THE ROLE OF PREGNANE X RECEPTOR IN RITONAVIR-INDUCED LIVER INJURY

Ritonavir (RTV) is a HIV protease inhibitor and an important component of anti-HIV therapy. Hepatotoxicity has been reported in ~10% of patients who receive RTV-containing regimens. However, the hepatotoxicity of RTV-containing regimens was significantly enhanced in subjects who were pretreated with rifampicin (RIF), a first-line anti-tuberculosis drug. RIF is also known as a ligand of human pregnane X receptor (PXR), a transcription factor that is highly expressed in the liver and regulates drug metabolism and many cellular functions. We hypothesize that RIF-mediated PXR activation potentiates RTV hepatotoxicity. We used a transgenic mouse model that expresses human PXR and human CYP3A4 (TgCYP3A4/hPXR). A CYP3A4 transgenic mouse model on the Pxr-null background (TgCYP3A4/Pxr-null) was used as the control. We found that pretreatment with RIF sensitized the TgCYP3A4/hPXR mice to RTV hepatotoxicity, and this sensitizing effect was abolished in the TgCYP3A4/Pxr-null mice. Furthermore, we found that PXR activation increased RTV bioactivation and unfolded protein response. In summary, PXR is a key modulator of RTV induced liver injury. The results from this study can be used to guide decisions on safety considerations regarding RTV-containing regimens in clinical practice

Comparison Between Urban and Rural of Anthropometry Indices in Women of Reproductive Age in Kano, Nigeria State

Recently, new indices have been developed for better prediction of health status. This study aimed to compare the new indices of anthropometric measurements of women of reproductive age (WRA) in urban and rural settings in Kano state. A cross sectional descriptive community-based study was performed in 240 WRA (15-49 years) in 4 randomly selected Local Government Areas (LGAs) in urban and rural settings each. A structured questionnaire was used to collect information on socio-demographic characteristics. Anthropometric indices which include body adiposity index (BAI), abdominal volume index (AVI), Conicity index (CI), a body shaped index (ABSI), a body shaped index z score (ABSI z score), hip index (HI), body roundness index (BRI) and ponderal index (PI) were measured. Socio-demographic result shows that age, occupation and monthly income were found to be significantly associated between the urban and rural participants whereas education, number of children and pregnancy status were not significantly associated. Urban and rural participants had a significant association in BAI (p=0.006), AVI (p=0.010), HI (p=0.030), BRI (p=0.003) and PI (p=0.002). There were no significant association in CI (p=0.219), ABSI (p=0.498) and ABSI z score (p=0.680). Further investigation of these indices and their association with nutritional status and different diseases could assist in efforts to prevent unfavorable health conditions among women of reproductive health

The effect of methanolic crude extract of ocimum gratisimum leaves on insulin resistance and glut-4 gene expression in monosodium glutamate induced obese rats

Obesity is a complex chronic global disease affecting people worldwide across all ages, sexes, ethnicities and nationalities. It is accompanied by remodeling of adipocyte, insulin resistance (IR) and type 2 diabetes. The present study was aimed to determine the effect of methanolic crude extract of Ocimum gratisimum leaves on insulin resistance and GLUT-4 gene expression in Monosodium induced obese Rats. Phytochemical screening of the crude extract of Ocimum gratisimum leaves was carried out before the grouping of animals. The study was conducted using thirty 30 male Wistar rats weighing between 100.0 – 150.0 g. The animals were divided into five groups of six each; Normal control (NC) rats, Obese control (DC) rats, Obese rats treated with Ocimum gratissimum (OG) 100 mg/kg B.W (OG-100), Obese rats treated with OG 200 mg/kg B.W (OG-200), Obese rats treated with orlistat 50 mg/kg B.W (OR-50). Obesity was induced by oral administration of 8 mg/g MSG for 7 days and animals were treated with respective doses orally for 1 week. The phytochemical screening of the crude extract of Ocimum gratisimum leaves revealed the presence of saponins, tannins, flavonoids, glycosides and the results obtained after induction of obesity with MSG showed significant (P<0.05) increase in weight of the rats. After 1 week of treatment with the extract, the weight, non-fasting blood glucose (NFBG) and HOMA-IR level of the rats decreased significantly (P<0.05) when compared to obese control rats. In addition, the level of serum insulin was increased significantly in all groups while fold expression of GLUT-4 gene was increased significantly (P<0.05) in OG-200 only. In conclusion, the use of methanolic crude extract of Ocimum gratissimum leaves can be a therapy in the treatment of obesity due to its significant hypoglycemic, anti hyperlipidemic and insulin resistance lowering properties

Poliovirus seroprevalence before and after interruption of poliovirus transmission in Kano State, Nigeria.

INTRODUCTION: In September 2015, Nigeria was removed from the list of polio-endemic countries after more than 12months had passed since the detection of last wild poliovirus case in the country on 24 July 2014. We are presenting here a report of two polio seroprevalence surveys conducted in September 2013 and October 2014, respectively, in the Kano state of northern Nigeria. METHODS: Health facility based seroprevalence surveys were undertaken at Murtala Mohammad Specialist Hospital, Kano. Parents or guardians of children aged 6-9months, 36-47months, 5-9years and 10-14years in 2013 and 6-9months and 19-22months (corresponding to 6-9months range at the time of 2013 survey) in 2014 presenting to the outpatient department, were approached for participation, screened for eligibility and asked to provide informed consent. A questionnaire was administered and a blood sample collected for polio neutralization assay. RESULTS: Among subjects aged 6-9months in the 2013 survey, seroprevalence was 58% (95% confidence interval [CI] 51-66%) to poliovirus type 1, 42% (95% CI 34-50%) to poliovirus type 2, and 52% (95% CI 44-60%) to poliovirus type 3. Among children 36-47months and older, seroprevalence was 85% or higher for all three serotypes. In 2014, seroprevalence in 6-9month infants was 72% (95% CI 65-79%) for type 1, 59% (95% CI 52-66%) for type 2, and 65% (95% CI 57-72%) for type 3 and in 19-22months, 80% (95% CI 74-85%), 57% (49-63%) and 78% (71-83%) respectively. Seroprevalence was positively associated with history of increasing oral poliovirus vaccine doses. CONCLUSIONS: There was significant improvement in seroprevalence in 2014 over the 2013 levels indicating a positive impact of recent programmatic interventions. However the continued low seroprevalence in 6-9month age is a concern and calls for improved immunization efforts to sustain the polio-free Nigeria

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

Travel burden and clinical presentation of retinoblastoma: analysis of 1024 patients from 43 African countries and 518 patients from 40 European countries

BACKGROUND: The travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe. METHODS: A cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries. RESULTS: Capture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI -12.4 to -5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease. CONCLUSIONS: Fewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Pregnane X receptor activation potentiates the hepatotoxicity of pharmacoenhancers

Ritonavir (RTV) is a first generation pharmacoenhancer used in anti-HIV therapy. Hepatotoxicity is one of the major safety concerns for HIV/AIDS patients receiving ritonavir (RTV)-containing antiretroviral regimens. In a recent series of clinical trials, the hepatotoxicity associated with RTV-containing regimens occurred in 100% of subjects who were pretreated with rifampicin (RIF) or efavirenz (EFV). Both RIF and EFV are potent ligands of human pregnane X receptor (PXR), a ligand-dependent transcription factor that upregulates Cytochrome P450 3A4 (CYP3A4) expression. Therefore, we hypothesize that drug mediated PXR activation potentiates RTV hepatotoxicity. Due to specie differences in PXR activation, humanized PXR and CYP3A4 mouse models were utilized. Pretreatment with both RIF and EFV potentiated RTV hepatotoxicity. Further studies showed that PXR mediated CYP3A4 induction increased RTV bioactivation in a humanized PXR/CYP3A4 mouse model which resulted in oxidative stress, endoplasmic reticulum stress and cellular injury. The second part of this dissertation focused on cobicistat (COBI), the new second generation pharmacoenhancer and structural analog of RTV. Clinical trials comparing the safety of COBI to RTV showed a similar rate of liver injury adverse events between the COBI and RTV treatment arms suggesting a similarity in their adverse effect profile. Based on our initial findings that the PXR/CYP3A4 axis plays an essential role in RTV hepatotoxicity, we explored the role of PXR/CYP3A4 axis in COBI hepatotoxicity. Using our humanized mouse models, hepatocellular injury was observed in PXR/CYP3A4-humanized mice pretreated with RIF followed by COBI which was similar to the phenotype observed with RTV. In addition, pretreatment with a constitutive androstane receptor (CAR) activator (another nuclear receptor), significantly up- regulated CYP3A4 expression and potentiated COBI hepatotoxicity in a CYP3A4-transgenic mouse model deficient in PXR. Further studies illustrated that induction of CYP3A4 increased COBI metabolism and bioactivation resulting in oxidative stress, endoplasmic reticulum stress, and hepatocellular injury as observed with RTV. Collectively, this work established the essential roles of hPXR and CAR ligands/activators that can induce CYP3A4 expression as risk factors for RTV/COBI hepatotoxicity. Our results can be used to develop novel strategies based upon PXR, CYP3A4, and their downstream pathways to ensure the safe use of RTV/COBI-containing regimens in the clinic

Phytochemistry and in vitro antiplasmodial properties of aqueous and ethanol stem bark extracts of Jatropha curcas (Physic Nut)

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