scholarly journals MBL2Variations and Malaria Susceptibility in Indian Populations

2013 ◽  
Vol 82 (1) ◽  
pp. 52-61 ◽  
Author(s):  
Aditya Nath Jha ◽  
Pandarisamy Sundaravadivel ◽  
Vipin Kumar Singh ◽  
Sudhanshu S. Pati ◽  
Pradeep K. Patra ◽  
...  
Keyword(s):  
Severe Malaria ◽  
Study Cohort ◽  
Content Type ◽  
Indian Populations ◽  
Functional Variants ◽  
Increased Risk ◽  
Mild Malaria ◽  
Recognition Protein ◽  
Asymptomatic Individuals ◽  
Endogamous Populations

ABSTRACTHuman mannose-binding lectin (MBL) encoded by theMBL2gene is a pattern recognition protein and has been associated with many infectious diseases, including malaria. We sought to investigate the contribution of functionalMBL2gene variations toPlasmodium falciparummalaria in well-defined cases and in matched controls. We resequenced the 8.7 kb of the entireMBL2gene in 434 individuals clinically classified with malaria from regions of India where malaria is endemic. The study cohort included 176 patients with severe malaria, 101 patients with mild malaria, and 157 ethnically matched asymptomatic individuals. In addition, 830 individuals from 32 socially, linguistically, and geographically diverse endogamous populations of India were investigated for the distribution of functionalMBL2variants. TheMBL2 −221C(X) allelic variant is associated with increased risk of malaria (mild malaria odds ratio [OR] = 1.9, correctedPvalue [PCorr] = 0.0036; severe malaria OR = 1.6,PCorr= 0.02). The exon1 variantsMBL2*B(severe malaria OR = 2.1,PCorr= 0.036; mild versus severe malaria OR = 2.5,PCorr= 0.039) andMBL2*C(mild versus severe malaria OR = 5.4,PCorr= 0.045) increased the odds of having malaria. The exon1MBL2*D/*B/*Cvariant increased the risk for severe malaria (OR = 3.4,PCorr= 0.000045). The frequencies of low MBL haplotypes were significantly higher in severe malaria (14.2%) compared to mild malaria (7.9%) and asymptomatic (3.8%). TheMBL2*LYPAhaplotypes confer protection, whereasMBL2*LXPAincreases the malaria risk. Our findings in Indian populations demonstrate thatMBL2functional variants are strongly associated with malaria and infection severity.

scholarly journals Associations between Aminoquinoline Resistance Genotypes and Clinical Presentations of Plasmodium falciparum Infection in Uganda

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Gloria Cuu ◽  
Victor Asua ◽  
Stephen Tukwasibwe ◽  
Sam L. Nsobya ◽  
Ann Nanteza ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Severe Malaria ◽  
Case Control Study ◽  
Case Control ◽  
Content Type ◽  
Parasite Fitness ◽  
Symptomatic Malaria ◽  
Clinical Presentations ◽  
Increased Risk ◽  
Control Study

ABSTRACT Mutations that mediate resistance of Plasmodium falciparum to aminoquinoline antimalarials are selected by prior drug use and may alter parasite fitness, but associations with clinical presentations are uncertain. We evaluated genotypes in samples from a case-control study of determinants of severe malaria in Ugandan children 4 months to 10 years of age. We studied 274 cases with severe malaria matched by age and geography to 275 uncomplicated malaria controls and 179 asymptomatic parasitemic controls. The overall prevalence of mutations of interest (considering mixed results as mutant) was 67.0% for PfCRT K76T, 8.5% for PfMDR1 N86Y, 71.5% for PfMDR1 Y184F, and 14.7% for PfMDR1 D1246Y. Compared to asymptomatic controls, the odds of mutant PfCRT 76T were lower for uncomplicated (odds ratio, 0.42 [95% confidence interval, 0.24 to 0.72]; P < 0.001) or severe (0.56 [0.32 to 0.97]; P = 0.031) malaria; the odds of mutant PfMDR1 86Y were lower for uncomplicated (0.33 [0.16 to 0.65]; P < 0.001) or severe (0.21 [0.09 to 0.45]; P < 0.001) malaria; and the odds of mutant PfMDR1 1246Y were higher for uncomplicated (1.83 [0.90 to 3.98]; P = 0.076) or severe (2.06 [1.01 to 4.55]; P = 0.033) malaria. The odds of mutant PfMDR1 184F were lower in severe than asymptomatic (0.59 [0.37 to 0.92]; P = 0.016) or uncomplicated (0.61 [0.41 to 0.90]; P = 0.009) malaria. Overall, the PfCRT 76T and PfMDR1 86Y mutations were associated with decreased risk of symptomatic malaria, PfMDR1 1246Y was associated with increased risk of symptomatic malaria, and PfMDR1 184F was associated with decreased risk of severe malaria. These results offer insights into parasite genotypes in children with different presentations, although the basis for the identified associations is likely complex.

scholarly journals Multifaceted Role of Heme during Severe Plasmodium falciparum Infections in India

2015 ◽  
Vol 83 (10) ◽  
pp. 3793-3799 ◽  
Author(s):  
Esther Dalko ◽  
Bidyut Das ◽  
Fabien Herbert ◽  
Constantin Fesel ◽  
Sulabha Pathak ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Severe Malaria ◽  
Rank Correlation ◽  
Interleukin 10 ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Canonical Correlations ◽  
Cytokines And Chemokines ◽  
Chemotactic Protein ◽  
Mild Malaria

Several immunomodulatory factors are involved in malaria pathogenesis. Among them, heme has been shown to play a role in the pathophysiology of severe malaria in rodents, but its role in human severe malaria remains unclear. Circulating levels of total heme and its main scavenger, hemopexin, along with cytokine/chemokine levels and biological parameters, including hemoglobin and creatinine levels, as well as transaminase activities, were measured in the plasma of 237Plasmodium falciparum-infected patients living in the state of Odisha, India, where malaria is endemic. All patients were categorized into well-defined groups of mild malaria, cerebral malaria (CM), or severe noncerebral malaria, which included acute renal failure (ARF) and hepatopathy. Our results show a significant increase in total plasma heme levels with malaria severity, especially for CM and malarial ARF. Spearman rank correlation and canonical correlation analyses have shown a correlation between total heme, hemopexin, interleukin-10, tumor necrosis factor alpha, gamma interferon-induced protein 10 (IP-10), and monocyte chemotactic protein 1 (MCP-1) levels. In addition, canonical correlations revealed that heme, along with IP-10, was associated with the CM pathophysiology, whereas both IP-10 and MCP-1 together with heme discriminated ARF. Altogether, our data indicate that heme, in association with cytokines and chemokines, is involved in the pathophysiology of both CM and ARF but through different mechanisms.

Sex steroid hormone exposures and risk for meningioma

2003 ◽  
Vol 99 (5) ◽  
pp. 848-853 ◽  
Author(s):  
Balraj S. Jhawar ◽  
Charlie S. Fuchs ◽  
Graham A. Colditz ◽  
Meir J. Stampfer
Keyword(s):  
Postmenopausal Women ◽  
Sex Hormones ◽  
Menopausal Status ◽  
Age At Menarche ◽  
Study Cohort ◽  
Medical Illness ◽  
Content Type ◽  
Increased Risk ◽  
Hormone Use ◽  
Fine Print

Object. The goal of this study was to investigate the risk of meningioma in relation to exogenous and endogenous sex hormones. Methods. The study participants were female registered nurses from 11 US states who were between 30 and 55 years of age when they enrolled in the Nurses' Health Study cohort. These women completed biennial questionnaires between 1976 and 1996. All participants were free from cancer and other major medical illness at the onset of the study. The primary endpoint was meningioma as self-reported in biennial and supplemental questionnaires. During 1,213,522 person-years of follow-up review, 125 cases of meningioma were confirmed. After adjusting for age and body mass index (BMI), compared with postmenopausal women who had never used postmenopausal hormones, the relative risk (RR) for premenopausal women was 2.48 (95% confidence interval [CI] 1.29–4.77; p = 0.01) and the RR for postmenopausal women who received hormone therapy was 1.86 (95% CI 1.07–3.24; p = 0.03). The authors found no excess risk associated with past hormone use. In models that additionally controlled for hormone use and menopausal status, the authors found that, compared with women whose menarche occurred before they were 12 years of age, the RR for women whose menarche occurred at ages 12 through 14 years was 1.29 (95% CI 0.86–1.92; p = 0.21) and the RR for women whose menarche occurred after age 14 years was 1.97 (95% CI 1.06–3.66; p = 0.03). The authors also observed a tendency, albeit nonsignificant, for increased risk of meningioma in parous as opposed to nulliparous women (multivariate RR = 2.39, 95% CI 0.76–7.53; p = 0.14). A trend toward an increasing risk of meningioma with increasing BMI was also noted (p for trend = 0.06). No association was found for past or current use of oral contraceptives. Conclusions. The risk for meningiomas was increased among women exposed to either endogenous or exogenous sex hormones. An unexpected relationship with increasing age at menarche was also noted; this remains unexplained.

scholarly journals Mild Plasmodium falciparum Malaria following an Episode of Severe Malaria Is Associated with Induction of the Interferon Pathway in Malawian Children

2012 ◽  
Vol 80 (3) ◽  
pp. 1150-1155 ◽  
Author(s):  
Malkie Krupka ◽  
Karl Seydel ◽  
Catherine M. Feintuch ◽  
Kenny Yee ◽  
Ryung Kim ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
T Cell ◽  
Severe Malaria ◽  
Severe Disease ◽  
Gene Set Enrichment Analysis ◽  
Malaria Episode ◽  
Type I ◽  
Asymptomatic Malaria ◽  
Content Type ◽  
Mild Malaria

Infection withPlasmodium falciparumcan lead to a range of severe to minimal symptoms, occasionally resulting in death in young children or nonimmune adults. In areas of high transmission, older children and adults generally suffer only mild or asymptomatic malaria infections and rarely develop severe disease. The immune features underlying this apparent immunity to severe disease remain elusive. To gain insight into host responses associated with severe and mild malaria, we conducted a longitudinal study of five children who first presented with severe malaria and, 1 month later, with mild malaria. Employing peripheral blood whole-genome profiling, we identified 68 genes that were associated with mild malaria compared to their expression in the severe malaria episode (paired Studentsttest,P< 0.05). These genes reflect the interferon (IFN) pathway and T cell biology and include IFN-induced protein transcripts 1 to 3, oligoadenylate synthetases 1 and 3, and the T cell markers cathepsin W and perforin. Gene set enrichment analysis identified Gene Ontology (GO) pathways associated with mild malaria to include the type I interferon-mediated signaling pathway (GO 0060337), T cell activation (GO 0042110), and other GO pathways representing many aspects of immune activation. In contrast, only six genes were associated with severe malaria, including thymidine kinase 1, which was recently found to be a biomarker of cerebral malaria susceptibility in the murine model, and carbonic anhydrase, reflecting the blood's abnormal acid base environment during severe disease. These data may provide potential insights to inform pathogenesis models and the development of therapeutics to reduce severe disease outcomes due toP. falciparuminfection.

scholarly journals Enhanced Basophil Reactivities during Severe Malaria and Their Relationship with the Plasmodium falciparum Histamine-Releasing Factor Translationally Controlled Tumor Protein

2012 ◽  
Vol 80 (8) ◽  
pp. 2963-2970 ◽  
Author(s):  
Stéphane Pelleau ◽  
Sylvie Diop ◽  
Méry Dia Badiane ◽  
Joana Vitte ◽  
Pierre Beguin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Severe Malaria ◽  
Ex Vivo ◽  
Statistical Significance ◽  
Basophil Activation ◽  
Content Type ◽  
Translationally Controlled Tumor Protein ◽  
Mild Malaria ◽  
Excessive Activation ◽  
Malaria Severity

ABSTRACTRecent studies suggest shared pathogenic pathways during malaria and allergy. Indeed, IgE, histamine, and the parasite-derivedPlasmodium falciparumhistamine-releasing factor translationally controlled tumor protein (PfTCTP) can be found at high levels in serum from patients experiencing malaria, but their relationship with basophil activation remains unknown. We recruitedP. falciparum-infected patients in Senegal with mild malaria (MM;n= 19) or severe malaria (SM;n= 9) symptoms and healthy controls (HC;n= 38). Levels of serum IgE, PfTCTP, and IgG antibodies against PfTCTP were determined by enzyme-linked immunosorbent assays (ELISA). Basophil reactivities to IgE-dependent and -independent stimulations were measuredex vivousing fresh blood by looking at the expression level of the basophil activation marker CD203c with flow cytometry. Unstimulated basophils from MM had significantly lower levels of CD203c expression compared to those from HC and SM. After normalization on this baseline level, basophils from SM showed an enhanced reactivity to calcimycin (A23187) and hemozoin. Although SM reached higher median levels of activation after anti-IgE stimulation, great interindividual differences did not allow the results to reach statistical significance. When primed with recombinant TCTP before anti-IgE, qualitative differences in terms of a better ability to control excessive activation could be described for SM. IgE levels were very high in malaria patients, but concentrations in MM and SM were similar and were not associated with basophil responses, which demonstrates that the presence of IgE alone cannot explain the various basophil reactivities. Indeed, PfTCTP could be detected in 32% of patients, with higher concentrations for SM. These PfTCTP-positive patients displayed significantly higher basophil reactivities to any stimulus. Moreover, the absence of anti-PfTCTP IgG was associated with higher responses in SM but not MM. Our results show an association between basophil reactivity and malaria severity and suggest a pathogenic role for plasmodial PfTCTP in the induction of this allergy-like mechanism.

Safety and efficacy of stereotactic radiosurgery for tumors of the spine

2004 ◽  
pp. 413-418 ◽  
Author(s):  
Deborah L. Benzil ◽  
Mehran Saboori ◽  
Alon Y. Mogilner ◽  
Ronald Rocchio ◽  
Chitti R. Moorthy
Keyword(s):  
Spinal Cord ◽  
Single Dose ◽  
Pain Relief ◽  
Total Dose ◽  
Stereotactic Radiosurgery ◽  
Medical Center ◽  
Primary Tumors ◽  
Content Type ◽  
Increased Risk ◽  
Fine Print

Object. The extension of stereotactic radiosurgery treatment of tumors of the spine has the potential to benefit many patients. As in the early days of cranial stereotactic radiosurgery, however, dose-related efficacy and toxicity are not well understood. The authors report their initial experience with stereotactic radiosurgery of the spine with attention to dose, efficacy, and toxicity. Methods. All patients who underwent stereotactic radiosurgery of the spine were treated using the Novalis unit at Westchester Medical Center between December 2001 and January 2004 are included in a database consisting of demographics on disease, dose, outcome, and complications. A total of 31 patients (12 men, 19 women; mean age 61 years, median age 63 years) received treatment for 35 tumors. Tumor types included 26 metastases (12 lung, nine breast, five other) and nine primary tumors (four intradural, five extradural). Thoracic tumors were most common (17 metastases and four primary) followed by lumbar tumors (four metastases and four primary). Lesions were treated to the 85 to 90% isodose line with spinal cord doses being less than 50%. The dose per fraction and total dose were selected on the basis of previous treatment (particularly radiation exposure), size of lesion, and proximity to critical structures. Conclusions. Rapid and significant pain relief was achieved after stereotactic radiosurgery in 32 of 34 treated tumors. In patients treated for metastases, pain was relieved within 72 hours and remained reduced 3 months later. Pain relief was achieved with a single dose as low as 500 cGy. Spinal cord isodoses were less than 50% in all patients except those with intradural tumors (mean single dose to spinal cord 268 cGy and mean total dose to spinal cord 689 cGy). Two patients experienced transient radiculitis (both with a biological equivalent dose (BED) > 60 Gy). One patient who suffered multiple recurrences of a conus ependymoma had permanent neurological deterioration after initial improvement. Pathological evaluation of this lesion at surgery revealed radiation necrosis with some residual/recurrent tumor. No patient experienced other organ toxicity. Stereotactic radiosurgery of the spine is safe at the doses used and provides effective pain relief. In this study, BEDs greater than 60 Gy were associated with an increased risk of radiculitis.

scholarly journals Vulnerable adults in police custody

2019 ◽  
Vol 22 (1) ◽  
pp. 5-8
Author(s):  
Ian Cummins
Keyword(s):  
Design Methodology ◽  
Research Literature ◽  
Police Custody ◽  
England And Wales ◽  
Content Type ◽  
Increased Risk ◽  
Vulnerable Adults

Purpose The purpose of this paper is to discuss the recent National Appropriate Adult Network (NAAN) report on the role of the appropriate adult. Design/methodology/approach This paper is based on the NAAN report and a review of relevant policy and research literature. Findings There to Help 2 highlights that there are still significant gaps in the provision of appropriate adult schemes across England and Wales. These gaps potentially place vulnerable adults at increased risk. Originality/value This paper is a review of recent research.

scholarly journals Vitamin K antagonist anticoagulant usage is associated with increased incidence and progression of osteoarthritis

2021 ◽  
Vol 80 (5) ◽  
pp. 598-604
Author(s):  
Cindy G Boer ◽  
Ingrid Szilagyi ◽  
N Long Nguyen ◽  
Tuhina Neogi ◽  
Ingrid Meulenbelt ◽  
...  
Keyword(s):  
Vitamin K ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Vitamin K Antagonist ◽  
Matrix Gla Protein ◽  
Study Cohort ◽  
Single Nucleotide Variants ◽  
Increased Risk ◽  
Coagulation Proteins ◽  
Clinical Prevention

ObjectivesVitamin K is hypothesised to play a role in osteoarthritis (OA) pathogenesis through effects on vitamin K-dependent bone and cartilage proteins, and therefore may represent a modifiable risk factor. A genetic variant in a vitamin K-dependent protein that is an essential inhibitor for cartilage calcification, matrix Gla protein (MGP), was associated with an increased risk for OA. Vitamin K antagonist anticoagulants (VKAs), such as warfarin and acenocoumarol, act as anticoagulants through inhibition of vitamin K-dependent blood coagulation proteins. VKAs likely also affect the functioning of other vitamin K-dependent proteins such as MGP.MethodsWe investigated the effect of acenocoumarol usage on progression and incidence of radiographic OA in 3494 participants of the Rotterdam Study cohort. We also examined the effect of MGP and VKORC1 single nucleotide variants on this association.ResultsAcenocoumarol usage was associated with an increased risk of OA incidence and progression (OR=2.50, 95% CI=1.94–3.20), both for knee (OR=2.34, 95% CI=1.67–3.22) and hip OA (OR=2.74, 95% CI=1.82–4.11). Among acenocoumarol users, carriers of the high VKORC1(BB) expression haplotype together with the MGP OA risk allele (rs1800801-T) had an increased risk of OA incidence and progression (OR=4.18, 95% CI=2.69–6.50), while this relationship was not present in non-users of that group (OR=1.01, 95% CI=0.78–1.33).ConclusionsThese findings support the importance of vitamin K and vitamin K-dependent proteins, as MGP, in the pathogenesis of OA. Additionally, these results may have direct implications for the clinical prevention of OA, supporting the consideration of direct oral anticoagulants in favour of VKAs.

scholarly journals IFN-λ4 is associated with increased risk and earlier occurrence of several common infections in African children

2021 ◽  
Author(s):  
Ludmila Prokunina-Olsson ◽  
Robert D. Morrison ◽  
Adeola Obajemu ◽  
Almahamoudou Mahamar ◽  
Sungduk Kim ◽  
...  
Keyword(s):  
Respiratory Infections ◽  
Genomic Region ◽  
First Episode ◽  
Genetic Associations ◽  
Gastrointestinal Infections ◽  
Type Iii ◽  
Functional Variants ◽  
Younger Age ◽  
Increased Risk ◽  
Pediatric Infections

AbstractGenetic polymorphisms within the IFNL3/IFNL4 genomic region, which encodes type III interferons, have been strongly associated with clearance of hepatitis C virus. We hypothesized that type III interferons might be important for the immune response to other pathogens as well. In a cohort of 914 Malian children, we genotyped functional variants IFNL4-rs368234815, IFNL4-rs117648444, and IFNL3-rs4803217 and analyzed episodes of malaria, gastrointestinal, and respiratory infections recorded at 30,626 clinic visits from birth up to 5 years of age. Compared to children with the rs368234815-TT/TT genotype (IFN-λ4-Null), rs368234815-dG allele was most strongly associated with an earlier time-to-first episode of gastrointestinal infections (p = 0.003). The risk of experiencing an infection episode during the follow-up was also significantly increased with rs368234815-dG allele, with OR = 1.53, 95%CI (1.13–2.07), p = 0.005 for gastrointestinal infections and OR = 1.30, 95%CI (1.02–1.65), p = 0.033 for malaria. All the associations for the moderately linked rs4803217 (r2 = 0.78 in this set) were weaker and lost significance after adjusting for rs368234815. We also analyzed all outcomes in relation to IFN-λ4-P70S groups. Our results implicate IFN-λ4 and not IFN-λ3 as the primary functional cause of genetic associations with increased overall risk and younger age at first clinical episodes but not with recurrence or intensity of several common pediatric infections.

scholarly journals Exploring the Epidemiology of Cancer after Solid Organ Transplantation (EpCOT): an observational cohort study

BMJ Open ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. e043731
Author(s):  
Adnan Sharif ◽  
Javeria Peracha ◽  
David Winter ◽  
Raoul Reulen ◽  
Mike Hawkins
Keyword(s):  
Organ Transplantation ◽  
Record Linkage ◽  
Solid Organ Transplantation ◽  
Organ Transplant ◽  
Solid Organ Transplant ◽  
Study Cohort ◽  
Solid Organ ◽  
Post Transplantation ◽  
Increased Risk ◽  
Risk Of Cancer

IntroductionSolid organ transplant patients are counselled regarding increased risk of cancer (principally due to their need for lifelong immunosuppression) and it ranks as one of their biggest self-reported worries. Post-transplantation cancer is common, associated with increased healthcare costs and emerging as a leading cause of post-transplant mortality. However, epidemiology of cancer post-transplantation remains poorly understood, with limitations including translating data from different countries and national data being siloed across different registries and/or data warehouses.Methods and analysisStudy methodology for Epidemiology of Cancer after Solid Organ Transplantation involves record linkage between the UK Transplant Registry (from NHS Blood and Transplant), Hospital Episode Statistics (for secondary care episodes from NHS Digital), National Cancer Registry (from cancer registration data hosted by Public Health England) and the National Death Registry (from NHS Digital). Deterministic record linkage will be conducted by NHS Digital, with a fully anonymised linked dataset available for analysis by the research team. The study cohort will consist of up to 85 410 solid organ transplant recipients,who underwent a solid organ transplant in England between 1 January 1985 and 31 December 2015, with up-to-date outcome data.Ethics and disseminationThis study has been approved by the Confidentiality Advisory Group (reference: 16/CAG/0121), Research Ethics Committee (reference: 15/YH/0320) and Institutional Review Board (reference: RRK5471). The results of this study will be presented at national and international conferences, and manuscripts with results will be submitted for publication in high-impact peer-reviewed journals. The information produced will also be used to develop national evidence-based clinical guidelines to inform risk stratification to enable risk-based clinical follow-up.Trial registration numberNCT02991105.

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