Phenotypic transition of microglia into astrocyte-like cells associated with disease onset in a model of inherited ALS.
Microglia and reactive astrocytes accumulate in the spinal cord of rats expressing the Amyotrophic lateral sclerosis (ALS)-linked SOD1 (G93A) mutation. We previously reported that the rapid progression of paralysis in ALS rats is associated with the appearance of proliferative astrocyte-like cells that surround motor neurons. These cells, designated as Aberrant Astrocytes (AbA cells) because of their atypical astrocytic phenotype, exhibit high toxicity to motor neurons. However, the cellular origin of AbA cells remains unknown. Because AbA cells are labeled with the proliferation marker Ki67, we analyzed the phenotypic makers of proliferating glial cells that surround motor neurons by immunohistochemistry. The number of Ki67 (+)AbA cells sharply increased in symptomatic rats, displaying large cell bodies with processes embracing motor neurons. Most were co-labeled with astrocytic marker GFAP concurrently with the microglial markers Iba1 and CD163. Cultures of spinal cord prepared from symptomatic SOD1 (G93A) rats yielded large numbers of microglia expressing Iba1, CD11b, and CD68. Cells sorted for CD11b expression by flow cytometry transformed into AbA cells within two weeks. During these two weeks, the expression of microglial markers largely disappeared, while GFAP and S100β expression increased. The phenotypic transition to AbA cells was stimulated by forskolin. These findings provide evidence for a subpopulation of proliferating microglial cells in SOD1 (G93A) rats that undergo a phenotypic transition into AbA cells after onset of paralysis that may promote the fulminant disease progression. These cells could be a therapeutic target for slowing paralysis progression in ALS.


Validation of the Oxford Depression Questionnaire: Sensitivity to change, minimal clinically important difference, and response threshold for the assessment of emotional blunting.
The Oxford Depression Questionnaire (ODQ) is a patient-reported scale for assessing emotional blunting in patients with major depressive disorder (MDD). This analysis was undertaken to further validate the scale in patients experiencing emotional blunting while receiving antidepressant treatment. Patients with MDD who experienced inadequate depressive-symptom resolution and emotional blunting on selective serotonin reuptake inhibitor or serotonin-noradrenaline reuptake inhibitor monotherapy (adequate dose for ≥6 weeks) were switched to vortioxetine 10-20 mg/day. ODQ total scores were assessed excluding and including the "antidepressant-as-cause" domain (ODQ-20 and ODQ-26, respectively). Anchor- and distribution-based methods were used to determine the minimal clinically important difference in ODQ scores in terms of change from baseline to week 8 of antidepressant treatment. After 8 weeks of vortioxetine treatment, the mean change in ODQ-20 and ODQ-26 scores from baseline was -24.8 and -30.1 points, respectively. Greater mean changes from baseline in ODQ-20 and ODQ-26 scores were seen in patients reporting no emotional blunting vs those still experiencing emotional blunting after 8 weeks of vortioxetine treatment (ODQ-20: -27.0 vs -22.6 points; ODQ-26: -32.8 vs -27.5 points, respectively). In patients considered clinically minimally improved (Clinical Global Impression-Improvement score, 3) after 8 weeks of vortioxetine treatment, respective mean (standard deviation) change in ODQ-20 and ODQ-26 score from baseline was -15.5 (18.1) and -20.0 (20.5) points. Short study duration. These results provide further validation of the clinical utility of the ODQ for assessing emotional blunting in patients with MDD. The suggested minimal clinically important difference for change in ODQ-20 and ODQ-26 scores is 16 and 20 points, respectively, after 8 weeks of antidepressant treatment. ClinicalTrials.gov identifier: NCT03835715.


A modified infrared spectrometer with high time resolution and its application for investigating fast conformational changes of the GTPase Ras.
Time-resolved infrared spectroscopy is a valuable tool for the investigation of proteins and protein interactions. The investigation of many biological processes is possible by means of caged compounds, which set free biologically active substances upon light activation. Some caged compounds could provide sub-nanosecond time resolution, e.g., para-hydroxyphenacyl-guanosine 5'-triphosphate (GTP) forms GTP in picoseconds. However, the time resolution in single shot experiments with rapid-scan Fourier transform infrared (FT-IR) spectrometers is limited to about 10 ms. Here we use an infrared diode laser instead of the conventional globar and achieve a time resolution of 100 ns. This allows for the time-resolved measurement of the fast Ras(off) to Ras(on) conformational change at room temperature. We quantified the activation parameters for this reaction and found that the free energy of activation for this reaction is mainly enthalpic. Investigation of the same reaction in the presence of the Ras binding domain of the effector Raf (RafRBD) reveals a four orders of magnitude faster reaction, indicating that Ras·RafRBD complex formation directly induces the conformational change. Recent developments of broadly tunable quantum cascade lasers will further improve time resolution and usability of the setup. The reported 100 ns time resolution is the best achieved for a non-repetitive experiment so far.


Do incentives, reminders or reduced burden improve healthcare professional response rates in postal questionnaires? two randomised controlled trials.
Healthcare professional response rates to postal questionnaires are declining and this may threaten the validity and generalisability of their findings. Methods to improve response rates do incur costs (resources) and increase the cost of research projects. The aim of these randomised controlled trials (RCTs) was to assess whether 1) incentives, 2) type of reminder and/or 3) reduced response burden improve response rates; and to assess the cost implications of such additional effective interventions. Two RCTs were conducted. In RCT A general dental practitioners (dentists) in Scotland were randomised to receive either an incentive; an abridged questionnaire or a full length questionnaire. In RCT B non-responders to a postal questionnaire sent to general medical practitioners (GPs) in the UK were firstly randomised to receive a second full length questionnaire as a reminder or a postcard reminder. Continued non-responders from RCT B were then randomised within their first randomisation to receive a third full length or an abridged questionnaire reminder. The cost-effectiveness of interventions that effectively increased response rates was assessed as a secondary outcome. There was no evidence that an incentive (52% versus 43%, Risk Difference (RD) -8.8 (95%CI -22.5, 4.8); or abridged questionnaire (46% versus 43%, RD -2.9 (95%CI -16.5, 10.7); statistically significantly improved dentist response rates compared to a full length questionnaire in RCT A. In RCT B there was no evidence that a full questionnaire reminder statistically significantly improved response rates compared to a postcard reminder (10.4% versus 7.3%, RD 3 (95%CI -0.1, 6.8). At a second reminder stage, GPs sent the abridged questionnaire responded more often (14.8% versus 7.2%, RD -7.7 (95%CI -12.8, -2.6). GPs who received a postcard reminder followed by an abridged questionnaire were most likely to respond (19.8% versus 6.3%, RD 8.1%, and 9.1% for full/postcard/full, three full or full/full/abridged questionnaire respectively). An abridged questionnaire containing fewer questions following a postcard reminder was the only cost-effective strategy for increasing the response rate (£15.99 per response). When expecting or facing a low response rate to postal questionnaires, researchers should carefully identify the most efficient way to boost their response rate. In these studies, an abridged questionnaire containing fewer questions following a postcard reminder was the only cost-effective strategy. An increase in response rates may be explained by a combination of the number and type of contacts. Increasing the sampling frame may be more cost-effective than interventions to prompt non-responders. However, this may not strengthen the validity and generalisability of the survey findings and affect the representativeness of the sample.


Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex.
Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder associated with mutations in TSC1, which codes for hamartin, or TSC2, which codes for tuberin. The brain is one of the most severely affected organs, and CNS lesions include cortical tubers and subependymal giant cell astrocytomas, resulting in mental retardation and seizures. Tuberin and hamartin function together as a complex in mammals and Drosophila. We report here the association of Pam, a protein identified as an interactor of Myc, with the tuberin-hamartin complex in the brain. The C terminus of Pam containing the RING zinc finger motif binds to tuberin. Pam is expressed in embryonic and adult brain as well as in cultured neurons. Pam has two forms in the rat CNS, an approximately 450-kDa form expressed in early embryonic stages and an approximately 350-kDa form observed in the postnatal period. In cortical neurons, Pam co-localizes with tuberin and hamartin in neurites and growth cones. Although Pam function(s) are yet to be defined, the highly conserved Pam homologs, HIW (Drosophila) and RPM-1 (Caenorhabditis elegans), are neuron-specific proteins that regulate synaptic growth. Here we show that HIW can genetically interact with the Tsc1.Tsc2 complex in Drosophila and could negatively regulate Tsc1.Tsc2 activity. Based on genetic studies, HIW has been implicated in ubiquitination, possibly functioning as an E3 ubiquitin ligase through the RING zinc finger domain. Therefore, we hypothesize that Pam, through its interaction with tuberin, could regulate the ubiquitination and proteasomal degradation of the tuberin-hamartin complex particularly in the CNS.


Hypertension and reproductive dysfunction: a possible role of inflammation and inflammation-associated lymphangiogenesis in gonads.
Hypertension is one of the most prevalent diseases that leads to end organ damage especially affecting the heart, kidney, brain, and eyes. Numerous studies have evaluated the association between hypertension and impaired sexual health, in both men and women. The detrimental effects of hypertension in men includes erectile dysfunction, decrease in semen volume, sperm count and motility, and abnormal sperm morphology. Similarly, hypertensive females exhibit decreased vaginal lubrication, reduced orgasm, and several complications in pregnancy leading to fetal and maternal morbidity and mortality. The adverse effect of hypertension on male and female fertility is attributed to hormonal imbalance and changes in the gonadal vasculature. However, mechanistic studies investigating the impact of hypertension on gonads in more detail on a molecular basis remain scarce. Hence, the aim of the current review is to address and summarize the effects of hypertension on reproductive health, and highlight the importance of research on the effects of hypertension on gonadal inflammation and lymphatics.


The nifedipine-rifampin interaction. Evidence for induction of gut wall metabolism.
The calcium channel blocker nifedipine is metabolized by cytochrome P450 3A4, which is present in liver and mucosa of the small bowel. Cytochrome P450 3A4 is inducible by the tuberculostatic rifampin in liver and the small bowel. The contribution of gut wall metabolism to total clearance of nifedipine before and during induction has not been determined in detail. We therefore investigated the nifedipine-rifampin interaction, with special emphasis on the contribution of gut wall metabolism to total metabolism of nifedipine before and during administration of rifampin. Pharmacokinetics of nifedipine were studied in six healthy volunteers on separate days by administration of 20 micrograms/kg body weight nifedipine iv and 20 mg nifedipine orally before and after 7 days of rifampin treatment (600 mg/day). Enzyme induction did not significantly alter pharmacokinetics of nifedipine after iv administration. In contrast, oral clearance of nifedipine increased from 1.5 +/- 0.2 liters/min to 20.9 +/- 8.3 liters/min (p < 0.01) and bioavailability decreased from 41.2 +/- 5.4% to 5.3 +/- 2.7% (p < 0.001). Although hepatic extraction of nifedipine was not significantly altered during induction (47.4 +/- 6.6% versus 67.4 +/- 20.2%; ns), the calculated extraction of nifedipine in gut wall mucosa increased from 21.8 +/- 13.3% to 75.8 +/- 28.2% (p < 0.05). We conclude that there is a relevant interaction between nifedipine and rifampin. The reduction of nifedipine bioavailability during enzyme induction is most likely due to rifampin-induced gut wall metabolism.


Retinoid X receptor-alpha-dependent transactivation by a naturally occurring structural variant of human constitutive androstane receptor (NR1I3).
The constitutive androstane receptor (CAR) mediates the hepatic induction of various xenobiotic metabolizing enzymes and transporters after specific chemical exposures. Recent reports have established the existence of several human CAR mRNA splice variants, including a prominently expressed form termed CAR3, a receptor that possesses a 5 amino acid insertion within its ligand binding domain. In this study, we demonstrate that, in contrast to the constitutively active reference form of the receptor, CAR3 is ligand-activated, transactivating an optimized DR-4 x 3 reporter in response to the human CAR ligand 6-(4-chlorophenyl)imidazo[2,1-b]thiazole-5-carbaldehyde O-(3, 4-dichlorobenzyl)oxime (CITCO). The transactivation response requires the DNA binding domain and AF-2 motif of CAR3 and is markedly enhanced by retinoid X receptor-alpha (RXR) cotransfection. The stimulatory effects of RXR involve a unique mechanism, because they were completely dependent on the RXR AF-2 function but independent of both the RXR A/B domain and its C domain/heterodimerization region. Mammalian two-hybrid results demonstrated that RXR enhanced CITCO-dependent interaction of CAR3 with the receptor interaction domain of SRC-1, indicating that RXR augments CAR3 activity by facilitating coactivator recruitment. It is noteworthy that clotrimazole also functions as a ligand activator of CAR3, in contrast to the inverse agonist activity exhibited by this agent on the reference form of the receptor. Furthermore, results of transfection assays reveal that CAR3 is capable of transactivating the natural CYP2B6 and CYP3A4 gene enhancers, exhibiting both ligand- and RXR-dependence. These results demonstrate that CAR3, unlike CAR1, is a ligand-activated receptor and that CAR3 may regulate gene expression in vivo in a manner distinct from the reference form of the receptor.


Store-Operated Ca2+ Entry (SOCE) and Purinergic Receptor-Mediated Ca2+ Homeostasis in Murine bv2 Microglia Cells: Early Cellular Responses to ATP-Mediated Microglia Activation.
Microglia activation is a neuroinflammatory response to parenchymal damage with release of intracellular metabolites, e.g., purines, and signaling molecules from damaged cells. Extracellular purines can elicit Ca2+-mediated microglia activation involving P2X/P2Y receptors with metabotropic (P2Y) and ionotropic (P2X) cell signaling in target cells. Such microglia activation results in increased phagocytic activity, activation of their inflammasome and release of cytokines to sustain neuroinflammatory (so-called M1/M2 polarization). ATP-induced activation of ionotropic P2X4 and P2X7 receptors differentially induces receptor-operated Ca2+ entry (ROCE). Although store-operated Ca2+ entry (SOCE) was identified to modulate ROCE in primary microglia, its existence and role in one of the most common murine microglia cell line, BV2, is unknown. To dissect SOCE from ROCE in BV2 cells, we applied high-resolution multiphoton Ca2+ imaging. After depleting internal Ca2+ stores, SOCE was clearly detectable. High ATP concentrations (1 mM) elicited sustained increases in intracellular [Ca2+]i whereas lower concentrations (≤100 μM) also induced Ca2+ oscillations. These differential responses were assigned to P2X7 and P2X4 activation, respectively. Pharmacologically inhibiting P2Y and P2X responses did not affect SOCE, and in fact, P2Y-responses were barely detectable in BV2 cells. STIM1S content was significantly upregulated by 1 mM ATP. As P2X-mediated Ca2+ oscillations were rare events in single cells, we implemented a high-content screening approach that allows to record Ca2+ signal patterns from a large number of individual cells at lower optical resolution. Using automated classifier analysis, several drugs (minocycline, U73122, U73343, wortmannin, LY294002, AZ10606120) were tested on their profile to act on Ca2+ oscillations (P2X4) and sustained [Ca2+]i increases. We demonstrate specific drug effects on purinergic Ca2+ pathways and provide new pharmacological insights into Ca2+ oscillations in BV2 cells. For example, minocycline inhibits both P2X7- and P2X4-mediated Ca2+-responses, and this may explain its anti-inflammatory action in neuroinflammatory disease. As a technical result, our novel automated bio-screening approach provides a biomedical engineering platform to allow high-content drug library screens to study neuro-inflammation in vitro.


Generalized models for advancing and receding contact angles of fakir droplets on pillared and pored surfaces.
Understanding how surface properties determine the mobility of a fakir droplet on patterned surfaces, which is typically characterized by advancing and receding contact angles, is important in the design of superhydrophobic surfaces for tailored applications. However, most analytical models of the contact angles are limited to a specific motion direction and surface type, e.g., receding on a pillared surface. Although it was suggested that the contact angles should be determined by the local configuration and dynamics of the droplet boundary, their link remains vague due to the lack of detailed visualizations. In this study, the contact line dynamics of a fakir droplet in both advancing and receding motions on not only micropillared but also micropored surfaces are visualized in reflection interference contrast microscopy along with the contact angle measurement. Based on the energy change induced by the displacement of a contact line and the deformation of a liquid-gas interface in between contact lines, theoretical models of the contact angles to encompass the two different motion directions and surface types are formulated. Moreover, further generalized models are established to serve as effective analytical models to predict the contact angles only based on the given structure dimensions and the inherent surface hydrophobicity.


Disease status and population origin effects on floral scent:: potential consequences for oviposition and fruit predation in a complex interaction between a plant, fungus, and noctuid moth.
In the Silene latifolia-Hadena bicruris nursery pollination system, the Hadena moth is both pollinator and seed predator of its host plant. Floral scent, which differs among S. latifolia individuals and populations, is important for adult Hadena to locate its host. However, the success of moth larvae is strongly reduced if hosts are infected by the anther smut fungus Microbotryum violaceum, a pathogen that is transmitted by flower visitors. There were no qualitative differences between the scent of flowers from healthy and diseased plants. In addition, electroantennographic measurements showed that Hadena responded to the same subset of 19 compounds in samples collected from healthy and diseased plants. However, there were significant quantitative differences in scent profiles. Flowers from diseased plants emitted both a lower absolute amount of floral scent and had a different scent pattern, mainly due to their lower absolute amount of lilac aldehyde, whereas their amount of (E)-beta-ocimene was similar to that in healthy flowers. Dual choice behavioral wind tunnel tests using differently scented flowers confirmed that moths respond to both qualitative and quantitative aspects of floral scent, suggesting that they could use differences in floral scent between healthy and infected plants to discriminate against diseased plants. Population mean fruit predation rates significantly increased with population mean levels of the emission rates of lilac aldehyde per flower, indicating that selection on floral scent compounds may not only be driven by effects on pollinator attraction but also by effects on fruit predation. However, variation in mean emission rates of scent compounds per flower generally could not explain the higher fruit predation in populations originating from the introduced North American range compared to populations native to Europe.


Cathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate.
There is currently no therapeutic drug treatment for traumatic brain injury (TBI) despite decades of experimental clinical trials. This may be because the mechanistic pathways for improving TBI outcomes have yet to be identified and exploited. As such, there remains a need to seek out new molecular targets and their drug candidates to find new treatments for TBI. This review presents supporting evidence for cathepsin B, a cysteine protease, as a potentially important drug target for TBI. Cathepsin B expression is greatly up-regulated in TBI animal models, as well as in trauma patients. Importantly, knockout of the cathepsin B gene in TBI mice results in substantial improvements of TBI-caused deficits in behavior, pathology, and biomarkers, as well as improvements in related injury models. During the process of TBI-induced injury, cathepsin B likely escapes the lysosome, its normal subcellular location, into the cytoplasm or extracellular matrix (ECM) where the unleashed proteolytic power causes destruction via necrotic, apoptotic, autophagic, and activated glia-induced cell death, together with ECM breakdown and inflammation. Significantly, chemical inhibitors of cathepsin B are effective for improving deficits in TBI and related injuries including ischemia, cerebral bleeding, cerebral aneurysm, edema, pain, infection, rheumatoid arthritis, epilepsy, Huntington's disease, multiple sclerosis, and Alzheimer's disease. The inhibitor E64d is unique among cathepsin B inhibitors in being the only compound to have demonstrated oral efficacy in a TBI model and prior safe use in man and as such it is an excellent tool compound for preclinical testing and clinical compound development. These data support the conclusion that drug development of cathepsin B inhibitors for TBI treatment should be accelerated.


Effectiveness of Prenatal Tetanus, Diphtheria, Acellular Pertussis Vaccination in the Prevention of Infant Pertussis in the U.S.
It is recommended that all pregnant women in the U.S. receive tetanus, diphtheria, acellular pertussis (Tdap) immunization to prevent infant pertussis. This study's objective was to examine the clinical effectiveness of prenatal Tdap, and whether effectiveness varies by gestational age at immunization. A nationwide cohort study of pregnant women with deliveries in 2010-2014 and their infants was performed. Commercial insurance claims data were analyzed in 2016-2017 to identify Tdap receipt by the pregnant women, and hospitalizations and outpatient visits for pertussis in their infants until the infants reached 18 months of age. Pertussis occurrence was compared between infants of mothers who received prenatal Tdap (overall and stratified by gestational age at administration) and infants of unvaccinated mothers. There were 675,167 mother-infant pairs in the cohort. Among infants whose mothers received prenatal Tdap, the rate of pertussis was 43% lower (hazard ratio=0.57, 95% CI=0.35, 0.92) than infants whose mothers did not receive prenatal or postpartum Tdap; this reduction was consistent across pertussis definitions (hazard ratio for inpatient-only pertussis=0.32, 95% CI=0.11, 0.91). Pertussis rates were also lower for infants whose mothers received Tdap during the third trimester. Infants whose mothers received Tdap at <27 weeks of gestation did not experience reductions in pertussis rates (hazard ratio for pertussis=1.10, 95% CI=0.54, 2.25). Infants of mothers who received prenatal Tdap experienced half the rate of pertussis as compared with infants of unimmunized mothers. These results do not provide evidence to support changing the currently recommended timing of Tdap administration in pregnancy.


Developments in the treatment of Fabry disease.
Enzyme replacement therapy (ERT) with recombinant α-galactosidase A (r-αGAL A) for the treatment of Fabry disease has been available for over 15 years. Long-term treatment may slow down disease progression, but cardiac, renal, and cerebral complications still develop in most patients. In addition, lifelong intravenous treatment is burdensome. Therefore, several new treatment approaches have been explored over the past decade. Chaperone therapy (Migalastat; 1-deoxygalactonojirimycin) is the only other currently approved therapy for Fabry disease. This oral small molecule aims to improve enzyme activity of mutated α-galactosidase A and can only be used in patients with specific mutations. Treatments currently under evaluation in (pre)clinical trials are second generation enzyme replacement therapies (Pegunigalsidase-alfa, Moss-aGal), substrate reduction therapies (Venglustat and Lucerastat), mRNA- and gene-based therapy. This review summarises the knowledge on currently available and potential future options for the treatment of Fabry disease.


Estimating the health impact of vaccination against ten pathogens in 98 low-income and middle-income countries from 2000 to 2030: a modelling study.
The past two decades have seen expansion of childhood vaccination programmes in low-income and middle-income countries (LMICs). We quantify the health impact of these programmes by estimating the deaths and disability-adjusted life-years (DALYs) averted by vaccination against ten pathogens in 98 LMICs between 2000 and 2030. 16 independent research groups provided model-based disease burden estimates under a range of vaccination coverage scenarios for ten pathogens: hepatitis B virus, Haemophilus influenzae type B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, Streptococcus pneumoniae, rotavirus, rubella, and yellow fever. Using standardised demographic data and vaccine coverage, the impact of vaccination programmes was determined by comparing model estimates from a no-vaccination counterfactual scenario with those from a reported and projected vaccination scenario. We present deaths and DALYs averted between 2000 and 2030 by calendar year and by annual birth cohort. We estimate that vaccination of the ten selected pathogens will have averted 69 million (95% credible interval 52-88) deaths between 2000 and 2030, of which 37 million (30-48) were averted between 2000 and 2019. From 2000 to 2019, this represents a 45% (36-58) reduction in deaths compared with the counterfactual scenario of no vaccination. Most of this impact is concentrated in a reduction in mortality among children younger than 5 years (57% reduction [52-66]), most notably from measles. Over the lifetime of birth cohorts born between 2000 and 2030, we predict that 120 million (93-150) deaths will be averted by vaccination, of which 58 million (39-76) are due to measles vaccination and 38 million (25-52) are due to hepatitis B vaccination. We estimate that increases in vaccine coverage and introductions of additional vaccines will result in a 72% (59-81) reduction in lifetime mortality in the 2019 birth cohort. Increases in vaccine coverage and the introduction of new vaccines into LMICs have had a major impact in reducing mortality. These public health gains are predicted to increase in coming decades if progress in increasing coverage is sustained. Gavi, the Vaccine Alliance and the Bill & Melinda Gates Foundation.


A carotenoid-deficient mutant of the plant-associated microbe Pantoea sp. YR343 displays an altered membrane proteome.
Membrane organization plays an important role in signaling, transport, and defense. In eukaryotes, the stability, organization, and function of membrane proteins are influenced by certain lipids and sterols, such as cholesterol. Bacteria lack cholesterol, but carotenoids and hopanoids are predicted to play a similar role in modulating membrane properties. We have previously shown that the loss of carotenoids in the plant-associated bacteria Pantoea sp. YR343 results in changes to membrane biophysical properties and leads to physiological changes, including increased sensitivity to reactive oxygen species, reduced indole-3-acetic acid secretion, reduced biofilm and pellicle formation, and reduced plant colonization. Here, using whole cell and membrane proteomics, we show that the deletion of carotenoid production in Pantoea sp. YR343 results in altered membrane protein distribution and abundance. Moreover, we observe significant differences in the protein composition of detergent-resistant membrane fractions from wildtype and mutant cells, consistent with the prediction that carotenoids play a role in organizing membrane microdomains. These data provide new insights into the function of carotenoids in bacterial membrane organization and identify cellular functions that are affected by the loss of carotenoids.


Optical visualisation of thermogenesis in stimulated single-cell brown adipocytes.
The identification of brown adipose deposits in adults has led to significant interest in targeting this metabolically active tissue for treatment of obesity and diabetes. Improved methods for the direct measurement of heat production as the signature function of brown adipocytes (BAs), particularly at the single cell level, would be of substantial benefit to these ongoing efforts. Here, we report the first application of a small molecule-type thermosensitive fluorescent dye, ERthermAC, to monitor thermogenesis in BAs derived from murine brown fat precursors and in human brown fat cells differentiated from human neck brown preadipocytes. ERthermAC accumulated in the endoplasmic reticulum of BAs and displayed a marked change in fluorescence intensity in response to adrenergic stimulation of cells, which corresponded to temperature change. ERthermAC fluorescence intensity profiles were congruent with mitochondrial depolarisation events visualised by the JC-1 probe. Moreover, the averaged fluorescence intensity changes across a population of cells correlated well with dynamic changes such as thermal power, oxygen consumption, and extracellular acidification rates. These findings suggest ERthermAC as a promising new tool for studying thermogenic function in brown adipocytes of both murine and human origins.


The role of local therapy in the treatment of solitary melanoma progression on immune checkpoint inhibition: A multicentre retrospective analysis.
In patients with metastatic melanoma, progression of a single tumour lesion (solitary progression) after response to immune checkpoint inhibition (ICI) is increasingly treated with local therapy. We evaluated the role of local therapy for solitary progression in melanoma. Patients with metastatic melanoma treated with ICI between 2010 and 2019 with solitary progression as first progressive event were included from 17 centres in 9 countries. Follow-up and survival are reported from ICI initiation. We identified 294 patients with solitary progression after stable disease in 15%, partial response in 55% and complete response in 30%. The median follow-up was 43 months; the median time to solitary progression was 13 months, and the median time to subsequent progression after treatment of solitary progression (TTSP) was 33 months. The estimated 3-year overall survival (OS) was 79%; median OS was not reached. Treatment consisted of systemic therapy (18%), local therapy (36%), both combined (42%) or active surveillance (4%). In 44% of patients treated for solitary progression, no subsequent progression occurred. For solitary progression during ICI (n = 143), the median TTSP was 29 months. Both TTSP and OS were similar for local therapy, ICI continuation and both combined. For solitary progression post ICI (n = 151), the median TTSP was 35 months. TTSP was higher for ICI recommencement plus local therapy than local therapy or ICI recommencement alone (p = 0.006), without OS differences. Almost half of patients with melanoma treated for solitary progression after initial response to ICI had no subsequent progression. This study suggests that local therapy can benefit patients and is associated with favourable long-term outcomes.


Personality disorder in an Early Intervention Psychosis cohort: Findings from the Social Epidemiology of Psychoses in East Anglia (SEPEA) study.
Personality Disorders (PD) often share clinical and phenomenological overlap with psychotic disorders, especially at onset. However, there is little research on comorbid PD among people experiencing first episode psychosis. We examined the prevalence of PD recording and its sociodemographic and clinical correlates in people accepted to Early Intervention in Psychosis (EIP) services. Participants were aged 16-35, accepted into 6 EIP services for suspected psychosis, as part of the Social Epidemiology of Psychoses in East Anglia (SEPEA) study. PD was recorded by clinicians according to ICD-10. Multilevel logistic regression was performed. Of 798 participants, 76 people (9.5%) received a clinical diagnosis of PD, with emotionally unstable PD (75.0%, N = 57) the most common subtype. In multivariable analysis, risk factors for PD included female sex (odds ratio [OR]: 3.4; 95% CI: 2.0-5.7), absence of psychotic disorder after acceptance to EIP (OR: 3.0; 95% CI: 1.6-5.5), more severe hallucinations (OR: 1.6; 95% CI: 1.2-2.1), and lower parental SES (OR: 1.4; 95% CI: 1.1-1.8). Compared with the white British, black and minority ethnic groups were less likely to receive a PD diagnosis (OR: 0.3; 95% CI: 0.1-0.7). There was no association between PD and neighbourhood-level deprivation or population-density. Recording of a PD diagnosis was three times more common amongst participants later found not to meet threshold criteria for psychotic disorder, implying phenomenological overlap at referral which highlights difficulties encountered in accurate diagnostic assessment, treatment and onward referral. People with PD experienced more individual-level, but not neighbourhood-level social disadvantage in an already disadvantaged sample.


Nurses' integrity and coping strategies: An integrative review.
Integrity is one of the core values in nursing that needs to be maintained by nurses in practice. However, the complexity in the nursing milieu can pose threats to integrity. An understanding of the common threats and coping strategies might assist nurses in preserving integrity in everyday practice. To review and synthesis the concept of integrity in nursing and identify common threats and coping strategies. Whittemore and Knafl's integrative review method was implemented. A search was performed in Scopus, Medline, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, and Proquest Health and Medical electronic databases published in English between 2000-2017. Two reviewers independently assessed eligibility for inclusion. Methodological appropriateness for the included studies was assessed using the critical appraisal skills programme. The constant comparative method of grounded theory was used to analyse and synthesise data from seven peer-reviewed articles. Two major conceptions of integrity were identified. These included the sense of wholeness with regard to personal-professional concerns and ethical-moral conducts. Five entities, self, patients, teamwork and work culture, the nature of work, and organisation, were identified as interweaving elements that may induce threats to integrity. When integrity is threatened, nurses use two key strategies to survive: adjusting and compensating. An emergent framework to facilitate understanding of nurses' threats to integrity is discussed. A threat to nurses' integrity takes form when there is an unmitigated gap between a nurse's expectation and reality. While the expectation comes from within the nurse, the reality materialises out of the complex interplays that occur in the healthcare workforce. Maintaining integrity demands a continual strive to balance personal expectations, professional concerns and nursing realities.


Mammography screening in the county of Fyn. November 1993-December 1999.
This report covers the outcome of the first three invitation rounds of the organised mammography screening programme in the county of Fyn. The programme started in November 1993, and the third invitation round ended on 31 December 1999. The screening takes place either at a special clinic located at University Hospital Odense or in a mobile unit. Women living in and around the city of Odense are examined at the clinic (about 55%), while the rest are examined in the mobile unit. Two-view mammography is used at the first screening. Women with dense breast tissue will continue to have two-view mammography (about 60%), whereas the rest will have singleview mammography at the subsequent screens. All screening images are exposed at the mammography-screening clinic and evaluated with double reading in the clinic. The programme targets women aged 50-69, except those undergoing treatment for breast cancer or going for regular check-ups following breast cancer. Based on the updated population register, the IT-Centre of the county of Fyn issues the invitations. Invited are all women aged 50-69 and living in the county of Fyn when their general practitioners' patients are invited. During the first 3 invitation rounds, 136,079 screening tests were made. Of these, 129,375 tests were made in the women aged 50-69 targeted by the programme. In addition, 6682 screening tests were made in women aged 70 and above, and 22 screening tests were made in women below the age of 50. As a consequence of the mammography screening 2657 assessments were made, 1145 women had surgery, 782 women were diagnosed with invasive breast cancer, and 109 women were diagnosed with ductal carcinoma in situ. A participation rate for the first invitation round was calculated immediately after the end of the round based on the number of participants divided by the number of women invited. This percentage was 88%. Invitation data are, however, not stored. It is therefore not possible now to calculate the participation rates in previous invitation rounds based on the same method. We have therefore chosen to calculate the participation rate as the coverage, i.e. the number of participants divided by the average number of women in the county of Fyn during a given invitation round. Calculated in this way, 84% participated in the first round, 84% in the second round, and 82% in the third round. It should be remembered that these figures do not take into account that some women are not invited because they 1) were undergoing current treatment for breast cancer or going for regular check-ups following breast cancer, or 2) did not participate in the previous round (and never actively informed the programme that they wanted an invitation to the next invitation round), relevant only for the second and third invitation round. For the second and third invitation rounds, the programme only invited women who participated in the previous invitation round, asked the clinic for an invitation, or entered the target population since the last invitation round. Therefore the participation rate in the second invitation round among actually invited women will be close to 94%, as 94% of those participating in the first round came for the second round. For the third invitation round, the participation rate among actually invited women will be close to 96%, as 96% of those participating in the first and second rounds came for the third round. One per cent of the participants in the first invitation round were diagnosed with invasive breast cancer or ductal carcinoma in situ. The detection rate was 0.5% in both the second and third invitation rounds. Ductal carcinoma in situ cases constituted 14% of the detected cases in the first and second rounds, and 10% in the third round. The percentage of invasive breast cancer 10 mm of less was 38%, 31%, and 32%, respectively, and 68%, 74%, and 73%, respectively, were node-negative. The screening programme of the county of Fyn fulfilled all the quality assessment parameters specified by the European guidelines on breast cancer screening, except two. The proportionate interval cancer rate was higher than specified in the guidelines, probably mainly due to the fact that the Fyn programme operates without early recalls. The proportion of stage II+ cancers was higher than specified in the guidelines, which seems, however, to be due to inconsistency between some of the performance indicators in the European guidelines. This analysis of the outcome from the first three invitation rounds of the mammography screening programme in the county of Fyn thus showed that it is a programme of high quality with a favourable profile of the prognostic indicators. The screening programme is hopefully well on its way to reducing breast cancer mortality in the county of Fyn.


An evaluation of active shape models for the automatic identification of cephalometric landmarks.
This paper describes an evaluation of the application of active shape models to cephalometric landmarking. Permissible deformations of a template were established from a training set of hand-annotated images and the resulting model was used to fit to unseen images. An evaluation of this technique in comparison to the accuracy achieved by previous methods is presented. Sixty-three randomly selected cephalograms were tested using a drop-one-out method. On average, 13 per cent of 16 landmarks were within 1 mm, 35 per cent within 2 mm, and 74 per cent within 5 mm. It was concluded that the current implementation does not give sufficient accuracy for completely automated landmarking, but could be used as a time-saving tool to provide a first-estimate location of the landmarks. The method is also of interest because it provides a framework for a range of future improvements.


Congenital fetal and neonatal visceral chylous effusions: neonatal chylothorax and chylous ascites revisited. A multicenter retrospective study.
This retrospective study was carried out at eight Neonatal Intensive Care Units (NICU) Centers worldwide on 33 newborns presenting at birth with pleural, pericardial, or abdominal chylous effusions. Diagnosis of chylous effusion is based on findings of fluid with a milk-like appearance, a concentration of triglycerides in pleural effusion >1.1 mmol/l, and a total cell count >1,000 cells/ml with a predominance of >80% lymphocytes. Thirty-three newborns met the inclusion criteria and were studied. Six subjects who presented at birth with fetal effusion were treated by in-utero pleuro-amniotic shunt. Five of these patients are alive at follow-up. At birth, pleural drainage was performed in 29/33 patients and abdominal drainage was carried out in 3/33. Total parenteral nutrition (TPN) was given to 32/33 patients; 19/23 patients were fed a medium-chain triglycerides (MCT). No adverse effects were observed. Eight patients were treated with Octreotide at dosages ranging from 1 to 7 mcg/kg/hour for 8 to 35 days. All patients showed decreased chylous production. Two patients were treated by pleurodesis. Twenty-two babies are alive after at least 6 months follow-up, 9/33 are deceased, and 2 were lost to follow-up. Clinical conditions of survivors are basically good except for lung involvement [chronic lung disease (CLD) or lung lymphangiectasia] and lymphedema. All patients were using a MCT diet at follow-up with good control of chylous effusion. Visceral chylous effusions of the fetus and neonate are rare disorders, and there currently is only partial agreement on decision-making strategies. We suggest the need for an international prospective trial in an effort to establish the efficacy and effectiveness of diagnostic and therapeutic options described in this article.


Interaction of the koinobiont parasitoid Microplitis rufiventris of the cotton leafworm, Spodoptera littoralis, with two entomopathogenic rhabditids, Heterorhabditis bacteriophora and Steinernema carpocapsae.
Entomopathogenic nematodes are generally considered beneficial organisms. However, they can affect beneficial insects such as parasitoids. The interaction between the entomopathogenic nematodes Heterorhabditis bacteriophora Poinar (Rhabditida: Heterorhabditidae) and Steinernema carpocapsae Weiser, and the parasitoid Microplitis rufiventris Kokujev (Hymenoptera: Braconidae) was investigated in the laboratory. In non-parasitized hosts, Spodoptera littoralis Boisduval (Lepidoptera: Noctuidae) larvae exposed to H. bacteriophora showed a higher percent mortality than those exposed to S. carpocapsae. Both nematodes were able to invade and propagate in non-parasitized S. littoralis larvae and those parasitized by M. rufiventris. Both nematode species reproduced in Microplitis-parasitized hosts, but there was a higher number of nematodes in non-parasitized larvae. S. carpocapsae yielded higher numbers of infective juveniles than H. bacteriophora. Generally, the number of nematodes harvested increased as their host's size increased. The interaction between the nematodes and parasitoid favored the nematodes when the nematodes were inoculated during the parasitoid egg stage or the young parasitoid larvae, thus giving the nematodes a better chance to grow and reproduce, resulting in the death of the parasitoid larvae. Conversely, when the nematodes were inoculated during the late larval instar of the parasitoid, the competition partially favored the wasp, thus giving approximately 50% of the wasps a better chance to develop, emerge, and reproduce, providing evidence that both nematodes and wasps could reproduce in the same host. Egg maturation of female wasps derived from nematode-infected hosts was not significantly different than those from control hosts. The combined application of nematodes and parasitoids may be beneficial if the detrimental effects of the nematodes on the parasitoid could be avoided by precisely timing the application strategies. It is clear that Microplitis larvae and the nematodes share the host larva and engage in a trophic interaction with each other. Intraguild predation is briefly discussed.


Multicenter study evaluating the impact of COVID-19 outbreak on dermatology outpatients in Turkey.
COVID-19 pandemic has a significant impact on public health, whether directly or indirectly. The first case was seen in Turkey on March 11, and the World Health Organization (WHO) declared a pandemic on March 12, 2020. The study aimed to document the effect of pandemic on dermatology outpatient clinics in Turkey. Fifteen tertiary hospitals from 13 provinces were included in the study, which was conducted between January 12 and May 12, 2020. The International Codes of Diseases (ICD-10) categories and patients' characteristics were evaluated before and after the pandemic. A total of 164 878 patients, 133 131 before and 31 747 after the pandemic, were evaluated. The daily hospital applications were found reduced by 77%. The three of the most frequent diagnoses; dermatitis, acne, and psoriasis remained unchanged after the pandemic. While the frequency of herpes zoster, scabies, urticaria, pityriasis rosea and sexually transmitted diseases increased significantly; allergic and irritant contact dermatitis decreased after the pandemic. The applications regarding cutaneous neoplasms were considerably reduced during the pandemic, and this effect was more pronounced in cities with higher COVID incidence. The pandemic caused a noteworthy reduction in the number of patients accessing dermatological care. The pandemic caused significant changes in the frequency of a wide range of dermatological diseases. The application of cutaneous neoplasms is considerably reduced after the pandemic, and this effect was more pronounced in cities where pandemics are frequent. Therefore, the pandemic has resulted on numerous impacts on many critical issues in dermatology and dermatological care.


Effects of ankle power training on movement time in mobility-impaired older women.
Reduced abilities to generate power put older adults at risk in situations that demand rapid movements. Slower movement times are associated with greater risk of falling and of being involved in a motor vehicle crash. The purpose of this study was to determine the effects of power training on foot movement time and, secondarily, on ankle strength and power in mobility-impaired older women. Fifty mobility-impaired women (70-88 yr) trained twice per week for 12 wk in one of three groups (weights, elastic bands, or placebo control). All groups performed seated warm-up exercises, followed by either concentric dorsiflexion (DF) and plantarflexion (PF) resistance exercises (weights and bands) performed "as fast as possible" or upper body flexibility exercises (control). Foot reaction/movement time and ankle DF and PF peak torque (30 degrees x s(-1)) and peak power (90 degrees x s(-1)) were measured before and after training. Participants who trained with elastic bands demonstrated improvements in movement time (decreased by 24 ms or 12%, P = 0.003). All groups demonstrated improvements in DF and PF strength and power, which were not statistically different. High-velocity/low-load (elastic bands) training improved movement time, which may have important implications in circumstances when rapid generation of torque is required (e.g., to avoid a fall or prevent a vehicle crash). Elastic bands are relatively inexpensive and provide a practical form of training that could be considered in programs designed for older adults with mobility limitations.


Preclinical rationale for entinostat in embryonal rhabdomyosarcoma.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR). We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors. ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts. Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.


Mental number line training in children with developmental dyscalculia.
Developmental dyscalculia (DD) is a specific learning disability that affects the acquisition of mathematical skills in children with normal intelligence and age-appropriate school education (prevalence 3-6%). One essential step in the development of mathematical understanding is the formation and automated access to a spatial representation of numbers. Many children with DD show a deficient development of such a mental number line. The present study aimed to develop a computer-based training program to improve the construction and access to the mental number line. Sixteen children with DD aged 8-10 years and 16 matched control children completed the 5-week computer training. All children played the game 15 min a day for 5 days a week. The efficiency of the training was evaluated by means of neuropsychological tests and functional magnetic resonance imaging (fMRI) during a number line task. In general, children with and without DD showed a benefit from the training indicated by (a) improved spatial representation of numbers and (b) the number of correctly solved arithmetical problems. Regarding group differences in brain activation, children with DD showed less activation in bilateral parietal regions, which reflects neuronal dysfunction in pivotal regions for number processing. Both groups showed reduced recruitment of relevant brain regions for number processing after the training which can be attributed to automatization of cognitive processes necessary for mathematical reasoning. Moreover, results point to a partial remediation of deficient brain activation in dyscalculics after consolidation of acquired and refined number representation. To conclude, the present study represents the first attempt to evaluate a custom-designed training program in a group of dyscalculic children and results indicate that the training leads to an improved spatial representation of the mental number line and a modulation of neural activation, which both facilitate processing of numerical tasks.


Big Data Approaches to Phenotyping Acute Ischemic Stroke Using Automated Lesion Segmentation of Multi-Center Magnetic Resonance Imaging Data.
Background and Purpose- We evaluated deep learning algorithms' segmentation of acute ischemic lesions on heterogeneous multi-center clinical diffusion-weighted magnetic resonance imaging (MRI) data sets and explored the potential role of this tool for phenotyping acute ischemic stroke. Methods- Ischemic stroke data sets from the MRI-GENIE (MRI-Genetics Interface Exploration) repository consisting of 12 international genetic research centers were retrospectively analyzed using an automated deep learning segmentation algorithm consisting of an ensemble of 3-dimensional convolutional neural networks. Three ensembles were trained using data from the following: (1) 267 patients from an independent single-center cohort, (2) 267 patients from MRI-GENIE, and (3) mixture of (1) and (2). The algorithms' performances were compared against manual outlines from a separate 383 patient subset from MRI-GENIE. Univariable and multivariable logistic regression with respect to demographics, stroke subtypes, and vascular risk factors were performed to identify phenotypes associated with large acute diffusion-weighted MRI volumes and greater stroke severity in 2770 MRI-GENIE patients. Stroke topography was investigated. Results- The ensemble consisting of a mixture of MRI-GENIE and single-center convolutional neural networks performed best. Subset analysis comparing automated and manual lesion volumes in 383 patients found excellent correlation (ρ=0.92; P<0.0001). Median (interquartile range) diffusion-weighted MRI lesion volumes from 2770 patients were 3.7 cm3 (0.9-16.6 cm3). Patients with small artery occlusion stroke subtype had smaller lesion volumes ( P<0.0001) and different topography compared with other stroke subtypes. Conclusions- Automated accurate clinical diffusion-weighted MRI lesion segmentation using deep learning algorithms trained with multi-center and diverse data is feasible. Both lesion volume and topography can provide insight into stroke subtypes with sufficient sample size from big heterogeneous multi-center clinical imaging phenotype data sets.


Patient education and provider decision support to control blood pressure in primary care: a cluster randomized trial.
Less than one third of the 65 million Americans with hypertension have adequate blood pressure (BP) control. This study examined the effectiveness of 2 interventions for improving patient BP control. This was a 2-level (primary care provider and patient) cluster randomized trial with 2-year follow-up occurring among patients with hypertension enrolled from a Veterans Affairs Medical Center primary care clinic. Primary care providers (n = 17) in the intervention received computer-generated decision support designed to improve guideline concordant medical therapy at each visit; control providers (n = 15) received a reminder at each visit. Patients received usual care or a bimonthly tailored nurse-delivered behavioral telephone intervention to improve hypertension treatment. The primary outcome was proportion of patients who achieved a BP <140/90 mm Hg (<130/85 for diabetic patients) over the 24-month intervention. Of the 816 eligible patients contacted, 190 refused and 38 were excluded. The 588 enrolled patients had a mean age of 63 years, 43% had adequate baseline BP control, and 482 (82%) completed the 24-month follow-up. There were no significant differences in amount of change in BP control in the 3 intervention groups as compared to the hypertension reminder control group. In secondary analyses, rates of BP control for all patients receiving the patient behavioral intervention (n = 294) improved from 40.1% to 54.4% at 24 months (P = .03); patients in the nonbehavioral intervention group improved from 38.2% to 43.9% (P = .38), but there was no between-group differences at the end of the study. The brief behavioral intervention showed improved outcomes over time, but there were not significant between group differences.


Cerebral oxygen desaturation occurs frequently in patients with hypertension undergoing major abdominal surgery.
Hypertensive patients are more likely to experience latent cerebral ischemia causing regional cerebral oxygen saturation (rSO2) decrease during general anesthesia. The aim of this prospective observational study was to assess the incidence of decreased rSO2 in hypertensive patients undergoing major abdominal surgery and the perioperative factors affecting this change in rSO2. A total of 41 hypertensive patients were enrolled and stratified according to their hypertension as controlled and uncontrolled. The intraoperative rSO2 and physiological data were routinely collected. The Mini-Mental State Exam (MMSE) was used to test cognitive function before surgery and after 4 days. Cerebral desaturation was defined as a decrease in rSO2 of more than 20% of the baseline value. There were 20 patients (49%) suffering intraoperative cerebral desaturation classified into cerebral desaturation group (group D) and those 21 without intraoperative desaturation classified into normal group (group N). The area under the curve below 90 and 80% of baseline (AUCrSO2 <90% of baseline and AUCrSO2 <80% of baseline) was lower in patients of group N (2752.4 ± 1453.3 min% and 0.0 min%) than in patients of group D (6264.9 ± 1832.3 min% and 4486.5 ± 1664.9 min%, P < 0.001). Comparing the two groups, the number of uncontrolled hypertensive individuals in group D (12/20) was significantly more than group N (4/21) (P = 0.007). A significant correlation was observed between relative decrease in MAP and relative decrease in rSO2 (r2 = 0.495, P < 0.001). Moreover, nine patients (45%) in group D occurred early postoperative cognitive function decline were more than three patients (14.3%) in group N (P = 0.031). This pilot study showed a large proportion of hypertensive patient experienced cerebral desaturation during major abdominal surgery and uncontrolled hypertension predisposed to this desaturation. NCT02147275 (registered at http://www.clinicaltrials.gov ).


Effect of cadmium telluride quantum dots on the dielectric and electro-optical properties of ferroelectric liquid crystals.
We present here the dielectric and electro-optical studies of cadmium telluride quantum dots (CdTe QDs) doped ferroelectric liquid crystals (FLCs). It has been observed that the doping of CdTe QDs not only induced a pronounced memory effect but also affected the physical parameters of FLC material (LAHS19). The modifications in the physical parameters and memory effect of LAHS19 are found to depend on the concentration ratio of CdTe QDs. The lower concentration of CdTe QDs (1-3 wt%) enhanced the values of spontaneous polarization and rotational viscosity of LAHS19 material but did not favor the memory effect, whereas a higher concentration of CdTe QDs (>5 wt%) degraded the alignment of LAHS19 material. The doping of ∼5 wt% of CdTe QDs is found to be the most suitable for achieving good memory effect without significantly affecting the material parameters.


Sluggish vagal brake reactivity to physical exercise challenge in children with selective mutism.
Cardiovascular response patterns to laboratory-based social and physical exercise challenges were evaluated in 69 children and adolescents, 20 with selective mutism (SM), to identify possible neurophysiological mechanisms that may mediate the behavioral features of SM. Results suggest that SM is associated with a dampened response of the vagal brake to physical exercise that is manifested as reduced reactivity in heart rate and respiration. Polyvagal theory proposes that the regulation of the vagal brake is a neurophysiological component of an integrated social engagement system that includes the neural regulation of the laryngeal and pharyngeal muscles. Within this theoretical framework, sluggish vagal brake reactivity may parallel an inability to recruit efficiently the structures involved in speech. Thus, the findings suggest that dampened autonomic reactivity during mobilization behaviors may be a biomarker of SM that can be assessed independent of the social stimuli that elicit mutism.


Metal ions affecting the gastrointestinal system including the liver.
In the present context, metal ions can be categorized into several classes including those that are essential for life and those that have no known biological function and thus can be considered only as potentially hazardous. Many complexities arise with regard to metal toxicity and there is a paucity of studies relating to many metals which are frequent components of the diet. For many people ingestion of mineral supplements is considered a risk-free health choice despite growing evidence to the contrary. Numerous approaches have been developed to assess risk associated with ingestion of metal ions. These include straightforward estimation of safe limits such as oral reference dose which are often based on data derived from animal experiments. More convoluted approaches such as the Target Hazard Quotient involve assessment of hazard with frequent exposure over long durations such as a lifetime. The latter calculation also affords facile consideration of the effects of many metals together. In many cases, rigorous data are unavailable, hence, large factors of uncertainty are employed to relate risk to humans. Owing to the nature of metal toxicity, data pertaining to the gastrointestinal tract and liver are often acquired from diseases of metal homeostasis or episodes of considerable metal overload. Whilst these studies provide evidence for mechanisms of metal-induced toxicity such as enhancing oxidative stress, extrapolation of these results to healthy individuals or patients with chronic inflammatory diseases is not straightforward. In summary, the diverse nature of metals and their effects on human tissues along with a paucity of studies on the full range of their effects, warrant further in-depth studies on the association of metals to ageing, chronic inflammatory diseases, and cancer.


Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease.
The objective of this study is to clarify the role of (G4C2)n expansions in the etiology of Parkinson disease (PD) in the worldwide multicenter Genetic Epidemiology of Parkinson's Disease (GEO-PD) cohort. C9orf72 (G4C2)n repeats were assessed in a GEO-PD cohort of 7,494 patients diagnosed with PD and 5,886 neurologically healthy control individuals ascertained in Europe, Asia, North America, and Australia. A pathogenic (G4C2)n>60 expansion was detected in only 4 patients with PD (4/7,232; 0.055%), all with a positive family history of neurodegenerative dementia, amyotrophic lateral sclerosis, or atypical parkinsonism, while no carriers were detected with typical sporadic or familial PD. Meta-analysis revealed a small increase in risk of PD with an increasing number of (G4C2)n repeats; however, we could not detect a robust association between the C9orf72 (G4C2)n repeat and PD, and the population attributable risk was low. Together, these findings indicate that expansions in C9orf72 do not have a major role in the pathogenesis of PD. Testing for C9orf72 repeat expansions should only be considered in patients with PD who have overt symptoms of frontotemporal lobar degeneration/amyotrophic lateral sclerosis or apparent family history of neurodegenerative dementia or motor neuron disease.


Feature extraction of the first difference of EMG time series for EMG pattern recognition.
This paper demonstrates the utility of a differencing technique to transform surface EMG signals measured during both static and dynamic contractions such that they become more stationary. The technique was evaluated by three stationarity tests consisting of the variation of two statistical properties, i.e., mean and standard deviation, and the reverse arrangements test. As a result of the proposed technique, the first difference of EMG time series became more stationary compared to the original measured signal. Based on this finding, the performance of time-domain features extracted from raw and transformed EMG was investigated via an EMG classification problem (i.e., eight dynamic motions and four EMG channels) on data from 18 subjects. The results show that the classification accuracies of all features extracted from the transformed signals were higher than features extracted from the original signals for six different classifiers including quadratic discriminant analysis. On average, the proposed differencing technique improved classification accuracies by 2-8%.


Treatment of hepatitis C virus infection in patients with end-stage renal disease.
Hepatitis C virus (HCV) infection is a major health problem in patients with end-stage renal disease (ESRD). The incidence of acute HCV infection during maintenance dialysis is much higher than that in the general population because of the risk of nosocomial transmission. Following acute HCV infection, most patients develop chronic HCV infection, and a significant proportion develop chronic hepatitis, cirrhosis, and even hepatocellular carcinoma. Overall, chronic hepatitis C patients on hemodialysis bear an increased risk of liver-related morbidity and mortality, either during dialysis or after renal transplantation. Interferon (IFN) therapy is modestly effective for the treatment of HCV infection in ESRD patients. Conventional or pegylated IFN monotherapy has been used to treat acute hepatitis C in ESRD patients with excellent safety and efficacy. Regarding chronic hepatitis C, approximately one-third of patients can achieve a sustained virological response (SVR) after conventional or pegylated IFN monotherapy. The combination of low-dose ribavirin and conventional or pegylated IFN has further improved the SVR rate in treatment-naïve or retreated ESRD patients in clinical trials. Similar to the treatment of patients with normal renal function, baseline and on-treatment HCV virokinetics are useful to guide optimized therapy in ESRD patients. Of particular note, IFN-based therapy is not recommended at the post-renal transplantation stage because of the low SVR rate and risk of acute graft rejection. In conclusion, ESRD patients with HCV infection should be encouraged to receive antiviral therapy, and those who achieve an SVR usually have long-term, durable, virological, biochemical, and histological responses.


Detection and significance of splenomegaly on chest radiographs of HIV-infected outpatients.
The purpose of this study was to determine the prevalence of splenomegaly on chest radiographs of HIV-infected outpatients and to correlate with CD4 cell counts, opportunistic conditions, liver disease and the presence of intrathoracic disease on chest radiographs. We reviewed sequential chest radiographs of 200 HIV Clinic outpatients at the Jacobi Medical Center, Bronx, New York, mixed with chest radiographs of 137 outpatients of unknown HIV status (control group) for the presence of splenomegaly and intrathoracic disease. Chest radiographic assessment of splenomegaly was correlated with computed tomography (CT) or ultrasound (US) in 90 out of 337 patients (27%). Clinical charts of all HIV-infected patients were reviewed for CD4 cell count, liver disease and opportunistic conditions including those associated with splenomegaly. The HIV-infected patients were divided into four groups by ascending CD4 cell count: Group 1 (0-50 cells/mm3), Group 2 (51-200 cells/mm3), Group 3 (201-500 cells/mm3) and Group 4 (>500 cells/ mm3). There were 118 men and 82 women with a mean age of 40 (range 20-60) years. Mean CD4 was 180 (range 2-1108) cells/mm3. We also reviewed all autopsies (n = 239) performed on HIV-infected patients between 1983 and 1995 at our institution to correlate splenic size with splenic pathology in that population. Splenomegaly was present on chest radiographs in 82 (41%) HIV-infected patients including: 36/84 (43%) Group 1, 23/49 (47%) Group 2, 18/46 (39%) Group 3, and 5/21 (24%) Group 4 (P = NS). Splenomegaly was present in 30/97 (31%) patients with no evidence of liver disease or opportunistic conditions known to be associated with splenomegaly. Forty-nine HIV-infected patients had 63 opportunistic conditions known to be associated with splenomegaly (mycobacterial and fungal infections, Kaposi sarcoma and lymphoma), half of whom had splenomegaly. Splenomegaly was present on chest radiographs in 18/137 (13%) controls. The presence or absence of splenomegaly on CT or US agreed with chest radiography in 89%. Among the autopsied patients, 135/239 (56%) had splenomegaly (splenic weight > or = 240 g). No specific pathogen was present in 93/135 (69%) enlarged spleens. In contrast, one or more opportunistic conditions were present in 26/104 (25%) normal weight spleens. In conclusion, splenomegaly is common in HIV-infected patients and was present in 41% of this series. Splenomegaly may be seen in HIV-infected patients without associated opportunistic conditions or liver disease and in the absence of specific splenic pathology. Chest radiography plays an important role in detecting splenomegaly and may lead to earlier diagnosis of HIV infection.


A Model to Estimate the Optimal Layout for Assistive Communication Touchscreen Devices in Children With Dyskinetic Cerebral Palsy.
Excess involuntary movements and slowness of movement in children with dyskinetic cerebral palsy often result in the inability to properly interact with augmentative and alternative communication (AAC) devices. This significantly limits communication. It is, therefore, essential to know how to adjust the device layout in order to maximize each child's rate of communication. The aim of this paper was to develop a mathematical model to estimate the information rate in children with dyskinetic cerebral palsy and to determine the optimal AAC layout for a touchscreen tablet that results in enhanced speed of communication. The model predicts information rate based on button size, number, spacing between buttons, and the probability of making an error or missing target buttons. Estimation of the information rate confirmed our hypothesis of lower channel capacity in children with dyskinetic cerebral palsy compared with age-matched healthy children. Information rate increased when the AAC layout was customized based on the optimal parameters predicted by the model. In conclusion, this paper quantifies the effect of motor impairments on communication with assistive communication devices and shows that communication performance can be improved by optimally matching the parameters of the AAC touchscreen device to the abilities of the child.


Expression of COX-2, Ki-67, cyclin D1, and P21 in endometrial endometrioid carcinomas.
COX-2, the isoform of cyclooxygenase inducible by cytokines, mitogens, and growth factors, appears to play an important role in inflammation and carcinogenesis. In the colon, COX-2 overexpression results in cell cycle alterations, and NSAIDs have proven effective in cancer chemoprevention. HNPCC (hereditary nonpolyposis colon cancer) is a clinically defined cancer susceptibility syndrome in which women are also at significantly increased risk for the development of endometrial carcinoma. The purpose of this study was to evaluate expression of COX-2 in benign and malignant endometrium in the context of other cell cycle and proliferation markers, including Ki-67, cyclin D1, and the cyclin-dependent kinase inhibitor, p21. Immunostains with COX-2, Ki-67, cyclin D1, and p21 antibodies were performed on formalin-fixed and paraffin-embedded tissue sections from 40 cases: 10 benign (5 atrophic and 5 proliferative) endometria, 6 hyperplasias (complex without atypia), and 24 endometrioid carcinomas (9 well, 4 moderately, and 11 poorly differentiated). Ki-67 was positive in all proliferative and neoplastic endometria. Cyclin D1 and p21 were both overexpressed in endometrial hyperplasia and endometrioid carcinomas. COX-2 was negative in the nonneoplastic endometrium, stained minimally in the well-differentiated endometrioid carcinomas, and stained most strongly in the moderately and poorly differentiated endometrioid carcinomas. Because cyclin D1 may function as an oncogene, its effects may dominate the usual inhibitory effect of a rising p21. Alternatively, it has been shown that p21 can promote cell cycle function by stabilizing cell cycle complexes. The overexpression of COX-2 in poorly differentiated endometrioid carcinoma and lack of expression in hyperplasia and well-differentiated carcinoma suggests that in this form of cancer, COX-2 may play a role in tumor progression rather than tumor initiation.


Novel Bruch's Membrane Opening Minimum Rim Area Equalizes Disc Size Dependency and Offers High Diagnostic Power for Glaucoma.
The purpose of this study was to assess the diagnostic power of the novel two-dimensional parameter Bruch's membrane opening minimal rim area (BMO-MRA) in spectral-domain optical coherence tomography (SD-OCT) for detection of glaucoma compared to minimal rim width (BMO-MRW) and retinal nerve fiber layer (RNFL) thickness in large and small optic discs. In this case-control, cross-sectional study, 207 eyes of 207 participants, including 89 controls and 97 patients with glaucoma and 21 with ocular hypertension (OHT), with a disc size <1.63 mm2 or >2.43 mm2 underwent SD-OCT, confocal laser scanning tomography (CSLT), visual field testing, and clinical examination. Bruch's membrane opening-MRA BMO-MRW, RNFL thickness of SD-OCT and disc margin rim area (DM-RA) of CSLT were evaluated and analyzed for diagnostic power to detect glaucoma. In healthy eyes with macrodiscs, mean BMO-MRW of 243.14 ± 43.12 μm was significantly smaller than BMO-MRW in microdiscs (338.97 ± 69.39; P < 0.001). Bruch's membrane opening-MRA was comparable between disc size groups with 1.22 ± 0.25 mm2 for macrodiscs and 1.26 ± 0.27 mm2 for microdiscs (P = 0.51), as was RNFL thickness (82.69 ± 15.76 μm versus 78.53 ± 11.01 μm, respectively; P = 0.28). Perimetric mean deviation was -8.7 ± 6.3 dB in glaucoma and -0.6 ± 1.60 dB in OHT patients. Correlation of BMO-MRA and visual field function was rho (ρ) = 0.70 (P < 0.001). Diagnostic power to differentiate glaucoma patients was highest for BMO-MRA. Partial area under the curve (pAUC) for BMO-MRA was 0.14 for specificity between 0.8 and 1.0, exceeding pAUCs of BMO-MRW (P < 0.001), RNFL thickness (P = 0.03), and DM-RA (P = 0.01). Bruch's membrane opening-based minimum rim area measurements offer advantages compared to one-dimensional parameters assessing neuroretinal rim by SD-OCT. In nonglaucomatous eyes, BMO-MRA values seem comparable for the full range of disc sizes. Bruch's membrane opening-MRA surpasses other parameters in diagnostic power for glaucoma.


Gut barrier in health and disease: focus on childhood.
The gut barrier is a functional unit, organized as a multi-layer system, made up of two main components: a physical barrier surface, which prevents bacterial adhesion and regulates paracellular diffusion to the host tissues, and a deep functional barrier, that is able to discriminate between pathogens and commensal microorganisms, organizing the immune tolerance and the immune response to pathogens. Other mechanisms, such as gastric juice and pancreatic enzymes (which both have antibacterial properties) participate in the luminal integrity of the gut barrier. From the outer layer to the inner layer, the physical barrier is composed of gut microbiota (that competes with pathogens to gain space and energy resources, processes the molecules necessary to mucosal integrity and modulates the immunological activity of deep barrier), mucus (which separates the intraluminal content from more internal layers and contains antimicrobial products and secretory IgA), epithelial cells (which form a physical and immunological barrier) and the innate and adaptive immune cells forming the gut-associated lymphoid tissue (which is responsible for antigen sampling and immune responses). Disruption of the gut barrier has been associated with many gastrointestinal diseases, but also with extra-intestinal pathological condition, such as type 1 diabetes mellitus, allergic diseases or autism spectrum disorders. The maintenance of a healthy intestinal barrier is therefore of paramount importance in children, for both health and economic reasons. Many drugs or compounds used in the treatment of gastrointestinal disorders act through the restoration of a normal intestinal permeability. Several studies have highlighted the role of probiotics in the modulation and reduction of intestinal permeability, considering the strong influence of gut microbiota in the modulation of the function and structure of gut barrier, but also on the immune response of the host. To date, available weapons for the maintenance and repair of gut barrier are however few, even if promising. Considerable efforts, including both a better understanding of the gut barrier features and mechanisms in health and disease, and the development of new pharmacological approaches for the modulation of gut barrier components, are needed for the prevention and treatment of gastrointestinal and extraintestinal diseases associated with gut barrier impairment.


Magnetically-targeted and near infrared fluorescence/magnetic resonance/photoacoustic imaging-guided combinational anti-tumor phototherapy based on polydopamine-capped magnetic Prussian blue nanoparticles.
In recent years, Prussian blue (PB)-based nanoagents have become a new platform in photothermal cancer treatment. However, there is little research for PB-based nanoagents to achieve synergistic phototherapy guided by multimodal imaging diagnosis and monitoring. Herein, a novel single wavelength near infrared (NIR) laser-induced magnetically targeted theranostic nanoplatform has been successfully designed and synthesized for the first time based on polydopamine (PDA)/aluminum phthalocyanine (AlPc)/bovine serum albumin (BSA) coated magnetic Prussian blue nanoparticles (Fe3O4@PB NPs) for multiple imaging-guided combinatorial cancer therapy. The resultant multifunctional Fe3O4@PB@PDA/AlPc/BSA nanocomposites show excellent stability and superparamagnetism, facilitating them to achieve superior photothermal therapy in physiological environments under magnetic guidance. In addition, the delivery vehicles can remarkably increase tumor accumulation of AlPc, thus leading to an enhanced photodynamic therapy efficacy. Furthermore, Fe3O4@PB@PDA/AlPc/BSA can be utilized as a multimodality nanoprobe for simultaneous diversified imaging, including near-infrared fluorescence imaging (NIRFI), magnetic resonance imaging (MRI), and photoacoustic imaging (PAI). Most importantly, without noticeable dark toxicity, the obtained Fe3O4@PB@PDA/AlPc/BSA nanocomposites are able to significantly suppress tumor growth via combined photothermal and photodynamic therapies upon a single 660 nm laser irradiation, achieving a superior synergetic manner compared to monotherapy both in vitro and in vivo. Therefore, our strategy provides Fe3O4@PB@PDA/AlPc/BSA nanocomposites for trimodality cancer imaging-guided synergistic therapy, with a great potential for new generation theranostics nanoagents.


Human papilloma virus correlates of high grade cervical dysplasia in HIV-infected women in Mombasa, Kenya: a cross-sectional analysis.
Women living with HIV are at increased risk to be co-infected with HPV, persistent high-risk (HR) human papillomavirus (HPV) infection and increased HR HPV viral load, which make them more at risk for cervical cancer. Despite their inherent vulnerability, there is a scarcity of data on potential high risk (pHR) and HR HPV genotypes in HIV- infected women with cervical dysplasia and HPV-type specific viral load in this population in Sub Saharan Africa. The aim of this analysis of HIV-infected women was to explore the virological correlates of high-grade cervical dysplasia (CIN 2+) in HIV-infected women, thereby profiling HPV genotypes. This analysis assesses baseline data obtained from a cohort study of 74 HIV-infected women with abnormal cytology attending a Comprehensive Care Centre for patients with HIV infection in Mombasa, Kenya. Quantitative real-time PCR was used for HPV typing and viral load. CIN 2 was observed in 16% (12/74) of women, CIN 3 in 23% (17/74), and, invasive cervical carcinoma (ICC) in 1% (1/74) of women. In women with CIN 3+, HPV 16 (44%), HPV 56 (33%), HPV 33 and 53 (HPV 53 (28%) were the most prevalent genotypes. HPV 53 was observed as a stand-alone HPV in one woman with ICC. A multivariate logistic regression adjusting for age, CD4 count and HPV co-infections suggested the presence of HPV 31 as a predictor of CIN 2+ (adjusted odds ratio [aOR]:4.9; p = 0.05; 95% (Confidence Interval) [CI]:1.03-22.5). Women with CIN2+ had a significantly higher viral log mean of HPV 16, (11.2 copies/ 10,000 cells; 95% CI: 9.0-13.4) than with CIN 1. The high prevalence of HPV 53 in CIN 3 and as a stand-alone genotype in the patient with invasive cervical cancer warrants that its clinical significance be further revisited among HIV-infected women. HPV 31, along with elevated means of HPV 16 viral load were predictors of CIN 2 + .


Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study.
3-Bromopyruvate (3BP) is a new, promising anticancer alkylating agent with several notable functions. In addition to inhibiting key glycolysis enzymes including hexokinase II and lactate dehydrogenase (LDH), 3BP also selectively inhibits mitochondrial oxidative phosphorylation, angiogenesis, and energy production in cancer cells. Moreover, 3BP induces hydrogen peroxide generation in cancer cells (oxidative stress effect) and competes with the LDH substrates pyruvate and lactate. There is only one published human clinical study showing that 3BP was effective in treating fibrolamellar hepatocellular carcinoma. LDH is a good measure for tumor evaluation and predicts the outcome of treatment better than the presence of a residual tumor mass. According to the Warburg effect, LDH is responsible for lactate synthesis, which facilitates cancer cell survival, progression, aggressiveness, metastasis, and angiogenesis. Lactate produced through LDH activity fuels aerobic cell populations inside tumors via metabolic symbiosis. In melanoma, the most deadly skin cancer, 3BP induced necrotic cell death in sensitive cells, whereas high glutathione (GSH) content made other melanoma cells resistant to 3BP. Concurrent use of a GSH depletor with 3BP killed resistant melanoma cells. Survival of melanoma patients was inversely associated with high serum LDH levels, which was reported to be highly predictive of melanoma treatment in randomized clinical trials. Here, we report a 28-year-old man presented with stage IV metastatic melanoma affecting the back, left pleura, and lung. The disease caused total destruction of the left lung and a high serum LDH level (4,283 U/L). After ethics committee approval and written patient consent, the patient received 3BP intravenous infusions (1-2.2 mg/kg), but the anticancer effect was minimal as indicated by a high serum LDH level. This may have been due to high tumor GSH content. On combining oral paracetamol, which depletes tumor GSH, with 3BP treatment, serum LDH level dropped maximally. Although a slow intravenous infusion of 3BP appeared to have minimal cytotoxicity, its anticancer efficacy via this delivery method was low. This was possibly due to high tumor GSH content, which was increased after concurrent use of the GSH depletor paracetamol. If the anticancer effectiveness of 3BP is less than expected, the combination with paracetamol may be needed to sensitize cancer cells to 3BP-induced effects.


Platelet-derived growth factor in idiopathic pulmonary fibrosis.
Fibrosis is a complex process involving an inflammatory reaction, fibroblast proliferation, and abnormal accumulation of interstitial collagens. Mononuclear cells are usually present in lung fibrosis. Activated monocytes and macrophages in culture have been shown to produce several growth factors including platelet-derived growth factor (PDGF). PDGF is a potent mitogen and chemoattractant for fibroblasts and smooth muscle cells and a stimulator of collagen synthesis. We have studied the expression of c-sis/PDGF-2 mRNA in lung tissues derived from five patients with idiopathic pulmonary fibrosis (IPF) and from four control individuals without IPF. Northern blot analysis of specimens obtained from four patients with IPF revealed the expression of the c-sis/PDGF-2 protooncogene. A control lung tissue without IPF did not express the c-sis protooncogene. In situ hybridization extended these studies demonstrating the expression of the c-sis mRNA in the five specimens with IPF but not in the four control specimens without IPF. The expression of c-sis mRNA was localized primarily in the epithelial cells. Invading alveolar macrophages also expressed c-sis mRNA. The expression of c-sis mRNA was accompanied by the expression of PDGF-like proteins in lung specimens with IPF but not in control lung specimens. These findings demonstrate the in vivo expression of the c-sis/PDGF-2 protooncogene and the production of PDGF-like proteins in the epithelial cells and macrophages of the fibrotic tissue. This localized and sustained production of PDGF-like mitogen may constitute an important contributing factor in the abnormal fibroblast proliferation and collagen production, events associated with pulmonary fibrosis.


Are Yellow Sticky Cards and Light Traps Effective on Tea Green Leafhoppers and Their Predators in Chinese Tea Plantations?
In Chinese tea plantations, yellow sticky cards and light traps are increasingly used to control insect pests, especially the tea green leafhopper Empoasca onukii. In this study, a 16-week open-field experiment with daily weather monitoring was designed to test the responses of tea green leafhopper, parasitoids and spiders to yellow sticky cards and three light traps with different wavelengths (covered with sticky cards). An exclosure experiment was also designed to further test the influence of the three light systems (without sticky card) on the same species. The results showed that all three light emitting diode (LED) light traps (white, green and yellow) and yellow sticky cards attracted many more E. onukii male adults than females during the course of the open field experiment, with less than 25% of trapped adults being females. Parasitoids and spiders were also attracted by these systems. Weather variables, especially rainfall, influenced the trapping efficiency. In the exclosure experiment, the population of leafhoppers in the yellow sticky card treatment did not decline significantly, but the number of spiders significantly decreased. The green and white light treatments without sticky cards showed a significant control of E. onukii and no obvious harm to spiders. These results suggest that yellow sticky cards and light traps have limited capacity to control tea green leafhoppers. However, light, especially green light, may be a promising population control measure for tea green leafhoppers, not as killing agents in the traps, but rather as a behavioral control system.


Cloning, overexpression, and biochemical characterization of the catalytic domain of MutY.
Proteolysis of MutY with trypsin indicated that this DNA mismatch repair enzyme could exist as two modules and that the N-terminal domain (Met1-Lys225), designated as p26, could serve as the catalytic domain [Manuel et al. (1996) J. Biol. Chem. 271, 16218-16226]. In this study, the p26 domain has been cloned, overproduced, and purified to homogeneity. Synthetic DNA duplexes containing mismatches, generated with regular bases and nucleotide analogs containing altered functional groups, have been used to characterize the substrate specificity and mismatch repair efficiency of p26. In general, p26 recognized and cleaved most of the substrates which were catalyzed by the intact protein. However, p26 displayed enhanced specificity for DNA containing an inosine. guanine mismatch, and the specificity constant (Kcat/Km) was 2-fold higher. The truncated MutY was able to cleave DNA containing an abasic site with equal efficiency. Dissociation constants (Kd) were obtained for p26 on noncleavable DNA substrates containing a tetrahydrofuran (abasic site analog) or a reduced abasic site. p26 bound these substrates with high specificity, and the Kd values were 3-fold higher when compared to the intact MutY. p26 contains both DNA glycosylase and AP lyase activities, and we provide evidence for a reaction mechanism that proceeds through an imino intermediate. Thus, we have shown for the first time that deletion of 125 amino acids at the C-terminus of MutY generates a stable catalytic domain which retains the functional identity of the intact protein.


Best Practices Guideline for the Pathologic Diagnosis of Breast Implant-Associated Anaplastic Large-Cell Lymphoma.
To provide guidelines for the accurate pathologic diagnosis of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), the preoperative evaluation of the patient with suspected BIA-ALCL, and the pathologic evaluation of the capsulectomy specimen. To better inform patients and healthcare providers about BIA-ALCL, we convened to review diagnostic procedures used in the evaluation of patients with suspected BIA-ALCL. We focused on the processing of the seroma fluid/effusion surrounding the implant, the handling of capsulectomy specimens following removal of implant(s), and the preoperative evaluation of the patient with suspected BIA-ALCL. Recommendations were based on the published literature and our experience to optimize procedures to obtain an accurate diagnosis and assess for tumor invasion and the extent of the disease. Early diagnosis of BIA-ALCL is important as the disease can progress and deaths have been reported. Because the most common presentation of BIA-ALCL is swelling of the breast with fluid collection, an accurate diagnosis requires cytologic evaluation of the effusion fluid surrounding the affected implant. The first priority is cytocentrifugation and filtration of fresh, unfixed effusion fluid to produce air-dried smears that are stained with Wright-Giemsa or other Romanowsky-type stains. Preparation of a cell block is desirable to allow for hematoxylin and eosin staining and immunohistochemical analysis of formalin-fixed, paraffin-embedded histologic sections. Cell block sections can be used for polymerase chain reaction-based investigation of T-cell receptor gene rearrangement to detect clonality. Fixation and mapping of the capsulectomy specimen to select multiple representative sections are advised to assess for microscopic tumor involvement and capsular invasion. It is appropriate to assess lymph node involvement by excisional biopsy material rather than fine needle aspiration, due to propensity for focal involvement.


A draft genome assembly of the Chinese sillago (Sillago sinica), the first reference genome for Sillaginidae fishes.
Sillaginidae, also known as smelt-whitings, is a family of benthic coastal marine fishes in the Indo-West Pacific that have high ecological and economic importance. Many Sillaginidae species, including the Chinese sillago (Sillago sinica), have been recently described in China, providing valuable material to analyze genetic diversification of the family Sillaginidae. Here, we constructed a reference genome for the Chinese sillago, with the aim to set up a platform for comparative analysis of all species in this family. Using the single-molecule real-time DNA sequencing platform Pacific Biosciences (PacBio) Sequel, we generated ∼27.3 Gb genomic DNA sequences for the Chinese sillago. We reconstructed a genome assembly of 534 Mb using a strategy that takes advantage of complementary strengths of two genome assembly programs, Canu and FALCON. The genome size was consistent with the estimated genome size based on k-mer analysis. The assembled genome consisted of 802 contigs with a contig N50 length of 2.6 Mb. We annotated 22,122 protein-coding genes in the Chinese sillago genomes using a de novo method as well as RNA sequencing data and homologies to other teleosts. According to the phylogenetic analysis using protein-coding genes, the Chinese sillago is closely related to Larimichthys crocea and Dicentrarchus labrax and diverged from their ancestor around 69.5-82.6 million years ago. Using long reads generated with PacBio sequencing technology, we have built a draft genome assembly for the Chinese sillago, which is the first reference genome for Sillaginidae species. This genome assembly sets a stage for comparative analysis of the diversification and adaptation of fishes in Sillaginidae.


Low plasma coenzyme Q(10) levels and breast cancer risk in Chinese women.
Low circulating levels of coenzyme Q(10) (CoQ(10)) have been associated with increased cancer incidence and poor prognosis for a number of cancer types, while a recent prospective study observed a positive association for CoQ(10) with breast cancer risk. We prospectively examined the association of plasma CoQ(10) with breast cancer risk in a nested case-control study of Chinese women within the Shanghai Women's Health Study (SWHS). Prediagnostic plasma samples were obtained from 340 cases and 653 age-matched controls and analyzed for total CoQ(10). A borderline significant inverse association for breast cancer incidence with plasma CoQ(10) level was observed by a conditional logistic regression model adjusted for age and age at first live birth, which became significant after elimination of cases diagnosed within 1 year of blood draw (P(trend) = 0.03). This association was independent of menopausal status. Plasma CoQ(10) levels were also observed to be significantly associated with circulating γ-tocopherol (r = 0.50; P < 0.0001) and α-tocopherol (r = 0.38; P < 0.0001) levels. Circulating levels of CoQ(10) were generally low in this population and the observed association with breast cancer risk may be limited to those women with exceptionally low values. This study reports an inverse relationship between circulating CoQ(10) and breast cancer risk, while the only other prospective study of CoQ(10) and breast cancer to date found a positive association. Lower levels of CoQ(10) in the SWHS population suggest that the 2 studies may not be contradictory and indicate a possible nonlinear (U-shaped) association of CoQ(10) with risk.


Efficacy of motor imagery in post-stroke rehabilitation: a systematic review.
Evaluation of how Motor Imagery and conventional therapy (physiotherapy or occupational therapy) compare to conventional therapy only in their effects on clinically relevant outcomes during rehabilitation of persons with stroke. Systematic review of the literature We conducted an electronic database search in seven databases in August 2005 and also hand-searched the bibliographies of studies that we selected for the review. Two reviewers independently screened and selected all randomized controlled trials that compare the effects of conventional therapy plus Motor Imagery to those of only conventional therapy on stroke patients. The outcome measurements were: Fugl-Meyer Stroke Assessment upper extremity score (66 points) and Action Research Arm Test upper extremity score (57 points). Due to the high variability in the outcomes, we could not pool the data statistically. We identified four randomized controlled trials from Asia and North America. The quality of the included studies was poor to moderate. Two different Motor imagery techniques were used (three studies used audiotapes and one study had occupational therapists apply the intervention). Two studies found significant effects of Motor Imagery in the Fugl-Meyer Stroke Assessment: Differences between groups amounted to 11.0 (1.0 to 21.0) and 3.2 (-4 to 10.3) respectively and in the Action Research Arm Test 6.1 (-6.2 to 18.4) and 15.8 (0.5 to 31.0) respectively. One study did not find a significant effect in the Fugl-Meyer Stroke Assessment and Color trail Test (p = 0.28) but in the task-related outcomes (p > 0.001). Current evidence suggests that Motor imagery provides additional benefits to conventional physiotherapy or occupational therapy. However, larger and methodologically sounder studies should be conducted to assess the benefits of Motor imagery.