Febuxostat ameliorates methotrexate-induced lung damage

Background: The intention of the present study was to assess the structural affection of the lung following methotrexate (MTX) overdose. The proposed underlying mechanisms involved in lung affection were studied. The possible modulation role of febuxostat over such affection was studied. Materials and methods: Twenty-four rats were divided into three groups: control, MTX-treated, febuxostat-treated. The study was continued for 2 weeks. Lung was processed for histological and immunohistochemical (inducible nitric oxide synthase [iNOS] and cyclooxygenase [COX]-2) studies. Inflammatory markers (tumour necrosis factor alpha [TNF-a], interleukin 1 [IL-1]), Western blot evaluation of nuclear factor kappa B (NF-kB) and oxidative/antioxidative markers were done. Results: Methotrexate-treated group exhibited inflammatory cellular infiltrations, thickened interalveolar septa, dilated congested blood vessels, extravasated blood, and apoptosis. The collagen fibres content increased 3-fold. MTX induced lung affection through oxidative stress (increase MDA/decrease GSH, SOD) and apoptosis. It induced sterile inflammation through an increase of NF-kB (2-fold), IL-1 (3-fold) and TNF-a (3-fold), COX-2 cells (2.5-fold) and iNOS (6-fold). With the use of febuxostat, the normal lung architecture was observed with a bit thickened interalveolar septum and extravasated blood. The collagen fibres content was minimal. Decrement of oxidative stress and sterile inflammation (COX-2 cells and iNOS were comparable to the control group. NF-kB, IL-1 and TNF-a became higher by 34%, 64% and 100%). Conclusions: The overdose of MTX displays inflammatory lung affection with residual fibrosis. It induces lung affection through oxidative stress, apoptosis and sterile inflammation. With the use of febuxostat, the normal lung architecture was preserved with a little structural affection or fibrotic residue. Febuxostat exerts its lung protection through its anti-inflammatory and antioxidant features

Green tea extract modulates lithium-induced thyroid follicular cell damage in rats

Background: The aim of the current work was to clarify the modulation role of green tea extract (GTE) over structural and functional affection of the thyroid gland after long term use of lithium carbonate (LC). The suggested underlying mechanisms participating in thyroid affection were researched. Materials and methods: Twenty-four Sprague-Dawley adult albino rats were included in the work. They are divided into three groups (control, LC, and concomitant LC + GTE). The work was sustained for 8 weeks. Biochemical assays were achieved (thyroid hormone profile, IL-6). Histological, histochemical (PAS) and immunohistochemical (caspase-3, TNF-α, PCNA) evaluations were done. Oxidative/antioxidative markers (MDA / GSH, SOD) and western blot evaluation of the Bcl2 family were done. Results: LC induced hypothyroidism (decrease T3, T4/increase TSH). The follicles were distended, others were involuted. Some follicles were disorganized, others showed detached follicular cells. Apoptotic follicular cells were proved (Bax and caspase-3 increased, Bcl2 decreased, Bax/Bcl2 ratio increased). The collagen fibers' content and proinflammatory markers (TNF-α and IL-6) increased. The proliferative nuclear activity was supported by increase expression of PCNA. Oxidative stress was established (increase MDA/decrease GSH, SOD). With the use of GTE, the thyroid hormone levels increased, while the TSH level decreased. Apoptosis is improved as Bax decreased, Bcl2 increased, and Bax/Bcl2 ratio was normal. The collagen fibers' content and proinflammatory markers (TNF-α and IL-6) decreased. The expression of PCNA and caspase-3 were comparable to the control group. The oxidative markers were improved (decrease MDA/increase GSH, SOD). Conclusions: In conclusion, prolonged use of LC results in hypothyroidism, which is accompanied by structural thyroid damage. LC induced thyroid damage through oxidative stress that prompted sterile inflammation and apoptosis. With the use of GTE, the thyroid gland achieved its structure and function. The protecting role of GTE is through antioxidant, antifibrotic, anti-inflammatory, and antiproliferative effects

Diabetes mellitus and obesity among South Asians with ischemic stroke across three countries

Background: Diabetes mellitus and central obesity are more common among South Asian populations than among White British people. This study explores the differences in diabetes and obesity in South Asians with stroke living in the United Kingdom, India, and Qatar compared with White British stroke patients. Methods: The study included the UK, Indian, and Qatari arms of the ongoing large Bio-Repository of DNA in Stroke (BRAINS) international prospective hospital-based study for South Asian stroke. BRAINS includes 4580 South Asian and White British recruits from UK, Indian, and Qatar sites with first-ever ischemic stroke. Results: The study population comprises 1751 White British (WB) UK residents, 1165 British South Asians (BSA), 1096 South Asians in India (ISA), and 568 South Asians in Qatar (QSA). ISA, BSA, and QSA South Asians suffered from higher prevalence of diabetes compared with WB by 14.5% (ISA: 95% confidence interval (CI) = 18.6–33.0, p < 0.001), 31.7% (BSA: 95% CI = 35.1–50.2, p < 0.001), and 32.7% (QSA: 95% CI = 28.1–37.3, p < 0.001), respectively. Although WB had the highest prevalence of body mass index (BMI) above 27 kg/m2 compared with South Asian patients (37% vs 21%, p < 0.001), South Asian patients had a higher waist circumference than WB (94.8 cm vs 90.8 cm, p < 0.001). Adjusting for traditional stroke risk factors, ISA, BSA, and QSA continued to display an increased risk of diabetes compared with WB by 3.28 (95% CI: 2.53–4.25, p < 0.001), 3.61 (95% CI: 2.90–4.51, p < 0.001), and 5.24 (95% CI: 3.93–7.00, p < 0.001), respectively. Conclusion: South Asian ischemic stroke patients living in Britain and Qatar have a near 3.5-fold risk of diabetes compared with White British stroke patients. Their body composition may partly help explain that increased risk. These findings have important implications for public health policymakers in nations with large South Asian populations

The global burden of cancer attributable to risk factors, 2010–19: a systematic analysis for the Global Burden of Disease Study 2019

BACKGROUND: Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. METHODS: The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk–outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. FINDINGS: Globally, in 2019, the risk factors included in this analysis accounted for 4·45 million (95% uncertainty interval 4·01–4·94) deaths and 105 million (95·0–116) DALYs for both sexes combined, representing 44·4% (41·3–48·4) of all cancer deaths and 42·0% (39·1–45·6) of all DALYs. There were 2·88 million (2·60–3·18) risk-attributable cancer deaths in males (50·6% [47·8–54·1] of all male cancer deaths) and 1·58 million (1·36–1·84) risk-attributable cancer deaths in females (36·3% [32·5–41·3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20·4% (12·6–28·4) and DALYs by 16·8% (8·8–25·0), with the greatest percentage increase in metabolic risks (34·7% [27·9–42·8] and 33·3% [25·8–42·0]). INTERPRETATION: The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden

Global Retinoblastoma Presentation and Analysis by National Income Level

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4) were female. Most patients (n = 3685 84.7%) were from low-and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 62.8%), followed by strabismus (n = 429 10.2%) and proptosis (n = 309 7.4%). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 95% CI, 12.94-24.80, and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 95% CI, 4.30-7.68). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs. © 2020 American Medical Association. All rights reserved

Higgs Boson Studies at the Tevatron

We combine searches by the CDF and D0 Collaborations for the standard model Higgs boson with mass in the range 90--200 GeV$/c^2$ produced in the gluon-gluon fusion, $WH$, $ZH$, $t{\bar{t}}H$, and vector boson fusion processes, and decaying in the $H\rightarrow b{\bar{b}}$, $H\rightarrow W^+W^-$, $H\rightarrow ZZ$, $H\rightarrow\tau^+\tau^-$, and $H\rightarrow \gamma\gamma$ modes. The data correspond to integrated luminosities of up to 10 fb$^{-1}$ and were collected at the Fermilab Tevatron in $p{\bar{p}}$ collisions at $\sqrt{s}=1.96$ TeV. The searches are also interpreted in the context of fermiophobic and fourth generation models. We observe a significant excess of events in the mass range between 115 and 140 GeV/$c^2$. The local significance corresponds to 3.0 standard deviations at $m_H=125$ GeV/$c^2$, consistent with the mass of the Higgs boson observed at the LHC, and we expect a local significance of 1.9 standard deviations. We separately combine searches for $H \to b\bar{b}$, $H \to W^+W^-$, $H\rightarrow\tau^+\tau^-$, and $H\rightarrow\gamma\gamma$. The observed signal strengths in all channels are consistent with the presence of a standard model Higgs boson with a mass of 125 GeV/$c^2$