Effect of ticlopidine in the prevention of radiation enteropathy.
Impairment of vascular function is considered to play an important role in chronic radiation enteropathy. In this experimental study, the role of ticlopidine, an inhibitor of ADP-induced platelet aggregation, was investigated in radiation enteropathy. 80 male Wistar albino rats, each weighing 170-200 g, were divided into four groups: (a) radiation alone (n = 20); (b) radiotherapy plus ticlopidine (n = 20); (c) ticlopidine control (n = 20) and (d) control (n = 20). Both radiation groups received 19 Gy radiation to the exteriorized intestinal segments in a single fraction. Ticlopidine or vehicle was administered 12 h after radiotherapy and continued for 1 month. Rats from every group were euthanized randomly at intervals of 6 weeks from 2 weeks to 26 weeks. Histopathological radiation injury was assessed using radiation injury scoring (RIS). Radiation with ticlopidine or radiation alone groups showed significant RIS deterioration compared with controls in all time points studied. Comparison of median RIS of radiotherapy and radiotherapy+ticlopidine groups at the 2nd, 14th and 26th weeks yielded statistically significant RIS in favour of radiotherapy+ticlopidine group (p = 0.05). However, these differences were less pronounced at the 8th and 20th week (p = 0.07). Both radiation groups had poor weight gain when compared with control and ticlopidine groups. The weight gain in radiotherapy+ticlopidine group was significantly superior to only radiation group between 10th and 20th weeks (p = 0.05). This study showed that inhibition of platelet aggregation with ticlopidine might be useful in radiation enteropathy. However, the precise role of antiaggregant therapies on radiation enteropathy should be comprehensively studied before clinical consideration.


Relaxant action of plumula nelumbinis extract on mouse airway smooth muscle.
The traditional herb Plumula Nelumbinis is widely used in the world because it has many biological activities, such as anti-inflammation, antioxidant, antihypertension, and butyrylcholinesterase inhibition. However, the action of Plumula Nelumbinis on airway smooth muscle (ASM) relaxation has not been investigated. A chloroform extract of Plumula Nelumbinis (CEPN) was prepared, which completely inhibited precontraction induced by high K(+) in a concentration-dependent manner in mouse tracheal rings, but it had no effect on resting tension. CEPN also blocked voltage-dependent L-type Ca(2+) channel- (VDCC-) mediated currents. In addition, ACh-induced precontraction was also completely blocked by CEPN and partially inhibited by nifedipine or pyrazole 3. Besides, CEPN partially reduced ACh-activated nonselective cation channel (NSCC) currents. Taken together, our data demonstrate that CEPN blocked VDCC and NSCC to inhibit Ca(2+) influx, resulting in relaxation of precontracted ASM. This finding indicates that CEPN would be a candidate of new potent bronchodilators.


Malnutrition and high childhood mortality among the Onge tribe of the Andaman and Nicobar Islands.
A study was conducted among the Onge tribe of the Andaman and Nicobar Islands with the objectives of identifying demographic factors responsible for the decline in their population and assessing their nutritional status, which is an important determinant of child survival. The study included estimation of indices of fertility and child mortality, and assessment of nutritional status. All individuals of the Onge community settled on Little Andaman Island were included. The mean total marital fertility rate was estimated to be 5.15 live births per woman and the general fertility rate was 200 live births per 1000 married-woman-years. Although the gross reproduction rate was estimated to be 2.2 female children per married woman, the net reproduction rate was only 0.9 surviving female child per married woman. The mean infant mortality rate during the past 30 years was 192.7 per 1000 live births, and the child survival rate was found to be only 53.2%. A mild to moderate degree of malnutrition was found in 85% of children of pre-school age and severe malnutrition in 10%. The Onges had low intakes of iron, vitamin A and vitamin C. All the screened Onges were found to be infested with one or more intestinal parasites. High childhood mortality appears to be the predominant demographic factor responsible for the decline in the Onge population. The high prevalence of undernutrition and micronutrient deficiency disorders could be important factors contributing to the high childhood mortality.


Effects of GnRH vaccination in wild and captive African Elephant bulls (Loxodonta africana) on reproductive organs and semen quality.
Although the African elephant (Loxodonta africana) is classified as endangered by the International Union for Conservation of Nature (IUCN), in some isolated habitats in southern Africa, contraception is of major interest due to local overpopulation. GnRH vaccination has been promoted as a non-invasive contraceptive measure for population management of overabundant wildlife. We tested the efficacy of this treatment for fertility control in elephant bulls. In total, 17 male African elephants that were treated with a GnRH vaccine were examined in two groups. In the prospective study group 1 (n = 11 bulls, ages: 8-36 years), semen quality, the testes, seminal vesicles, ampullae and prostate, which were all measured by means of transrectal ultrasound, and faecal androgen metabolite concentrations were monitored over a three-year period. Each bull in the prospective study received 5 ml of Improvac® (1000 μg GnRH conjugate) intramuscularly after the first examination, followed by a booster six weeks later and thereafter every 5-7 months. In a retrospective study group (group 2, n = 6, ages: 19-33 years), one examination was performed on bulls which had been treated with GnRH vaccine for 5-11 years. In all bulls of group 1, testicular and accessory sex gland sizes decreased significantly after the third vaccination. In six males examined prior to vaccination and again after more than five vaccinations, the testis size was reduced by 57.5%. Mean testicular height and length decreased from 13.3 ± 2.6 cm x 15.2 ± 2.8 cm at the beginning to 7.6 ± 2.1 cm x 10.2 ± 1.8 cm at the end of the study. Post pubertal bulls (>9 years, n = 6) examined prior to vaccination produced ejaculates with viable spermatozoa (volume: 8-175 ml, sperm concentration: 410-4000x106/ml, total motility: 0-90%), while after 5-8 injections, only 50% of these bulls produced ejaculates with a small number of immotile spermatozoa. The ejaculates of group 2 bulls (vaccinated >8 times) were devoid of spermatozoa. Faecal androgen metabolite concentrations measured in captive males decreased significantly after the fourth vaccination. None of the males entered musth during the treatment period. Our results showed a marked decrease in semen quality, testicle and secondary sex gland sizes following repeated GnRH vaccinations. After 2-4 years of continuous treatment every 5-7 months, the effects were similar to surgical castration.


The Cameroon Mobile Phone SMS (CAMPS) trial: a randomized trial of text messaging versus usual care for adherence to antiretroviral therapy.
Mobile phone technology is a novel way of delivering health care and improving health outcomes. This trial investigates the use of motivational mobile phone text messages (SMS) to improve adherence to antiretroviral therapy (ART) over six months. CAMPS was a single-site randomized two-arm parallel design trial in Yaoundé, Cameroon. We enrolled and randomized HIV-positive adults on ART, aged 21 years and above to receive a weekly standardized motivational text message versus usual care alone. The primary outcome was adherence measured using a visual analogue scale (VAS), number of doses missed (in the week preceding the interview) and pharmacy refill data. Outcomes were measured at 3 and 6 months. Service providers and outcome assessors were blinded to allocation. Analysis was by intention-to-treat. Between November and December 2010, 200 participants were randomized, with 101 in the intervention group and 99 in the control group. At 6 months, overall retention was 81.5%. We found no significant effect on adherence by VAS>95% (risk ratio [RR] 1.06, 95% confidence interval [CI] 0.89, 1.29; p = 0.542; reported missed doses (RR 1.01, 95% CI 0.87, 1.16; p>0.999) or number of pharmacy refills (mean difference [MD] 0.1, 95% CI: 0.23, 0.43; p = 0.617. One participant in the intervention arm reported a possible disclosure of status. Standardized motivational mobile phone text messages did not significantly improve adherence to ART in this study. Other types of messaging or longer term studies are recommended. 1. Pan-African Clinical Trials Registry; PACTR201011000261458 2. Clinicaltrials.gov; NCT01247181.


Seasonal arsenic accumulation in stream sediments at a groundwater discharge zone.
Seasonal changes in arsenic and iron accumulation rates were examined in the sediments of a brook that receives groundwater discharges of arsenic and reduced iron. Clean glass bead columns were deployed in sediments for known periods over the annual hydrologic cycle to monitor changes in arsenic and iron concentrations in bead coatings. The highest accumulation rates occurred during the dry summer period (July-October) when groundwater discharges were likely greatest at the sample locations. The intermediate flow period (October-March), with higher surface water levels, was associated with losses of arsenic and iron from bead column coatings at depths below 2-6 cm. Batch incubations indicated iron releases from solids to be induced by biological reduction of iron (oxy)hydroxide solids. Congruent arsenic releases during incubation were limited by the high arsenic sorption capacity (0.536 mg(As)/mg(Fe)) of unreacted iron oxide solids. The flooded spring (March-June) with high surface water flows showed the lowest arsenic and iron accumulation rates in the sediments. Comparisons of accumulation rates across a shoreline transect were consistent with greater rates at regions exposed above surface water levels for longer times and greater losses at locations submerged below surface water. Iron (oxy)hydroxide solids in the shallowest sediments likely serve as a passive barrier to sorb arsenic released to pore water at depth by biological iron reduction.


Fibroblast growth factor-9 inhibits astrocyte differentiation of adult mouse neural progenitor cells.
Fibroblast growth factor-9 (FGF9) is expressed in the CNS and is reported to be a mitogen for glial cells, to promote neuronal survival, and to retard oligodendrocyte differentiation. Here we examined the effects of FGF9 on the differentiation, survival, and proliferation of adult neural progenitor cells derived from the adult mouse subventricular zone. FGF9 by itself induced neurosphere proliferation, but its effects were modest compared with those of epidermal growth factor and FGF2. When neurospheres were dissociated and plated for differentiation, FGF9 increased total cell number over time in a dose-dependent manner. Ki67 immunostaining and bromodeoxyuridine incorporation indicated that this was at least partially due to the continued presence of proliferative nestin-positive neural progenitor cells and betaIII tubulin-positive neuronal precursors. FGF9 also promoted cell survival as indicated by a decreased number of TUNEL-positive cells over time. Assessment of differentiation showed that FGF9 increased neuron generation that reflected the increase in total cell number; however, the percentage of progenitor cells differentiating into neurons was slightly decreased. FGF9 had a modest effect on oligodendrocyte generation, although it appeared to slow the maturation of oligodenrocytes at higher concentrations. The most marked effect on differentiation was an almost total lack of glial fibrillary acidic protein (GFAP)-positive astrocytes up to 7 days following FGF9 addition, indicating that astrocyte differentiation was strongly inhibited. Total inhibition required prolonged treatment, although a 1-hr pulse was sufficient for partial inhibition, and bone morphogenic protein-4 could partially overcome the FGF9 inhibition of astrocyte differentiation. FGF9 therefore has multiple effects on adult neural precursor cell function, enhancing neuronal precursor proliferation and specifically inhibiting GFAP expression.


Sex differences in foetal origins of child emotional symptoms: a test of evolutionary hypotheses in a large, general population cohort.
Based on previous findings from the Wirral Child Health and Development Study (WCHADS), and on evolutionary hypotheses, we preregistered analyses of data from a large epidemiological sample (https://osf.io/fn5g9/register/564d31db8c5e4a7c9694b2be), to test for sex-dependent moderation by prenatal maternal depressive symptoms of the association between postnatal maternal depressive symptoms and child emotional problems. A total of 8,354 mothers and children were followed from pregnancy to 3.5 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). Self-report measures of prenatal and postnatal maternal depressive symptoms, and maternal report of child emotional symptoms were administered. There was a three-way interaction between maternal prenatal and postnatal depression, and child sex (Coeff .042 95% CI 0.015 to 0.068, p = .002). This arose from moderation by prenatal depression, in opposite directions in boys and in girls. In boys, the association between postnatal depression and child emotional symptoms was weaker following lower prenatal depressive symptoms (interaction term coeff = .030, p = .001), and in girls, to a lesser extent, the association was stronger following lower prenatal depressive symptoms (interaction term coeff = -.012, p = .221). We replicated the finding from the WCHADS that prenatal depression modifies the association between postnatal depression and children's emotional problems in a sex-dependent fashion. In ALSPAC, the sex difference was explained mainly by a protective effect of low prenatal depression in boys, while in WCHADS, it arose from greater vulnerability of girls to postnatal depression following low prenatal depression. In the light of these findings, in evaluating and implementing early interventions, there is need to consider that risks associated with postnatal depression may vary depending on maternal mood during pregnancy and may differ between boys and girls.


Automatic tracking of arbitrarily shaped implanted markers in kilovoltage projection images: a feasibility study.
Certain types of commonly used fiducial markers take on irregular shapes upon implantation in soft tissue. This poses a challenge for methods that assume a predefined shape of markers when automatically tracking such markers in kilovoltage (kV) radiographs. The authors have developed a method of automatically tracking regularly and irregularly shaped markers using kV projection images and assessed its potential for detecting intrafractional target motion during rotational treatment. Template-based matching used a normalized cross-correlation with simplex minimization. Templates were created from computed tomography (CT) images for phantom studies and from end-expiration breath-hold planning CT for patient studies. The kV images were processed using a Sobel filter to enhance marker visibility. To correct for changes in intermarker relative positions between simulation and treatment that can introduce errors in automatic matching, marker offsets in three dimensions were manually determined from an approximately orthogonal pair of kV images. Two studies in anthropomorphic phantom were carried out, one using a gold cylindrical marker representing regular shape, another using a Visicoil marker representing irregular shape. Automatic matching of templates to cone beam CT (CBCT) projection images was performed to known marker positions in phantom. In patient data, automatic matching was compared to manual matching as an approximate ground truth. Positional discrepancy between automatic and manual matching of less than 2 mm was assumed as the criterion for successful tracking. Tracking success rates were examined in kV projection images from 22 CBCT scans of four pancreas, six gastroesophageal junction, and one lung cancer patients. Each patient had at least one irregularly shaped radiopaque marker implanted in or near the tumor. In addition, automatic tracking was tested in intrafraction kV images of three lung cancer patients with irregularly shaped markers during 11 volumetric modulated arc treatments. Purpose-built software developed at our institution was used to create marker templates and track the markers embedded in kV images. Phantom studies showed mean ± standard deviation measurement uncertainty of automatic registration to be 0.14 ± 0.07 mm and 0.17 ± 0.08 mm for Visicoil and gold cylindrical markers, respectively. The mean success rate of automatic tracking with CBCT projections (11 frames per second, fps) of pancreas, gastroesophageal junction, and lung cancer patients was 100%, 99.1% (range 98%-100%), and 100%, respectively. With intrafraction images (approx. 0.2 fps) of lung cancer patients, the success rate was 98.2% (range 97%-100%), and 94.3% (range 93%-97%) using templates from 1.25 mm and 2.5 mm slice spacing CT scans, respectively. Correction of intermarker relative position was found to improve the success rate in two out of eight patients analyzed. The proposed method can track arbitrary marker shapes in kV images using templates generated from a breath-hold CT acquired at simulation. The studies indicate its feasibility for tracking tumor motion during rotational treatment. Investigation of the causes of misregistration suggests that its rate of incidence can be reduced with higher frequency of image acquisition, templates made from smaller CT slice spacing, and correction of changes in intermarker relative positions when they occur.


The CH25H-CYP7B1-RORα axis of cholesterol metabolism regulates osteoarthritis.
Osteoarthritis-the most common form of age-related degenerative whole-joint disease1-is primarily characterized by cartilage destruction, as well as by synovial inflammation, osteophyte formation and subchondral bone remodelling2,3. However, the molecular mechanisms that underlie the pathogenesis of osteoarthritis are largely unknown. Although osteoarthritis is currently considered to be associated with metabolic disorders, direct evidence for this is lacking, and the role of cholesterol metabolism in the pathogenesis of osteoarthritis has not been fully investigated4-6. Various types of cholesterol hydroxylases contribute to cholesterol metabolism in extrahepatic tissues by converting cellular cholesterol to circulating oxysterols, which regulate diverse biological processes7,8. Here we show that the CH25H-CYP7B1-RORα axis of cholesterol metabolism in chondrocytes is a crucial catabolic regulator of the pathogenesis of osteoarthritis. Osteoarthritic chondrocytes had increased levels of cholesterol because of enhanced uptake, upregulation of cholesterol hydroxylases (CH25H and CYP7B1) and increased production of oxysterol metabolites. Adenoviral overexpression of CH25H or CYP7B1 in mouse joint tissues caused experimental osteoarthritis, whereas knockout or knockdown of these hydroxylases abrogated the pathogenesis of osteoarthritis. Moreover, retinoic acid-related orphan receptor alpha (RORα) was found to mediate the induction of osteoarthritis by alterations in cholesterol metabolism. These results indicate that osteoarthritis is a disease associated with metabolic disorders and suggest that targeting the CH25H-CYP7B1-RORα axis of cholesterol metabolism may provide a therapeutic avenue for treating osteoarthritis.


Cultural adaptation of physical activity self-report instruments.
The validity of physical activity (PA) self-report measures can be a problem when using these measures with target populations that differ from the population for which the measures were originally developed. Describe an approach to further tailor PA self-report measures to a target community, and report on focus group and cognitive interview findings. Topics relevant to culturally tailoring measures are discussed, including translation, focus groups, and cognitive interviews. We describe examples from our own work, including focus groups and cognitive interviews conducted to assess Latinos' interpretations of PA questions derived from various epidemiological surveys that were developed in White communities. Findings from focus groups and cognitive interviews provide valuable information about the comprehension, interpretation, and cultural relevance of the PA questions to Latino communities. It is recommended that investigators collect formative data to better assess the equivalence of items being applied to a different cultural group. Guidelines for cultural attunement of self-report instruments are described to promote more uniform and rigorous processes of adaptation and facilitate cross-cultural investigations.


Local active suppression by suppressor cells in the decidua: a review.
The immunological survival of the antigen-bearing mammalian feto-placental unit is determined by the functional properties of the tissues at the feto-maternal interface. Antigen-specific systemic suppressor mechanisms such as suppressor T cells and nonantigen-specific suppressive serum factors appear not to play a major role in protection of the fetus. A novel type of non-MHC specific suppressor cell accumulates locally in the decidua of successfully allopregnant mice. This decidua-associated suppressor is a small lymphocytic cell possessing cytoplasmic granules, lacks T cell markers, and is deficient in number and activity at the implantation sites of viable xenogeneic Mus caroli embryos gestating in the uterus of Mus musculus animals at the time that maternal lymphoid cells begin to infiltrate the xenoembryos. These Mus caroli embryos subsequently resorb. Further experimental studies suggest that the trophoblast cells associated with successful pregnancy recruit bone-marrow derived maternal non-T suppressor cells to the decidua and thus, by an indirect mechanism, may act to protect the fetus from effector cells of the mother's immune system.


Application of luminescent Eu:Gd2O3 nanoparticles to the visualization of protein micropatterns.
Nanoparticle phosphors made of lanthanide oxides are a promising new class of tags in biochemistry because of their large Stokes shift, sharp emission spectra, long luminescence lifetime, and good photostability. We demonstrate the application of these nanoparticles to the visualization of protein micropatterns. Luminescent europium-doped gadolinium oxide (Eu:Gd2O3) nanoparticles are synthesized by spray pyrolysis. The size distribution is from 5 to 200 nm. The particles are characterized by means of laser-induced fluorescent spectroscopy and transmission electron microscopy (TEM). The main emission peak is at 612 nm. The nanoparticles are coated with avidin through physical adsorption. biotinylated bovine serum albumin (BSA-b) is patterned on a silicon wafer using a microcontact printing technique. The wafer is then incubated in a solution of avidin-coated nanoparticles. Fluorescent microscopic images reveal that the nanoparticles are organized onto designated area, as defined by the microcontact printing process. The luminescent nanoparticles do not suffer photobleaching during the observation, which demonstrates their suitability as luminescent labels for fluorescence microscopy studies. More detailed studies are preformed using atomic-force microscopy (AFM) at a single nanoparticle level. The specific and the nonspecific binding densities of the particles are qualitatively evaluated.


Molecular basis of Rrn3-regulated RNA polymerase I initiation and cell growth.
Cell growth is regulated during RNA polymerase (Pol) I transcription initiation by the conserved factor Rrn3/TIF-IA in yeast/humans. Here we provide a structure-function analysis of Rrn3 based on a combination of structural biology with in vivo and in vitro functional assays. The Rrn3 crystal structure reveals a unique HEAT repeat fold and a surface serine patch. Phosphorylation of this patch represses human Pol I transcription, and a phospho-mimetic patch mutation prevents Rrn3 binding to Pol I in vitro and reduces cell growth and Pol I gene occupancy in vivo. Cross-linking indicates that Rrn3 binds Pol I between its subcomplexes, AC40/19 and A14/43, which faces the serine patch. The corresponding region of Pol II binds the Mediator head that cooperates with transcription factor (TF) IIB. Consistent with this, the Rrn3-binding factor Rrn7 is predicted to be a TFIIB homolog. This reveals the molecular basis of Rrn3-regulated Pol I initiation and cell growth, and indicates a general architecture of eukaryotic transcription initiation complexes.


Exploitation of Nanotechnology for the Monitoring of Waterborne Pathogens: State-of-the-Art and Future Research Priorities.
Contaminated drinking water is one of the most important environmental contributors to the human disease burden. Monitoring of water for the presence of pathogens is an essential part of ensuring drinking water safety. In order to assess water quality it is essential to have methods available to sample and detect the type, level and viability of pathogens in water which are effective, cheap, quick, sensitive, and where possible high throughput. Nanotechnology has the potential to drastically improve the monitoring of waterborne pathogens when compared to conventional approaches. To date, there have been no reviews that outline the applications of nanotechnology in this area despite increasing exploitation of nanotechnology for this purpose. This review is therefore the first overview of the state-of-the-art in the application of nanotechnology to waterborne pathogen sampling and detection schemes. Research in this field has been centered on the use of engineered nanomaterials. The effectiveness and limitations of nanomaterial-based approaches is outlined. A future outlook of the advances that are likely to emerge in this area, as well as recommendations for areas of further research are provided.


Failure of Myf5 to support myogenic differentiation without myogenin, MyoD, and MRF4.
The basic helix-loop-helix (bHLH) transcription factors-MyoD, Myf5, myogenin, and MRF4-can each activate the skeletal muscle-differentiation program in transfection assays. However, their functions during embryogenesis, as revealed by gene-knockout studies in mice, are distinct. MyoD and Myf5 have redundant functions in myoblast specification, whereas myogenin and either MyoD or MRF4 are required for differentiation. Paradoxically, myoblasts from myogenin mutant or MyoD/MRF4 double-mutant neonates differentiate normally in vitro, despite their inability to differentiate in vivo, suggesting that the functions of the myogenic bHLH factors are influenced by the cellular environment and that the specific myogenic defects observed in mutant mice do not necessarily reflect essential functions of these factors. Understanding the individual roles of these factors is further complicated by their ability to cross-regulate one another's expression. To investigate the functions of Myf5 in the absence of contributions from other myogenic bHLH factors, we generated triple-mutant mice lacking myogenin, MyoD, and MRF4. These mice appear to contain a normal number of myoblasts, but in contrast to myogenin or MyoD/MRF4 mutants, differentiated muscle fibers fail to form in vivo and myoblasts from neonates of this triple-mutant genotype are unable to differentiate in vitro. These results suggest that physiological levels of Myf5 are insufficient to activate the myogenic program in the absence of other myogenic factors and suggest that specialized functions have evolved for the myogenic bHLH factors to switch on the complete program of muscle gene expression.


Epigenetic targeting of ovarian cancer stem cells.
Emerging results indicate that cancer stem-like cells contribute to chemoresistance and poor clinical outcomes in many cancers, including ovarian cancer. As epigenetic regulators play a major role in the control of normal stem cell differentiation, epigenetics may offer a useful arena to develop strategies to target cancer stem-like cells. Epigenetic aberrations, especially DNA methylation, silence tumor-suppressor and differentiation-associated genes that regulate the survival of ovarian cancer stem-like cells (OCSC). In this study, we tested the hypothesis that DNA-hypomethylating agents may be able to reset OCSC toward a differentiated phenotype by evaluating the effects of the new DNA methytransferase inhibitor SGI-110 on OCSC phenotype, as defined by expression of the cancer stem-like marker aldehyde dehydrogenase (ALDH). We demonstrated that ALDH(+) ovarian cancer cells possess multiple stem cell characteristics, were highly chemoresistant, and were enriched in xenografts residual after platinum therapy. Low-dose SGI-110 reduced the stem-like properties of ALDH(+) cells, including their tumor-initiating capacity, resensitized these OCSCs to platinum, and induced reexpression of differentiation-associated genes. Maintenance treatment with SGI-110 after carboplatin inhibited OCSC growth, causing global tumor hypomethylation and decreased tumor progression. Our work offers preclinical evidence that epigenome-targeting strategies have the potential to delay tumor progression by reprogramming residual cancer stem-like cells. Furthermore, the results suggest that SGI-110 might be administered in combination with platinum to prevent the development of recurrent and chemoresistant ovarian cancer.


Redirecting NK cells mediated tumor cell lysis by a new recombinant bifunctional protein.
Natural killer (NK) cells are at the crossroad between innate and adaptive immunity and play a major role in cancer immunosurveillance. NK cell stimulation depends on a balance between inhibitory and activating receptors, such as the stimulatory lectin-like receptor NKG2D. To redirect NK cells against tumor cells, we designed bifunctional proteins able to specifically bind tumor cells and to induce their lysis by NK cells, after NKG2D engagement. To this aim, we used the 'knob into hole' heterodimerization strategy, in which 'knob' and 'hole' variants were generated by directed mutagenesis within the CH3 domain of human IgG1 Fc fragments fused to an anti-CEA or anti-HER2 scFv or to the H60 murine ligand of NKG2D, respectively. We demonstrated the capacity of the bifunctional proteins produced to specifically coat tumor cells surface with H60 ligand. Most importantly, we demonstrated that these bifunctional proteins were able to induce an NKG2D-dependent and antibody-specific tumor cell lysis by murine NK cells. Overall, the results show the possibility to redirect NK cytotoxicity to tumor cells by a new format of recombinant bispecific antibody, opening the way of potential NK cell-based cancer immunotherapies by specific activation of the NKG2D receptor at the tumor site.


Multiwavelength laser designed for single-frame digital holography.
In this paper, we present a tailored multiwavelength Yb-fiber laser source in the 1.03 μm spectral region for spatially multiplexed digital holographic acquisitions. The wavelengths with bandwidths below 0.1 nm were spectrally separated by approximately 1 nm by employing fiber Bragg gratings for spectral control. As a proof of concept, the shape of a cylindrically shaped object with a diameter of 48 mm was measured. The holographic acquisition was performed in single-shot dual-wavelength mode with a synthetic wavelength of 1.1 mm, and the accuracy was estimated to be 3% of the synthetic wavelength.


The Molecular Biology Database Collection: 2003 update.
The Molecular Biology Database Collection is an online resource listing key databases of value to the biological community. This Collection is intended to bring fellow scientists' attention to high-quality databases that are available throughout the world, rather than just be a lengthy listing of all available databases. As such, this up-to-date listing is intended to serve as the jumping-off point from which to find specialized databases that may be of use in advancing biological research. The databases included in this Collection provide new value to the underlying data by virtue of curation, new data connections or other innovative approaches. Short, searchable summaries and updates for each of the databases included in this Collection are available through the Nucleic Acids Research Web site at http://nar.oupjournals.org.


Induction of apoptosis by Panduratin A isolated from Kaempferia pandurata in human colon cancer HT-29 cells.
We previously showed that panduratin A isolated from an extract of Kaempferia pandurata (Zingiberaceae) was a strong inhibitor of cyclooxygenase-2 (COX-2) in RAW264.7 cells, suggesting a potential use of panduratin A as an anti-inflammatory agent. In the present study, we have investigated the effects of panduratin A on cytoplasmic levels of COX-2, as well as proliferation and apoptosis in human colon cancer cells HT-29. Cell proliferation and induction of apoptosis was determined by the MTT assay, DNA fragmentation measurement, flow cytometric analysis, nuclear staining and Western blotting. The MTT assay indicated that panduratin A exhibited cytotoxicity with an IC50 value of 28 microM. The cytotoxic effects of panduratin A were found to be accompanied by the dose-dependent induction of apoptosis as assessed by DNA fragmentation and apoptotic bodies. In addition, treatment with an apoptosis-inducing concentration of panduratin A resulted in cleavage of poly(ADP-ribose) polymerase (PARP) with a concomitant decrease in procaspase-3 protein. Our study provides evidence for cell growth inhibition and induction of apoptosis by panduratin A in human colon cancer cells, suggesting its potential use as a cancer chemopreventive and therapeutic agent.


Patient out-of-pocket spending in cranial neurosurgery: single-institution analysis of 6569 consecutive cases and literature review.
OBJECTIVE With drastic changes to the health insurance market, patient cost sharing has significantly increased in recent years. However, the patient financial burden, or out-of-pocket (OOP) costs, for surgical procedures is poorly understood. The goal of this study was to analyze patient OOP spending in cranial neurosurgery and identify drivers of OOP spending growth. METHODS For 6569 consecutive patients who underwent cranial neurosurgery from 2013 to 2016 at the authors' institution, the authors created univariate and multivariate mixed-effects models to investigate the effect of patient demographic and clinical factors on patient OOP spending. The authors examined OOP payments stratified into 10 subsets of case categories and created a generalized linear model to study the growth of OOP spending over time. RESULTS In the multivariate model, case categories (craniotomy for pain, tumor, and vascular lesions), commercial insurance, and out-of-network plans were significant predictors of higher OOP payments for patients (all p < 0.05). Patient spending varied substantially across procedure types, with patients undergoing craniotomy for pain ($1151 ± $209) having the highest mean OOP payments. On average, commercially insured patients spent nearly twice as much in OOP payments as the overall population. From 2013 to 2016, the mean patient OOP spending increased 17%, from $598 to $698 per patient encounter. Commercially insured patients experienced more significant growth in OOP spending, with a cumulative rate of growth of 42% ($991 in 2013 to $1403 in 2016). CONCLUSIONS Even after controlling for inflation, case-mix differences, and partial fiscal periods, OOP spending for cranial neurosurgery patients significantly increased from 2013 to 2016. The mean OOP spending for commercially insured neurosurgical patients exceeded $1400 in 2016, with an average annual growth rate of 13%. As patient cost sharing in health insurance plans becomes more prevalent, patients and providers must consider the potential financial burden for patients receiving specialized neurosurgical care.


Calcified epidural hematoma in pediatric age group: A report of two cases.
The authors present a rare case of calcified (ossified) chronic epidural hematoma developed in a six-and-a-half-year-old female patient who was operated for cerebellar astrocytoma 6 months earlier. There was no history of trauma. Ossified epidural hematoma was seen as an incidental finding in the follow-up in computed tomography scan after 6 months of primary glioma surgery. Ossified chronic epidural hematoma with thick collagenous wall and newly formed bone on dura was excised. The development of calcified chronic subdural hematoma after decompressive intracranial surgery is a well-known occurrence, but the fact that a calcified epidural hematoma, which is rare and which can also develop after decompressive surgery, and the occurrence of calcified (ossified) epidural hematoma after postfossa a glioma surgery is not yet reported. The second case is a 9-year-old male anemic child with a history of fall while playing 5 months earlier who presented with headache of 3 months duration. He had bifrontal calcified epidural hematoma operated by craniotomy and excision of calcified dural edge.


The cell-layer- and cell-type-specific distribution of GalNAc-transferases in the ocular surface epithelia is altered during keratinization.
It has been hypothesized that the biosynthesis of O-linked glycans on proteins, particularly on the highly O-glycosylated mucins, by the corneal and conjunctival epithelium is necessary for the protection and maintenance of a healthy ocular surface. The initial step in O-glycosylation is the enzymatic addition of N-acetyl galactosamine (GalNAc) to serine and threonine residues by a large family of polypeptide GalNAc-transferases (GalNAc-Ts). The purpose of this study was to determine the cellular distribution of GalNAc-Ts in the normal ocular surface epithelia and to compare their distribution with that in pathologically keratinized conjunctival epithelia. Five conjunctival biopsy specimens and 5 corneas from normal individuals, and 14 conjunctival specimens from patients with ocular cicatricial pemphigoid (OCP) were used. Based on the histologic characteristics of their epithelia, OCP specimens were divided into two groups: less advanced, nonkeratinized (n = 6), and late-stage, keratinized (n = 8). Five monoclonal antibodies raised against the GalNAc-T1, -T2, -T3, -T4, and -T6 isoenzymes, were used for immunofluorescence microscopic localization according to standard protocols. Immunohistochemical studies revealed the presence of GalNAc-T2, -T3, and -T4 isoforms within the stratified epithelium of the cornea and the conjunctiva. The GalNAc-T4 isoenzyme was found in the apical cell layers, whereas GalNAc-T2 was found in the supranuclear region of the basal cell layers of both cornea and conjunctiva. GalNAc-T3 was distributed throughout the entire ocular surface epithelium, whereas GalNAc-T1 was found in scattered cells in conjunctiva only. Binding of antibody to GalNAc-T6 was restricted exclusively to conjunctival goblet cells. There were distinct alterations in expression patterns of GalNAc-T2, -T6, and -T1 in nonkeratinized OCP epithelia compared with normal epithelia. Both GalNAc-T2 and -T6 were expressed in the apical stratified epithelia, and T1 was detected in all cell layers in five of six biopsy specimens. By comparison with nonkeratinized OCP epithelia, a marked reduction in the binding of GalNAc-T antibody was observed in the late-stage keratinized conjunctival epithelia of patients with OCP. In all samples, apical GalNAc-T2 was absent, and GalNAc-T6 was entirely absent. Only one of eight samples was positive for GalNAc-T1. The presence of GalNAc-T isoenzymes in the human corneal and conjunctival epithelia is cell-layer and cell-type specific. The increased distribution of GalNAc-Ts observed in early stages of the keratinization process in patients with OCP suggests a compensatory attempt of the ocular surface epithelium to synthesize mucin-type O-glycans to maintain a wet-surface phenotype. This early increase in isoenzymes in nonkeratinized OCP epithelia is reduced as keratinization proceeds in the disease.


Worldwide Variation in the Use of Nuclear Cardiology Camera Technology, Reconstruction Software, and Imaging Protocols.
This study sought to describe worldwide variations in the use of myocardial perfusion imaging hardware, software, and imaging protocols and their impact on radiation effective dose (ED). Concerns about long-term effects of ionizing radiation have prompted efforts to identify strategies for dose optimization in myocardial perfusion scintigraphy. Studies have increasingly shown opportunities for dose reduction using newer technologies and optimized protocols. Data were submitted voluntarily to the INCAPS (International Atomic Energy Agency Nuclear Cardiology Protocols Study) registry, a multinational, cross-sectional study comprising 7,911 imaging studies from 308 labs in 65 countries. The study compared regional use of camera technologies, advanced post-processing software, and protocol characteristics and analyzed the influence of each factor on ED. Cadmium-zinc-telluride and positron emission tomography (PET) cameras were used in 10% (regional range 0% to 26%) and 6% (regional range 0% to 17%) of studies worldwide. Attenuation correction was used in 26% of cases (range 10% to 57%), and advanced post-processing software was used in 38% of cases (range 26% to 64%). Stress-first single-photon emission computed tomography (SPECT) imaging comprised nearly 20% of cases from all world regions, except North America, where it was used in just 7% of cases. Factors associated with lower ED and odds ratio for achieving radiation dose ≤9 mSv included use of cadmium-zinc-telluride, PET, advanced post-processing software, and stress- or rest-only imaging. Overall, 39% of all studies (97% PET and 35% SPECT) were ≤9 mSv, while just 6% of all studies (32% PET and 4% SPECT) achieved a dose ≤3 mSv. Newer-technology cameras, advanced software, and stress-only protocols were associated with reduced ED, but worldwide adoption of these practices was generally low and varied significantly between regions. The implementation of dose-optimizing technologies and protocols offers an opportunity to reduce patient radiation exposure across all world regions.


Selective vesicle aggregation achieved via the self-assembly of terpyridine-based building blocks.
Herein, we report the self-assembly of a mono terpyridine-based building block modified with long alkyl chains, which gives rise to vesicular aggregates in aqueous media. The vesicles are responsive to transition metal ions, and form different kinds of aggregates after metal-ligand coordination. In particular, Ni(ii) shows a unique influence on morphological transitions, whereby vesicles aggregate and fuse upon the addition of Ni(ii) ions. Spectroscopic and morphological studies are highlighted in this work. Furthermore, the formed vesicles could behave as a matrix for encapsulating fluorescent dyes with similar molecular structure via co-assembly, enabling more accurate observation of vesicle aggregation via confocal laser scanning techniques.


Predictive validity for the clinical diagnosis of a new parent questionnaire, the CABI, compared with CBCL.
The questionnaires completed by the parents give a first general information on the behavioral problems of the child-adolescent, as a useful orientation to the clinical evaluation. The Child and Adolescent Behavior Inventory (CABI) is a 75-item parent questionnaire, which explores a large number of problem areas. The study of its predictive validity for the clinical diagnosis, in comparison with the Diagnostic and Statistical Manual of Mental Disorders (DSM)-oriented scales of the Child Behavior Checklist (CBCL), can assess whether its use may be advantageous. Parents/caregivers of 462 children and adolescents responded to both CABI and CBCL as a preliminary routine investigation. The results were compared with those of diagnoses obtained after the completion of the usual clinical procedure. Accuracy values (probability of correct classification) resulted high for both instruments and significantly better for CABI anxiety and attention-deficit hyperactivity disorder (ADHD) scales, and for CBCL oppositional defiant disorder (ODD) and conduct disorder (CD) scales; no significant difference was found for depression scales. All the areas under the curve (AUC) of the receiver operating characteristic analysis reached excellent values, suggesting a very good predictive ability of the five scales of the two instruments. The comparison of AUC showed the CABI's anxiety and ADHD scales to give significantly higher values than those of CBCL, indicating that these two scales have a better predictive ability. The study indicates a very good comparative (vs CBCL) and predictive validity of the CABI, suggesting an advantage in the use of this shorter questionnaire, available for free use both for clinical practice and supposedly for screening and epidemiological evaluations.


Pathology Laboratory Surveillance in the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance of Sexually Transmitted Infections and Blood-Borne Viruses: Protocol for a Cohort Study.
Passive surveillance is the principal method of sexually transmitted infection (STI) and blood-borne virus (BBV) surveillance in Australia whereby positive cases of select STIs and BBVs are notified to the state and territory health departments. A major limitation of passive surveillance is that it only collects information on positive cases and notifications are heavily dependent on testing patterns. Denominator testing data are important in the interpretation of notifications. The aim of this study is to establish a national pathology laboratory surveillance system, part of a larger national sentinel surveillance system called ACCESS (the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance). ACCESS is designed to utilize denominator testing data to understand trends in case reporting and monitor the uptake and outcomes of testing for STIs and BBVs. ACCESS involves a range of clinical sites and pathology laboratories, each with a separate method of recruitment, data extraction, and data processing. This paper includes pathology laboratory sites only. First established in 2007 for chlamydia only, ACCESS expanded in 2012 to capture all diagnostic and clinical monitoring tests for STIs and BBVs, initially from pathology laboratories in New South Wales and Victoria, Australia, to at least one public and one private pathology laboratory in all Australian states and territories in 2016. The pathology laboratory sentinel surveillance system incorporates a longitudinal cohort design whereby all diagnostic and clinical monitoring tests for STIs and BBVs are collated from participating pathology laboratories in a line-listed format. An anonymous, unique identifier will be created to link patient data within and between participating pathology laboratory databases and to clinical services databases. Using electronically extracted, line-listed data, several indicators for each STI and BBV can be calculated, including the number of tests, unique number of individuals tested and retested, test yield, positivity, and incidence. To date, over 20 million STI and BBV laboratory test records have been extracted for analysis for surveillance monitoring nationally. Recruitment of laboratories is ongoing to ensure appropriate coverage for each state and territory; reporting of indicators will occur in 2019 with publication to follow. The ACCESS pathology laboratory sentinel surveillance network is a unique surveillance system that collects data on diagnostic testing, management, and care for and of STIs and BBVs. It complements the ACCESS clinical network and enhances Australia's capacity to respond to STIs and BBVs. DERR1-10.2196/13625.


Disulfide-linked gamma delta T cell antigen receptors expressed on T cells derived from patients with primary immunodeficiency disorders.
T cell lines or clones from two patients, one with a partial DiGeorge syndrome and one with severe common variable immunodeficiency expressed disulfide-linked gamma delta T cell antigen receptor (TCR) comprised of a gamma-chain polypeptide of 40-43 kD, and a delta-chain polypeptide of 37-40 kD. This gamma delta TCR appears to be similar to that found on T cell clones, and lines derived from peripheral blood lymphocytes from normal donors. Previous studies have shown that T cell lines derived from the peripheral blood of patients with immunodeficiency disorders express non-disulfide-linked gamma delta TCR. In contrast to the latter and coincident with findings in the present study, the vast majority of T cell lines and clones derived from the peripheral blood of normal donors express disulfide-linked gamma delta TCR.


Prostaglandin synthesis elicited by adrenergic stimuli is mediated via alpha-2C and alpha-1A adrenergic receptors in cultured smooth muscle cells of rabbit aorta.
This study was performed to characterize the subtype of adrenergic receptor(s) (AR) involved in prostacyclin synthesis [measured as 6-keto-prostaglandin (PG)F1 alpha] elicited by AR agonists in cultured vascular smooth muscle cells of rabbit aorta. Both alpha-1 and alpha-2 AR agonists enhanced 6-keto-PGF1 alpha synthesis in a dose-dependent manner with the following order of potency: norepinephrine greater than BHT 933 greater than UK 14304 greater than xylazine greater than phenylephrine greater than or equal to methoxamine greater than cirazoline. Isoproterenol and oxymetazoline did not alter 6-keto-PGF1 alpha synthesis. Methoxamine-induced 6-keto-PGF1 alpha synthesis was not reduced by the alpha-2 AR antagonist rauwolscine. The affinities of AR antagonists (PA2 value) in inhibiting methoxamine-induced 6-keto-PGF1 alpha synthesis were of the following order: prazosin greater than WB 4101 greater than corynanthine greater than yohimbine. Administration of WB 4101 and the irreversible alpha-1B AR antagonist chloroethylclonidine reduced norepinephrine (in the presence of rauwolscine, 10(-8) M)- or methoxamine-induced 6-keto-PGF1 alpha synthesis; WB 4101 was more potent than chloroethylclonidine. UK 14304-induced 6-keto-PGF1 alpha synthesis was not reduced by chloroethylclonidine or BRL 44408, a selective alpha-2A AR antagonist, but it was inhibited by other alpha AR antagonists. The affinities of AR antagonists (PA2 values) in inhibiting UK 14304-induced 6-keto-PGF1 alpha synthesis were of the following order: rauwolscine greater than yohimbine greater than BAM 1303 greater than BRL 41992 greater than WB 4101 greater than ARC 239 greater than or equal to prazosin greater than SKF 104078 greater than or equal to corynanthine. The order of affinity of alpha-2 AR antagonists in inhibiting UK 14304-induced 6-keto-PGF1 alpha synthesis in vascular smooth muscle cells was similar to that derived from radioligand binding studies in opossum kidney cell line receptors classified as alpha-2C receptors. These data suggest that 6-keto-PGF1 alpha synthesis elicited by adrenergic stimuli in cultured vascular smooth muscle cells of rabbit aorta is mediated primarily via alpha-2C and to a lesser extent alpha-1A receptors.


Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration.
For investigation of the pathogenesis of cerebral malaria, immediate postmortem samples from brain and other tissues of patients dying with Plasmodium falciparum malaria, with (CM) or without (NCM) cerebral malaria, were processed for electron microscopy. Counts of parasitized erythrocytes (PRBCs) in cerebral and other vessels showed that the proportion of PRBCs was higher in CM than in NCM, and also that the proportion of PRBCs was higher in the brain than in other organs examined in both CM and NCM. Cerebral vessels from CM patients were more tightly packed with RBCs than those from NCM patients, but there was no significant difference in the amount or degree of endothelial damage or numbers of vessels with endothelial pseudopodia. Fibrillar (fibrin) deposits were present in a small proportion of vessels, but no thrombosis was present. There was neither acute nor chronic inflammation, and leukocytes were absent within or outside cerebral vessels. There was no immune complex deposition in cerebral vessels. Parasites in cerebral vessels were mainly trophozoites or schizonts. Occasional RBC remnants following parasite release were seen. Some parasites were degenerate, resembling crisis forms. PRBCs adhered to endothelium via surface knobs. It is concluded that there is no evidence for an inflammatory or immune pathogenesis for human cerebral malaria and that the clinical effects probably relate to anoxia and the metabolic activities of the parasites.


Oral mucosal endotoxin tolerance induction in chronic periodontitis.
The oral mucosa is exposed to a high density and diversity of gram-positive and gram-negative bacteria, but very little is known about how immune homeostasis is maintained in this environment, particularly in the inflammatory disease chronic periodontitis (CP). The cells of the innate immune response recognize bacterial structures via the Toll-like receptors (TLR). This activates intracellular signaling and transcription of proteins essential for the induction of an adaptive immune response; however, if unregulated, it can lead to destructive inflammatory responses. Using single-immunoenzyme labeling, we show that the human oral mucosa (gingiva) is infiltrated by large numbers of TLR2(+) and TLR4(+) cells and that their numbers increase significantly in CP, relative to health (P < 0.05, Student's t test). We also show that the numbers of TLR2(+) but not TLR4(+) cells increase linearly with inflammation (r(2) = 0.33, P < 0.05). Double-immunofluorescence analysis confirms that TLR2 is coexpressed by monocytes (MC)/macrophages (mphi) in situ. Further analysis of gingival tissues by quantitative real-time PCR, however, indicates that despite a threefold increase in the expression of interleukin-1beta (IL-1beta) mRNA during CP, there is significant (30-fold) downregulation of TLR2 mRNA (P < 0.05, Student's t test). Also showing similar trends are the levels of TLR4 (ninefold reduction), TLR5 (twofold reduction), and MD-2 (sevenfold reduction) mRNA in CP patients compared to healthy persons, while the level of CD14 was unchanged. In vitro studies with human MC indicate that MC respond to an initial stimulus of lipopolysaccharide (LPS) from Porphyromonas gingivalis (PgLPS) or Escherichia coli (EcLPS) by upregulation of TLR2 and TLR4 mRNA and protein; moreover, IL-1beta mRNA is induced and tumor necrosis factor alpha (TNF-alpha), IL-10, IL-6, and IL-8 proteins are secreted. However, restimulation of MC with either PgLPS or EcLPS downregulates TLR2 and TLR4 mRNA and protein and IL-1beta mRNA and induces a ca. 10-fold reduction in TNF-alpha secretion, suggesting the induction of endotoxin tolerance by either LPS. Less susceptible to tolerance than TNF-alpha were IL-6, IL-10, and IL-8. These studies suggest that certain components of the innate oral mucosal immune response, most notably TLRs and inflammatory cytokines, may become tolerized during sustained exposure to bacterial structures such as LPS and that this may be one mechanism used in the oral mucosa to attempt to regulate local immune responses.


Comparative analysis of quantitative trait loci controlling glucosinolates, myrosinase and insect resistance in Arabidopsis thaliana.
Evolutionary interactions among insect herbivores and plant chemical defenses have generated systems where plant compounds have opposing fitness consequences for host plants, depending on attack by various insect herbivores. This interplay complicates understanding of fitness costs and benefits of plant chemical defenses. We are studying the role of the glucosinolate-myrosinase chemical defense system in protecting Arabidopsis thaliana from specialist and generalist insect herbivory. We used two Arabidopsis recombinant inbred populations in which we had previously mapped QTL controlling variation in the glucosinolate-myrosinase system. In this study we mapped QTL controlling resistance to specialist (Plutella xylostella) and generalist (Trichoplusia ni) herbivores. We identified a number of QTL that are specific to one herbivore or the other, as well as a single QTL that controls resistance to both insects. Comparison of QTL for herbivory, glucosinolates, and myrosinase showed that T. ni herbivory is strongly deterred by higher glucosinolate levels, faster breakdown rates, and specific chemical structures. In contrast, P. xylostella herbivory is uncorrelated with variation in the glucosinolate-myrosinase system. This agrees with evolutionary theory stating that specialist insects may overcome host plant chemical defenses, whereas generalists will be sensitive to these same defenses.


Growth schedule of Xanthium canadense: Does it optimize the timing of reproduction?
The effects of nutrition on the timing of reproductive initiation of a short-day annual plant Xanthium canadense (cocklebur) were examined with the following hypotheses in mind: If the plant always follows an optimal growth schedule, low-nutrient plants will initiate reproductive growth earlier than high-nutrient plants. On the other hand, if the plant flowers in response to photoperiodic stimuli, both plants will initiate reproductive growth on the same day. The sand-culture experiment showed that high-nutrient plants flowered earlier than the low-nutrient plants, leading to rejection of the first hypothesis. The predicted optimal flowering time is 2 days later than the actual flowering time in high-nutrient plants and 10 days earlier in low-nutrient plants. These deviations from the optimal times reduced the reproductive yield by 0.1% and 2.3%, respectively. The ratio of the final reproductive yield to the vegetative mass at flower initiation was 1.10 in high-nutrient plants and 0.63 in low-nutrient plants. Since the expected ratio for the optimal growth schedule is 1.0, high-nutrient plants followed the opitmal growth schedule more closely than the low-nutrient plants. Cocklebur is a fast-growing annual which is common in relatively nutrient-rich environments. This study suggests that cocklebur adapts itself to such environments through its photoperiodic response.


Coral species composition drives key ecosystem function on coral reefs.
Rapid and unprecedented ecological change threatens the functioning and stability of ecosystems. On coral reefs, global climate change and local stressors are reducing and reorganizing habitat-forming corals and associated species, with largely unknown implications for critical ecosystem functions such as herbivory. Herbivory mediates coral-algal competition, thereby facilitating ecosystem recovery following disturbance such as coral bleaching events or large storms. However, relationships between coral species composition, the distribution of herbivorous fishes and the delivery of their functional impact are not well understood. Here, we investigate how herbivorous fish assemblages and delivery of two distinct herbivory processes, grazing and browsing, differ among three taxonomically distinct, replicated coral habitats. While grazing on algal turf assemblages was insensitive to different coral configurations, browsing on the macroalga Laurencia cf. obtusa varied considerably among habitats, suggesting that different mechanisms may shape these processes. Variation in browsing among habitats was best predicted by the composition and structural complexity of benthic assemblages (in particular the cover and composition of corals, but not macroalgal cover), and was poorly reflected by visual estimates of browser biomass. Surprisingly, the lowest browsing rates were recorded in the most structurally complex habitat, with the greatest cover of coral (branching Porites habitat). While the mechanism for the variation in browsing is not clear, it may be related to scale-dependent effects of habitat structure on visual occlusion inhibiting foraging activity by browsing fishes, or the relative availability of alternate dietary resources. Our results suggest that maintained functionality may vary among distinct and emerging coral reef configurations due to ecological interactions between reef fishes and their environment determining habitat selection.


Cauliflower fractal forms arise from perturbations of floral gene networks.
Throughout development, plant meristems regularly produce organs in defined spiral, opposite, or whorl patterns. Cauliflowers present an unusual organ arrangement with a multitude of spirals nested over a wide range of scales. How such a fractal, self-similar organization emerges from developmental mechanisms has remained elusive. Combining experimental analyses in an Arabidopsis thaliana cauliflower-like mutant with modeling, we found that curd self-similarity arises because the meristems fail to form flowers but keep the "memory" of their transient passage in a floral state. Additional mutations affecting meristem growth can induce the production of conical structures reminiscent of the conspicuous fractal Romanesco shape. This study reveals how fractal-like forms may emerge from the combination of key, defined perturbations of floral developmental programs and growth dynamics.


Support during pregnancy for women at increased risk of low birthweight babies.
Studies consistently show a relationship between social disadvantage and low birthweight. Many countries have programs offering special assistance to women thought to be at risk for giving birth to a low birthweight infant. These programs may include advice and counselling (about nutrition, rest, stress management, alcohol and recreational drug use), tangible assistance (eg transportation to clinic appointments, help with household responsibilities), and emotional support. The programs may be delivered by multidisciplinary teams of health professionals, by specially trained lay workers, or by a combination of lay and professional workers. The objective of this review was to assess the effects of programs offering additional social support for pregnant women who are believed to be at risk for giving birth to preterm or low birthweight babies. We searched the Cochrane Pregnancy and Childbirth Group trials register (30 January 2003). Randomized trials of additional support during at-risk pregnancy by either a professional (social worker, midwife, or nurse) or specially trained lay person, compared to routine care. Additional support was defined as some form of emotional support (eg counselling, reassurance, sympathetic listening) and information/advice, either in home visits or during clinic appointments, and could include tangible assistance (eg transportation to clinic appointments, assistance with the care of other children at home). Reviewers independently assessed trial quality and extracted data. Double data entry was performed. Study authors were contacted to request additional information. Sixteen trials involving 13,651 women were included. The trials were generally of good to excellent quality, although 3 used an allocation method likely to introduce bias. Programs offering additional social support for at-risk pregnant women were not associated with improvements in any perinatal outcomes, but there was a reduction in the likelihood of caesarean birth and an increased likelihood of elective termination of pregnancy. Some improvements in immediate maternal psychosocial outcomes were found in individual trials. Pregnant women need the support of caring family members, friends, and health professionals. While programs which offer additional support during pregnancy are unlikely to prevent the pregnancy from resulting in a low birthweight or preterm baby, they may be helpful in reducing the likelihood of caesarean birth.


Effects of spatial separation and stimulus probability on the event-related potentials elicited by occasional changes in sound location.
The ability to extract information about the spatial location of sounds plays an important role in auditory scene analysis. The present study examined the effects of spatial separation and stimulus probability on auditory event-related potentials (ERPs) to changes in sound location. In Experiment 1, we found that difference waves between ERPs elicited by standard and deviant stimuli showed a biphasic negative-positive response peaking around 126 and 226 ms after deviant onset. The amplitude of both responses increased with decreasing deviant stimulus probability, and increasing stimulus deviance. When the same stimuli were presented with equal probability for all locations (Experiment 2), there were no significant differences in the ERP amplitude and latency. These results suggest that the data reported in Experiment 1 are the result of contextual changes, rather than changes in simple acoustic features. Brain electrical source analyses are consistent with generators located in auditory cortices posterior to Heschel's gyrus. Although occasional changes in sound location elicit earlier peaks than the mismatch negativity (MMN) response reported for other types of deviation, their topographical distribution and behavior are consistent with MMN. The early latency of MMN for changes in sound location is interpreted in the context of an early-warning system to alert the organism to new sound sources in the environment.


Co-evolutionary rates of functionally related yeast genes.
Evolutionary knowledge is often used to facilitate computational attempts at gene function prediction. One rich source of evolutionary information is the relative rates of gene sequence divergence, and in this report we explore the connection between gene evolutionary rates and function. We performed a genome-scale evaluation of the relationship between evolutionary rates and functional annotations for the yeast Saccharomyces cerevisiae. Non-synonymous (dN) and synonymous (dS) substitution rates were calculated for 1,095 orthologous gene sets common to S. cerevisiae and six other closely related yeast species. Differences in evolutionary rates between pairs of genes (DeltadN & DeltadS) were then compared to their functional similarities (sGO), which were measured using Gene Ontology (GO) annotations. Substantial and statistically significant correlations were found between DeltadN and sGO, whereas there is no apparent relationship between DeltadS and sGO. These results are consistent with a mode of action for natural selection that is based on similar rates of elimination of deleterious protein coding sequence variants for functionally related genes. The connection between gene evolutionary rates and function was stronger than seen for phylogenetic profiles, which have previously been employed to inform functional inference. The co-evolution of functionally related yeast genes points to the relevance of specific function for the efficacy of natural selection and underscores the utility of gene evolutionary rates for functional predictions.


Evolution of the neuromatrix theory of pain. The Prithvi Raj Lecture: presented at the third World Congress of World Institute of Pain, Barcelona 2004.
The neuromatrix theory of pain proposes that pain is a multidimensional experience produced by characteristic "neurosignature" patterns of nerve impulses generated by a widely distributed neural network-the "body-self neuromatrix"-in the brain. These neurosignature patterns may be triggered by sensory inputs, but they may also be generated independently of them. Acute pains evoked by brief noxious inputs have been meticulously investigated by neuroscientists, and their sensory transmission mechanisms are generally well understood. In contrast, chronic pain syndromes, which are often characterized by severe pain associated with little or no discernable injury or pathology, remain a mystery. Furthermore, chronic psychological or physical stress is often associated with chronic pain, but the relationship is poorly understood. The neuromatrix theory of pain provides a new conceptual framework to examine these problems. It proposes that the output patterns of the body-self neuromatrix activate perceptual, homeostatic, and behavioral programs after injury, pathology, or chronic stress. Pain, then, is produced by the output of a widely distributed neural network in the brain rather than directly by sensory input evoked by injury, inflammation, or other pathology. The neuromatrix, which is genetically determined and modified by sensory experience, is the primary mechanism that generates the neural pattern that produces pain. Its output pattern is determined by multiple influences, of which the somatic sensory input is only a part, that converge on the neuromatrix.


Effects of Flow-Induced Microfluidic Chip Wall Deformation on Imaging Flow Cytometry.
Imaging flow cytometry is a powerful tool by virtue of its capability for high-throughput cell analysis. The advent of high-speed optical imaging methods on a microfluidic platform has significantly improved cell throughput and brought many degrees of freedom to instrumentation and applications over the last decade, but it also poses a predicament on microfluidic chips. Specifically, as the throughput increases, the flow speed also increases (currently reaching 10 m/s): consequently, the increased hydrodynamic pressure on the microfluidic chip deforms the wall of the microchannel and produces detrimental effects lead to defocused and blur image. Here, we present a comprehensive study of the effects of flow-induced microfluidic chip wall deformation on imaging flow cytometry. We fabricated three types of microfluidic chips with the same geometry and different degrees of stiffness made of polydimethylsiloxane (PDMS) and glass to investigate material influence on image quality. First, we found the maximum deformation of a PDMS microchannel was >60 μm at a pressure of 0.6 MPa, while no appreciable deformation was identified in a glass microchannel at the same pressure. Second, we found the deviation of lag time that indicating velocity difference of migrating microbeads due to the deformation of the microchannel was 29.3 ms in a PDMS microchannel and 14.9 ms in a glass microchannel. Third, the glass microchannel focused cells into a slightly narrower stream in the X-Y plane and a significantly narrower stream in the Z-axis direction (focusing percentages were increased 30%, 32%, and 5.7% in the glass channel at flow velocities of 0.5, 1.5, and 3 m/s, respectively), and the glass microchannel showed stabler equilibrium positions of focused cells regardless of flow velocity. Finally, we achieved the world's fastest imaging flow cytometry by combining a glass microfluidic device with an optofluidic time-stretch microscopy imaging technique at a flow velocity of 25 m/s. © 2019 International Society for Advancement of Cytometry.


The use of megaprostheses for reconstruction of large skeletal defects in the extremities: a critical review.
In the case of primary malignant tumors, extensive metastatic disease, major trauma or end-stage revision arthroplasty, the orthopaedic surgeon often has to deal with the need to reconstruct large skeletal defects, or replace bone of low quality. In the past years this was frequently impossible, and the only solution was amputation of the extremity. Later, the introduction of custom-made endoprostheses capable of reconstructing large skeletal defects, also known as megaprostheses, allowed for sparing of the extremity. This was especially valuable in the case of oncologic orthopaedic surgery, as advances in the medical treatment of sarcoma patients improved prognosis and limb-preserving surgery proved to have comparable patient survival rates to amputation. However, custom-made designs were implicated in frequent mechanical failures. Furthermore, they were extremely difficult to revise. The introduction of modular endoprostheses in the 1980s marked a new era in orthopaedic oncologic surgery. Modular megaprostheses consist of a number of different components in readily available sets, which can be assembled in various combinations to best address the specific bone defect. Moreover, they proved to have considerably lower rate of mechanical failures, which were also much easier to address during revision surgery by replacing only the parts that failed. The functional outcome after reconstruction with megasprostheses is often very satisfactory and the patient can enjoy a good quality of life. Nowadays, the major challenge is to eliminate the rate of non-mechanical complications associated with surgery of that magnitude, namely the risk for wound dehiscence and necrosis, deep infection, as well as local recurrence of the tumor. In our present mini-review, we attempt to make a critical approach of the available literature, focusing on the multiple aspects of reconstructive surgery using megaprostheses. We present the evolution of megasprosthetic implants, the indications for their use, and describe the outcome of surgery, so that the non-specialized orthopedic surgeon also becomes familiar with that kind of surgery which is usually performed in tertiary centers. A special interest lays in the recent developments that promise for even better results and fewer complications.


Is Migration at Older Age Associated With Poorer Psychological Well-Being? Evidence from Chinese Older Immigrants in the United States.
The migrating age of an individual has far-reaching implications for their acculturation experience, social integration, and well-being. This study addressed two questions: Is migrating at older age associated with poorer psychological well-being? If so, what factors account for such differences? Using data of 3,138 Chinese elderly people in Chicago, we compared the levels of depression and quality of life among individuals who migrated in young adulthood (before 35), adulthood (35-49), midlife (50-64), and later life (65+). Negative binominal and logistic regressions were performed to examine the associations between age at migration and the two outcomes, controlling for demographics and four sets of explanatory variables (socioeconomic status, health status, acculturation level, and family/social relations). The findings revealed mixed results. Migrating in later life was associated with more depressive symptoms, but also a higher chance of reporting good quality of life. Late-life immigrants' greater depression was partially contributed to their low income, lack of access to health care, poor physical health, and weak social relations. In contrast, regardless of the explanatory variables, migrating at middle age was associated with lower quality of life. Acknowledging that the older immigrant population is segmented with unique susceptibilities improves understanding of heterogeneity among the older immigrant populations and allows for targeted intervention. Gerontological practitioners should include migration history during their intakes and more actively screen for depression with socially isolated Chinese older immigrants who migrated at a later age.


Transcranial brain sonography in Parkinson's disease with restless legs syndrome.
Substantia nigra (SN) hyperechogenicity assessed by transcranial brain sonography (TCS) is a characteristic finding in idiopathic Parkinson's disease (PD). In contrast, SN hypoechogenicity on TCS has been recently demonstrated in restless legs syndrome (RLS). RLS is one of the most common sleep problems in PD, but the pathophysiologic relationship between these two disorders has not been thoroughly elucidated. We compared the SN echogenicities of PD patients with and without RLS to investigate whether comorbid RLS in PD affects SN echogenicity and to explain the echogenic differences between idiopathic RLS (iRLS) and secondary PD-related RLS (pRLS). Sixty-three PD patients (median age 64.6 +/- 10.6 years), 40 iRLS patients (53.1 +/- 11.7 years), and 40 healthy controls (69.1 +/- 2.3 years) were enrolled in our study. All subjects answered a sleep questionnaire and underwent TCS. PD patients were subdivided into two groups, PD with RLS (PD+RLS, n = 26) and PD without RLS (PD-RLS, n = 37), and the sonographic findings of each group were compared. Although significant hyperechogenicity was detected in both the SN and SN/midbrain ratios in both PD subgroups compared with the controls and the iRLS group (P < 0.001), there were no significant differences in SN echogenicity between the PD+RLS and PD-RLS groups. Meanwhile, iRLS patients showed significant SN hypoechogenicity. In conclusion, comorbid RLS in PD did not have an impact on the sonographic SN findings. These results suggest that the pathogenesis of pRLS and iRLS involve different mechanisms. Further study will be required to clarify the association between RLS and PD.


Uptake of New Lipid-coated Nanoparticles Containing Falcarindiol by Human Mesenchymal Stem Cells.
Nanoparticles are the focus of an increased interest in drug delivery systems for cancer therapy. Lipid-coated nanoparticles are inspired in structure and size by low-density lipoproteins (LDLs) because cancer cells have an increased need for cholesterol to proliferate, and this has been exploited as a mechanism for delivering anticancer drugs to cancer cells. Moreover, depending on drug chemistry, encapsulating the drug can be advantageous to avoid degradation of the drug during circulation in vivo. Therefore, in this study, this design is used to fabricate lipid-coated nanoparticles of the anticancer drug falcarindiol, providing a potential new delivery system of falcarindiol in order to stabilize its chemical structure against degradation and improve its uptake by tumors. Falcarindiol nanoparticles, with a phospholipid and cholesterol monolayer encapsulating the purified drug core of the particle, were designed. The lipid monolayer coating consists of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol (Chol), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE PEG 2000) along with the fluorescent label DiI (molar ratios of 43:50:5:2). The nanoparticles are fabricated using the rapid injection method, which is a fast and simple technique to precipitate nanoparticles by good-solvent for anti-solvent exchange. It consists of a rapid injection of an ethanol solution containing the nanoparticle components into an aqueous phase. The size of the fluorescent nanoparticles is measured using dynamic light scattering (DLS) at 74.1 ± 6.7 nm. The uptake of the nanoparticles is tested in human mesenchymal stem cells (hMSCs) and imaged using fluorescence and confocal microscopy. The uptake of the nanoparticles is observed in hMSCs, suggesting the potential for such a stable drug delivery system for falcarindiol.


Transient combination therapy targeting the immune synapse abrogates T cell responses and prolongs allograft survival in mice.
T cells play a major role in allograft rejection, which occurs after T cell activation by the engagement of several functional molecules to form an immune synapse with alloantigen presenting cells. In this study, the immune synapse was targeted using mAbs directed to the TCR beta-chain (TCRβ) and lymphocyte function-associated antigen-1 (LFA1) to induce long-term allograft survival. Evaluation of antigen-specific T cell responses was performed by adoptively transferring CFSE labeled transgenic OT-II cells into wild-type mice and providing OVA peptide by intravenous injection. Graft survival studies were performed in mice by transplanting BALB/c ear skins onto the flanks of C57BL/6 recipients. The anti-TCRβ plus anti-LFA1 mAb combination (but not either mAb alone) abrogated antigen-specific T cell responses invitro and invivo. Transient combination therapy with these agents resulted in significantly prolonged skin allograft survival in mice (51±10 days; p<0.01) when compared to treatment with either anti-TCRβ mAb (24±5 days) or anti-LFA1 mAb (19±3 days) alone or no treatment (10±1 days). When lymphoid tissues from these mice were analyzed at different times post-transplant, only those receiving the combination of anti-TCRβ and anti-LFA1 mAbs demonstrated long-lasting reductions in total T cell numbers, cellular and humoral anti-donor responses, and expression of CD3 on the surface of T cells. These results demonstrate that transient anti-TCRβ and anti-LFA1 mAb combination therapy abrogates antigen-reactive T cell responses with long-lasting effects that significantly prolong allograft survival.


Performance of magnesium ammonium phosphate precipitation and its effect on biological treatability of leather tanning industry wastewaters.
Leather tanning industry is one of the several industries discharging significant amount of nitrogen. Magnesium ammonium phosphate (MAP) precipitation is a promising pretreatment for leather tanning industry wastewaters for the control of toxic parameters; excess suspended solids as well as nitrogen which increase the cost and complexity of following biological treatment. Application of MAP precipitation, however, modifies the characteristics and biological treatability of wastewaters. In this study, characteristics and biological treatability of MAP precipitation effluent were experimentally investigated using the wastewaters obtained from a bovine leather processing plant. An experimental study involving the determination of COD fractions and kinetic parameters of biological treatment was conducted for both gravity settling and MAP precipitation. Results of the study indicated that MAP precipitation, in addition to high degree of nitrogen removal, yielded a soluble, readily biodegradable effluent which was also free from toxics. MAP precipitation provided an effluent COD of almost half of that of gravity settling. Reduced value of soluble residual microbial products (Sp) obtained with MAP precipitation effluent was an additional benefit.


Actinomycete integrative and conjugative elements.
This paper reviews current knowledge on actinomycete integrative and conjugative elements (AICEs). The best characterised AICEs, pSAM2 of Streptomyces ambofaciens (10.9 kb), SLP1 (17.3 kb) of Streptomyces coelicolor and pMEA300 of Amycolatopsis methanolica (13.3 kb), are present as integrative elements in specific tRNA genes, and are capable of conjugative transfer. These AICEs have a highly conserved structural organisation, with functional modules for excision/integration, replication, conjugative transfer, and regulation. Recently, it has been shown that pMEA300 and the related elements pMEA100 of Amycolatopsis mediterranei and pSE211 of Saccharopolyspora erythraea form a novel group of AICEs, the pMEA-elements, based on the unique characteristics of their replication initiator protein RepAM. Evaluation of a large collection of Amycolatopsis isolates has allowed identification of multiple pMEA-like elements. Our data show that, as AICEs, they mainly coevolved with their natural host in an integrated form, rather than being dispersed via horizontal gene transfer. The pMEA-like elements could be separated into two distinct populations from different geographical origins. One group was most closely related to pMEA300 and was found in isolates from Australia and Asia and pMEA100-related sequences were present in European isolates. Genome sequence data have enormously contributed to the recent insight that AICEs are present in many actinomycete genera. The sequence data also provide more insight into their evolutionary relationships, revealing their modular composition and their likely combined descent from bacterial plasmids and bacteriophages. Evidence is accumulating that AICEs act as modulators of host genome diversity and are also involved in the acquisition of secondary metabolite clusters and foreign DNA via horizontal gene transfer. Although still speculative, these AICEs may play a role in the spread of antibiotic resistance factors into pathogenic bacteria. The novel insights on AICE characteristics presented in this review may be used for the effective construction of new vectors that allows us to engineer and optimise strains for the production of commercially and medically interesting secondary metabolites, and bioactive proteins.


Intranasal steroids versus placebo or no intervention for chronic rhinosinusitis.
This review is one of six looking at the primary medical management options for patients with chronic rhinosinusitis.Chronic rhinosinusitis is common and is characterised by inflammation of the lining of the nose and paranasal sinuses leading to nasal blockage, rhinorrhoea, facial pressure/pain and loss of sense of smell. The condition can occur with or without nasal polyps. The use of topical (intranasal) corticosteroids has been widely advocated for the treatment of chronic rhinosinusitis given the belief that inflammation is a major component of this condition. To assess the effects of intranasal corticosteroids in people with chronic rhinosinusitis. The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2015, Issue 8); MEDLINE; EMBASE; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 11 August 2015. Randomised controlled trials (RCTs) with a follow-up period of at least three months comparing intranasal corticosteroids (e.g. beclomethasone dipropionate, triamcinolone acetonide, flunisolide, budesonide) against placebo or no treatment in patients with chronic rhinosinusitis. We used the standard methodological procedures expected by Cochrane. Our primary outcomes were disease-specific health-related quality of life (HRQL), patient-reported disease severity and the commonest adverse event - epistaxis. Secondary outcomes included general HRQL, endoscopic nasal polyp score, computerised tomography (CT) scan score and the adverse events of local irritation or other systemic adverse events. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. We included 18 RCTs with a total of 2738 participants. Fourteen studies had participants with nasal polyps and four studies had participants without nasal polyps. Only one study was conducted in children. Intranasal corticosteroids versus placebo or no intervention Only one study (20 adult participants without polyps) measured our primary outcome disease-specific HRQL using the Rhinosinusitis Outcome Measures-31 (RSOM-31). They reported no significant difference (numerical data not available) (very low quality evidence).Our second primary outcome, disease severity , was measured using the Chronic Sinusitis Survey in a second study (134 participants without polyps), which found no important difference (mean difference (MD) 2.84, 95% confidence interval (CI) -5.02 to 10.70; scale 0 to 100). Another study (chronic rhinosinusitis with nasal polyps) reported an increased chance of improvement in the intranasal corticosteroids group (RR 2.78, 95% CI 1.76 to 4.40; 109 participants). The quality of the evidence was low.Six studies provided data on at least two of the individual symptoms used in the EPOS 2012 criteria to define chronic rhinosinusitis (nasal blockage, rhinorrhoea, loss of sense of smell and facial pain/pressure). When all four symptoms in the EPOS criteria were available on a scale of 0 to 3 (higher = more severe symptoms), the average MD in change from baseline was -0.26 (95% CI -0.37 to -0.15; 243 participants; two studies; low quality evidence). Although there were more studies and participants when only nasal blockage and rhinorrhoea were considered (MD -0.31, 95% CI -0.38 to -0.24; 1702 participants; six studies), the MD was almost identical to when loss of sense of smell was also considered (1345 participants, four studies; moderate quality evidence).When considering the results for the individual symptoms, benefit was shown in the intranasal corticosteroids group. The effect size was larger for nasal blockage (MD -0.40, 95% CI -0.52 to -0.29; 1702 participants; six studies) than for rhinorrhoea (MD -0.25, 95% CI -0.33 to -0.17; 1702 participants; six studies) or loss of sense of smell (MD -0.19, 95% CI -0.28 to -0.11; 1345 participants; four studies). There was heterogeneity in the analysis for facial pain/pressure (MD -0.27, 95% CI -0.56 to 0.02; 243 participants; two studies). The quality of the evidence was moderate for nasal blockage, rhinorrhoea and loss of sense of smell, but low for facial pain/pressure.There was an increased risk of epistaxis with intranasal corticosteroids (risk ratio (RR) 2.74, 95% CI 1.88 to 4.00; 2508 participants; 13 studies; high quality evidence).Considering our secondary outcome, general HRQL, one study (134 participants without polyps) measured this using the SF-36 and reported a statistically significant benefit only on the general health subscale. The quality of the evidence was very low.It is unclear whether there is a difference in the risk of local irritation (RR 0.94, 95% CI 0.53 to 1.64; 2124 participants; 11 studies) (low quality evidence).None of the studies treated or followed up patients long enough to provide meaningful data on the risk of osteoporosis or stunted growth (children). Other comparisons We identified no other studies that compared intranasal corticosteroids plus co-intervention A versus placebo plus co-intervention A. Most of the evidence available was from studies in patients with chronic rhinosinusitis with nasal polyps. There is little information about quality of life (very low quality evidence). For disease severity, there seems to be improvement for all symptoms (low quality evidence), a moderate-sized benefit for nasal blockage and a small benefit for rhinorrhoea (moderate quality evidence). The risk of epistaxis is increased (high quality evidence), but these data included all levels of severity; small streaks of blood may not be a major concern for patients. It is unclear whether there is a difference in the risk of local irritation (low quality evidence).


HIV-1 Env-specific cytotoxic T-lymphocyte responses in exposed, uninfected Kenyan sex workers: a prospective analysis.
The prospective significance of HIV-specific cytotoxic T lymphocyte (CTL) responses in highly exposed, persistently seronegative populations is unknown. In 1996-1997 we screened for CTL responses against HIV clade B Env in 39 recently enrolled Kenyan female sex workers, and followed these women prospectively. Annual HIV incidence was 5.8%. CTL were independently associated with age and recent HIV-1 exposure,but were not prospectively associated with protection in a multivariable model that included HIV-1 exposure and duration of sex work.


Optimizing the analysis strategy for the CANVAS Program: A prespecified plan for the integrated analyses of the CANVAS and CANVAS-R trials.
Two large cardiovascular outcome trials of canagliflozin, comprising the CANVAS Program, will complete in early 2017: the CANagliflozin cardioVascular Assessment Study (CANVAS) and the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R). Accruing data for the sodium glucose co-transporter 2 (SGLT2) inhibitor class has identified questions and opportunities that were not apparent when the trials were designed. Accordingly, a series of modifications have been made to the planned analyses. These updates will ensure that the data from the CANVAS Program will maximize advances in scientific knowledge and patient care. The specification of the analysis strategy prior to knowledge of the trial results, their design by the independent scientific trial Steering Committee, the detailed a priori definition of the analysis plans, and the external review provided by the US Food and Drug Administration all provide maximally efficient and robust utilization of the data. The CANVAS Program should significantly advance our understanding of the effects of canagliflozin, and the broader SGLT2 inhibitor class, on a range of important efficacy and safety outcomes.


Regulation of embryonic cell adhesion by the prion protein.
Prion proteins (PrPs) are key players in fatal neurodegenerative disorders, yet their physiological functions remain unclear, as PrP knockout mice develop rather normally. We report a strong PrP loss-of-function phenotype in zebrafish embryos, characterized by the loss of embryonic cell adhesion and arrested gastrulation. Zebrafish and mouse PrP mRNAs can partially rescue this knockdown phenotype, indicating conserved PrP functions. Using zebrafish, mouse, and Drosophila cells, we show that PrP: (1) mediates Ca(+2)-independent homophilic cell adhesion and signaling; and (2) modulates Ca(+2)-dependent cell adhesion by regulating the delivery of E-cadherin to the plasma membrane. In vivo time-lapse analyses reveal that the arrested gastrulation in PrP knockdown embryos is due to deficient morphogenetic cell movements, which rely on E-cadherin-based adhesion. Cell-transplantation experiments indicate that the regulation of embryonic cell adhesion by PrP is cell-autonomous. Moreover, we find that the local accumulation of PrP at cell contact sites is concomitant with the activation of Src-related kinases, the recruitment of reggie/flotillin microdomains, and the reorganization of the actin cytoskeleton, consistent with a role of PrP in the modulation of cell adhesion via signaling. Altogether, our data uncover evolutionarily conserved roles of PrP in cell communication, which ultimately impinge on the stability of adherens cell junctions during embryonic development.


Butyrylcholinesterase for protection from organophosphorus poisons: catalytic complexities and hysteretic behavior.
Butyrylcholinesterase is a promiscuous enzyme that displays complex kinetic behavior. It is toxicologically important because it detoxifies organophosphorus poisons (OP) by making a covalent bond with the OP. The OP and the butyrylcholinesterase are both inactivated in the process. Inactivation of butyrylcholinesterase has no adverse effects. However, inactivation of acetylcholinesterase in nerve synapses can be lethal. OP-inhibited butyrylcholinesterase and acetylcholinesterase can be reactivated with oximes provided the OP has not aged. Strategies for preventing the toxicity of OP include (a) treatment with an OP scavenger, (b) reaction of non-aged enzyme with oximes, (c) reactivation of aged enzyme, (d) slowing down aging with peripheral site ligands, and (e) design of mutants that rapidly hydrolyze OP. Option (a) has progressed through phase I clinical trials with human butyrylcholinesterase. Option (b) is in routine clinical use. The others are at the basic research level. Butyrylcholinesterase displays complex kinetic behavior including activation by positively charged esters, ability to hydrolyze amides, and a lag time (hysteresis) preceding hydrolysis of benzoylcholine and N-methylindoxyl acetate. Mass spectrometry has identified new OP binding motifs on tyrosine and lysine in proteins that have no active site serine. It is proposed, but not yet proven, that low dose exposure involves OP modification of proteins that have no active site serine.


Bacterial genomics and adaptation to life on plants: implications for the evolution of pathogenicity and symbiosis.
Many bacteria form intimate associations with plants. Despite the agricultural and biotechnological significance of these bacteria, no whole genome sequences have yet been described. Plant-associated bacteria form a phylogenetically diverse group, with representative species from many major taxons. Sequence information from genomes of closely related bacteria, in combination with technological developments in the field of functional genomics, provides new opportunities for determining the origin and evolution of traits that contribute to bacterial fitness and interactions with plant hosts.


Political legitimacy and approval of political protest and violence among children and adolescents.
A question of general theoretical relevance for political socialization research concerns the role played by basic political orientations in structuring specific political opinions. This report investigates the relationship between beliefs in the legitimacy of political objects and approval of political protest and violence among a sample of children and adolescents. The setting for the research was a Florida town. Four aspects of political legitimacy are defined and measured. Measures of approval of political protest and political violence are distinguished conceptually and empirically. Beliefs in political legitimacy are shown to be of considerable importance in structuring opinions about political violence but have little impact on opinions about protest.