenic gene, CCAAT/enhancer binding protein-α in 3T3-L1 preadipocytes. Oral administration of AHR significantly suppressed body weight gain, adipose tissue weight, serum leptin levels, and adipocyte cell size in HFD-induced obese mice. Moreover, AHR significantly decreased hepatic mRNA expression levels of cholesterol synthesis genes, such as 3-hydroxy-3-methylglutaryl CoA reductase, sterol regulatory element-binding transcription factor (SREBP)-2, and low-density lipoprotein receptor, as well as fatty acid synthesis genes, such as SREBP-1c and fatty acid synthase. Serum triglyceride levels were also lowered by AHR, likely as a result of the upregulating gene involved in fatty acid β-oxidation, carnitine palmitoyltransferase 1a, in the liver. AHR treatment activated gene expression of peroxisome proliferator-activated receptor-γ, which might have promoted HSL and LPL-medicated lipolysis, thereby reducing white adipose tissue weight. In conclusion, AHR treatment can improve metabolic alterations induced by HFD in mice by modifying expression levels of genes involved in adipogenesis, lipogenesis, and lipolysis in the white adipose tissue and liver.


Nanoparticle stability in lake water shaped by natural organic matter properties and presence of particulate matter.
Predicting nanoparticle (NP) fate in the environment continues to remain a challenge, especially for natural surface water systems, where NPs can hetero-aggregate with natural organic and mineral suspended matter. Here we present the interactions and aggregation behavior of TiO2 NPs with natural organic matter (NOM) in a natural lake water. NP fate in a synthetic water of the same pH and ionic composition was also tested in the presence and absence of NOM analogs to gain insight into the different stabilizing effects of each NOM type. Several complementary analytical techniques were utilized to assess lake NOM composition, including pyrolysis-gas chromatography-mass spectrometry, gel permeation chromatography, the polarity rapid-assessment method, and Nanoparticle Tracking Analysis. In the natural lake water, the TiO2 NPs preferentially interacted with mostly anionic NOM of high and medium molecular weight (~1200-1450 and 400-520 Da). Specifically, strong interactions with proteins and polyhydroxy aromatics were observed. NP fate and stability were determined in both raw lake water containing mineral particulate matter and total NOM (NOMtot) and filtered lake water containing only NOM <0.8 μm (NOM<0.8), with different aggregation profiles observed over time. Additionally, three times the number of TiO2 NPs remained in suspension when only NOM<0.8 was present compared to the unfiltered water containing mineral particulate matter and NOMtot. These results demonstrate the contrasting NP fates in the aquatic environment according to the presence of NOMtot vs. NOM<0.8 and further suggest that the use of pure NOM analogs may not accurately represent NP interactions and fate in the natural system.


Modeling white matter microstructure.
Quantitative magnetic resonance imaging can be combined with advanced biophysical models to measure microstructural features of white matter. Non-invasive microstructural imaging has the potential to revolutionize neuroscience, and acquiring these measures in clinically feasible times would greatly improve patient monitoring and clinical studies of drug efficacy. However, a good understanding of microstructural imaging techniques is essential to set realistic expectations and to prevent over-interpretation of results. This review explains the methodology behind microstructural modeling and imaging, and gives an overview of the breakthroughs and challenges associated with it.


Virtual neuropathology: three-dimensional visualization of lesions due to toxic insult.
A first-pass approach incorporating high-field magnetic resonance imaging (MRI) was used for rapid detection of neuropathologic lesions in fixed rat brains. This inherently 3-dimensional and nondestructive technique provides high-resolution, high-contrast images of fixed neuronal tissue in the absence of sectioning or staining. This technique, magnetic resonance microscopy (MRM), was used to identify diverse lesions in 2 well-established rat neurotoxicity models. The intrinsic contrast in the images delineated lesions that were identified using a battery of histologic stains, some of which would not be used in routine screening. Furthermore, the MRM images provided the locations of lesions, which were verified upon subsequent sectioning and staining of the same samples. The inherent contrast generated by water properties is exploited in MRM by choosing suitable pulse sequences, or proton stains. This approach provides the potential for a comprehensive initial MRM screen for neurotoxicity in preclinical models with the capability for extrapolation to clinical analyses using classical MRI.


The Effect of Intravenous Dexamethasone on Sugammadex Reversal Time in Children Undergoing Adenotonsillectomy.
Dexamethasone has been shown to cause inhibition of sugammadex reversal in functionally innervated human muscle cells. In this prospective, double-blind, randomized, controlled study, we evaluated the effect of dexamethasone on the reversal time of sugammadex in children undergoing tonsillectomy and/or adenoidectomy. We recruited 60 patients with ASA physical status I to II, between the ages of 3 and 8 years, scheduled for elective tonsillectomy and/or adenoidectomy. After the induction of anesthesia, patients in group D received IV dexamethasone at a dose of 0.5 mg/kg within a total volume of 5 mL saline, whereas patients in group S received only 5 mL IV saline as the control group. At the end of surgery, all patients were given a single bolus dose (2 mg/kg) of sugammadex at reappearance of T2. Demographic data, hemodynamic variables, time to recovery (a train-of-four ratio of 0.9), time to tracheal extubation, and adverse effects were recorded. There was no statistical significance between 2 groups in time to recovery and time to extubation. Time to recovery was 97.7 ± 23.9 seconds in group D and 91.1 ± 39.5 seconds in group S (P = 0.436; 95% confidence interval, -10.3 to 23.5). Time to extubation was 127.9 ± 23.2 seconds and 123.8 ± 38.7 seconds in group D and in group S, respectively (P = 0.612; 95% confidence interval, -11.9 to 20.05). IV dexamethasone, given after induction of anesthesia, at a dose of 0.5 mg/kg, does not substantively affect the reversal time of sugammadex in pediatric patients undergoing adenoidectomy and/or tonsillectomy.


Granulocyte-angiotensin system. Identification of angiotensinogen as the plasma protein substrate of leukocyte cathepsin G.
Cathepsin G, a human lysosomal neutral protease, converts angiotensin I to angiotensin II and cleaves angiotensin II from a plasma protein substrate. Experiments were designed that identified and characterized cathepsin G substrate as human angiotensinogen. A total of 2, 5, and 10 micrograms of purified substrate, incubated with 2 microL of partially purified human renin (2 Goldblatt units/mg) for 60 min at 37 degrees C, generated 2, 9, and 22 pmol of angiotensin I. Cathepsin G substrate and renin substrate activities copurified during Affi-Gel Blue affinity chromatography, hydroxylapatite chromatography, phenyl-Sepharose chromatography, and S-200 gel filtration. Disc gel electrophoresis of 10 micrograms of purified protein gave a single band containing both activities. The amino-terminal sequence contained the covalent structure of angiotensin I and was Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-X-Glu-Ser-Thr-Cys-Gl u-. Reduced and unreduced angiotensinogens were subjected to sodium dodecyl sulfate gel electrophoresis, and each gel showed two bands of Mr 65 000 and 62 000. The isoelectric point of the Mr 65 000 form was pH 4.5-4.3 and the Mr 62 000 form was pH 4.9. Functional, structural, and physiochemical evidence demonstrates that the substrate of cathepsin G is angiotensinogen. Thus, human neutrophils may utilize angiotensin I or angiotensinogen as substrate for angiotensin II generation. The granulocyte-angiotensin system does not require renin or converting enzyme and may function as a mobile effector pathway which modulates tissue blood flow and/or vascular permeability.


[Coronary angiography: indications, results and complications in 5.000 consecutive patients].
There are guidelines about equipment, premises, personnel, indications and complications rates for coronary angiography, that every center performing this procedure should adhere. To report the experience with 5.000 coronary angiographies and to assess the compliance of the center with the current guidelines. Prospective registry of 5.000 patients aged 60+/-11 years (3.475 males) subjected to coronary angiography since 1992, assessing all aspects of the procedure with special emphasis on complications. The indications for 80% of procedures was suspected coronary atherosclerosis. The main risk factors were hypertension and smoking. Coronary atherosclerosis was demonstrated in 62%, mainly one vessel disease. These were two deaths due to the procedure (0.04%), three patients (0.06%) had an acute myocardial infarction or a stroke. These figures are lower than referential values. In this center, coronary angiography is a safe procedure, with complications rates that are even lower than referential values.


Antitumor efficacy of Kisspeptin in human malignant mesothelioma cells.
Kisspeptin signaling, via its receptors GPR54, could be an essential players in the inhibition of mesothelioma progression, invasion and metastasis formation. The loss of KiSS1 by tumor cells has been associated with a metastatic phenotype but the mechanistic insights of this process are still unknown. The blockade of the metastatic process at early stage is a hot topic in cancer research. We studied the role of KiSS1 on proliferation, invasiveness, migration abilities of mesothelioma cell lines focusing on the effect on epithelial-to-mesenchymal transition (EMT). Treatment with the KiSS1 peptide or with a synthesis peptide with longer half-life, the FTM080, significantly inhibited cell proliferation, migration and invasion of mesothelioma cell lines; the same treatment reduced the activity of MMP-2 and MMP-9 determining consequently a marked reduction in the invasiveness of primary tumors and metastases. Thespecificexpression of EMT markers, as E-caderin, Vimentin, Slug and Snail, suggested the inhibition of EMT after treatment with KiSS1 as well as the preservation of epithelial components. Our results support anti-proliferative effect of KiSS1 in cancer cells and suggest that targeting the KiSS1/GPR54 system may represent a novel therapeutic approach for mesothelioma.


Use of home telemonitoring to support multidisciplinary care of heart failure patients in Finland: randomized controlled trial.
Heart failure (HF) patients suffer from frequent and repeated hospitalizations, causing a substantial economic burden on society. Hospitalizations can be reduced considerably by better compliance with self-care. Home telemonitoring has the potential to boost patients' compliance with self-care, although the results are still contradictory. A randomized controlled trial was conducted in order to study whether the multidisciplinary care of heart failure patients promoted with telemonitoring leads to decreased HF-related hospitalization. HF patients were eligible whose left ventricular ejection fraction was lower than 35%, NYHA functional class ≥2, and who needed regular follow-up. Patients in the telemonitoring group (n=47) measured their body weight, blood pressure, and pulse and answered symptom-related questions on a weekly basis, reporting their values to the heart failure nurse using a mobile phone app. The heart failure nurse followed the status of patients weekly and if necessary contacted the patient. The primary outcome was the number of HF-related hospital days. Control patients (n=47) received multidisciplinary treatment according to standard practices. Patients' clinical status, use of health care resources, adherence, and user experience from the patients' and the health care professionals' perspective were studied. Adherence, calculated as a proportion of weekly submitted self-measurements, was close to 90%. No difference was found in the number of HF-related hospital days (incidence rate ratio [IRR]=0.812, P=.351), which was the primary outcome. The intervention group used more health care resources: they paid an increased number of visits to the nurse (IRR=1.73, P<.001), spent more time at the nurse reception (mean difference of 48.7 minutes, P<.001), and there was a greater number of telephone contacts between the nurse and intervention patients (IRR=3.82, P<.001 for nurse-induced contacts and IRR=1.63, P=.049 for patient-induced contacts). There were no statistically significant differences in patients' clinical health status or in their self-care behavior. The technology received excellent feedback from the patient and professional side with a high adherence rate throughout the study. Home telemonitoring did not reduce the number of patients' HF-related hospital days and did not improve the patients' clinical condition. Patients in the telemonitoring group contacted the Cardiology Outpatient Clinic more frequently, and on this way increased the use of health care resources. Clinicaltrials.gov NCT01759368; http://clinicaltrials.gov/show/NCT01759368 (Archived by WebCite at http://www.webcitation.org/6UFxiCk8Z).


SERIES: eHealth in primary care. Part 3: eHealth education in primary care.
Education is essential to the integration of eHealth into primary care, but eHealth is not yet embedded in medical education. In this opinion article, we aim to support organisers of Continuing Professional Development (CPD) and teachers delivering medical vocational training by providing recommendations for eHealth education. First, we describe what is required to help primary care professionals and trainees learn about eHealth. Second, we elaborate on how eHealth education might be provided. We consider four essential topics. First, an understanding of existing evidence-based eHealth applications and conditions for successful development and implementation. Second, required digital competencies of providers and patients. Third, how eHealth changes patient-provider and provider-provider relationships and finally, understanding the handling of digital data. Educational activities to address these topics include eLearning, blended learning, courses, simulation exercises, real-life practice, supervision and reflection, role modelling and community of practice learning. More specifically, a CanMEDS framework aimed at defining curriculum learning goals can support eHealth education by describing roles and required competencies. Alternatively, Kern's conceptual model can be used to design eHealth training programmes that match the educational needs of the stakeholders using eHealth. Vocational and CPD training in General Practice needs to build on eHealth capabilities now. We strongly advise the incorporation of eHealth education into vocational training and CPD activities, rather than providing it as a separate single module. How learning goals and activities take shape and how competencies are evaluated clearly requires further practice, evaluation and study.


The diacetamidodideoxyuronic-acid-containing glycan chain of Bacillus stearothermophilus NRS 2004/3a represents the secondary cell-wall polymer of wild-type B. stearothermophilus strains.
The diacetamidodideoxymannuronic-acid-containing glycan of Bacillus stearothermophilus NRS 2004/3a with the repeating unit structure [-->4)-beta-D-ManpA2,3(NAc)2-(1-->6)-alpha-D-Glcp-(1-->4)-beta-D-+ ++ManpA2,3 (NAc)2-(1-->3)-alpha-D-GlcpNAc-(1-->], was examined to identify its linkage to the bacterial cell wall. In a previous paper it was suggested that this glycan is covalently linked to the surface layer (S-layer) glycoprotein of that organism. By improved chromatographic techniques (gel permeation over Sephacryl S-1000 SF; C4 reversed-phase HPLC) the diacetamidodideoxyuronic-acid-containing material was completely separated from the S-layer glycoprotein. This implicates only low, if any, specific affinity between these cell-wall components. To obtain sufficient amounts for the chemical characterization of its linkage region, the identical diacetamidodideoxyuronic-acid-containing material was isolated from sonicated cells of that organism by a purification procedure different to that for preparation of S-layers. This method allowed collection of the intact molecule including its linkage region. From the combined results of the chemical characterization and 600 MHz NMR spectroscopy it is proposed that the diacetamidodideoxyuronic-acid-containing glycan chain, consisting of approximately six tetrasaccharide repeating units, is directly linked via a pyrophosphate bridge to carbon 6 of muramic acid residues of the peptidoglycan sacculus. About 20-25% of the muramic acid residues are substituted with these polysaccharide chains. Thus, the diacetamidodideoxyuronic-acid-containing glycan represents a secondary cell-wall polymer of B. stearothermophilus NRS 2004/3a.


The polarization properties of a tilted polarizer.
Polarizers are key components in optical science and technology. Thus, understanding the action of a polarizer beyond oversimplifying approximations is crucial. In this work, we study the interaction of a polarizing interface with an obliquely incident wave experimentally. To this end, a set of Mueller matrices is acquired employing a novel procedure robust against experimental imperfections. We connect our observation to a geometric model, useful to predict the effect of polarizers on complex light fields.


Saturation of the southern ocean CO2 sink due to recent climate change.
Based on observed atmospheric carbon dioxide (CO2) concentration and an inverse method, we estimate that the Southern Ocean sink of CO2 has weakened between 1981 and 2004 by 0.08 petagrams of carbon per year per decade relative to the trend expected from the large increase in atmospheric CO2. We attribute this weakening to the observed increase in Southern Ocean winds resulting from human activities, which is projected to continue in the future. Consequences include a reduction of the efficiency of the Southern Ocean sink of CO2 in the short term (about 25 years) and possibly a higher level of stabilization of atmospheric CO2 on a multicentury time scale.


Quantum ratchet in two-dimensional semiconductors with Rashba spin-orbit interaction.
Ratchet is a device that produces direct current of particles when driven by an unbiased force. We demonstrate a simple scattering quantum ratchet based on an asymmetrical quantum tunneling effect in two-dimensional electron gas with Rashba spin-orbit interaction (R2DEG). We consider the tunneling of electrons across a square potential barrier sandwiched by interface scattering potentials of unequal strengths on its either sides. It is found that while the intra-spin tunneling probabilities remain unchanged, the inter-spin-subband tunneling probabilities of electrons crossing the barrier in one direction is unequal to that of the opposite direction. Hence, when the system is driven by an unbiased periodic force, a directional flow of electron current is generated. The scattering quantum ratchet in R2DEG is conceptually simple and is capable of converting a.c. driving force into a rectified current without the need of additional symmetry breaking mechanism or external magnetic field.


A dynamic stochastic model for DNA replication initiation in early embryos.
Eukaryotic cells seem unable to monitor replication completion during normal S phase, yet must ensure a reliable replication completion time. This is an acute problem in early Xenopus embryos since DNA replication origins are located and activated stochastically, leading to the random completion problem. DNA combing, kinetic modelling and other studies using Xenopus egg extracts have suggested that potential origins are much more abundant than actual initiation events and that the time-dependent rate of initiation, I(t), markedly increases through S phase to ensure the rapid completion of unreplicated gaps and a narrow distribution of completion times. However, the molecular mechanism that underlies this increase has remained obscure. Using both previous and novel DNA combing data we have confirmed that I(t) increases through S phase but have also established that it progressively decreases before the end of S phase. To explore plausible biochemical scenarios that might explain these features, we have performed comparisons between numerical simulations and DNA combing data. Several simple models were tested: i) recycling of a limiting replication fork component from completed replicons; ii) time-dependent increase in origin efficiency; iii) time-dependent increase in availability of an initially limiting factor, e.g. by nuclear import. None of these potential mechanisms could on its own account for the data. We propose a model that combines time-dependent changes in availability of a replication factor and a fork-density dependent affinity of this factor for potential origins. This novel model quantitatively and robustly accounted for the observed changes in initiation rate and fork density. This work provides a refined temporal profile of replication initiation rates and a robust, dynamic model that quantitatively explains replication origin usage during early embryonic S phase. These results have significant implications for the organisation of replication origins in higher eukaryotes.


Prioritising access to pandemic influenza vaccine: a review of the ethics literature.
The world is threatened by future pandemics. Vaccines can play a key role in preventing harm, but there will inevitably be shortages because there is no possibility of advance stockpiling. We therefore need some method of prioritising access. This paper reports a critical interpretative review of the published literature that discusses ethical arguments used to justify how we could prioritise vaccine during an influenza pandemic. We found that the focus of the literature was often on proposing different groups as priorities (e.g. those with pre-existing health conditions, the young, the old, health care workers etc.). Different reasons were often suggested as a means of justifying such priority groupings (e.g. appeal to best overall outcomes, fairness, belonging to a vulnerable or 'at risk' group etc.). We suggest that much of the literature, wrongly, assumes that we are able to plan priority groups prior to the time of a particular pandemic and development of a particular vaccine. We also point out the surprising absence of various issues from the literature (e.g. how vaccines fit within overall pandemic planning, a lack of specificity about place, issues of global justice etc.). The literature proposes a wide range of ways to prioritise vaccines, focusing on different groups and 'principles'. Any plan to use pandemic vaccine must provide justifications for its prioritisation. The focus of this review was influenza pandemic vaccines, but lessons can be learnt for future allocations of coronavirus vaccine, if one becomes available.


Optimization of hydrophilic/hydrophobic phase separation in sPEEK membranes by hydrothermal treatments.
Via SAXS, herein, we studied how a sPEEK microstructure evolves when it is immersed in water at a wide range of temperatures (20-100 °C) and time scales (from a few hours to dozens of days). In particular, we scrutinized the behavior of sPEEK at the temperature and time associated with the appearance of a well-defined nanosegregated morphology. At 80 °C, we observed nanoscale swelling along with smoothing of the water/polymer interface over a long period of time (several days). Herein, two of the main membrane properties, i.e., water uptake and proton conductivity, were studied for different immersion times and temperatures. It was found that the abovementioned properties were remarkably correlated with the evolution of the membrane microstructure, which was partly conserved after drying. The present findings helped us to understand that the thermally activated evolutions observed at both the nanoscale and macroscale were associated with the sPEEK β-relaxation crossover. Therefore, the very different swelling behaviors of sPEEK and Nafion are correlated to the much higher β-relaxation of sPEEK vs. Nafion (75 °C vs. -20 °C - dry state). From a practical viewpoint, this study emphasizes, for membranes alternative to Nafion, the importance and impact of the membrane pretreatment on their functional properties.


MPIIGaze: Real-World Dataset and Deep Appearance-Based Gaze Estimation.
Learning-based methods are believed to work well for unconstrained gaze estimation, i.e. gaze estimation from a monocular RGB camera without assumptions regarding user, environment, or camera. However, current gaze datasets were collected under laboratory conditions and methods were not evaluated across multiple datasets. Our work makes three contributions towards addressing these limitations. First, we present the MPIIGaze dataset, which contains 213,659 full face images and corresponding ground-truth gaze positions collected from 15 users during everyday laptop use over several months. An experience sampling approach ensured continuous gaze and head poses and realistic variation in eye appearance and illumination. To facilitate cross-dataset evaluations, 37,667 images were manually annotated with eye corners, mouth corners, and pupil centres. Second, we present an extensive evaluation of state-of-the-art gaze estimation methods on three current datasets, including MPIIGaze. We study key challenges including target gaze range, illumination conditions, and facial appearance variation. We show that image resolution and the use of both eyes affect gaze estimation performance, while head pose and pupil centre information are less informative. Finally, we propose GazeNet, the first deep appearance-based gaze estimation method. GazeNet improves on the state of the art by 22 percent (from a mean error of 13.9 degrees to 10.8 degrees) for the most challenging cross-dataset evaluation.


Validation of the professional self-identity questionnaire for medical students during clinical practice in Japan.
To validate the Professional Self Identity Questionnaire (PSIQ) for medical students during clinical practice. We conducted a single-year longitudinal questionnaire study using the PSIQ. The PSIQ rates the nine items of "teamwork", "communication", "conducting assessment", "cultural awareness", "ethical awareness", "using records", "dealing with emergencies", "reflection", and "teaching" on a scale of 1-7 points. The study participants consisted of 118 fifth- and sixth-grade medical students who completed a mandatory 4-week clinical practice in a community-based medical education (CBME) curriculum. The data were collected before and after the CBME curriculum and after clinical practice at the time of graduation. To validate the internal structure of the PSIQ, we calculated Cronbach's alpha in the three phases. Additionally, to assess construct validity, we analyzed the trends and differences in each of the nine items of the PSIQ using repeated measures analysis of variance (ANOVA). We also showed the differences in effect size before and after the CBME curriculum. The data of 105 medical students were analyzed. Cronbach's alpha in the three phases was 0.932, 0.936, and 0.939, respectively. PSIQ scores increased progressively for all items, and the F-test for repeated measures ANOVA of nine items' average score across the three phases showed a significant difference F(2,208) = 63.59, p<0.001. The effect size for professional identity of cultural awareness before and after the CBME curriculum was 0.67, or medium. We validated the PSIQ for medical students during clinical practice. Reflecting on professional identity may provide an opportunity for meaningful feedback on readiness to become a doctor.


Characterization of DNA lesions induced by CaCrO4 in synchronous and asynchronous cultured mammalian cells.
Alkaline elution studies demonstrated CaCrO4-induced DNA single strand breaks and DNA-protein crosslinks. DNA single strand breaks increased following treatment with 10-400 microM CaCrO4 in Chinese hamster ovary cells maintained with a minimal salts/glucose medium. DNA single strand breaks were rapidly repaired when extracellular CaCrO4 was removed even following exposure levels of CaCrO4 (200 microM for 2 hr) which reduced survival to 0.6%. Under these exposure conditions the trypan blue exclusion was greater than 80%, whereas cell growth was inhibited by 46% within 24 hr. The DNA-protein crosslinks induced by 10 microM CaCrO4 were repaired in the absence of metal within 24 hr. In contrast, the amount of DNA-protein crosslinks measured 24 hr after a 2-hr treatment with 50, 100, and 200 microM CaCrO4 remained unchanged at the 50 microM level or increased at the two higher concentrations. Thus, at concentrations of 50 microM or greater there was no repair of the DNA protein crosslinks, and this may have been due to cytotoxicity of the metal. CaCrO4 at 10 or 25 microM exposure for 6 hr also induced DNA-protein crosslinking in Chinese hamster ovary cells maintained in normal tissue culture growth media. The lack of repair of DNA-protein crosslinks at the 25 microM level, which did not substantially reduce cell survival, indicated the persistence of these lesions in a noncytotoxic form. Uptake of CaCrO4 was linear with all of the concentrations tested. Analysis of the cell cycle sensitivity to CaCrO4 revealed that cells in early S phase were the most sensitive to the cytotoxic and strand breaking activity of CaCrO4. Compared with other phases of the cell cycle, there was also an elevated level of DNA-protein crosslinks when cells were treated in early S phase and incubated 24 hr without CaCrO4. These results implicate the DNA-protein crosslink as an important lesion that may be responsible for the cytotoxic and carcinogenic properties of chromate.


Citrus fruit extracts with carvacrol and thymol eliminated 7-log acid-adapted Escherichia coli O157:H7, Salmonella typhimurium, and Listeria monocytogenes: A potential of effective natural antibacterial agents.
Despite the widespread belief that citrus fruit extracts (CFEs) are microbiologically safe due to their acidity, limited bactericidal effect results in low applicability as antibacterial agent and outbreaks occurred by acid-adapted pathogens. Here, we examined the antibacterial effects of CFEs [lime (Citrus medica), lemon (Citrus limon), calamansi (Citrus microcarpa)] combined with essential oil components (EOCs; carvacrol and thymol) against non-acid-adapted/acid-adapted Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes under 22 °C for 5 min. CFEs (<20%) alone or small amounts of EOCs (2.0 mM; 0.032%) alone could not inactivate the target bacteria effectively. However, combined treatments exhibited marked synergy: CFE + EOCs eliminated all the bacteria (>6.9 log CFU/ml). Among the CFEs tested, the highest synergism was shown by calamansi, an exotic citrus fruit previously unrecognized as an antibacterial agent. Although acid-adaptation improved bacterial survival, calamansi (<20%) + EOCs (<0.032%) completely inactivated even the most resistant pathogen (E. coli O157:H7). Validation test also showed that all tested commercial juice products also eliminated acid-adapted pathogens when used with EOCs. Physicochemical analysis of tested CFEs (pH measurement and HPLC analysis of components) revealed that low pH and flavanone (hesperidin) did not contribute to the synergistic bactericidal effects. Rather, the high citric acid content is likely to contribute to the strong synergistic effect with EOCs by damaging susceptible bacterial membranes. Sensory scores for CFEs were not altered by addition of EOCs at concentrations up to 1.5 mM. This study provides new insight into the utility of CFEs with EOCs to improve not only the microbiological safety of food products containing CFEs but also their applicability as natural antibacterial complex.


Body size and incident colorectal cancer: a prospective study of older women.
Obesity is a controversial risk factor for colorectal cancer (CRC) in older women. We evaluated associations between multiple body size parameters and incident CRC in the prospective, population-based Iowa Women's Health Study (IWHS). IWHS participants, ages 55 to 69 years, provided data regarding height; weight; weight at ages 50, 40, 30, 18 years; hip circumference; and waist circumference at baseline (1986). Derived variables included body mass index (BMI), waist-to-hip ratio (WHR), and "overweight years" (OWY; conceptually similar to cigarette pack-years). Incident CRC cases (n = 1,464) were ascertained from the State Health Registry of Iowa, through 2005. Multivariable Cox regression models were fit to estimate body size-associated CRC risks. Among 36,941 women (619,961 person-years), baseline height, weight, BMI, hip circumference, waist circumference, and WHR were all positively associated with incident CRC (P(trend) ≤ 0.003 for each). Baseline BMI yielded the highest CRC risk estimates (obese III versus normal, RR = 1.56; 95% CI = 1.10-2.22; P(trend) < 0.001) and was more closely associated with distal than proximal tumors (P(trend) < 0.001 versus 0.06). Conversely, height was more closely associated with proximal than distal tumors (P(trend) < 0.001 versus 0.04). Other body size parameters were less predictive of incident CRC. These data strongly support a positive association between increased body size and CRC risk among older women. Further investigation of when increased body size has the greatest effect on CRC risk (i.e., early adulthood versus later adulthood) might also be informative, particularly with respect to defining subsite-specific pathways of colorectal carcinogenesis.


A simple, fast, and accurate method of phylogenomic inference.
The explosive growth of genomic data provides an opportunity to make increased use of protein markers for phylogenetic inference. We have developed an automated pipeline for phylogenomic analysis (AMPHORA) that overcomes the existing bottlenecks limiting large-scale protein phylogenetic inference. We demonstrated its high throughput capabilities and high quality results by constructing a genome tree of 578 bacterial species and by assigning phylotypes to 18,607 protein markers identified in metagenomic data collected from the Sargasso Sea.


Broadband light coupling to dielectric slot waveguides with tapered plasmonic nanoantennas.
We propose and theoretically verify an efficient mechanism of broadband coupling between incident light and on-chip dielectric slot waveguide by employing a tapered plasmonic nanoantenna. The nanoantenna receives free space radiation and couples it to a dielectric slot waveguide with the efficiency of up to 20% in a broad spectral range, having a small footprint as compared with the currently used narrowband dielectric grating couplers. We argue that the frequency selective properties of such nanoantennas also allow for using them as ultrasmall on-chip multiplexer/demultiplexer devices.


Prognosis in children with rhabdomyosarcoma: a report of the intergroup rhabdomyosarcoma studies I and II. Intergroup Rhabdomyosarcoma Committee.
Prestudy patient characteristics and specific therapy of all eligible patients with rhabdomyosarcoma entered into Intergroup Rhabdomyosarcoma (RMS) Studies I (IRS-I) (1972 to 1978, n = 686) or II (IRS-II) (1978 to 1984, n = 1,002) were examined for their relationship to survival within each of the four clinical groups using univariate and multivariate analyses. The estimated survival at 5 years from the start of treatment was 56% in IRS-I and 62% in IRS-II (P = .006). The largest survival difference between studies was in patients with group III tumors (52% v 65%). The clinical group was the most important patient characteristic related to survival in both studies. Survival progressively decreased for patients from clinical group I (localized disease, completely resected) to group IV (metastatic disease at the onset). In clinical group I, the only patient characteristic consistently related to survival was histology. Patients with alveolar tumors had the poorest survival, while those with botryoid/embryonal lesions had the best survival. In clinical group II, no characteristic was consistently related to survival. In clinical group III, an orbital primary site was associated with a favorable survival. In clinical group IV, patients with genitourinary tumors had a significant survival advantage. Use of disease-free survival as an end point gave very similar results. This information, from the largest available data base on prognostic indicators in childhood RMS in the context of aggressive multimodal therapies, is being used to plan therapy in the forthcoming study (IRS-IV).


[Impact of violence on the health of families at Fortaleza, Ceará State].
The study describes the impact of the violence on the quality of life of the families, which were attended at the Relatives and Friends Violence Victims Association (ARFVV) in Fortaleza, Ceará State. The case study was accomplished among five mothers that were involved in a NGO on the battle against the violence. The semi-structured interview, the participation at the institution's meetings and the documental research were the data collecting techniques, being these last ones, submitted to the thematic analysis and discussed according to the literature and Letters of Health Promotion. The impacts caused by the violence comprise the physical, emotional and social family's health, cause changes on behavior between the members, and lead to the increasing of smoking, drinking, social isolation and exacerbate revolt feelings, vengeance and pessimism. The NGO's work has been important to support the families on the conflicts overcoming, health familiar restoration, redeeming the self-expectation, the hope on the justice and social mobility. The health of families' victims from violence is affected on the biological, emotional and social aspects, favoring the process of sickness. These have appealed to the support from NGOs to transform the 'victim condition' - violence hostage to the 'responsible citizenship' - guardians of peace on the battle against the urban violence.


In search of causality: a systematic review of the relationship between the built environment and physical activity among adults.
Empirical evidence suggests that an association between the built environment and physical activity exists. This evidence is mostly derived from cross-sectional studies that do not account for other causal explanations such as neighborhood self-selection. Experimental and quasi-experimental designs can be used to isolate the effect of the built environment on physical activity, but in their absence, statistical techniques that adjust for neighborhood self-selection can be used with cross-sectional data. Previous reviews examining the built environment-physical activity relationship have not differentiated among findings based on study design. To deal with self-selection, we synthesized evidence regarding the relationship between objective measures of the built environment and physical activity by including in our review: 1) cross-sectional studies that adjust for neighborhood self-selection and 2) quasi-experiments. In September 2010, we searched for English-language studies on built environments and physical activity from all available years in health, leisure, transportation, social sciences, and geographical databases. Twenty cross-sectional and 13 quasi-experimental studies published between 1996 and 2010 were included in the review. Most associations between the built environment and physical activity were in the expected direction or null. Land use mix, connectivity and population density and overall neighborhood design were however, important determinants of physical activity. The built environment was more likely to be associated with transportation walking compared with other types of physical activity including recreational walking. Three studies found an attenuation in associations between built environment characteristics and physical activity after accounting for neighborhood self-selection. More quasi-experiments that examine a broader range of environmental attributes in relation to context-specific physical activity and that measure changes in the built environment, neighborhood preferences and their effect on physical activity are needed.


TEM ExosomeAnalyzer: a computer-assisted software tool for quantitative evaluation of extracellular vesicles in transmission electron microscopy images.
Extracellular vesicles (EVs) function as important conveyers of information between cells and thus can be exploited as drug delivery systems or disease biomarkers. Transmission electron microscopy (TEM) remains the gold standard method for visualisation of EVs, however the analysis of individual EVs in TEM images is time-consuming if performed manually. Therefore, we present here a software tool for computer-assisted evaluation of EVs in TEM images. TEM ExosomeAnalyzer detects EVs based on their shape and edge contrast criteria and subsequently analyses their size and roundness. The software tool is compatible with common negative staining protocols and isolation methods used in the field of EV research; even with challenging TEM images (EVs both lighter and darker than the background, images containing artefacts or precipitated stain, etc.). If the fully-automatic analysis fails to produce correct results, users can promptly adjust the detected seeds of EVs as well as their boundaries manually. The performance of our tool was evaluated for three different modes with variable levels of human interaction, using two datasets with various heterogeneity. The semi-automatic mode analyses EVs with high success rate in the homogenous dataset (F1 score 0.9094, Jaccard coefficient 0.8218) as well as in the highly heterogeneous dataset containing EVs isolated from cell culture medium and patient samples (F1 score 0.7619, Jaccard coefficient 0.7553). Moreover, the extracted size distribution profiles of EVs isolated from malignant ascites of ovarian cancer patients overlap with those derived by cryo-EM and are comparable to NTA- and TRPS-derived data. In summary, TEM ExosomeAnalyzer is an easy-to-use software tool for evaluation of many types of vesicular microparticles and is available at http://cbia.fi.muni.cz/exosome-analyzer free of charge for non-commercial and research purposes. The web page contains also detailed description how to use the software tool including a video tutorial.


Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer's disease.
Biomarkers of brain Aβ amyloid deposition can be measured either by cerebrospinal fluid Aβ42 or Pittsburgh compound B positron emission tomography imaging. Our objective was to evaluate the ability of Aβ load and neurodegenerative atrophy on magnetic resonance imaging to predict shorter time-to-progression from mild cognitive impairment to Alzheimer's dementia and to characterize the effect of these biomarkers on the risk of progression as they become increasingly abnormal. A total of 218 subjects with mild cognitive impairment were identified from the Alzheimer's Disease Neuroimaging Initiative. The primary outcome was time-to-progression to Alzheimer's dementia. Hippocampal volumes were measured and adjusted for intracranial volume. We used a new method of pooling cerebrospinal fluid Aβ42 and Pittsburgh compound B positron emission tomography measures to produce equivalent measures of brain Aβ load from either source and analysed the results using multiple imputation methods. We performed our analyses in two phases. First, we grouped our subjects into those who were 'amyloid positive' (n = 165, with the assumption that Alzheimer's pathology is dominant in this group) and those who were 'amyloid negative' (n = 53). In the second phase, we included all 218 subjects with mild cognitive impairment to evaluate the biomarkers in a sample that we assumed to contain a full spectrum of expected pathologies. In a Kaplan-Meier analysis, amyloid positive subjects with mild cognitive impairment were much more likely to progress to dementia within 2 years than amyloid negative subjects with mild cognitive impairment (50 versus 19%). Among amyloid positive subjects with mild cognitive impairment only, hippocampal atrophy predicted shorter time-to-progression (P < 0.001) while Aβ load did not (P = 0.44). In contrast, when all 218 subjects with mild cognitive impairment were combined (amyloid positive and negative), hippocampal atrophy and Aβ load predicted shorter time-to-progression with comparable power (hazard ratio for an inter-quartile difference of 2.6 for both); however, the risk profile was linear throughout the range of hippocampal atrophy values but reached a ceiling at higher values of brain Aβ load. Our results are consistent with a model of Alzheimer's disease in which Aβ deposition initiates the pathological cascade but is not the direct cause of cognitive impairment as evidenced by the fact that Aβ load severity is decoupled from risk of progression at high levels. In contrast, hippocampal atrophy indicates how far along the neurodegenerative path one is, and hence how close to progressing to dementia. Possible explanations for our finding that many subjects with mild cognitive impairment have intermediate levels of Aβ load include: (i) individual subjects may reach an Aβ load plateau at varying absolute levels; (ii) some subjects may be more biologically susceptible to Aβ than others; and (iii) subjects with mild cognitive impairment with intermediate levels of Aβ may represent individuals with Alzheimer's disease co-existent with other pathologies.


The importance of long-term follow-up in child and adolescent obesity prevention interventions.
Pediatric overweight and obesity continues to be a major public health concern. Once established it is difficult to treat; therefore well-designed and evaluated prevention interventions are vitally important. There is considerable evidence to suggest that obesity prevention initiatives can change children's behaviours and weight status over the short- or medium-term; however, there is far less evidence on which to judge the impact over the longer term. In response to the rise in short- and medium-term obesity prevention studies for children and adolescents over recent years, the Prevention Stream of the Australasian Child and Adolescent Obesity Research Network highlight five points as to why the dearth of obesity prevention studies with long-term follow-up should be urgently addressed. Furthermore, recommendations to strengthen the evidence base and outline key implications for research design in this area and the support required for long-term follow-up studies are detailed.


An oral developmental neurotoxicity study of decabromodiphenyl ether (DecaBDE) in rats.
Decabromodiphenyl ether (DecaBDE; CASRN 1163-19-5) is a flame retardant used in a variety of manufactured products. A single oral dose of 20.1 mg/kg administered to mice on postnatal day 3 has been reported to alter motor activity at 2, 4, and 6 months of age. To further evaluate these results, a developmental neurotoxicity study was conducted in the most commonly used species for studies of this type, the rat, according to international validated testing guidelines and Good Laboratory Practice Standards. DecaBDE was administered orally via gavage in corn oil to dams from gestation day 6 to weaning at doses of 0, 1, 10, 100, or 1,000 mg/kg/day. Standard measures of growth, development, and neurological endpoints were evaluated in the offspring. Motor activity was assessed at 2 months of age. Additional motor activity assessments were conducted at 4 and 6 months of age. Neuropathology and morphometry evaluations of the offspring were performed at weaning and adulthood. No treatment-related neurobehavioral changes were observed in detailed clinical observations, startle response, or learning and memory tests. No test substance-related changes were noted in motor activity assessments performed at 2, 4, or 6 months of age. Finally, no treatment-related neuropathological or morphometric alterations were found. Under the conditions of this study, the no-observed-adverse-effect level for developmental neurotoxicity of DecaBDE was 1,000 mg/kg/day, the highest dose tested.


A pilot study of activity engagement in the first six months after stem cell transplantation.
PRPOSE/OBJECTIVES: to describe the natural pace and pattern of activity resumption in the first six months after stem cell transplantation (SCT). longitudinal, descriptive survey. bone marrow transplantation program of a National Cancer Institute-designated comprehensive cancer center in the northeastern United States. 18 men and 18 women who underwent either autologous (83%) or allogeneic (17%) transplantation. participants were surveyed 30 days, 100 days, and six months after SCT. Descriptive statistics were followed by exploratory linear mixed modeling with factors of time, gender, and the interaction between time and gender. a modified checklist version of the Activity Card Sort was used to measure activity retention. participants generally were performing 49% of their usual activities 30 days after transplantation, 70% of their premorbid activities 100 days after transplantation, and 77% of their premorbid activities six months after transplantation. Level of activity engagement increased over time, with the greatest changes observed from 30-100 days after SCT. Men retained more of their activities than women in the domains of low physical-demand leisure and social activities. rehabilitation screening may be most helpful in the period from 100 days to six months, when activity levels begin to plateau. Activity recovery may differ for men and women; future research should explore how this could affect rehabilitation needs. nurses can use structured surveys to explore and promote patients' satisfaction with and ability to engage in daily activities and ensure appropriate referrals to rehabilitation during recovery from SCT.


Distinct functional and macrostructural brain changes in Parkinson's disease and multiple system atrophy.
Parkinson's disease (PD) and the parkinsonian variant of multiple system atrophy (MSAp) are neurodegenerative disorders that can be difficult to differentiate clinically. This study provides the first characterization of the patterns of task-related functional magnetic resonance imaging (fMRI) changes across the whole brain in MSAp. We used fMRI during a precision grip force task and also performed voxel-based morphometry (VBM) on T1 -weighted images in MSAp patients, PD patients, and healthy controls. All groups were matched on age, and the patient groups had comparable motor symptom durations and severities. There were three main findings. First, MSAp and PD had reduced fMRI activation in motor control areas, including the basal ganglia, thalamus, insula, primary sensorimotor and prefrontal cortices, and cerebellum compared with controls. Second, there were no activation differences among the disease groups in the basal ganglia, thalamus, insula, or primary sensorimotor cortices, but PD had more extensive activation deficits throughout the cerebrum compared with MSAp and controls. Third, VBM revealed reduced volume in the basal ganglia, middle and inferior cerebellar peduncles, pons, and throughout the cerebrum in MSAp compared with controls and PD, and additionally throughout the cerebellar cortex and vermis in MSAp compared with controls. Collectively, these results provide the first evidence that fMRI activation is abnormal in the basal ganglia, cerebellum, and cerebrum in MSAp, and that a key distinguishing feature between MSAp and PD is the extensive and widespread volume loss throughout the brain in MSAp.


Stem Cell Markers in Neuroblastoma-An Emerging Role for LGR5.
The prognostic value of cancer stem cell markers in various cancer subtypes is a well documented research area. Our findings show that the stem cell marker Lgr5 is associated with an aggressive phenotype in neuroblastoma. Here, we discuss these findings within the context of recent studies in several cancers such as lung, colorectal and intestinal cancer, glioblastoma and ewing's sarcoma. Neuroblastoma continues to be an elusive disease, due to its heterogeneous presentation ranging from spontaneous regression to aggressive metastatic disease and intertwined genetic variability. Currently, the most significant prognostic marker of high risk disease and poor prognosis is amplification of the MYCN oncogene, which is found in approximately 25% of cases (Huang and Weiss, 2013). With this in mind, there is still much to learn about the driving mechanisms of this aggressive pediatric tumor. Neuroblastoma development is thought to be the result of aberrant differentiation of the cell of origin, embryonic neural crest cells which then migrate and invade during the developmental stage (Joshi et al., 2007). Aberrant cells are those which would, under normal conditions form the mature tissues of the sympathetic ganglia and adrenal medulla. Tumors are known to develop indiscriminately along the radius of the sympathetic ganglia, although it is well established that the adrenal glands are fundamentally the most common primary site (Jessen and Mirsky, 2005).


Destructive Photon Echo Formation in Six-Wave Mixing Signals of a MoSe2 Monolayer.
Monolayers of transition metal dichalcogenides display a strong excitonic optical response. Additionally encapsulating the monolayer with hexagonal boron nitride allows to reach the limit of a purely homogeneously broadened exciton system. On such a MoSe2 -based system, ultrafast six-wave mixing spectroscopy is performed and a novel destructive photon echo effect is found. This process manifests as a characteristic depression of the nonlinear signal dynamics when scanning the delay between the applied laser pulses. By theoretically describing the process within a local field model, an excellent agreement with the experiment is reached. An effective Bloch vector representation is developed and thereby it is demonstrated that the destructive photon echo stems from a destructive interference of successive repetitions of the heterodyning experiment.


Unmyelinated axon loss with postnatal hypertonia after fetal hypoxia.
White matter (WM) injury due to myelination defects is believed to be responsible for the motor deficits seen in cerebral palsy. We tested the hypothesis that the predominant injury is to functional electrical connectivity in unmyelinated WM fibers by conducting a longitudinal study of central WM tracts in newborn rabbit kits with hypertonia in our model of cerebral palsy. Pregnant rabbits at 70% gestation underwent 40-minute uterine ischemia. Motor deficits in newborn kits, including muscle hypertonia, were assessed by neurobehavioral testing. Major central WM tracts, including internal capsule, corpus callosum, anterior commissure, and fimbria hippocampi, were investigated for structural and functional injury using diffusion tensor magnetic resonance imaging (MRI), electrophysiological recordings of fiber conductivity in perfused brain slices, electron microscopy, and immunohistochemistry of oligodendrocyte lineage. Motor deficits were observed on postnatal day 1 (P1) when WM tracts were unmyelinated. Myelination occurred later and was obvious by P18. Hypertonia was associated with microstructural WM injury and unmyelinated axon loss at P1, diagnosed by diffusion tensor MRI and electron microscopy. Axonal conductivity from electrophysiological recordings in hypertonic P18 kits decreased only in unmyelinated fibers, despite a loss in both myelinated and unmyelinated axons. Motor deficits in cerebral palsy were associated with loss of unmyelinated WM tracts. The contribution of injury to myelinated fibers that was observed at P18 is probably a secondary etiological factor in the motor and sensory deficits in the rabbit model of cerebral palsy.