59 research outputs found

    Humanized cereblon mice reveal two distinct pathways of immunomodulatory drugs

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    Immunomodulatory drugs (IMiDs), including thalidomide derivatives such as lenalidomide and pomalidomide, offer therapeutic benefit in several hematopoietic malignancies and autoimmune/inflammatory diseases. However, it is difficult to study the IMiD mechanism of action in murine disease models because murine cereblon (CRBN), the substrate receptor for IMiD action, is resistant to some of IMiDs therapeutic effects. To overcome this difficulty, we generated humanized cereblon (CRBNI391V) mice thereby providing an animal model to unravel complex mechanisms of action in a murine physiological setup. In our current study, we investigated the degradative effect toward IKZF1 and CK-1α, a target substrate of IMiDs. Unlike WT mice which were resistant to lenalidomide and pomalidomide, T lymphocytes from CRBNI391V mice responded with a higher degree of IKZF1 and CK-1α protein degradation. Furthermore, IMiDs resulted in an increase in IL-2 among CRBNI391V mice but not in the WT group. We have also tested a thalidomide derivative, FPFT-2216, which showed an inhibitory effect toward IKZF1 protein level. As opposed to pomalidomide, FPFT-2216 and lenalidomide degrades CK-1α. Additionally, we assessed the potential therapeutic effects of IMiDs in dextran sodium sulfate (DSS)-induced colitis. In both WT and humanized mice, lenalidomide showed a significant therapeutic effect in the DSS model of colitis, while the effect of pomalidomide was less pronounced. Thus, while IMiDs’ degradative effect on IKZF1 and CK-1α, and up-regulation of IL-2, is dependent on CRBN, the therapeutic benefit of IMiDs in a mouse model of inflammatory bowel disease occurs through a CRBN–IMiD binding region independent pathway

    Relationship between cerebral oxygenation, cardiac output, and blood pressure during transitional period in extremely low gestational age neonates

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    ObjectiveTo describe the relationship between cerebral oxygenation, cardiac output, arterial blood pressure (BP), and cerebral blood flow velocity in extremely low gestational age neonates (ELGANs) during transition.MethodsThis study comprises secondary analyses from a prospective observational study conducted at a tertiary Neonatal Intensive Care Unit. Recruited ELGANs underwent cerebral saturation (CrSO2) monitoring and serial echocardiography during 72 h from birth. Correlative analyses of CrSO2 and cerebral fractional tissue oxygen extraction (CFTOE) with left (LVO) and right ventricular output (RVO), superior vena cava (SVC) flow, middle cerebral artery blood flow mean velocity (MCA.MV), systolic (SBP), diastolic (DBP), and mean (MBP) BP were conducted.ResultsFifty ELGANs with median (range) gestational age of 25.9 (23.1–27.9) weeks were recruited. Echocardiography was performed sequentially at a median (range) age 5.0 (3.8–6.6), 17.3 (15.4–19.4), 31.0 (27.0–34.1), and 53.7 (49.3–58.3) hours. RVO, LVO, CrSO2, and SBP increased over time but no changes in MBP, DBP, CFTOE, MCA.MV or SVC flow were noted. A weak correlation was identified between CrSO2 and SBP (r2 = 0.11, p = 0.047) and MBP (r2 = 0.12, p = 0.04) at 17.3 (15.4–19.4) hours. No correlation of either CrSO2 or CFTOE with any measures of blood flow was identified.ConclusionThere is a weak correlation between measures of cardiac output, BP, and MCA.MV with both CrSO2 and CFTOE in ELGANs during transition. Whether this finding suggests intact cerebral autoregulation requires prospective evaluation in a cohort of sick ELGANs

    Country-Specific vs. Common Birthweight-for-Gestational Age References to Identify Small for Gestational Age Infants Born at 24-28 weeks: An International Study

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    BACKGROUND Controversy exists as to whether birthweight-for-gestational age references used to classify infants as small for gestational age (SGA) should be country specific or based on an international (common) standard. We examined whether different birthweight-for-gestational age references affected the association of SGA with adverse outcomes among very preterm neonates. METHODS Singleton infants (n = 23 788) of 24(0) -28(6) weeks' gestational age in nine high-resource countries were classified as SGA (<10th centile) using common and country-specific references based on birthweight and estimated fetal weight (EFW). For each reference, the adjusted relative risk (aRR) for the association of SGA with composite outcome of mortality or major morbidity was estimated. RESULTS The percentage of infants classified as SGA differed slightly for common compared with country specific for birthweight references [9.9% (95% CI 9.5, 10.2) vs. 11.1% (95% CI 10.7, 11.5)] and for EFW references [28.6% (95% CI 28.0, 29.2) vs. 24.6% (95% CI 24.1, 25.2)]. The association of SGA with the composite outcome was similar when using common or country-specific references for the total sample for birthweight [aRRs 1.47 (95% CI 1.43, 1.51) and 1.48 (95% CI 1.44, 1.53) respectively] and for EFW references [aRRs 1.35 (95% CI 1.31, 1.38) and 1.39 (95% CI 1.35, 1.43) respectively]. CONCLUSION Small for gestational age is associated with higher mortality and morbidity in infants born <29 weeks' gestational age. Although common and country-specific birthweight/EFW references identified slightly different proportions of SGA infants, the risk of the composite outcome was comparable

    Use of Intravenous Albumin:A Guideline From the International Collaboration for Transfusion Medicine Guidelines

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    Background: Albumin is used commonly across a wide range of clinical settings to improve hemodynamics, to facilitate fluid removal, and to manage complications of cirrhosis. The International Collaboration for Transfusion Medicine Guidelines developed guidelines for the use of albumin in patients requiring critical care, undergoing cardiovascular surgery, undergoing kidney replacement therapy, or experiencing complications of cirrhosis. Study Design and Methods: Cochairs oversaw the guideline development process and the panel included researchers, clinicians, methodologists, and a patient representative. The evidence informing this guideline arises from a systematic review of randomized clinical trials and systematic reviews, in which multiple databases were searched (inception through November 23, 2022). The panel reviewed the data and formulated the guideline recommendations using Grading of Recommendations Assessment, Development, and Evaluation methodology. The guidelines were revised after public consultation. Results: The panel made 14 recommendations on albumin use in adult critical care (three recommendations), pediatric critical care (one recommendation), neonatal critical care (two recommendations), cardiovascular surgery (two recommendations), kidney replacement therapy (one recommendation), and complications of cirrhosis (five recommendations). Of the 14 recommendations, two recommendations had moderate certainty of evidence, five recommendations had low certainty of evidence, and seven recommendations had very low certainty of evidence. Two of the 14 recommendations suggested conditional use of albumin for patients with cirrhosis undergoing large-volume paracentesis or with spontaneous bacterial peritonitis. Twelve of 14 recommendations did not suggest albumin use in a wide variety of clinical situations where albumin commonly is transfused. Interpretation: Currently, few evidence-based indications support the routine use of albumin in clinical practice to improve patient outcomes. These guidelines provide clinicians with actionable recommendations on the use of albumin.</p

    Effects of Language Context on Ratings of Shy and Unsociable Behaviors in English Language Learning Children

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    Purpose The primary goal of this study was to explore the effect of the language context on the socially withdrawn behaviors of school aged-children who are English Language Learners (ELLs) from middle to high SES backgrounds. This is one of the first studies to address the frequently confused concepts of shyness and unsociability as independent constructs within the ELL population. This study also investigated the feasibility of an experimental parent and child questionnaire that examines shyness and unsociability across native and English speaking contexts. Method Children and parents (34 ELL and 37 native English speaking) were administered an experimental questionnaire examining shy and unsociable behavior in native language and English-speaking contexts. Results Parents and children from the ELL group reported significantly higher ratings of shy behavior in English versus native language contexts, whereas unsociable ratings did not differ across language contexts. Conclusions Shyness and unsociability are distinguishable behaviors in ELL children and these constructs should be considered when examining withdrawal. Additionally, examining ELL children’s behavior across language contexts provides a valuable method for investigating language influenced behavioral problems. This study demonstrates the need for service providers to evaluate behavior across subtype and language context before pathologizing withdrawal in ELL children

    Incidence of Influenza in Healthy Adults and Healthcare Workers: A Systematic Review and Meta-Analysis

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    BACKGROUND: Working in healthcare is often considered a risk factor for influenza; however, this risk has not been quantified. We aimed to systematically review evidence describing the annual incidence of influenza among healthy adults and healthcare workers (HCWs). METHODS AND FINDINGS: We searched OVID MEDLINE (1950 to 2010), EMBASE (1947 to 2010) and reference lists of identified articles. Observational studies or randomized trials reporting full season or annual influenza infection rates for healthy, working age adult subjects and HCWs were included. Influenza infection was defined as a four-fold rise in antibody titer, or positive viral culture or polymerase chain reaction. From 24,707 citations, 29 studies covering 97 influenza seasons with 58,245 study participants were included. Pooled influenza incidence rates (IR) (95% confidence intervals (CI)) per 100 HCWs per season and corresponding incidence rate ratios (IRR) (95% CI) as compared to healthy adults were as follows. All infections: IR 18.7 (95% CI, 15.8 to 22.1), IRR 3.4 (95% CI, 1.2 to 5.7) in unvaccinated HCWs; IR 6.5 (95% CI, 4.6 to 9.1), IRR 5.4 (95% CI, 2.8 to 8.0) in vaccinated HCWs. Symptomatic infections: IR 7.5 (95% CI, 4.9 to 11.7), IRR 1.5 (95% CI, 0.4 to 2.5) in unvaccinated HCWs, IR 4.8 (95% CI, 3.2 to 7.2), IRR 1.6 (95% CI, 0.5 to 2.7) in vaccinated HCWs. CONCLUSIONS: Compared to adults working in non-healthcare settings, HCWs are at significantly higher risk of influenza

    Neutrinos

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    229 pages229 pages229 pagesThe Proceedings of the 2011 workshop on Fundamental Physics at the Intensity Frontier. Science opportunities at the intensity frontier are identified and described in the areas of heavy quarks, charged leptons, neutrinos, proton decay, new light weakly-coupled particles, and nucleons, nuclei, and atoms

    Interdisciplinary-driven hypotheses on spatial associations of mixtures of industrial air pollutants with adverse birth outcomes

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    Background: Adverse birth outcomes (ABO) such as prematurity and small for gestational age confer a high risk of mortality and morbidity. ABO have been linked to air pollution; however, relationships with mixtures of industrial emissions are poorly understood. The exploration of relationships between ABO and mixtures is complex when hundreds of chemicals are analyzed simultaneously, requiring the use of novel approaches. Objective: We aimed to generate robust hypotheses spatially linking mixtures and the occurrence of ABO using a spatial data mining algorithm and subsequent geographical and statistical analysis. The spatial data mining approach aimed to reduce data dimensionality and efficiently identify spatial associations between multiple chemicals and ABO. Methods: We discovered co-location patterns of mixtures and ABO in Alberta, Canada (2006–2012). An ad-hoc spatial data mining algorithm allowed the extraction of primary co-location patterns of 136 chemicals released into the air by 6279 industrial facilities (National Pollutant Release Inventory), wind-patterns from 182 stations, and 333,247 singleton live births at the maternal postal code at delivery (Alberta Perinatal Health Program), from which we identified cases of preterm birth, small for gestational age, and low birth weight at term. We selected secondary patterns using a lift ratio metric from ABO and non-ABO impacted by the same mixture. The relevance of the secondary patterns was estimated using logistic models (adjusted by socioeconomic status and ABO-related maternal factors) and a geographic-based assignment of maternal exposure to the mixtures as calculated by kernel density. Results: From 136 chemicals and three ABO, spatial data mining identified 1700 primary patterns from which five secondary patterns of three-chemical mixtures, including particulate matter, methyl-ethyl-ketone, xylene, carbon monoxide, 2-butoxyethanol, and n-butyl alcohol, were subsequently analyzed. The significance of the associations (odds ratio > 1) between the five mixtures and ABO provided statistical support for a new set of hypotheses. Conclusion: This study demonstrated that, in complex research settings, spatial data mining followed by pattern selection and geographic and statistical analyses can catalyze future research on associations between air pollutant mixtures and adverse birth outcomes

    Minithoracotomy vs Conventional Sternotomy for Mitral Valve Repair: A Randomized Clinical Trial

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    Importance: The safety and effectiveness of mitral valve repair via thoracoscopically-guided minithoracotomy (minithoracotomy) compared with median sternotomy (sternotomy) in patients with degenerative mitral valve regurgitation is uncertain. Objective: To compare the safety and effectiveness of minithoracotomy vs sternotomy mitral valve repair in a randomized trial. Design, Setting, and Participants: A pragmatic, multicenter, superiority, randomized clinical trial in 10 tertiary care institutions in the UK. Participants were adults with degenerative mitral regurgitation undergoing mitral valve repair surgery. Interventions: Participants were randomized 1:1 with concealed allocation to receive either minithoracotomy or sternotomy mitral valve repair performed by an expert surgeon. Main Outcomes and Measures: The primary outcome was physical functioning and associated return to usual activities measured by change from baseline in the 36-Item Short Form Health Survey (SF-36) version 2 physical functioning scale 12 weeks after the index surgery, assessed by an independent researcher masked to the intervention. Secondary outcomes included recurrent mitral regurgitation grade, physical activity, and quality of life. The prespecified safety outcomes included death, repeat mitral valve surgery, or heart failure hospitalization up to 1 year. Results: Between November 2016 and January 2021, 330 participants were randomized (mean age, 67 years, 100 female [30%]); 166 were allocated to minithoracotomy and 164 allocated to sternotomy, of whom 309 underwent surgery and 294 reported the primary outcome. At 12 weeks, the mean between-group difference in the change in the SF-36 physical function T score was 0.68 (95% CI, −1.89 to 3.26). Valve repair rates (≈ 96%) were similar in both groups. Echocardiography demonstrated mitral regurgitation severity as none or mild for 92% of participants at 1 year with no difference between groups. The composite safety outcome occurred in 5.4% (9 of 166) of patients undergoing minithoracotomy and 6.1% (10 of 163) undergoing sternotomy at 1 year. Conclusions and relevance: Minithoracotomy is not superior to sternotomy in recovery of physical function at 12 weeks. Minithoracotomy achieves high rates and quality of valve repair and has similar safety outcomes at 1 year to sternotomy. The results provide evidence to inform shared decision-making and treatment guidelines. Trial Registration: isrctn.org Identifier: ISRCTN1393045

    Control of root-knot nematode by using composted sawdust in tomato root

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    The effect of composted sawdust at different concentrations (0, 10, 20... 100% v/v in soil) on tomato plant growth and pigments were investigated with or without the presence of root-knot nematode, Meloidogyne javanica at different inoculum levels (0, 1000, 2000, 3000, 4000, 5000) in clay pots (having diameter 30 cm and depth 60 cm). An increase in the composted sawdust concentration in the field soil progressively increased the availability of chlorides, sulphates, carbonates, bicarbonates, P, K, Mg, Mn, Cu, Zn and Fe. However, reverse trend was evaluated in nitrogen content of the soil with gradual increment in sawdust. Different physical properties such as porosity, pH, conductivity, water holding and cation exchange capacity also increased gradually with gradual sawdust amendment in the soil. Sawdust application enhanced the plant growth as well as leaf pigments in both nematode infected as well as non-infected tomato plants, being maximum in the soil containing 30% composted sawdust. Growth and leaf pigments also showed reductions with respect to increase in nematode inoculum density compared to nematode union-culated plants (that is, controls). However, least amount of tomato growth and leaf pigments were found at 3000 nematode inoculum level. Sawdust treatments favorably affect the root invasion by root-knot nematode juveniles (J2 and J3 + J4) and galls up to 30% but adversely affected onward treatments although, a gradual increase in sawdust concentration in the soil would correspondingly decrease the number of egg masses and eggs per egg mass (that is, fecundity) of the root-knot nematodes. All the above said nematode parameters were also improved with all considered nematode inoculum levels but 3000 was the optimum level for them. After visualizing the results, it can be suggested that 30% composted sawdust was the most economical level as it enhances the growth and pigments irrespective of the presence or absence of root-knot nematode. At the same time, it also controls the root-knot nematodes in particularly in 30% onward dust amendments.Keywords: Meloidogyne javanica, nematode,sawdust.African Journal of Biotechnology, Vol 13(41) 4070-408
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