Cognition and education benefits of increased hemoglobin and blood oxygenation in children with sickle cell disease

BACKGROUND: Among individuals with sickle cell disease (SCD), decreased hemoglobin is associated with lower oxygen saturation (SpO2) and increased risk of stroke, both of which are associated with lower intelligence quotient (IQ) scores. Thus, increasing hemoglobin and SpO2 in individuals with SCD may increase IQ and educational attainment. METHODS: A cohort simulation model was built to determine academic performance and educational attainment based on cognitive function (measured by IQ) of a pediatric SCD cohort randomly assigned to treatment and control groups. The model contained two key stages: childhood (\u3c10 years) and adolescence (≥10 years). In stage 1, increased hemoglobin and increased SpO2 (assigned to the treatment group) were determinants of higher IQ, prevention of IQ deterioration over time. Increased hemoglobin was also a determinant of decreased stroke risk. In stage 2, improvement in adolescent IQ as a result of treatment was a determinant of academic performance. RESULTS: In a simulated cohort of 2000 children and adolescents with SCD (52.5% female, 50% treated), stroke incidence was predicted to be 44.4% lower among the treated group than the untreated group (4.5% versus 8.1%, respectively). The average IQ among the treated group was estimated to be 91.1 compared with 82.9 in the untreated group (a 9.9% difference; P\u3c0.001). Finally, high school (≥12 years of education) completion rates were estimated to be 64.7% higher among the treated group: 76.1% of the treated group was projected to complete high school compared with 46.2% of the untreated group. CONCLUSIONS: Our model predicts that an average improvement in hemoglobin of 1.1 g/dL (11 g/L) among individuals with SCD may be associated with improved neurocognition and educational outcomes. These improvements may also generate benefits not captured by our model, including improved quality of life, employment, and income

The time of the Roma in times of crisis: Where has European neoliberal capitalism failed?

This paper argues that the economic and financial crisis that has ensnared Europe from the late 2000s has been instrumental in reshaping employment and social relations in a detrimental way for the majority of the European people. It argues that the crisis has exacerbated the socio-economic position of most Roma people, immigrants as well as of other vulnerable groups. This development is approached here as an outcome of the widening structural inequalities that underpin the crisis within an increasingly neoliberalised Europe. Through recent policy developments and public discourses from a number of European countries I show how rising inequalities nurture racialised social tensions. My account draws on classic and contemporary theoretical propositions that have been propounded about the nature of capitalism, its contemporary re-articulation as well as its ramification for the future of Europe

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics

The presentation, clinical features, complications, and treatment of congenital dacryocystocele

Purpose To determine the incidence and presenting features of congenital dacryocystocele in the United Kingdom. To report on those cases complicated by dacryocystitis, respiratory compromise, and the treatment undertaken. Methods A prospective observational study of cases of congenital dacryocystocele presenting in the United Kingdom between September 2014 and October 2015. Infants <3 months of age presenting with a cystic swelling in the medial canthal area were included. Cases were identified via the British Ophthalmology Surveillance Unit (BOSU) reporting system. Results A total of 49 cases were reported during the study period. This gives an incidence of 1 in 18 597 live births. There was a 71% response rate to the questionnaire. The average age at presentation was 16.94 days. Dacryocystoceles were unilateral in 91% of cases. Dacryocystitis was a complicating factor in 49% of patients and 17% had respiratory distress. Uncomplicated dacryocystocele responded well to conservative measures in 86%. Surgical intervention was required in 23% of patients. Those cases complicated by dacryocystitis (29%) and nasal obstruction (17%) were more likely to require surgical intervention compared to those with dacryocystocele alone (14%). Digital massage appears to reduce the likelihood of requiring surgical intervention. The mean time to resolution was 19 days. Conclusions Congenital dacryocystocele is a rare presentation in the United Kingdom. Dacryocystitis and respiratory compromise commonly complicate a dacryocystocele. The use of digital massage as an early intervention is advocated and conservative measures may be sufficient in cases of uncomplicated dacryocystocele

The Concise Guide to PHARMACOLOGY 2023/24:Catalytic receptors

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and nearly 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16180. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.</p

Catechol Polymers for pH-Responsive, Targeted Drug Delivery to Cancer Cells

A novel cell-targeting, pH-sensitive polymeric carrier was employed in this study for delivery of the anticancer drug bortezomib (BTZ) to cancer cells. Our strategy is based on facile conjugation of BTZ to catechol-containing polymeric carriers that are designed to be taken up selectively by cancer cells through cell surface receptor-mediated mechanisms. The polymer used as a building block in this study was poly(ethylene glycol), which was chosen for its ability to reduce nonspecific interactions with proteins and cells. The catechol moiety was exploited for its ability to bind and release borate-containing therapeutics such as BTZ in a pH-dependent manner. In acidic environments, such as in cancer tissue or the subcellular endosome, BTZ dissociates from the polymer-bound catechol groups to liberate the free drug, which inhibits proteasome function. A cancer-cell-targeting ligand, biotin, was presented on the polymer carriers to facilitate targeted entry of drug-loaded polymer carriers into cancer cells. Our study demonstrated that the cancer-targeting drug-polymer conjugates dramatically enhanced cellular uptake, proteasome inhibition, and cytotoxicity toward breast carcinoma cells in comparison with nontargeting drug-polymer conjugates. The pH-sensitive catechol-boronate binding mechanism provides a chemoselective approach for controlling the release of BTZ in targeted cancer cells, establishing a concept that may be applied in the future toward other boronic acid-containing therapeutics to treat a broad range of diseases

Parity-Violating Inelastic Electron-Proton Scattering at Low Q2Q^2 Above the Resonance Region

We report the measurement of the parity-violating asymmetry for the inelastic scattering of electrons from the proton, at $Q^2 = 0.082$ GeV$^2$ and $W = 2.23$ GeV, above the resonance region. The result $A_{\rm Inel} = - 13.5 \pm 2.0 ({\rm stat}) \pm 3.9 ({\rm syst})$~ppm agrees with theoretical calculations, and helps to validate the modeling of the $\gamma Z$ interference structure functions $F_1^{\gamma Z}$ and $F_2^{\gamma Z}$ used in those calculations, which are also used for determination of the two-boson exchange box diagram ($\Box_{\gamma Z}$) contribution to parity-violating elastic scattering measurements. A positive parity-violating asymmetry for inclusive $\pi^-$ production was observed, as well as positive beam-normal single-spin asymmetry for scattered electrons and a negative beam-normal single-spin asymmetry for inclusive $\pi^-$ production.Comment: 18 pages, 9 figures, version accepted in Physical Review