A conserved repetitive DNA element located in the centromeres of cereal chromosomes.
Repetitive DNA sequences have been demonstrated to play an important role for centromere function of eukaryotic chromosomes, including those from fission yeast, Drosophila melanogaster, and humans. Here we report on the isolation of a repetitive DNA element located in the centromeric regions of cereal chromosomes. A 745-bp repetitive DNA clone pSau3A9, was isolated from sorghum (Sorghum bicolor). This DNA element is located in the centromeric regions of all sorghum chromosomes, as demonstrated by fluorescence in situ hybridization. Repetitive DNA sequences homologous to pSau3A9 also are present in the centromeric regions of chromosomes from other cereal species, including rice, maize, wheat, barley, rye, and oats. Probe pSau3A9 also hybridized to the centromeric region of B chromosomes from rye and maize. The repetitive nature and its conservation in distantly related plant species indicate that the pSau3A9 family may be associated with centromere function of cereal chromosomes. The absence of DNA sequences homologous to pSau3A9 in dicot species suggests a faster divergence of centromererelated sequences compared with the telomere-related sequences in plants.


Differential expression of calcineurin A subunit mRNA isoforms during rat hippocampal and cerebellar development.
Calcineurin (protein phosphatase 2B) is a calcium-dependent serine-threonine phosphatase. It has diverse roles and is centrally involved in synaptic plasticity. The catalytic A subunit of calcineurin has three isoforms, alpha, beta and gamma. Their expression and ontogeny in the brain has not been systematically investigated; such data become important with a report that PPP3CC, the gene encoding calcineurin Agamma, is a susceptibility gene for schizophrenia, and the finding that its expression is decreased in the disorder. We used in situ hybridization histochemistry to measure the relative transcript abundance of calcineurin Agamma and the other catalytic isoforms, Aalpha and Abeta, during development of the Sprague-Dawley rat hippocampus and cerebellum. All three isoforms are present in both regions at all time points [embryonic day 19 (E19) to postnatal day 42 (P42)] and undergo developmental regulation, but differ in their ontogenic profile. Calcineurin Aalpha and Abeta mRNAs increased from E19 through to adulthood, whereas Agamma mRNA was most highly expressed during early developmental stages. Calcineurin Aalpha and Abeta mRNAs positively correlated with synaptophysin mRNA (a synaptic marker), whilst Agamma mRNA was either unrelated to, or negatively correlated, with this transcript. These data confirm that all three calcineurin A subunits are expressed in the rodent brain, and indicate that calcineurin Agamma may have different roles than Aalpha and Abeta. The data also suggest a potential importance of calcineurin Agamma in neurodevelopment, and in the genetically influenced neurodevelopmental disturbance that is thought to underlie schizophrenia.


Divergent pathways? Racial/ethnic differences in older women's labor force withdrawal.
The purpose of this study was to investigate how women's labor force withdrawal behavior varies across race/ethnicity and to identify life course factors that generate these differences. Using a sample of 7,235 women from the 1992-2004 Health and Retirement Study, we estimated cross-sectional multinomial logit models to explore racial/ethnic differences in labor force status at first interview. We then examined the prospective risk of exiting the labor force via retirement, work disability, or death using discrete-time hazard models. Black and Hispanic women had twice the odds of Whites of being work-disabled at first interview. Whereas younger minorities had lower odds of being retired at first interview, older minorities had higher odds. The prospective results showed that both Blacks and Hispanics had higher risks of work disability but not of retirement or of dying in the labor force. Overall, racial/ethnic differences in mid- and later life work behavior stemmed primarily from disparities in life course capital. This study shows that substantial racial/ethnic disparities in labor force exit behavior have already emerged by midlife. It is important to note that distinguishing between alternative pathways out of the labor force demonstrates that work disability is a more common experience for Black and Hispanic women than for Whites.


Long-term Surgical Outcomes of 180-Degree Suture Trabeculotomy in Korean Patients With Primary Congenital Glaucoma.
To investigate the surgical outcomes of 180-degree suture trabeculotomy in Korean patients with primary congenital glaucoma (PCG). This retrospective study included 21 eyes of 17 children with PCG who underwent 180-degree suture trabeculotomy as a first surgical procedure. Surgical success was defined as (1) an intraocular pressure (IOP)<22 mm Hg with or without medication; (2) no additional intraocular surgery; and (3) no evidence of progressive optic disc cupping. The main outcome measure was the success rate of 180-degree suture trabeculotomy. Secondary outcome measures were IOP, number of glaucoma medications, and occurrence of complications. Of the 21 eyes included, 18 (85.7%) were classified as having achieved success at the final visit (mean last follow-up or failure time, 54.91±45.68 mo). Median age at surgery was 11.97 months with mean IOP 29.8±9.6 mm Hg, on average of 1.52 medications. The mean IOP at the final visit was 16.9±5.6 mm Hg on an average of 0.38 medications. The surgical success rate of 180-degree suture trabeculotomy at 1, 3, and 5 years was 95.0%, 87.7%, and 78.9%, respectively (Kaplan-Meier analysis). Three eyes underwent second operations and the mean time to failure was 29.39±19.75 months. Hyphema was observed in 10 eyes, but it cleared up within 7.6 days. The 180-degree suture trabeculotomy performed for PCG had a significant IOP-lowering effect and caused no remarkable complications.


Risk factors that may be driving the emergence of drug resistance in tuberculosis patients treated in Yangon, Myanmar.
The majority of new tuberculosis cases emerging every year occur in low and middle-income countries where public health systems are often characterised by weak infrastructure and inadequate resources. This study investigates healthcare seeking behaviour, knowledge and treatment of tuberculosis patients in Myanmar-which is facing an acute drug-resistant tuberculosis epidemic-and identifies factors that may increase the risk of emergence of drug-resistant tuberculosis. We randomly selected adult smear-positive pulmonary tuberculosis patients diagnosed between September 2014 and March 2015 at ten public township health centres in Yangon, the largest city in Myanmar. Data on patients' healthcare seeking behaviour, treatment at the township health centres, co-morbidities and knowledge was collected through patient interviews and extraction from hospital records. A retrospective descriptive cross-sectional analysis was conducted. Of 404 TB patients selected to participate in the study, 11 had died since diagnosis, resulting in 393 patients being included in the final analysis. Results indicate that a high proportion of patients (16%; 95% CI = 13-20) did not have a treatment supporter assigned to improve adherence to medication, with men being more likely to have no treatment supporter assigned. Use of private healthcare providers was very common; 59% (54-64) and 30.3% (25.9-35.0) of patients reported first seeking care at private clinics and pharmacies respectively. We found that 8% (6-11) of tuberculosis patients had confirmed diabetes. Most patients had some knowledge about tuberculosis transmission and the consequences of missing treatment. However, 5% (3-8) stated that they miss taking tuberculosis medicines at least weekly, and patients with no knowledge of consequences of missing treatment were more likely to miss doses. This study analysed healthcare seeking behaviour and treatment related practices of tuberculosis patients being managed under operational conditions in a fragile health system. Findings indicate that ensuring that treatment adherence support is arranged for all patients, monitoring of response to treatment among the high proportion of tuberculosis patients with diabetes and engagement with private healthcare providers could be strategies addressed to reduce the risk of emergence of drug-resistant tuberculosis.


Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the West Bengal cohort of the A1chieve study.
The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. Data was collected at baseline, 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from West Bengal, India. A total of 1133 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 897), insulin detemir (n = 94), insulin aspart (n = 90), basal insulin plus insulin aspart (n = 28) and other insulin combinations (n = 19). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 8.5%) and insulin user (mean HbA1c: 8.9%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naïve: -1.3%, insulin users: -1.6%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.


Echo frequency selectivity of duration-tuned inferior collicular neurons of the big brown bat, Eptesicus fuscus, determined with pulse-echo pairs.
During hunting, insectivorous bats such as Eptesicus fuscus progressively vary the repetition rate, duration, frequency and amplitude of emitted pulses such that analysis of an echo parameter by bats would be inevitably affected by other co-varying echo parameters. The present study is to determine the variation of echo frequency selectivity of duration-tuned inferior collicular neurons during different phases of hunting using pulse-echo (P-E) pairs as stimuli. All collicular neurons discharge maximally to a tone at a particular frequency which is defined as the best frequency (BF). Most collicular neurons also discharge maximally to a BF pulse at a particular duration which is defined as the best duration (BD). A family of echo iso-level frequency tuning curves (iso-level FTC) of these duration-tuned collicular neurons is measured with the number of impulses in response to the echo pulse at selected frequencies when the P-E pairs are presented at varied P-E duration and gap. Our data show that these duration-tuned collicular neurons have narrower echo iso-level FTC when measured with BD than with non-BD echo pulses. Also, IC neurons with low BF and short BD have narrower echo iso-level FTC than IC neurons with high BF and long BD have. The bandwidth of echo iso-level FTC significantly decreases with shortening of P-E duration and P-E gap. These data suggest that duration-tuned collicular neurons not only can facilitate bat's echo recognition but also can enhance echo frequency selectivity for prey feature analysis throughout a target approaching sequence during hunting. These data also support previous behavior studies showing that bats prepare their auditory system to analyze expected returning echoes within a time window to extract target features after pulse emission.


Polymyalgia rheumatica.
Polymyalgia rheumatica is a chronic, inflammatory disorder of unknown cause that affects people over age 50 years. Classic symptoms include pain and long-term morning stiffness of the neck, shoulders, hips, upper arms, and thighs. Although markers of inflammation are often raised, no specific laboratory test exists for the disorder and the diagnosis is based on clinical assessment. Provisional classification criteria were published in April, 2012, by a collaborative initiative of the European League Against Rheumatism and the American College of Rheumatology. Several other disorders can mimic polymyalgia rheumatica. In particular, clinical manifestations can be difficult to differentiate from other forms of inflammatory arthritis such as spondyloarthritis and rheumatoid arthritis. Imaging studies such as ultrasonography and MRI typically show a predominantly periarticular inflammatory process. A subset of patients has an associated inflammatory vasculopathy affecting large arteries (giant cell arteritis). The standard treatment is low-dose glucocorticoids, which provide symptomatic relief for most patients. However, disease relapses are common, and treatment with glucocorticoids is associated with substantial morbidity. Improved understanding of disease pathogenesis might allow for more targeted immunotherapy.


Resveratrol protects against Cisplatin-induced cardiotoxicity by alleviating oxidative damage.
The clinical use of cisplatin, a potent antineoplastic agent, is limited by its severe adverse effects. The present study was designed to evaluate the effects of resveratrol on cisplatin-induced cardiac injury. Resveratrol is a potent free radical scavenger. In the present study, we tested whether resveratrol would prevent cisplatin-induced cardiotoxicity in rats. Plasma-enzyme activities and histologic myocardial changes were examined. The anticancer role of resveratrol and/or cisplatin were measured by MTT. Our data showed that cisplatin led to cardiac-function deterioration, myocardial injury, increased lactate dehydrogenase, creatine kinase, malondialdehyde activities, and decreased activities of superoxide dismutase, glutathione, glutathione peroxidase, and catalase. Treatment with resveratrol effectively hindered the adverse effects of cisplatin in a dose-dependent manner, such as myocardial injury and impaired heart function. An in vitro cytotoxic study showed that resveratrol could increase the antineoplastic activity of cisplatin to A549 adenocarcinoma cells. All the above lines of evidence suggest that resveratrol protects cardiomyocytes from cisplatin-induced cardiotoxicity via the suppression of oxidative stress.


Accuracy of an automated method of 3D soft tissue landmark detection.
Due to technological advances, the quantification of facial form can now be done via three-dimensional (3D) photographic systems such as stereophotogrammetry. To enable comparison with traditional cephalometry, soft-tissue anatomical landmark definitions have been modified to incorporate the third dimension. Annotating these landmarks manually, however, is still a time-consuming and arduous process. To develop an automated algorithm to accurately identify anatomical landmarks on three-dimensional soft tissue images. Thirty 3dMD images were selected from a private orthodontic practice consisting of 15 males and 15 females between 9 and 17 years of age. The soft-tissue 3D images were aligned along a reference plane to setup a Cartesian coordinate system. Screened by 2 observers, 21 landmarks were manually annotated and their coordinates defined. An automated landmark identification algorithm, based on their anatomical definitions, was developed to compare the landmark validity against the manually identified counterpart. Twenty-one landmarks were analysed in detail. Inter-observer and intra-observer reliability using ICC was >0.9. The average difference and standard deviation between manual and automated methods for all landmarks was 3.2 and 1.64 mm, respectively. Sixteen out of twenty-one landmarks had a mean difference less than 4 mm. The landmarks of greatest agreement (≤2 mm) were mainly in the midline: pronasale, subnasale, subspinale, labiale superius, stomion, with the exception of chelion right. Five linear facial measurements were found to have moderate to good agreement between the manual and automated identification methods. The developed algorithm was determined to be clinically relevant in the detection of midsagittal landmarks and associated measurements within the studied sample of adolescent Caucasian subjects.


Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma.
Targeting tumor angiogenesis is a potential therapeutic strategy for glioblastoma because of its high vascularization. Tivozanib is an oral pan-VEGF receptor tyrosine kinase inhibitor that hits a central pathway in glioblastoma angiogenesis. We conducted a phase II study to test the effectiveness of tivozanib in patients with recurrent glioblastoma. Ten adult patients were enrolled and treated with tivozanib 1.5 mg daily, 3 weeks on/1 week off in 28-day cycles. Brain MRI and blood biomarkers of angiogenesis were performed at baseline, within 24-72 h of treatment initiation, and monthly thereafter. Dynamic contrast enhanced MRI, dynamic susceptibility contrast MRI, and vessel architecture imaging were used to assess vascular effects. Resting state MRI was used to assess brain connectivity. Best RANO criteria responses were: 1 complete response, 1 partial response, 4 stable diseases, and 4 progressive disease (PD). Two patients were taken off study for toxicity and 8 patients were taken off study for PD. Median progression-free survival was 2.3 months and median overall survival was 8.1 months. Baseline abnormal tumor vascular permeability, blood flow, tissue oxygenation and plasma sVEGFR2 significantly decreased and plasma PlGF and VEGF increased after treatment, suggesting an anti-angiogenic effect of tivozanib. However, there were no clear structural changes in vasculature as vessel caliber and enhancing tumor volume did not significantly change. Despite functional changes in tumor vasculature, tivozanib had limited anti-tumor activity, highlighting the limitations of anti-VEGF monotherapy. Future studies in glioblastoma should leverage the anti-vascular activity of agents targeting VEGF to enhance the activity of other therapies.


Gene activity in primary T cells infected with HIV89.6: intron retention and induction of genomic repeats.
HIV infection has been reported to alter cellular gene activity, but published studies have commonly assayed transformed cell lines and lab-adapted HIV strains, yielding inconsistent results. Here we carried out a deep RNA-Seq analysis of primary human T cells infected with the low passage HIV isolate HIV89.6. Seventeen percent of cellular genes showed altered activity 48 h after infection. In a meta-analysis including four other studies, our data differed from studies of HIV infection in cell lines but showed more parallels with infections of primary cells. We found a global trend toward retention of introns after infection, suggestive of a novel cellular response to infection. HIV89.6 infection was also associated with activation of several human endogenous retroviruses (HERVs) and retrotransposons, of interest as possible novel antigens that could serve as vaccine targets. The most highly activated group of HERVs was a subset of the ERV-9. Analysis showed that activation was associated with a particular variant of ERV-9 long terminal repeats that contains an indel near the U3-R border. These data also allowed quantification of >70 splice forms of the HIV89.6 RNA and specified the main types of chimeric HIV89.6-host RNAs. Comparison to over 100,000 integration site sequences from the same infected cell populations allowed quantification of authentic versus artifactual chimeric reads, showing that 5' read-in, splicing out of HIV89.6 from the D4 donor and 3' read-through were the most common HIV89.6-host cell chimeric RNA forms. Analysis of RNA abundance after infection of primary T cells with the low passage HIV89.6 isolate disclosed multiple novel features of HIV-host interactions, notably intron retention and induction of transcription of retrotransposons and endogenous retroviruses.


Vaccination with a modified vaccinia virus Ankara (MVA)-vectored HIV-1 immunogen induces modest vector-specific T cell responses in human subjects.
We investigated whether vaccination of healthy HIV-seronegative and HIV-1-seropositive antiretroviral therapy-treated subjects with recombinant modified vaccinia virus Ankara expressing an HIV-1 immunogen (MVA.HIVA) induced MVA-specific T cell responses. Using IFN-γ Elispot assays, we observed new or increased responses to MVA virus in 52% of HIV-seronegative subjects and 93% HIV-1 seropositive subjects; MVA-specific T cell frequencies were generally low and correlated poorly with T cell responses to the HIV-1 immunogen. In two vaccinees, responses were mapped to CD8+ T cell epitopes present in replication-competent vaccinia virus. These data support further evaluation of MVA as a viral vector for HIV-1 immunogens.


Debranching aortic surgery.
Conventional open surgery still remains as the gold standard of care for aortic arch and thoracoabdominal pathology. In centers of excellence, open repair of the arch has been performed with 5% immediate mortality and a low rate of complications; however overall mortality rates are around 15%, being up to 40% of all patients rejected for treatment due to their age or comorbidities. For thoracoabdominal aortic pathology, data reported from centers of excellence show immediate mortality rates from 5% to 19%, spinal cord ischemia from 2.7% to 13.2%, and renal failure needing dialysis from 4.6% to 5.6%. For these reasons, different alternatives that use endovascular techniques, including debranching procedures, have been developed. The reported results for hybrid debranching procedures are controversial and difficult to interpret because series are retrospective, heterogenic and including a small number of patients. Clearly, an important selection bias exists: debranching procedures are performed in elderly patients with more comorbidities and with thoracoabdominal aortic aneurysms that have more complex and extensive disease. Considering this fact, debranching procedures still remain a useful alternative: for aortic arch pathology debranching techniques can avoid or reduce the time of extracorporeal circulation (ECC) or cardiac arrest which may be beneficial in high-risk patients that otherwise would be rejected for treatment. And compared to pure endovascular techniques, they can be used in emergency cases with applicability in a wide range of anatomies. For thoracoabdominal aortic aneurysms, they are mainly useful when other lesser invasive endovascular options are not feasible due to anatomical limitations or when they are not available in cases where delaying the intervention is not an option.


Phase angle description of perturbation correlation analysis and its application to time-resolved infrared spectra.
A method of spectral analysis, phase angle description of perturbation correlation analysis, is proposed. This method is based on global phase angle description of generalized two-dimensional (2D) correlation spectroscopy, proposed by Shin-ichi Morita et al., and perturbation-correlation moving-window 2D (PCMW2D) correlation spectroscopy, proposed by Shigeaki Morita et al. For a spectral data set collected under an external perturbation, such as time-resolved infrared spectra, this method provides only one phase angle spectrum. A phase angle of the Fourier frequency domain correlation between a spectral intensity (e.g., absorbance) variation and a perturbation variation (e.g., scores of the first principle component) as a function of spectral variable (e.g., wavenumber) is plotted. Therefore, a degree of time lag of each band variation with respect to the perturbation variation is directly visualized in the phase angle spectrum. This method is applied to time-resolved infrared spectra in the O-H stretching region of the water sorption process into a poly(2-methoxyethyl acrylate) (PMEA) film. The time-resolved infrared (IR) spectra show three broad and overlapping bands in the region. Each band increases toward saturated water sorption with different relaxation times. In comparison to conventional methods of generalized 2D correlation spectroscopy and global phase angle mapping, the method proposed in the present study enables the easier visualization of the sequence as a degree of phase angle in the spectrum.


Hepatic steatosis in HCV-infected persons in the direct-acting antiviral era.
Hepatitis C virus (HCV) infects 130-170 million people worldwide. Recently, direct-acting antivirals have been shown to eradicate HCV infection in 90-95 % of non-cirrhotic patients depending on genotype, treatment experience, and regimen used. Similar rates are achieved among compensated cirrhotics, although longer treatment duration and/or ribavirin may be required. HCV uses host lipid metabolism for its lifecycle and can cause hepatic steatosis and insulin resistance. Hepatic steatosis, defined as excessive triglyceride deposition in hepatocytes, affects approximately half of HCV-infected individuals. Genetic factors and co-morbidities can drive further steatosis, which in turn can instigate fibrosis and progression to cirrhosis and hepatocellular carcinoma. Polymorphisms in genes that modulate lipid deposition in hepatocytes such as patatin-like phospholipase domain-containing protein 3 (PNPLA3) and transmembrane six superfamily member 2 (TM6SF2) predispose people to steatosis. Metabolic syndrome, obesity, and insulin resistance are increasing worldwide and further contribute to hepatic steatosis, and alcohol has long been recognized as a cause of lipid deposition in the liver. HIV and antiretroviral drugs, but not HBV, may further drive hepatic steatosis. While many of these factors limit response to interferon-based regimens for treating HCV, responses to direct-acting antivirals appear not to be impaired. The effect of HCV eradication on hepatic steatosis and progression to fibrosis, cirrhosis, and hepatocellular carcinoma warrants further study in the era of direct-acting antivirals.


Phase I dose escalation study of gemcitabine plus irinotecan in advanced solid tumors.
To determine the maximally tolerated dose (MTD), recommended phase II dose (RPTD) and toxicity profile of gemcitabine plus irinotecan combination. Thirty-nine evaluable patients with advanced solid tumors were treated with gemcitabine (Gem) and irinotecan (Iri) on days 1, 8 and 15 of a 28-day cycle. Dose levels included Gem/Iri 700/50, 900/50, 900/75, 500/50 mg/m(2) respectively. Dose-limiting toxicity (DLT) was assessed during cycle one; toxicity evaluation was closely monitored throughout the course of treatment. Treatment continued until disease progression or unacceptable toxicity. DLTs primarily consisted of grade > or = 3 thrombocytopenia lasting > or = 4 days often accompanied by grade > or = 3 neutropenia. Other grade > or = 3 toxicities included vomiting, diarrhea, fatigue and elevated alkaline phosphatase. Three patients had a partial response. Stable disease as best response was seen in 16 patients, ranging from 2-18 months. The MTD/RPTD is gemcitabine 500 mg/m(2) plus irinotecan 50 mg/m(2) on days 1, 8 and 15 of a 28-day cycle. Given the toxicity profile and negative results of phase III studies, no further testing of this treatment combination is recommended.


The prevalence of loot boxes in mobile and desktop games.
Loot boxes are items in video games that may be bought for real-world money but provide randomized rewards. Formal similarities between loot boxes and gambling have led to concerns that they may provide a 'gateway' to gambling amongst children. However, the availability of loot boxes is unclear. This study aimed to determine what proportion of top-grossing video games contained loot boxes, and how many of those games were available to children. Survey of the 100 top-grossing games on both the Google Play store and the Apple App store, and the top 50 most-played games on Steam according to the data aggregator SteamSpy. The prevalence of loot boxes was measured for each platform outlined above, split by age rating. A total of 58.0% of the top games on the Google Play store contained loot boxes, 59.0% of the top iPhone games contained loot boxes and 36.0% of the top games on the Steam store contained loot boxes; 93.1% of the Android games that featured loot boxes and 94.9% of the iPhone games that featured loot boxes were deemed suitable for children aged 12+. Age ratings were more conservative for desktop games. Only 38.8% of desktop games that featured loot boxes were available to children aged 12+. Loot boxes appear to be prevalent in video games that are deemed suitable for children, especially on mobile platforms.


Health systems research in the time of health system reform in India: a review.
Research on health systems is an important contributor to improving health system performance. Importantly, research on program and policy implementation can also create a culture of public accountability. In the last decade, significant health system reforms have been implemented in India. These include strengthening the public sector health system through the National Rural Health Mission (NRHM), and expansion of government-sponsored insurance schemes for the poor. This paper provides a situation analysis of health systems research during the reform period. We reviewed 9,477 publications between 2005 and 2013 in two online databases, PubMed and IndMED. Articles were classified according to the WHO classification of health systems building blocks. Our findings indicate the number of publications on health systems progressively increased every year from 92 in 2006 to 314 in 2012. The majority of papers were on service delivery (40%), with fewer on information (16%), medical technology and vaccines (15%), human resources (11%), governance (5%), and financing (8%). Around 70% of articles were lead by an author based in India, the majority by authors located in only four states. Several states, particularly in eastern and northeastern India, did not have a single paper published by a lead author located in a local institution. Moreover, many of these states were not the subject of a single published paper. Further, a few select institutions produced the bulk of research. Of the foreign author lead papers, 77% came from five countries (USA, UK, Canada, Australia, and Switzerland). The growth of published research during the reform period in India is a positive development. However, bulk of this research is produced in a few states and by a few select institutions Further strengthening health systems research requires attention to neglected health systems domains like human resources, financing, and governance. Importantly, research capacity needs to be strengthened in states and institutions that have a scarcity of researchers, as well as states that have been the focus of little research. While more funding for health systems research is required, this funding needs to be targeted at deficient health systems domains, geographical areas, and institutions.


Hyper-heuristic Evolution of Dispatching Rules: A Comparison of Rule Representations.
Dispatching rules are frequently used for real-time, online scheduling in complex manufacturing systems. Design of such rules is usually done by experts in a time consuming trial-and-error process. Recently, evolutionary algorithms have been proposed to automate the design process. There are several possibilities to represent rules for this hyper-heuristic search. Because the representation determines the search neighborhood and the complexity of the rules that can be evolved, a suitable choice of representation is key for a successful evolutionary algorithm. In this paper we empirically compare three different representations, both numeric and symbolic, for automated rule design: A linear combination of attributes, a representation based on artificial neural networks, and a tree representation. Using appropriate evolutionary algorithms (CMA-ES for the neural network and linear representations, genetic programming for the tree representation), we empirically investigate the suitability of each representation in a dynamic stochastic job shop scenario. We also examine the robustness of the evolved dispatching rules against variations in the underlying job shop scenario, and visualize what the rules do, in order to get an intuitive understanding of their inner workings. Results indicate that the tree representation using an improved version of genetic programming gives the best results if many candidate rules can be evaluated, closely followed by the neural network representation that already leads to good results for small to moderate computational budgets. The linear representation is found to be competitive only for extremely small computational budgets.


Benzylsulfanyl benzo-heterocycle amides and hydrazones as new agents against drug-susceptible and resistant Mycobacterium tuberculosis.
A series of benzylsulfanyl benzo-heterocycle amides and hydrazones were synthesized and evaluated for anti-tubercular activities. The isonicotinyl hydrazone derivatives 12d, 12e and 12f exhibited good anti-tubercular activity against Mycobacterium tuberculosis H37Rv (ATCC #27294) with MIC values of 0.23, 0.24 and 0.24 μM, respectively, and were also active against SDR-TB, MDR-TB and XDR-TB. More importantly, compound 12e also showed low cytotoxicity and good metabolic stability, and could significantly reduce the mycobacterial burden in a mouse model infected with autoluminescent H37Ra strain, which may serve as a lead compound for further development.


In situ formation of H-bonding imidazole chains in break-junction experiments.
As a small molecule possessing both strong H-bond donor and acceptor functions, 1H-imidazole can participate in extensive homo- or heteromolecular H-bonding networks. These properties are important in Nature, as imidazole moieties are incorporated in many biologically-relevant compounds. Imidazole also finds applications ranging from corrosion inhibition to fire retardants and photography. We have found a peculiar behaviour of imidazole during scanning tunnelling microscopy-break junction (STM-BJ) experiments, in which oligomeric chains connect the two electrodes and allow efficient charge transport. We attributed this behaviour to the formation of hydrogen-bonding networks, as no evidence of such behaviour was found in 1-methylimidazole (incapable of participating in intramolecular hydrogen bonding). The results are supported by DFT calculations, which confirmed our hypothesis. These findings pave the road to the use of hydrogen-bonding networks for the fabrication of dynamic junctions based on supramolecular interactions.


Color removal ability of a streptomycin resistant decolorizing strain Rhodococcus erythropolis (ATCC:4277.1).
Rhodococcua erythropolis (ATCC 4277.1) is a streptomycin resistant mutant of ATCC 4277, which can decolorize the sulfonated azo dye of Orange II and Amido Black. Pseudomonaes luteola is a decolorizing strain, which was isolated from sludge resulting from the treatment of dyeing wastewater. This study had two purposes: 1) to determine the color removal capacity of R. erythropolis (ATCC 4277.1) for Red 22, V2RP and RP2B dyes; and 2) to compare the decolorization capability of R. erythropolis (ATCC 4277.1) to that of P. luteola, a wild type decolorizing strain. R. erythropolis (ATCC 4277.1) grew well in broth containing the azo dyes of Red 22, V2RP or RP2B, and the color of azo dyes could be removed within five days of incubation. The total percentage of color removal was 70%, 30% and 23%, respectively. Color removal by R. erythropolis occurred through a process of degradation, since after five day's incubation in a dye containing broth, the color of R. erythropolis cells remained the same as their original pinkish white color. Comparison of the color removing ability between R. erythropolis and P. luteola showed that the specific color removal (SCR) of R. erythropolis was 1.52 mg of RP2B degraded per gram of dried cells, and that of SCR of P. luteola was 31.7 mg, which was 30 fold higher than that of R. erythropolis.


The sound of soft alcohol: Crossmodal associations between interjections and liquor.
An increasing number of studies reveal crossmodal correspondences between speech sounds and perceptual features such as shape and size. In this study, we show that an interjection Koreans produce when downing a shot of liquor reliably triggers crossmodal associations in American English, German, Spanish, and Chinese listeners who do not speak Korean. Based on how this sound is used in advertising campaigns for the Korean liquor soju, we derive predictions for different crossmodal associations. Our experiments show that the same speech sound is reliably associated with various perceptual, affective, and social meanings. This demonstrates what we call the 'pluripotentiality' of iconicity, that is, the same speech sound is able to trigger a web of interrelated mental associations across different dimensions. We argue that the specific semantic associations evoked by iconic stimuli depend on the task, with iconic meanings having a 'latent' quality that becomes 'actual' in specific semantic contexts. We outline implications for theories of iconicity and advertising.


Edge-ray method for analysis of radiation transfer among specular reflectors.
The analysis of radiation transfer in specular reflector configurations, with multiple or distorted images of an extended radiation source, appears to be so complicated that the need for detailed ray tracing is usually considered inescapable. I show that the number of calculations can be greatly reduced when the source is isotropic. Starting from the fact that the radiation received from an isotropic source depends only on the emissive power of the source and on the angular contour subtended by the source, I show that only edge rays need to be traced, no matter what the curvature of the reflector. Edge rays are rays that pass through the edge of the source or of the reflector. This approach makes it possible to obtain the exact solution for configurations for which the number of reflections is not impractically high. For the solution of general configurations I propose a fast numerical procedure. Based on interpolation between the impact points of a small number of edge rays, it offers high accuracy and unli ted resolution; the convergence is rapid as the number of rays is increased. A test that uses the example of a generalizedcompound parabolic concentrator demonstrates that with this method one can achieve accuracies that are far better than with conventional ray-trace methods while tracing a number of rays that are orders of magnitude smaller.


A novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae.
The Saccharomyces cerevisiae Rap1 protein binds with high affinity to sites within the poly(C(1-3)A) tracts at telomeres, where it plays a role in both telomere length regulation and the initiation of telomeric silencing. Rap1p initiates silencing at telomeres by interacting through its carboxy-terminal domain with Sir3p and Sir4p, both of which are required for repression. This same domain of Rap1p also negatively regulates telomere elongation, through an unknown mechanism. We have identified a new Rap1-interacting factor (Rif2p) that plays a role in telomere length regulation. Rif2p has considerable functional similarities with a Rap1p-interacting factor (Rif1p) identified previously. Mutations in RIF1 or RIF2 (unlike mutations in the silencing genes SIR3 and SIR4) result in moderate telomere elongation and improved telomeric silencing. However, deletion of both RIF1 and RIF2 in the same cell results in a dramatic increase in telomere length, similar to that seen with a carboxy-terminal truncation of Rap1p. In addition, overexpression of either RIF1 or RIF2 decreases telomere length, and co-overexpression of these proteins can reverse the telomere elongation effect of overexpression of the Rap1p carboxyl terminus. Finally, we show that Rif1p and Rif2p can interact with each other in vivo. These results suggest that telomere length regulation is mediated by a protein complex consisting of Rif1p and Rif2p, each of which has distinct regulatory functions. One role of Rap1p in telomere length regulation is to recruit these proteins to the telomeres.


Chestnut Breeding in the United States for Disease and Insect Resistance.
The genus Castanea (family Fagaceae) is found in north temperate climates around the world, and is highly prized in many different cultures for its nutritious nuts and valuable timber. Selection for larger, better-tasting nuts has been ongoing in Asia and Europe for centuries. Early trade routes moved European chestnut trees (C. sativa) west of their native range (in the Caucasus mountains), and the Romans then moved them across their empire to provide support posts for grapevines, as well as for the nuts. Cultivar selection in Turkey, Italy, Spain, and Portugal has been extensive, and regional favorites developed. The many uses of the wood of American chestnut made this "all purpose" tree extremely valuable in its native range in North America. Nut production was important as a food source for rural families and many species of birds and animals. The other American species in the genus Castanea are classed as chinquapins, and may be divided into several or lumped as a single species. The small nuts from these trees and bushes serve primarily as mast for wildlife. Two serious diseases of chestnut trees changed the direction of chestnut research in the United States. Ink disease, caused by the root pathogen Phytophthora cinnamomi, was discovered to be the cause of widespread death of chestnuts and chinquapins in the southern United States, which had been observed since about 1850. This imported pathogen probably came into the southern United States before 1824. The second chestnut disaster was the introduction of chestnut blight disease, which was first found in the United States in 1904. The pathogen causing the lethal cankers is an Ascomycete now known as Cryphonectria parasitica. The longest continuing chestnut breeding program in the United States is in Connecticut.


The inferior temporal cortex is a potential cortical precursor of orthographic processing in untrained monkeys.
The ability to recognize written letter strings is foundational to human reading, but the underlying neuronal mechanisms remain largely unknown. Recent behavioral research in baboons suggests that non-human primates may provide an opportunity to investigate this question. We recorded the activity of hundreds of neurons in V4 and the inferior temporal cortex (IT) while naïve macaque monkeys passively viewed images of letters, English words and non-word strings, and tested the capacity of those neuronal representations to support a battery of orthographic processing tasks. We found that simple linear read-outs of IT (but not V4) population responses achieved high performance on all tested tasks, even matching the performance and error patterns of baboons on word classification. These results show that the IT cortex of untrained primates can serve as a precursor of orthographic processing, suggesting that the acquisition of reading in humans relies on the recycling of a brain network evolved for other visual functions.


The attitudes to CPAP treatment inventory: development and initial validation of a new tool for measuring attitudes to CPAP treatment.
Continuous positive airway pressure (CPAP) is the treatment of choice for obstructive sleep apnoea syndrome (OSAS), but low adherence rates are common. The aim was to develop the attitudes to CPAP treatment inventory (ACTI), and to investigate the validity and reliability of the instrument among patients with OSAS. ACTI was developed on the basis of: (i) in-depth interviews with 23 patients; (ii) examination of the scientific literature; and (iii) consensus agreement of a multi-professional expert panel. This yielded five different types of attitudes to CPAP treatment. A prospective longitudinal design was used. Two-hundred and eighty-nine patients with OSAS were recruited at three different CPAP centres. Data were collected with ACTI and obtained from medical records. The homogeneity and internal consistency reliability were satisfactorily reflected by the item-total correlations (0.59-0.81) and Cronbach's alpha (0.89), respectively. Construct validity was confirmed with factor analysis (principal component analysis with orthogonal rotation; PCF). The PCF based on baseline data resulted in a one single-factor solution explaining 69% of the total variance. A confirmatory factor analysis was performed 2 weeks after CPAP initiation, resulting in the same factor solution. No indication of uniform differential item functioning was found. The predictive validity was tested with receiver operating characteristic analyses, and a cut-off of 10 on the ACTI gave a sensitivity of 93% and a specificity of 44% for CPAP termination within 6 months. The satisfactory measurement properties of this new pragmatic instrument are promising and indicate that ACTI can be useful in clinical practice to reliably measure attitudes to CPAP treatment.


Sudden death: lessons from subsets in population studies.
Sudden coronary death is an important feature of clinical coronary disease, the incidence doubling with each decade of age after age 45 and with women lagging behind men in incidence by 20 years. Fifty percent of the sudden deaths in men and 64% in women occur in persons without prior coronary heart disease, and 18% of coronary attacks in men and 24% in women present as sudden death. More than half of coronary mortality is in the form of sudden death. Persons with overt established coronary heart disease are at 3-fold to 12-fold increased risk depending on age, the risk ratio diminishing with advancing age. When overt coronary disease is established, the major coronary risk factors have little discernible effect on the risk of sudden death. Risk appears related chiefly to the degree of myocardial damage as indicated by electrocardiographic abnormality and evidence of cardiac failure. In subjects free of overt coronary heart disease, the risk of sudden death varies widely in relation to risk factors, including systolic pressure, serum cholesterol, vital capacity, cigarette smoking, relative weight, heart rate and electrocardiographic abnormality. Multivariate combination of these risk factors allows an efficient prediction of sudden death in both sexes. The key to the prevention of sudden death in the general population is to prevent coronary attacks by avoidance or correction of the aforementioned risk factors. No risk factors thus far identified are clearly specific for sudden death.(ABSTRACT TRUNCATED AT 250 WORDS)


Association analysis of 29,956 individuals confirms that a low-frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion.
A recent study identified a low-frequency variant at CCND2 associated with lower risk of type 2 diabetes, enhanced insulin response to a glucose challenge, higher height, and, paradoxically, higher BMI. We aimed to replicate the strength and effect size of these associations in independent samples and to assess the underlying mechanism. We genotyped the variant in 29,956 individuals and tested its association with type 2 diabetes and related traits. The low-frequency allele was associated with a lower risk of type 2 diabetes (OR 0.53; P = 2 × 10(-13); 6,647 case vs. 12,645 control subjects), higher disposition index (β = 0.07 log10; P = 2 × 10(-11); n = 13,028), and higher Matsuda index of insulin sensitivity (β = 0.02 log10; P = 5 × 10(-3); n = 13,118) but not fasting proinsulin (β = 0.01 log10; P = 0.5; n = 6,985). The low frequency allele was associated with higher adult height (β = 1.38 cm; P = 6 × 10(-9); n = 13,927), but the association of the variant with BMI (β = 0.36 kg/m(2); P = 0.02; n = 24,807), estimated in four population-based samples, was less than in the original publication where the effect estimate was biased by analyzing case subjects with type 2 diabetes and control subjects without diabetes separately. Our study establishes that a low-frequency allele in CCND2 halves the risk of type 2 diabetes primarily through enhanced insulin secretion.


LVA and HVA Ca(2+) currents in ventricular muscle cells of the Lymnaea heart.
The single-electrode voltage-clamp technique was used to characterize voltage-gated Ca(2+) currents in dissociated Lymnaea heart ventricular cells. In the presence of 30 mM tetraethylammonium (TEA), two distinct Ca(2+) currents could be identified. The first current activated between -70 and -60 mV. It was fully available for activation at potentials more negative than -80 mV. The current was fast to activate and inactivate. The inactivation of the current was voltage dependent. The current was larger when it was carried by Ca(2+) compared with Ba(2+), although changing the permeant ion had no observable effect on the kinetics of the evoked currents. The current was blocked by Co(2+) and La(3+) (1 mM) but was particularly sensitive to Ni(2+) ions ( approximately 50% block with 100 microM Ni(2+)) and insensitive to low doses of the dihydropyridine Ca(2+) channel antagonist, nifedipine. All these properties classify this current as a member of the low-voltage-activated (LVA) T-type family of Ca(2+) currents. The activation threshold of the current (-70 mV) suggests that it has a role in pacemaking and action potential generation. Muscle contractions were first seen at -50 mV, indicating that this current might supply some of the Ca(2+) necessary for excitation-contraction coupling. The second, a high-voltage-activated (HVA) current, activated at potentials between -40 and -30 mV and was fully available for activation at potentials more negative than -60 mV. This current was also fast to activate and with Ca(2+) as the permeant ion, inactivated completely during the 200-ms voltage step. Substitution of Ba(2+) for Ca(2+) increased the amplitude of the current and significantly slowed the rate of inactivation. The inactivation of this current appeared to be current rather than voltage dependent. This current was blocked by Co(2+) and La(3+) ions (1 mM) but was sensitive to micromolar concentrations of nifedipine ( approximately 50% block 10 microM nifedipine) that were ineffective at blocking the LVA current. These properties characterize this current as a L-type Ca(2+) current. The voltage sensitivity of this current suggests that it is also important in generating the spontaneous action potentials, and in providing some of the Ca(2+) necessary for excitation-contraction coupling. These data provide the first detailed description of the voltage-dependent Ca(2+) currents present in the heart muscle cells of an invertebrate and indicate that pacemaking in the molluscan heart has some similarities with that of the mammalian heart.


[Descriptive analysis of the social, clinical, laboratorial and anthropometric profiles of inflammatory bowel disease inwards patients from the "Clementino Fraga Filho" University Hospital, Rio de Janeiro, RJ, Brazil].
The epidemiologic survey in Brazil is limited probably due to a diagnosis deficiency and a small number of population-based studies performed. The majority of the prevalence studies available have evaluated inflammatory bowel diseases outpatients, but the knowledge of the profile of inflammatory bowel diseases inpatients is important in order to detect predictive markers of disease severity that will allow earlier medical intervention decreasing the rate of hospitalization and reducing the Health System costs. To determine social, clinical, laboratorial and anthropometric profiles of hospitalized adults inflammatory bowel diseases patients of a tertiary university hospital. Prospective study was performed with 43 inflammatory bowel diseases inpatients from clinical and surgical wards and emergency section of university hospital. We characterized demographic data, presence of comorbidities, disease location and behavior, surgical past-history, extra intestinal manifestations using standardized definitions. Laboratory results were abstracted from medical records and anthropometric measures were performed during our visit. The vast majority of the inflammatory bowel diseases patients had Crohn's disease (72.1%), with ileocolic involvement (60%), with a penetrating disease behavior (77.4%) while ulcerative colitis group presented mostly pancolitis (50%). Articular pain was the most common (44.2%) extra intestinal manifestation of inflammatory bowel diseases patients and 97.7% of them had at least one type of complication related to disease. Although, the previous use of specific medical therapies to inflammatory bowel diseases before the hospitalization (more frequently corticosteroids) was done (79%), the majority of the patients were hospitalized because of inflammatory bowel diseases activity. Disease activity was present in 80.7% of Crohn's disease and 50% ulcerative colitis patients. Inflammatory bowel diseases mortality rate was 5.5% (2/36). Comorbidities presence occurred only in 30.2% of inflammatory bowel diseases patients. The predominant surgery performed was intestinal resection. The interval between the symptoms appearance and the definitive diagnosis was less than 1 year in more than 70% of inflammatory bowel diseases patients. Laboratory findings detected were a decreased serum albumin (85.7%) and anemia (69.8%). The majority of the patients had at least one anthropometric alteration. The social stratification of the inflammatory bowel diseases group was similar to the Brazilian population. The inflammatory bowel diseases inpatients from the university hospital wards had more severe evolution of these illnesses with an active and extensive disease with complications and frequent extra intestinal manifestations, despite the prolonged use of corticosteroids. The higher prevalence of Crohn's disease inpatients than ulcerative colitis could reflect a higher aggressive behavior of this disease. The reduced serum albumin, anemia and anthropometric alterations are common inflammatory bowel diseases inpatients and could be related to a major severity of inflammatory bowel diseases evolution.


Do ethnic differences in cord blood leptin levels differ by birthweight category? Findings from the Born in Bradford cohort study.
There is evidence that South Asian individuals have higher fat mass for a given weight than Europeans. One study reported that the greater fatness for a given birthweight may increase with increasing birth weight, suggesting that any attempt to increase mean birth weight in South Asians would markedly increase their fatness. Our objective was to examine whether differences in cord leptin values between White British and Pakistani infants vary by birth weight category. We examined the difference in cord leptin levels between 659 White British and 823 Pakistani infants recruited to the Born in Bradford cohort study, by clinical categories and thirds of the birth weight distribution. Pakistani infants had a lower mean birthweight but higher cord leptin levels than White British infants [ratio of geometric mean(RGM) of cord leptin adjusted for birth weight = 1.36 (95% CI 1.26,1.46)]. Birthweight was positively associated with cord leptin levels in both groups, with no evidence that the regression lines in the two groups diverged from each other with increasing birthweight.The relative ethnic difference in cord leptin was similar in low (<2500 g), normal and high (≥4000 g) birthweight infants(P-value for interaction = 0.91). It was also similar across thirds of the birthweight distribution [RGM (95% CI) in lowest, mid and highest thirds were 1.37 (1.20, 1.57), 1.36 (1.20, 1.54) and 1.31 (1.16, 1.52), respectively, P-interaction = 0.51]. We found marked differences in cord leptin levels between Pakistani and White British infants but no evidence that this difference increases with increasing birthweight.


Prediction of Outcome in Neonates with Hypoxic-Ischemic Encephalopathy II: Role of Amplitude-Integrated Electroencephalography and Cerebral Oxygen Saturation Measured by Near-Infrared Spectroscopy.
Few data have been published on the combined use of amplitude-integrated electroencephalography (aEEG) and near-infrared spectroscopy (NIRS) for outcome prediction in neonates cooled for hypoxic-ischemic encephalopathy (HIE). Our aim was to evaluate the predictive values and the most powerful predictive combinations of single aEEG and NIRS parameters and the respective cut-off values with regard to short-term outcomes in HIE II. aEEG and NIRS were prospectively studied at the Medical University of Vienna in the first 102 h of life with regard to magnetic resonance imaging (MRI). Thirty-two neonates diagnosed with HIE II treated with hypothermia were investigated. The measurement period was divided into 6-h epochs. According to MRI, 2 outcome groups were defined and predictive values of aEEG parameters, regional cerebral oxygen saturation (rScO2), and the additional value of both methods combined were studied. Receiver operating curves (ROC) were obtained and area under the curve (AUC) values were calculated. ROC were then used to detect the optimal cut-off points, sensitivity, specificity, positive predictive values, and negative predictive values. At all time epochs, combined parameter scores were more predictive than single parameter scores. The highest AUC were observed between 18 and 60 h of cooling for the aEEG summation score (0.72-0.84) and for (background pattern + seizures) × rScO2 (0.79-0.85). At 42-60 h sensitivity was similar between those 2 scores (87.5-90.0%), but the addition of NIRS to aEEG led to an increase in specificity (from 52.4-59.1% to 72.7-90.5%). In HIE II, aEEG and NIRS are important predictors of short-term outcome. The combination of both methods improves prognostication. The highest predictive abilities were observed between 18 and 60 h of cooling.


Cranberry juice for the prevention of recurrences of urinary tract infections in children: a randomized placebo-controlled trial.
Cranberry juice prevents recurrences of urinary tract infections (UTIs) in adult women. The objective of this study was to evaluate whether cranberry juice is effective in preventing UTI recurrences in children. A double-blind randomized placebo-controlled trial was performed in 7 hospitals in Finland. A total of 263 children treated for UTI were randomized to receive either cranberry juice (n = 129) or placebo (n = 134) for 6 months. Eight children were omitted because of protocol violations, leaving 255 children for the final analyses. The children were monitored for 1 year, and their recurrent UTIs were recorded. Twenty children (16%) in the cranberry group and 28 (22%) in the placebo group had at least 1 recurrent UTI (difference, -6%; 95% confidence interval [CI], -16 to 4%; P = .21). There were no differences in timing between these first recurrences (P = .32). Episodes of UTI totaled 27 and 47 in the cranberry and placebo groups, respectively, and the UTI incidence density per person-year at risk was 0.16 episodes lower in the cranberry group (95% CI, -.31 to -.01; P = .035). The children in the cranberry group had significantly fewer days on antimicrobials (-6 days per patient-year; 95% CI, -7 to -5; P < .001). The intervention did not significantly reduce the number of children who experienced a recurrence of UTI, but it was effective in reducing the actual number of recurrences and related antimicrobial use.


Effects of nitrous oxide on cerebral metabolic rate in rats anaesthetized with isoflurane.
It has been demonstrated in several species that a significant increase in cerebral blood flow (CBF) occurs when nitrous oxide is added to a volatile anaesthetic. This blood flow response could result from an increase in cerebral metabolic rate or from a direct effect of nitrous oxide on cerebral vessels. To investigate this, the cerebral metabolic rate for glucose (CMRglu) was determined autoradiographically in rats receiving isoflurane anaesthesia with or without nitrous oxide. An increase in anaesthetic depth from 0.5 to 1.0 MAC achieved with isoflurane alone caused a significant reduction in CMRglu (52 (SD11) mumol/100 g min-1 vs 39 (8)mumol/100 g min-1). In contrast, the addition of 70% nitrous oxide (0.5 MAC) to 0.5 MAC isoflurane anaesthesia (1 MAC total) left CMRglu unchanged (54 (4) mumol/100 g min-1). We conclude that 70% nitrous oxide does not alter cerebral metabolic rate when administered with 0.5 MAC isoflurane. Because CBF increases substantially under very similar conditions, our data indicate that the CBF effects of nitrous oxide, when administered with a volatile agent, were direct and mediated by factors other than changes in cerebral metabolic rate.


Effects of lead exposure before pregnancy and dietary calcium during pregnancy on fetal development and lead accumulation.
Millions of women of child-bearing age have substantial bone lead stores due to lead exposure as children. Dietary calcium ingested simultaneously with lead exposure can reduce lead absorption and accumulation. However, the effects of dietary calcium on previously accumulated maternal lead stores and transfer to the fetus have not been investigated. We studied the effects of lead exposure of female rats at an early age on fetal development during a subsequent pregnancy. We gave 5-week-old female Sprague-Dawley rats lead as the acetate in their drinking water for 5 weeks; controls received equimolar sodium acetate. This was followed by a 1-month period without lead exposure before mating. We randomly assigned pregnant rats (n = 39) to diets with a deficient (0.1%) or normal (0.5%) calcium content during pregnancy. A total of 345 pups were delivered alive. Lead-exposed dams and their pups had significantly higher blood lead concentrations than controls, but the concentrations were in the range of those found in many pregnant women. Pups born to dams fed the calcium-deficient diet during pregnancy had higher blood and organ lead concentrations than pups born to dams fed the 0. 5% calcium diet. Pups born to lead-exposed dams had significantly (p<0.0001) lower mean birth weights and birth lengths than controls. There were significant inverse univariate associations between dam or pup organ lead concentrations and birth weight or length. The 0.5% calcium diet did not increase in utero growth. Stepwise regression analysis demonstrated that greater litter size and female sex were significantly associated with reduced pup birth weight and length. However, lead exposure that ended well before pregnancy was significantly (p<0.0001) associated with reduced birth weight and length, even after litter size, pup sex, and dam weight gain during pregnancy were included in the regression analysis. The data demonstrate that an increase in dietary calcium during pregnancy can reduce fetal lead accumulation but cannot prevent lead-induced decreases in birth weight and length. The results provide evidence that dietary nutrients can influence the transfer of toxins to the fetus during pregnancy. If these results are applicable to women, an increase in diet calcium during pregnancy could reduce the transfer of lead from prepregnancy maternal exposures to the fetus.


Interaction between perceived maternal care, anxiety symptoms, and the neurobehavioral response to palatable foods in adolescents.
Studies in rodents have shown that early life trauma leads to anxiety, increased stress responses to threatening situations, and modifies food intake in a new environment. However, these associations are still to be tested in humans. This study aimed to verify complex interactions among anxiety diagnosis, maternal care, and baseline cortisol on food intake in a new environment in humans. A community sample of 32 adolescents and young adults was evaluated for: psychiatric diagnosis using standardized interviews, maternal care using the Parental Bonding Inventory (PBI), caloric consumption in a new environment (meal choice at a snack bar), and salivary cortisol. They also performed a brain fMRI task including the visualization of palatable foods vs. neutral items. The study found a three-way interaction between anxiety diagnosis, maternal care, and baseline cortisol levels on the total calories consumed (snacks) in a new environment. This interaction means that for those with high maternal care, there were no significant associations between cortisol levels and food intake in a new environment. However, for those with low maternal care and who have an anxiety disorder (affected), cortisol was associated with higher food intake; whereas for those with low maternal care and who did not have an anxiety disorder (resilient), cortisol was negatively associated with lower food intake. In addition, higher anxiety symptoms were associated with decreased activation in the superior and middle frontal gyrus when visualizing palatable vs. neutral items in those reporting high maternal care. These results in humans mimic experimental research findings and demonstrate that a combination of anxiety diagnosis and maternal care moderate the relationship between the HPA axis functioning, anxiety, and feeding behavior in adolescents and young adults.


Tuning characteristics of narrowband THz radiation generated via optical rectification in periodically poled lithium niobate.
The tuning properties of pulsed narrowband THz radiation generated via optical rectification in periodically poled lithium niobate have been investigated. Using a disk-shaped periodically poled crystal tuning was easily accomplished by rotating the crystal around its axis and observing the generated THz radiation in forward direction. In this way no beam deflection during tuning was observed. The total tuning range extended from 180 GHz up to 830 GHz and was limited by the poling period of 127 microm which determines the maximum THz frequency in forward direction.


More efficient mastication allows increasing intake without compromising digestibility or necessitating a larger gut: comparative feeding trials in banteng (Bos javanicus) and pygmy hippopotamus (Hexaprotodon liberiensis).
The digestion of plant material in mammalian herbivores basically depends on the chemical and structural composition of the diet, the mean particle size to which the forage is processed, and the ingesta retention time. These different factors can be influenced by the animal, and they can presumably compensate for each other. The pygmy hippopotamus, a non-ruminating foregut fermenter, has longer mean retention times than ruminants; however hippos do not achieve higher (fibre) digestibilities on comparable diets, which could be due to ineffective mastication. We performed feeding trials with six pygmy hippos (Hexaprotodon liberiensis) and six banteng cattle (Bos javanicus) on a grass diet. As predicted, both species achieved similar dry matter, organic matter, crude protein and gross energy digestibilities. However, neutral and acid detergent fibre digestibility was lower in pygmy hippos. Apparently, in these species, fibre digestibility was more influenced by particle size, which was larger in pygmy hippos compared to banteng, than by retention time. In spite of their higher relative food intake, the banteng in this study did not have greater relative gut fills than the hippos. Ruminants traditionally appear intake-limited when compared to equids, because feed particles above a certain size cannot leave the rumen. But when compared to nonruminating foregut fermenters, rumination seems to free foregut fermenters from an intrinsic food intake limitation. The higher energy intakes and metabolic rates in wild cattle compared to hippos could have life-history consequences, such as a higher relative reproductive rate.


A medical informatics perspective on health informatics 3.0. Findings from the Yearbook 2011 section on health informatics 3.0.
To summarize current advances of the so-called Web 3.0 and emerging trends of the semantic web. We provide a synopsis of the articles selected for the IMIA Yearbook 2011, from which we attempt to derive a synthetic overview of the today's and future activities in the field. while the state of the research in the field is illustrated by a set of fairly heterogeneous studies, it is possible to identify significant clusters. While the most salient challenge and obsessional target of the semantic web remains its ambition to simply interconnect all available information, it is interesting to observe the developments of complementary research fields such as information sciences and text analytics. The combined expression power and virtually unlimited data aggregation skills of Web 3.0 technologies make it a disruptive instrument to discover new biomedical knowledge. In parallel, such an unprecedented situation creates new threats for patients participating in large-scale genetic studies as Wjst demonstrate how various data set can be coupled to re-identify anonymous genetic information. The best paper selection of articles on decision support shows examples of excellent research on methods concerning original development of core semantic web techniques as well as transdisciplinary achievements as exemplified with literature-based analytics. This selected set of scientific investigations also demonstrates the needs for computerized applications to transform the biomedical data overflow into more operational clinical knowledge with potential threats for confidentiality directly associated with such advances. Altogether these papers support the idea that more elaborated computer tools, likely to combine heterogeneous text and data contents should soon emerge for the benefit of both experimentalists and hopefully clinicians.


In Vitro Evaluation of Manual Torque Values Applied to Implant-Abutment Complex by Different Clinicians and Abutment Screw Loosening.
Preload is applied to screws manually or using a torque wrench in dental implant systems, and the preload applied must be appropriate for the purpose. The aim of this study was to assess screw loosening and bending/torsional moments applied by clinicians of various specialties following application of manual tightening torque to combinations of implants and abutments. Ten-millimeter implants of 3.7 and 4.1 mm diameters and standard or solid abutments were used. Each group contained five implant-abutment combinations. The control and experimental groups comprised 20 and 160 specimens, respectively. Implants in the experimental group were tightened by dentists of different specialties. Torsional and bending moments during tightening were measured using a strain gauge. Control group and implants with preload values close to the ideal preload were subjected to a dynamic loading test at 150 N, 15 Hz, and 85,000 cycles. The implants that deformed in this test were examined using an optical microscope to assess deformities. Manual tightening did not yield the manufacturer-recommended preload values. Dynamic loading testing suggested early screw loosening/fracture in samples with insufficient preload.


Neoadjuvant FOLFIRINOX in Patients With Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level Meta-Analysis.
FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated. We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III-IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method. We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with FOLFIRINOX. Most studies (n = 20) presented intention-to-treat results. The median number of administered neoadjuvant FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] = 60.1% to 74.6%), and the R0-resection rate was 83.9% (95% CI = 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patient-level survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months (95% CI = 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI = 14.5 to 21.5 months). Pooled event rates for grade III-IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI = 10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI = 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI = 8.1 to 14.2). No deaths were attributed to FOLFIRINOX. This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial.


Assessment of Neuromuscular Function Using Percutaneous Electrical Nerve Stimulation.
Percutaneous electrical nerve stimulation is a non-invasive method commonly used to evaluate neuromuscular function from brain to muscle (supra-spinal, spinal and peripheral levels). The present protocol describes how this method can be used to stimulate the posterior tibial nerve that activates plantar flexor muscles. Percutaneous electrical nerve stimulation consists of inducing an electrical stimulus to a motor nerve to evoke a muscular response. Direct (M-wave) and/or indirect (H-reflex) electrophysiological responses can be recorded at rest using surface electromyography. Mechanical (twitch torque) responses can be quantified with a force/torque ergometer. M-wave and twitch torque reflect neuromuscular transmission and excitation-contraction coupling, whereas H-reflex provides an index of spinal excitability. EMG activity and mechanical (superimposed twitch) responses can also be recorded during maximal voluntary contractions to evaluate voluntary activation level. Percutaneous nerve stimulation provides an assessment of neuromuscular function in humans, and is highly beneficial especially for studies evaluating neuromuscular plasticity following acute (fatigue) or chronic (training/detraining) exercise.


High-resolution elemental localization in vacuolate plant cells by nanoscale secondary ion mass spectrometry.
By combining the capabilities of advanced sample preparation methodologies with the latest generation of secondary ion mass spectrometry instrumentation, we show that chemical information on the distribution of even dilute species in biological samples can be obtained with spatial resolutions of better than 100 nm. Here, we show the distribution of nickel and other elements in leaf tissue of the nickel hyperaccumulator plant Alyssum lesbiacum prepared by high-pressure freezing and freeze substitution.


UV Photodissociation Mass Spectrometry Accurately Localize Sites of Backbone Deuteration in Peptides.
Hydrogen/deuterium exchange mass spectrometry (HDX-MS) is now a routinely used technique to inform on protein structure, dynamics, and interactions. Localizing the incorporated deuterium content on a single residue basis increases the spatial resolution of this technique enabling detailed structural analysis. Here, we investigate the use of ultraviolet photodissociation (UVPD) at 213 nm to measure deuterium levels at single residue resolution in HDX-MS experiments. Using a selectively labeled peptide, we show that UVPD occurs without H/D scrambling as the peptide probe accurately retains its solution-phase deuterium labeling pattern. Our results indicate that UVPD provides an attractive alternative to electron mediated dissociation for increasing the spatial resolution of the HDX-MS experiment, capable of yielding high fragmentation efficiency, high fragment ion diversity, and low precursor ion charge-state dependency.


Direct EPR detection of atomic nitrogen in an atmospheric nitrogen plasma jet.
In this study, an atmospheric nitrogen plasma jet generated by a custom-built micro-plasma device was analyzed at room temperature by continuous wave and pulse EPR spectroscopy in real time. Transiently formed nitrogen atoms were detected without the necessity to use spin-traps or other reagents for their stabilization. In contrast to results from optical emission spectroscopy, only signals from the 4S ground state of 14N and 15N could be detected. EPR data analysis revealed an isotropic g value of 1.9971 and isotropic hyperfine coupling constants of a(14N) = (10.47 ± 0.02) MHz and a(15N) = (14.69 ± 0.02) MHz. Moreover, lifetime and relaxation data could be determined; both are discussed in terms of spectral widths and actual concentrations of the transiently formed nitrogen species within the plasma jet. The data show that the lifetimes of atomic nitrogen and charged particles such as N+ must be different, and for the latter below the observation time window of EPR spectroscopy. We demonstrate that the real-time (pulsed) EPR technique is a fast and reliable alternative to detect atomic nitrogen in atmospheric pressure plasma jets. The method may be used for a continuous monitoring of the quality of plasma jets.


Immunohematopoietic stem cell transplantation in Cape Town: a ten-year outcome analysis in adults.
Immunohematopoietic stem cell transplantation has curative potential in selected hematologic disorders. Stem cell transplantation was introduced into South Africa in 1970 as a structured experimental and clinical program. In this report, we summarize the demography and outcome by disease category, gender, and type of procedure in patients older than 18 years of age who were seen from April 1995 to December 2002. This retrospective analysis included 247 individuals over 18 years of age for whom complete data were available. These patients received grafts mostly from peripheral blood with the appropriate stem cell population recovered by apheresis. Patient ages ranged from 20 to 65 years with a median age of 42 years. There were 101 females and 146 males. There were no withdrawals and 63% survived to the end of the study. At 96 months of follow-up, a stable plateau was reached for each disease category. Median survival was 3.3 years (n=6, 14.6%) for acute lymphoblastic anemia, 3.1 years (n=44, 18%) for acute myeloid leukemia, 2.8 years (n=47, 19%) for chronic granulocytic leukemia, 2.8 years (n=71, 29%) for lymphoma, 1.5 years (n=23, 9%) for myeloma, 1.43 years (n=10, 4%) for aplasia, and 1.4 years (n=38, 15%) for a miscellaneous group comprising less than 10 examples each. Multivariate analysis showed that only diagnosis and age had a significant impact on survival, but these two variables might be interrelated. There was no significant difference in outcome by source of graft. The results confirm that procedures carried out in a properly constituted and dedicated unit, which meets established criteria and strictly observes treatment protocols, generate results comparable to those in a First World referral center. Low rates of transplant-related mortality, rejection and graft-versus-host disease are confirmed, but the benefits cannot be extrapolated outside of academically oriented and supervised facilities.


A popliteal artery aneurysm presenting with ab extrinseco popliteal vein occlusion and compartment syndrome: a case report.
Aneurysms of popliteal artery are the most frequently reported aneurysm after abdominal aorta. An unusual presentation is compression to adjacent structure. A 67 years old caucasian man presenting deep vein thrombosis signs to the right leg including functional impotence was admitted in emergency setting to Vascular Surgery Unit. A pulsing mass was present in the popliteal cave at inspection. The computed tomography angiography demonstrated a 53.2 mm popliteal artery aneurysm causing an ab extrinseco compression of the popliteal vein and a dislocation of popliteal nerve. A surgical open reconstruction with a reinforced Dacron graft was performed via a posterior approach. Patient was discharged on the fourth postoperative day with no functional impotence. At three and six months Doppler ultrasound followup both popliteal arterial graft and popliteal vein were patent. An unusual presentation of a popliteal artery aneurysm can be a popliteal compartment syndrome, especially in large aneurysms. Deep popliteal vein compression and/or popliteal nerve dislocation signs can rarely represent the clinical symptoms. The popliteal artery aneurysm repair is generally required to avoid a distal embolization and rupture. Through a surgical open repair was possible to achieve both popliteal cave decompression and the popliteal artery aneurysm repair.


The influence of glyphosate on the microbiota and production of botulinum neurotoxin during ruminal fermentation.
The aim of the present study is to investigate the impact of glyphosate on the microbiota and on the botulinum neurotoxin (BoNT) expression during in vitro ruminal fermentation. This study was conducted using two DAISY(II)-incubators with four ventilated incubation vessels filled with rumen fluid of a 4-year-old non-lactating Holstein-Friesian cow. Two hundred milliliter rumen fluid and 800 ml buffer solution were used with six filter bags containing 500 mg concentrated feed or crude fiber-enriched diet. Final concentrations of 0, 1, 10, and 100 µg/ml of glyphosate in the diluted rumen fluids were added and incubated under CO2-aerated conditions for 48 h. The protozoal population was analyzed microscopically and the ruminal flora was characterized using the fluorescence in situ hybridization technique. Clostridium botulinum and BoNT were quantified using most probable number and ELISA, respectively. Results showed that glyphosate had an inhibitory effect on select groups of the ruminal microbiota, but increased the population of pathogenic species. The BoNT was produced during incubation when inoculum was treated with high doses of glyphosate. In conclusion, glyphosate causes dysbiosis which favors the production of BoNT in the rumen. The global regulations restrictions for the use of glyphosate should be re-evaluated.


The effects of sample selection bias on racial differences in child abuse reporting.
The aim was to examine whether design features of Wave 1, 1980 National Incidence Study (NIS) data resulted in sample selection bias when certain victims of maltreatment were excluded. Logistic regression models for the probability of child abuse reports to the child protective services (CPS) were estimated using maximum likelihood methods for Black (n = 511) and White (n = 2499) child abuse cases. The models were estimated with and without correction for selection bias using a two-step procedure proposed by Heckman. Substantial differences were found in the characteristics of Black and White victims by source of report and by type of maltreatment. Also found were sizeable differences within each racial group between sampled agencies and nonsampled agencies. Sample selection bias affected the estimation of both White and Black child abuse reporting rates. In the Black sample, however, the effect of sample selection bias was to reduce the statistical significance of the impacts of reporting agency and physical and sexual abuse on report rates. In the White sample, most significant factors in the basic model remained statistically significant with correction for selection bias. Selection bias was found to be caused by the exclusion of family, friends, and neighbors in the NIS sample design. Such exclusion has the effect of altering the interpretation of the determinants of child abuse reporting among Blacks, but not among Whites. Thus, conclusions about racial differences in child maltreatment must be reached cautiously, given the NIS study design.


Australian women seeking counseling have higher use of health services.
Despite a high prevalence of psychological distress and poor mental health in the Australian community, use of counseling services is very low. There has been only limited research examining the profile of those who do access counseling services, mainly in terms of demographic and health behavior variables. To extend our understanding of those who currently access counseling services, this study aimed to examine the broader pattern of health service utilization by women who consulted counselors, psychologists, or social workers in the past year compared with those who did not among a population-based sample of middle-aged Australian women, and to determine whether health service utilization was independently associated with use of counseling services, controlling for other known predictors. The cross-sectional population-based mail survey data for this study came from the third survey of the mid-aged cohort of the Australian Longitudinal Study on Women's Health, conducted in 2001. The sample comprised 11,201 women aged 50-55. The main study variable was a question asking whether they had consulted a counselor/psychologist/social worker in the past year. Only 6.9% of women had consulted a counselor/psychologist/social worker in the past year. After controlling for self-reported mental health status, health behaviors and demographic variables in multivariate analysis, consulting a counselor/psychologist/social worker in the past year was significantly and positively associated with consultations with general practitioners (> or =5 consultations; odds ratio [OR], 4.14; 95% confidence interval [CI], 2.35-7.27; p < .0001), specialist (> or =3 consultations; OR, 2.09; 95% CI, 1.66-2.63; p < .0001), and hospital doctor (OR, 1.35; 95% CI, 1.10-1.66; p = .004). Use of counseling services was not associated with use of other allied and complementary health services in multivariate analyses. Further research is needed to determine whether the strong independent link between self-reported use of counseling and other medical and health services among middle-aged women is best explained by general practice referral patterns, availability of services, economic factors, or different help-seeking patterns among women.


Deaths from acute abdominal conditions and geographical access to surgical care in India: a nationally representative spatial analysis.
Few population-based studies quantify mortality from surgical conditions and relate mortality to access to surgical care in low-income and middle-income countries. We linked deaths from acute abdominal conditions within a nationally representative, population-based mortality survey of 1·1 million households in India to nationally representative facility data. We calculated total and age-standardised death rates for acute abdominal conditions. Using 4064 postal codes, we undertook a spatial clustering analysis to compare geographical access to well-resourced government district hospitals (24 h surgical and anaesthesia services, blood bank, critical care beds, basic laboratory, and radiology) in high-mortality or low-mortality clusters from acute abdominal conditions. 923 (1·1%) of 86,806 study deaths at ages 0-69 years were identified as deaths from acute abdominal conditions, corresponding to 72,000 deaths nationally in 2010 in India. Most deaths occurred at home (71%) and in rural areas (87%). Compared with 567 low-mortality geographical clusters, the 393 high-mortality clusters had a nine times higher age-standardised acute abdominal mortality rate and significantly greater distance to a well-resourced hospital. The odds ratio (OR) of being a high-mortality cluster was 4·4 (99% CI 3·2-6·0) for living 50 km or more from well-resourced district hospitals (rising to an OR of 16·1 [95% CI 7·9-32·8] for >100 km). No such relation was seen for deaths from non-acute surgical conditions (ie, oral, breast, and uterine cancer). Improvements in human and physical resources at existing government hospitals are needed to reduce deaths from acute abdominal conditions in India. Full access to well-resourced hospitals within 50 km by all of India's population could have avoided about 50,000 deaths from acute abdominal conditions, and probably more from other emergency surgical conditions. Bill & Melinda Gates Foundation, Dalla Lana School of Public Health, Canadian Institute of Health Research.


The expression and localization of N-myc downstream-regulated gene 1 in human trophoblasts.
The protein N-Myc downstream-regulated gene 1 (NDRG1) is implicated in the regulation of cell proliferation, differentiation, and cellular stress response. NDRG1 is expressed in primary human trophoblasts, where it promotes cell viability and resistance to hypoxic injury. The mechanism of action of NDRG1 remains unknown. To gain further insight into the intracellular action of NDRG1, we analyzed the expression pattern and cellular localization of endogenous NDRG1 and transfected Myc-tagged NDRG1 in human trophoblasts exposed to diverse injuries. In standard conditions, NDRG1 was diffusely expressed in the cytoplasm at a low level. Hypoxia or the hypoxia mimetic cobalt chloride, but not serum deprivation, ultraviolet (UV) light, or ionizing radiation, induced the expression of NDRG1 in human trophoblasts and the redistribution of NDRG1 into the nucleus and cytoplasmic membranes associated with the endoplasmic reticulum (ER) and microtubules. Mutation of the phosphopantetheine attachment site (PPAS) within NDRG1 abrogated this pattern of redistribution. Our results shed new light on the impact of cell injury on NDRG1 expression patterns, and suggest that the PPAS domain plays a key role in NDRG1's subcellular distribution.


Development of a standard operating procedure for the DCFH2-DA acellular assessment of reactive oxygen species produced by nanomaterials.
Improved strategies are required for testing nanomaterials (NMs) to make hazard and risk assessment more efficient and sustainable. Including reduced reliance on animal models, without decreasing the level of human health protection. Acellular detection of reactive oxygen species (ROS) may be useful as a screening assay to prioritize NMs of high concern. To improve reliability and reproducibility, and minimize uncertainty, a standard operating procedure (SOP) has been developed for the detection of ROS using the 2',7'-dichlorodihydrofluorescein diacetate (DCFH2-DA) assay. The SOP has undergone an inter- and intra-laboratory comparison, to evaluate robustness, reliability, and reproducibility, using representative materials (ZnO, CuO, Mn2O3, and BaSO4 NMs), and a number of calibration tools to normalize data. The SOP includes an NM positive control (nanoparticle carbon black (NPCB)), a chemical positive control (SIN-1), and a standard curve of fluorescein fluorescence. The interlaboratory comparison demonstrated that arbitrary fluorescence units show high levels of partner variability; however, data normalization improved variability. With statistical analysis, it was shown that the SIN-1 positive control provided an extremely high level of reliability and reproducibility as a positive control and as a normalization tool. The NPCB positive control can be used with a relatively high level of reproducibility, and in terms of the representative materials, the reproducibility CuO induced-effects was better than for Mn2O3. Using this DCFH2-DA acellular assay SOP resulted in a robust intra-laboratory reproduction of ROS measurements from all NMs tested, while effective reproduction across different laboratories was also demonstrated; the effectiveness of attaining reproducibility within the interlaboratory assessment was particle-type-specific.


Subsurface Raman spectroscopy and mapping using a globally illuminated non-confocal fiber-optic array probe in the presence of Raman photon migration.
We report the use of a fiber-optic probe with global illumination and an array of 50 collection fibers (PhAT probe, Kaiser Optical Systems, Inc.) to obtain Raman spectra and 50 spatial element maps of polymers through overlayers of other polymers that are highly scattering. Band target entropy minimization (BTEM) is used to recover the spectra of the subsurface components and generate maps of their distributions. This approach to subsurface mapping is tested with model systems consisting of two or three layers of polyethylene, polytetrafluoroethylene (Teflon), and polyoxymethylene (Delrin) arranged in different geometries. Raman spectra and maps were obtained through overlayer thicknesses of up to 13 mm. Subsurface spatial resolution is achieved because each fiber views an asymmetric distribution of Raman scattered light from surface and subsurface components that depends on the position of the fiber relative to the depth and position of a component and the extent of photon diffusion through the system.


Immunosenescent CD8+ T cells and C-X-C chemokine receptor type 3 chemokines are increased in human hypertension.
The pathogenic role of T cells in hypertension has been documented well in recent animal studies. However, the existence of T-cell-driven inflammation in human hypertension has not been confirmed. Therefore, we undertook immunologic characterization of T cells from patients with hypertension and measured circulating levels of C-X-C chemokine receptor type 3 chemokines, which are well-known tissue-homing chemokines for T cells. We analyzed immunologic markers on T cells from patients with hypertension by multicolor flow cytometry. We then measured circulating levels of the C-X-C chemokine receptor type 3 chemokines, monokine induced by γ interferon (IFN), IFN γ-induced protein 10, and IFN-inducible T-cell α chemoattractant, in patients with hypertension and in age- and sex-matched control subjects by the cytometric bead array method. In addition, we examined histological features of IFN-inducible T-cell α chemoattractant expression from renal biopsy specimens of patients with hypertensive nephrosclerosis and control subjects. The total T-cell population from patients with hypertension showed an increased fraction of immunosenescent, proinflammatory, cytotoxic CD8(+) T cells. Circulating levels of C-X-C chemokine receptor type 3 chemokines were significantly higher in patients with hypertension than in control subjects. Furthermore, immunohistochemical staining revealed increased expression of the T-cell chemokine, IFN-inducible T-cell α chemoattractant, in the proximal and distal tubules of patients with hypertensive nephrosclerosis. Immunosenescent CD8(+) T cells and C-X-C chemokine receptor type 3 chemokines are increased in human hypertension, suggesting a role for T-cell-driven inflammation in hypertension. A more detailed characterization of CD8(+) T cells may offer new opportunities for the prevention and treatment of human hypertension.


People With Low Back Pain Display a Different Distribution of Erector Spinae Activity During a Singular Mono-Planar Lifting Task.
This study aimed to investigate the variation in muscle activity and movement in the lumbar and lumbothoracic region during a singular mono-planar lifting task, and how this is altered in individuals experiencing low back pain (LBP). Muscle activity from the lumbar and lumbothoracic erector spinae of 14 control and 11 LBP participants was recorded using four 13 × 5 high-density surface electromyography (HDEMG) grids. Root mean squared HDEMG signals were used to create spatial maps of the distribution of muscle activity. Three-dimensional kinematic data were recorded focusing on the relationship between lumbar and thoracic movements. In the task, participants lifted a 5 kg box from knee height to sternal height, and then returned the box to the starting position. The center of muscle activity for LBP participants was found to be systematically more cranial throughout the task compared to the control participants (P < 0.05). Participants with LBP also had lower signal entropy (P < 0.05) and lower absolute root mean squared values (P < 0.05). However, there were no differences between groups in kinematic variables, with no difference in contributions between lumbar and thoracic motion segments (P > 0.05). These results indicate that participants with LBP utilize an altered motor control strategy to complete a singular lifting task which is not reflected in their movement strategy. While no differences were identified between groups in the motion between lumbar and thoracic motion segments, participants with LBP utilized a less homogenous, less diffuse and more cranially focussed contraction of their erector spinae to complete the lifting movement. These results may have relevance for the persistence of LBP symptoms and the development of new treatments focussing on muscle retraining in LBP.


Development, problem behavior, and quality of life in a population based sample of eight-year-old children with Down syndrome.
Children with Down syndrome (DS) have delayed psychomotor development. We investigated levels of development, problem behavior, and Health-Related Quality of Life (HRQoL) in a population sample of Dutch eight-year-old children with DS. Developmental outcomes were compared with normative data of eight-year-old children from the general population. Over a three-year-period all parents with an eight-year-old child with DS were approached by the national parent organization. Developmental skills were assessed by means of the McCarthy Scales of Children's Ability. To measure emotional and behavioral problems we used the Child Behavior Checklist. HRQoL was assessed with the TNO-AZL Children's Quality of Life questionnaire. Analyses of variance were applied to compare groups. A total of 337 children participated. Mean developmental age was substantially lower than mean calendar age (3.9 years, SD 0.87 and 8.1 years, SD 0.15 respectively). Mean developmental age was significantly lower among boys than girls (3.6 (SD 0.85) and 4.2 years (SD 0.82) respectively; p<0.001). Compared with the general population, children with DS had more emotional and behavioral problems (p<0.001). However on the anxious/depressed scale, they scored significantly more favorably (p<0.001). Significantly lower HRQoL scores for the scales gross motor skills, autonomy, social functioning and cognitive functioning were found (p-values<0.001). Hardly any differences were observed for the scales physical complaints, positive and negative emotions. Eight-year-old children with DS have an average developmental delay of four years, more often have emotional and behavioral problems, and have a less favorable HRQoL compared with children from the general population.