共找到 20 条结果
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor in Chief. This paper is being retracted due to many inaccuracies in the original data in Figures 1D, 1E, 2A, 2B, 2E, 3B, 4B, 5A being identified that have raised concerns over the validity of the overall findings.
DNA replication is an extremely complex process, involving thousands of replication forks progressing along chromosomes. These forks are frequently slowed down or stopped by various obstacles, such as secondary DNA structures, chromatin-acting proteins or a lack of nucleotides. This slowing down, known as replicative stress, plays a central role in tumour development. Complex processes, which are not yet fully understood, are set up to respond to this stress. Certain nucleases, such as MRE11 and DNA2, degrade the neo-replicated DNA at the level of blocked forks, allowing the replication to restart. The interferon pathway is a defense mechanism against pathogens that detects the presence of foreign nucleic acids in the cytoplasm and activates the innate immune response. DNA fragments resulting from genomic DNA metabolism (repair, retrotransposition) can diffuse into the cytoplasm and activate this pathway. A pathological manifestation of this process is the Aicardi-Goutières syndrome, a rare disease characterized by chronic inflammation leading to neurodegenerative and developmental problems. In this encephalopathy, it has been suggested that DNA replication may generate cytosolic DNA fragments, but the mechanisms involved have not been characterized. SAMHD1 is frequently mutated in the Aicardi-Goutières syndrome as well as in some cancers, but its role in the etiology of these diseases was largely unknown. We show that cytosolic DNA accumulates in SAMHD1-deficient cells, particularly in the presence of replicative stress, activating the interferon response. SAMHD1 is important for DNA replication under normal conditions and for the processing of stopped forks, independent of its dNTPase activity. In addition, SAMHD1 stimulates the exonuclease activity of MRE11 in vitro. When SAMHD1 is absent, degradation of neosynthesized DNA is inhibited, which prevents activation of the replication checkpoint and leads to failure to restart the replication forks. Resection of the replication forks is performed by an alternative mechanism which releases DNA fragments into the cytosol, activating the interferon response. The results obtained show, for the first time, a direct link between the response to replication stress and the production of interferons. These results have important implications for our understanding of the Aicardi-Goutières syndrome and cancers related to SAMHD1. For example, we have shown that MRE11 and RECQ1 are responsible for the production of DNA fragments that trigger the inflammatory response in cells deficient for SAMHD1. We can therefore imagine that blocking the activity of these enzymes could decrease the production of DNA fragments and, ultimately, the activation of innate immunity in these cells. In addition, the interferon pathway plays an essential role in the therapeutic efficacy of irradiation and certain chemotherapeutic agents such as oxaliplatin. Modulating this response could therefore be of much wider interest in anti-tumour therapy. La réplication de l’ADN est un processus extrêmement complexe, impliquant des milliers de fourches de réplication progressant le long des chromosomes. Ces fourches sont fréquemment ralenties ou arrêtées par différents obstacles, tels que des structures secondaires de l’ADN, des protéines agissant sur la chromatine ou encore un manque de nucléotides. Ce ralentissement, qualifié de stress réplicatif, joue un rôle central dans le développement tumoral. Des processus complexes, qui ne sont pas encore totalement connus, sont mis en place pour répondre à ce stress. Certaines nucléases, comme MRE11 et DNA2, dégradent l’ADN néorépliqué au niveau des fourches bloquées, ce qui permet le redémarrage des réplisomes. La voie interféron est un mécanisme de défense contre les agents pathogènes qui détecte la présence d’acides nucléiques étrangers dans le cytoplasme et active la réponse immunitaire innée. Des fragments d’ADN issus du métabolisme de l’ADN génomique (réparation, rétrotransposition) peuvent diffuser dans le cytoplasme et activer cette voie. Une manifestation pathologique de ce processus est le syndrome d’Aicardi-Goutières, une maladie rare caractérisée par une inflammation chronique générant des problèmes neurodégénératifs et développementaux. Dans le cadre de cette encéphalopathie, il a été suggéré que la réplication de l’ADN pouvait générer des fragments d’ADN cytosoliques, mais les mécanismes impliqués n’avaient pas été caractérisés. SAMHD1 est fréquemment muté dans le syndrome d’Aicardi-Goutières ainsi que dans certains cancers, mais son rôle dans l’étiologie de ces maladies était jusqu’à présent largement inconnu. Nous montrons que de l’ADN cytosolique s’accumule dans les cellules déficientes pour SAMHD1, particulièrement en présence de stress réplicatif, activant la réponse interféron. Par ailleurs, SAMHD1 est important pour la réplication de l’ADN en conditions normales et pour le processing des fourches arrêtées, indépendamment de son activité dNTPase. De plus, SAMHD1 stimule l’activité exonucléase de MRE11 in vitro. Lorsque SAMHD1 est absent, la dégradation de l’ADN néosynthétisé est inhibée, ce qui empêche l’activation du checkpoint de réplication et entraine un défaut de redémarrage des fourches de réplication. De plus, la résection des fourches de réplication est réalisée par un mécanisme alternatif qui libère des fragments d’ADN dans le cytosol, activant la réponse interféron. Les résultats obtenus montrent, pour la première fois, un lien direct entre la réponse au stress réplicatif et la production d’interférons. Ces résultats ont des conséquences importantes dans notre compréhension du syndrome d’Aicardi Goutières et des cancers liés à SAMHD1. Par exemple, nous avons démontré que MRE11 et RECQ1 sont responsables de la production des fragments d’ADN qui déclenchent la réponse inflammatoire dans les cellules déficientes pour SAMHD1. Nous pouvons donc imaginer que bloquer l’activité de ces enzymes pourrait diminuer la production des fragments d’ADN et, in fine, l’activation de l’immunité innée dans ces cellules. Par ailleurs, la voie interférons joue un rôle essentiel dans l’efficacité thérapeutique de l’irradiation et de certains agents chimiothérapiques comme l’oxaliplatine. Moduler cette réponse pourrait donc avoir un intérêt beaucoup plus large en thérapie anti-tumorale.
Globally, with a neonatal mortality rate of 27/1000 live births, Sub-Saharan Africa has the highest rate in the world and is responsible for 43% of all infant fatalities. In the first week of life, almost three-fourths of neonatal deaths occur and about one million babies died on their first day of life. Previous studies lack conclusive evidence regarding the overall estimate of early neonatal mortality in Sub-Saharan Africa. Therefore, this review aimed to pool findings reported in the literature on magnitude of early neonatal mortality in Sub-Saharan Africa. This review's output is the aggregate of magnitude of early neonatal mortality in sub-Saharan Africa. Up until June 8, 2023, we performed a comprehensive search of the databases PubMed/Medline, PubMed Central, Hinary, Google, Cochrane Library, African Journals Online, Web of Science, and Google Scholar. The studies were evaluated using the JBI appraisal check list. STATA 17 was employed for the analysis. Measures of study heterogeneity and publication bias were conducted using the I2 test and the Eggers and Beggs tests, respectively. The Der Simonian and Laird random-effect model was used to calculate the combined magnitude of early neonatal mortality. Besides, subgroup analysis, sensitivity analysis, and meta regression were carried out to identify the source of heterogeneity. Fourteen studies were included from a total of 311 articles identified by the search with a total of 278,173 participants. The pooled magnitude of early neonatal mortality in sub-Saharan Africa was 80.3 (95% CI 66 to 94.6) per 1000 livebirths. Ethiopia had the highest pooled estimate of early neonatal mortality rate, at 20.1%, and Cameroon had the lowest rate, at 0.5%. Among the included studies, both the Cochrane Q test statistic (χ2 = 6432.46, P <0.001) and I2 test statistic (I2 = 99.80%, p <0.001) revealed statistically significant heterogeneity. Egger's weighted regression (p <0.001) and funnel plot show evidence of publication bias in this meta-analysis. This review demonstrated that the pooled magnitude of early neonatal mortality in sub-Saharan Africa is substantial. Therefore, governmental and nongovernmental agencies, international organizations, healthcare providers and institutions and academic and research institutions should give a due attention and design strategies to reduce early neonatal mortality in Sub-Saharan Africa.
MODY2 (maturity-onset diabetes of the young type 2, MIM125851) is a monogenic diabetes with an autosomal dominant transmission caused by a variant of the GCK gene. MODY2 is often confused with type 1 or type 2 diabetes, but despite a slightly elevated blood glucose level, it does not induce long-term vascular complications, nor does it require pharmacological treatment. Genetic testing for the diagnosis of MODY2 is currently reserved for genetic specialists and some physicians. Still, access to it by primary care healthcare professionals (HCPs), coupled with appropriate training, would improve the diagnosis and management of patients with MODY2. Thus, to evaluate the implementation in primary care of genetic testing for the screening of MODY2 (iMOgene study), an implementation pilot study has been designed supported by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. Two primary care clinics will be involved in the region of Saguenay-Lac-Saint-Jean (Québec, Canada). An asynchronous online training on MODY2 and genetic testing, including pre/post questionnaires, will be provided to the HCPs. Satisfaction, adoption and maintenance indicators will be collected throughout the project for each clinic. Questionnaires for patients and professionals and focus groups with HCPs will be conducted to assess implementation. This study will document the implementation process of genetic testing in primary care by identifying facilitating and limiting factors to establish specifications for scaling up. The present protocol has been approved by the research ethic committee of the 'Centre intégré universitaire de santé et de services sociaux of Saguenay-Lac-Saint-Jean' (CIUSSS-SLSJ) on 9 January 2024 and by the 'Comité central d'éthique de la recherche' (CCER) of the 'Ministère de la Santé et des Services Sociaux' of Quebec (Canada) on 30 January 2024. The informed consent of participants will be obtained orally. Dissemination of the study results will involve peer-review publications, presentations at major national and international scientific conferences.
During the last 30 years, investigations on the microbiome of different tsetse species have generated substantial data on the bacterial flora of these cyclical vectors of African trypanosomes, with the overarching goal of improving the control of trypanosomiases. It is in this context that the presence of Wolbachia and Sodalis glossinidius was studied in wild populations of Glossina fuscipes quanzensis from the Democratic Republic of Congo. Tsetse flies were captured with pyramidal traps. Of the 700 Glossina f. quanzensis captured, 360 were dissected and their midguts collected and analyzed. Sodalis glossinidius and Wolbachia were identified by PCR. The Wolbachia-positive samples were genetically characterized with five molecular markers. PCR revealed 84.78% and 15.55% midguts infected by Wolbachia and S. glossinidius, respectively. The infection rates varied according to capture sites. Of the five molecular markers used to characterize Wolbachia, only the fructose bis-phosphate aldolase gene was amplified for about 60% of midguts previously found with Wolbachia infections. The sequencing results confirmed the presence of Wolbachia and revealed the presence of S. glossinidius in the midgut of Glossina f. quanzensis. A low level of midguts were naturally co-infected by both bacteria. The data generated in this study open a framework for investigations aimed at understanding the contribution of these symbiotic microorganisms to the vectorial competence of Glossina fuscipes quanzensis. Au cours des 30 dernières années, les recherches sur le microbiome de différentes espèces de glossines ont généré des données substantielles sur la flore bactérienne de ces vecteurs cycliques des trypanosomes africains, l’objectif principal étant d’améliorer le contrôle des trypanosomiases. C’est dans cette optique que la présence de Wolbachia et Sodalis glossinidius a été étudiée dans des populations sauvages de Glossina fuscipes quanzensis de la République démocratique du Congo. Les glossines ont été capturées avec des pièges pyramidaux. Parmi les 700 Glossina f. quanzensis capturés, 360 ont été disséqués et leur estomac récupéré et analysé. Sodalis glossinidius et Wolbachia ont été identifiés par PCR. Les échantillons positifs pour Wolbachia ont été génétiquement caractérisés avec cinq marqueurs moléculaires. La PCR a révélé que 84,78 % et 15,55 % de l’intestin moyen étaient respectivement infectés par Wolbachia et S. glossinidius. Les taux d’infection variaient selon les sites de capture. Sur les cinq marqueurs moléculaires utilisés pour caractériser Wolbachia, seul le gène de la fructose bis-phosphate aldolase a été amplifié pour environ 60 % des intestins moyens précédemment identifiés porteurs de Wolbachia. Les résultats du séquençage ont confirmé la présence de Wolbachia et ont révélé la présence de S. glossinidius dans l’intestin moyen de Glossina f. quanzensis. Un faible taux des intestins moyens était naturellement co-infecté par les deux bactéries. Les données de cette étude ouvrent un cadre pour des recherches visant à comprendre la contribution de ces microorganismes symbiotiques sur la compétence vectorielle de Glossina fuscipes quanzensis.
The premise of this piece is that a priority of international health should be to increase the number of investigators in the US and other developed countries who engage in research and other kinds of scholarly work in underdeveloped parts of the world, particularly sub-Saharan Africa where the overall disease burden is the highest and the gap in biomedical research infrastructure is the widest. The author's aim is to encourage medical students, resident doctors, and medical school faculty to devote a part of their career to teach, acquire clinical skills, or participate in research with health professionals at teaching hospitals in Africa. After briefly describing the thinking that led the author to Nigeria 30 years ago to teach and study biochemical aspects of health problems in rural and urban areas, he discusses some of the factors one needs to consider before entering into an international partnership, including identifying the right foreign collaborators, selecting a suitable research site, setting realistic goals, learning the local culture and indigenous language, and defining a theme for your program. Lastly, the piece points out potential pitfalls and problems that are often overlooked or underestimated in the early phases of planning an international partnership, including lukewarm institutional support at home, inflexible institutional review boards, dominance of the program by the US partner, maintaining continuity, and striking the right balance between scholarly work and humanitarian efforts. My hope is that US students and faculty in the health professions who read this piece will be stimulated and encouraged to consider how they might integrate into their curriculum or academic life visits lasting several months or more each year during which they would teach or train others or engage in research at a teaching hospital in some country in Africa.
We sought to clone and characterize the murine Hox-b3 gene. In Xenopus embryos, the homologous gene has been shown to be responsive to retinoic acid, an agent which has profound effects on tissue growth and development. By plaque hybridization, using a partial, murine Hox-b3 cDNA as a probe, we screened a genomic library and isolated a series of overlapping clones. Restriction fragments from positive clones were sequenced by the dideoxy method on an automated DNA sequencer. We report the genomic sequence of the murine Hox-b3 gene. The sequence has been submitted to the GenBank database (accession number U02278). Our sequence extends from the P1 promoter through the coding sequence of the gene to the 3'-untranslated region. In common with other homeobox genes, there is an intron between the conserved hexapeptide and the homeobox. It is 866 bp long and has 3'- and 5'-splice sites very similar to the consensus, a long polypyrimidine tract and a potential branch point near the 3'-splice site. We have analyzed the sequence 5' to the initiation codon and the intron for putative control elements, and have identified a series of putative transcription factor binding sites in the P1 promoter and intron, including two for the retinoid X receptor-beta. Their possible significance is discussed. The sequences we have identified may be responsible for the observed pattern of expression of the gene. This sequence and the clones from which it is derived will enable a molecular dissection of the P1 promoter region.
Physiologically based pharmacokinetic (PBPK) models allow to simulate the behaviour of compounds in diverse physiological populations. However, the categorization of individuals into distinct populations raises questions regarding the classification criteria. In previous research, simulations of the pharmacokinetics of the mycotoxin aflatoxin B1 (AFB1), were performed in the black South African population, using PBPK modeling. This study investigates the prevalence of clinical CYP450 phenotypes (CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5) across Sub-Saharan Africa (SSA), to determine the feasibility of defining SSA as a single population. SSA was subdivided into Central, East, South and West Africa. The phenotype data were assigned to the different regions and a fifth SSA group was composed of all regions' weighted means. Available data from literature only covered 7.30% of Central, 56.9% of East, 38.9% of South and 62.9% of West Africa, clearly indicating critical data gaps. A pairwise proportion test was performed between the regions on enzyme phenotype data. When achieving statistical significance (p < 0.05), a Cohen's d-test was performed to determine the degree of the difference. Next, per region populations were built using SimCYP starting from the available SSA based SouthAfrican_Population FW_Custom population, supplemented with the phenotype data from literature. Simulations were performed using CYP probe substrates in all populations, and derived PK parameters (Cmax, Tmax, AUCss and CL) were plotted in bar charts. Significant differences between the African regions regarding CYP450 phenotype frequencies were shown for CYP2B6, CYP2C19 and CYP2D6. Limited regional data challenge the representation of SSA populations in these models. The scarce availability of in vivo data for SSA regions restricted the ability to fully validate the developed PBPK populations. However, observed literature data from specific SSA regions provided partial validation, indicating that SSA populations should ideally be modelled at a regional level rather than as a single entity. The findings, emerging from the initial AFB1-focused PBPK work, underscore the need for more extensive and region-specific data to enhance model accuracy and predictive value across SSA.
This article has been retracted; please see Elsevier Policy on Article Withdrawal: http://www.elsevier.com/locate/withdrawalpolicy This article has been retracted at the request of the Editor-in-Chief of The International Journal of Biochemistry and Cell Biology, as the authors have plagiarised sections of several other papers that had been previously published (Hale et al. J Gen Virol 2008;89:2359-76; Bornholdt & Prasad Nat Struc Mol Biol 2006;13:559-60; Chen & Krug EMBO J 1999;18:2273-83; Garcia-Sastre Emerg Infec Dis 2006;12:44-47). Furthermore, one of the co-authors listed denied any involvement in the preparation of the manuscript in question. One of the conditions of submission of a paper for publication is that all the authors declare explicitly that their work is original and has not appeared in a publication elsewhere. Re-use of any data and statements should be appropriately cited. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and we apologize to readers of the journal that this was not detected during the submission process.
To set the scene for this Directed Issue on Mechanisms of Tissue Repair of The International Journal of Biochemistry and Cell Biology, this introductory overview briefly describes the process of wound healing and highlights some of the key recent advances in this field of research. It emphasizes the importance of cell-cell and cell-matrix interactions, particularly relating to the role of cell surface adhesion molecules, and describes developments that have led to a better understanding of the dynamic nature of matrix turnover with reference to negative and positive mediators that regulate procollagen gene expression and protein production. An important component of this Directed Issue is concerned with the development of tissue fibrosis, which accompanies a number of disease states and demonstrates remarkable parallels with the normal wound healing process; excessive amounts of matrix are laid down but the resolution of scarring, which would be anticipated in wound healing, is impaired. The possible mechanisms involved in fibrosis are discussed here. Since cytokines play an important role in regulating cell function such as proliferation, migration and matrix synthesis, it is the balance of these mediators which is likely to play a key role in regulating the initiation, progression and resolution of wounds. Finally, this review highlights areas of tissue repair research in which recent developments have important clinical implications that may lead to novel therapeutic strategies.
The poultry industry in sub-Saharan Africa (SSA) is faced with feed insecurity, associated with high cost of feeds, and feed safety, associated with locally produced feeds often contaminated with mycotoxins. Mycotoxins, including aflatoxins (AFs), fumonisins (FBs), trichothecenes, and zearalenone (ZEN), are common contaminants of poultry feeds and feed ingredients from SSA. These mycotoxins cause deleterious effects on the health and productivity of chickens and can also be present in poultry food products, thereby posing a health hazard to human consumers of these products. This review summarizes studies of major mycotoxins in poultry feeds, feed ingredients, and poultry food products from SSA as well as aflatoxicosis outbreaks. Additionally reviewed are the worldwide regulation of mycotoxins in poultry feeds, the impact of major mycotoxins in the production of chickens, and the postharvest use of mycotoxin detoxifiers. In most studies, AFs are most commonly quantified, and levels above the European Union regulatory limits of 20 μg/kg are reported. Trichothecenes, FBs, ZEN, and OTA are also reported but are less frequently analyzed. Co-occurrences of mycotoxins, especially AFs and FBs, are reported in some studies. The effects of AFs on chickens' health and productivity, carryover to their products, as well as use of mycotoxin binders are reported in few studies conducted in SSA. More research should therefore be conducted in SSA to evaluate occurrences, toxicological effects, and mitigation strategies to prevent the toxic effects of mycotoxins.
There is now a growing body of evidence which suggests links between the regulation of protein synthesis and the disruption of cell behaviour that typifies cancer. This directed issue of the International Journal of Biochemistry and Cell Biology presents several review articles of relevance to this field. The topics covered include the significance of the regulation and overexpression of polypeptide chain initiation factors for cell transformation and malignancy, the role of mRNA structure in the control of synthesis of key growth regulatory proteins, the actions of the eIF2 alpha-specific protein kinase PKR in the control cell growth and apoptosis, and the involvement of the elongation factor eEF1 in oncogenesis. The purpose of this article is to give an overview of the field and to indicate where we may expect developments to occur in the next few years.
In Africa, the first Plasmodium falciparum artemisinin partial resistance mutation was Kelch13 (K13) 561H, detected and validated at appreciable frequency in Rwanda in 2014. Surveillance to better define the extent of the emergence in Rwanda and neighboring countries is critical. We used novel liquid blood drop preservation with pooled sequencing to provide cost-effective rapid assessment of resistance mutation frequencies at multiple collection sites across Rwanda and neighboring regions in Uganda, Tanzania, and the Democratic Republic of the Congo. Malaria-positive samples (N = 5465) from 39 health facilities collected between May 2022 and March 2023 were sequenced in 199 pools. In Rwanda, K13 561H and 675V were detected in 90% and 65% of sites, with an average frequency of 19.0% (range, 0%-54.5%) and 5.0% (0%-35.5%), respectively. In Tanzania, 561H had high frequency in multiple sites. 561H appeared at 1.6% in Uganda. 561H was absent from the Democratic Republic of the Congo, although 675V was seen at low frequency. Concerningly, candidate mutations were observed: 441L, 449A, and 469F co-occurred with validated mutations, suggesting that they are arising under the same pressures. Other markers for decreased susceptibility to artemether-lumefantrine are common: P falciparum multidrug resistance protein 1 N86 at 98.0% (range, 63.3%-100%) and 184F at 47.0% (0%-94.3%) and P falciparum chloroquine resistance transporter 76T at 14.7% (0%-58.6%). Additionally, sulfadoxine-pyrimethamine-associated mutations show high frequencies. K13 mutations are rapidly expanding in the region, further endangering control efforts with the potential of engendering partner drug resistance.
Energy metabolism alterations are found in a large number of rare and common diseases of genetic or environmental origin. The number of patients that could benefit from bioenergetic modulation therapy (BIOMET) is therefore very important and includes individuals with pathologies as diverse as mitochondrial diseases, acute coronary syndrome, chronic kidney disease, asthma or even cancer. Although, the alteration of energy metabolism is disease specific and sometimes patient specific, the strategies for BIOMET could be common and target a series of bioenergetic regulatory mechanisms discussed in this article. An excellent training of scientists in the field of energy metabolism, related human diseases and drug discovery is also crucial to form a young generation of MDs, PHDs and Pharma or CRO-group leaders who will discover novel personalized bioenergetic medicines, through pharmacology, genetics, nutrition or adapted exercise training. The Mitochondrial European Educational Training (MEET) consortium was created to pursue this goal, and we dedicated here a special issue of Organelle in Focus (OiF) to highlight their objectives. A total of 10 OiFs articles constitute this Directed Issue on Mitochondrial Medicine. As part of this editorial article, we asked timely questions to the PR. Jan W. Smeitink, professor of Mitochondrial Medicine and CEO of Khondrion, a mitochondrial medicine company. He shared with us his objectives and strategies for the study of mitochondrial diseases and the identification of future treatments. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies.
The morbidity and socioeconomic effects of onchocerciasis, a parasitic disease that is primarily endemic in sub-Saharan Africa, have motivated large morbidity and transmission control programmes. Annual community-directed ivermectin treatment has substantially reduced prevalence. Elimination requires intensified efforts, including more efficacious treatments. We compared parasitological efficacy and safety of moxidectin and ivermectin. This double-blind, parallel group, superiority trial was done in four sites in Ghana, Liberia, and the Democratic Republic of the Congo. We enrolled participants (aged ≥12 years) with at least 10 Onchocerca volvulus microfilariae per mg skin who were not co-infected with Loa loa or lymphatic filariasis microfilaraemic. Participants were randomly allocated, stratified by sex and level of infection, to receive a single oral dose of 8 mg moxidectin or 150 μg/kg ivermectin as overencapsulated oral tablets. The primary efficacy outcome was skin microfilariae density 12 months post treatment. We used a mixed-effects model to test the hypothesis that the primary efficacy outcome in the moxidectin group was 50% or less than that in the ivermectin group. The primary efficacy analysis population were all participants who received the study drug and completed 12-month follow-up (modified intention to treat). This study is registered with ClinicalTrials.gov, number NCT00790998. Between April 22, 2009, and Jan 23, 2011, we enrolled and allocated 998 participants to moxidectin and 501 participants to ivermectin. 978 received moxidectin and 494 ivermectin, of which 947 and 480 were included in primary efficacy outcome analyses. At 12 months, skin microfilarial density (microfilariae per mg of skin) was lower in the moxidectin group (adjusted geometric mean 0·6 [95% CI 0·3-1·0]) than in the ivermectin group (4·5 [3·5-5·9]; difference 3·9 [3·2-4·9], p<0·0001; treatment difference 86%). Mazzotti (ie, efficacy-related) reactions occurred in 967 (99%) of 978 moxidectin-treated participants and in 478 (97%) of 494 ivermectin-treated participants, including ocular reactions (moxidectin 113 [12%] participants and ivermectin 47 [10%] participants), laboratory reactions (788 [81%] and 415 [84%]), and clinical reactions (944 [97%] and 446 [90%]). No serious adverse events were considered to be related to treatment. Skin microfilarial loads (ie, parasite transmission reservoir) are lower after moxidectin treatment than after ivermectin treatment. Moxidectin would therefore be expected to reduce parasite transmission between treatment rounds more than ivermectin could, thus accelerating progress towards elimination. UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases.
 Antiretroviral (ARV) exposure influences the early-life gut microbiota in regions with high human immunodeficiency virus (HIV) burdens. Understanding how ARV drugs affect the infant gut microbiota is important for optimising short-term and long-term health outcomes.  This scoping review synthesises current evidence on the gut microbiota of infants born to mothers with HIV (MWH) in sub-Saharan Africa, focusing on the effects of in utero and postnatal ARV exposure. By examining emerging data in this context, we highlight potential implications for infant health and identify key areas for future research.  Online databases were systematically searched using comprehensive search strategies. In addition, grey literature was explored. Three authors independently screened titles and abstracts for relevance, evaluated full-text articles for eligibility and performed data extraction.  The scoping review highlights differences in gut microbiota because of HIV exposure and ARV drugs in infants born to sub-Saharan African MWH. Of interest is a disturbance in the gut bacterial balance in infants with HIV, who harboured enriched with more diverse and potentially harmful bacteria relative to HIV-exposed uninfected infants. There was agreement from some countries, that is Nigeria and Zimbabwe, that their gut microbiota genomes comprise Bifidobacterium longum subspecies infantis and Enterococcus.  Both antiretroviral therapy and HIV influence the gut microbiota in infants born to MWH. Pathogenic overgrowth within the infant gut microbiota for individuals with HIV may impair immune maturation during early-life, with lasting consequences for host health.Contribution: This highlights the need for further research into probiotic interventions for infants in high HIV-burden settings.
Malaria has posed a momentous health and economic burden to the Sub-Saharan African region. The Sub-Saharan African region accounts for more than 90% of global malaria-related mortality and morbidity. Pregnant women and children under 5 years old are the most vulnerable. Mosquitoes transmit the plasmodium which is the parasite responsible for malaria. The climatic conditions, poverty, and poor healthcare system of the Sub-Saharan African region are some factors fueling this menace. There have been concerted efforts to annihilate malaria but the scuffle has been a tedious one. Malarial eradication campaigns have been focused on mosquito control through the use of insecticide-treated bed nets, use of indoor insecticide sprays, and use of larvicides. The use of artemisinin in combination with other drugs has been effective to some extent. Despite the aforementioned strategies, the pervasiveness of malaria infection in the Sub-Saharan African region is worrisome. Thus, strengthening the already existing control measures, finding novel measures through intensive research, and embracing malaria vaccination could help accelerate the overcoming of this scuffle. In this review, we utilized relevant published data from various databases to reexamine the factors fueling malaria pervasiveness in this region and spelled out point-by-point intervention protocols to end malaria scuffle.
Malaria has been a very strong selection pressure in recent human evolution, particularly in Africa. Of the one million deaths per year due to malaria, more than 90% are in sub-Saharan Africa, a region with high levels of genetic variation and population substructure. However, there have been few studies of nucleotide variation at genetic loci that are relevant to malaria susceptibility across geographically and genetically diverse ethnic groups in Africa. Invasion of erythrocytes by Plasmodium falciparum parasites is central to the pathology of malaria. Glycophorin A (GYPA) and B (GYPB), which determine MN and Ss blood types, are two major receptors that are expressed on erythrocyte surfaces and interact with parasite ligands. We analyzed nucleotide diversity of the glycophorin gene family in 15 African populations with different levels of malaria exposure. High levels of nucleotide diversity and gene conversion were found at these genes. We observed divergent patterns of genetic variation between these duplicated genes and between different extracellular domains of GYPA. Specifically, we identified fixed adaptive changes at exons 3-4 of GYPA. By contrast, we observed an allele frequency spectrum skewed toward a significant excess of intermediate-frequency alleles at GYPA exon 2 in many populations; the degree of spectrum distortion is correlated with malaria exposure, possibly because of the joint effects of gene conversion and balancing selection. We also identified a haplotype causing three amino acid changes in the extracellular domain of glycophorin B. This haplotype might have evolved adaptively in five populations with high exposure to malaria.
Immune-mediated sensory neuronopathies (SNN) can occur alongside autoimmune disorders (e.g., Sjögren syndrome), involve autoantibodies (such as anti-FGFR3 or anti-AGO antibodies), or present in isolation. The underlying mechanisms remain unclear. This study aimed to investigate the role of proinflammatory cytokines in these conditions. Blood levels of IL-1β, IL-6, IL-17, TNF-α, INF α-2, and INF-γ were measured using a Bioplex T200 platform and the Bio-Plex Pro Reagent Kit III in 113 patients with SNN between 2.4 and 464.4 months after symptom onset, categorized based on disease course (acute, subacute, chronic). Eighteen patients had anti-AGO antibodies, 48 had anti-FGFR3 antibodies, and 14 had an autoimmune disease without detectable anti-AGO or FGFR3 antibodies. Disease extent was measured by the SNN score, while the disease severity was evaluated using the modified Rankin score. Immunoreactivity against IL-6 and INF-γ was measured via ELISA. Multicomponent analysis utilizing cytokines levels identified four distinct patient subgroups characterized by differences in age at onset and SNN score. No significant differences were observed among the subgroups regarding disease course and severity, presence of anti-AGO or anti-FGFR3 antibodies, or association with an autoimmune disease. A small subgroup of three younger patients exhibited the highest levels of TNF-α, IL-6, and IL-1β. Another subgroup of seven patients displayed elevated INF α-2 levels and tended towards highest SNN scores. The largest group (95 subjects) comprised older individuals with relatively lower cytokine levels and decreased anti-IL-6 immunoreactivity. These cytokine profiles suggest diverse underlying mechanisms within immune-mediated SNN. Further investigation is warranted to determine whether certain profiles, particularly those involving young patients with elevated proinflammatory cytokines, might benefit from targeted treatments.
Despite numerous studies on arylsulfatase A, the structure of the glycans present in each of its two subunits has not been determined. This is important because the carbohydrate component of human arylsulfatase A synthesized in tumor tissues and transformed cells has been shown to undergo apparent changes. This study elucidates some of their major features. Glycan chain analysis of native and deglycosylated arylsulfatase A as well as its subunits was performed with the use of a Glycan Differentiation Kit and lectin affinity chromatography. Each of the two subunits of arylsulfatase A from placenta, separated electrophoretically on polyacrylamide gel in reducing conditions, reacted with digoxigenin-labelled Galantus nivalis agglutinin and Aleuria aurantia agglutinin, while those from liver enzyme reacted with the former only. The subunits of both enzymes did not react with Sambucus nigra, Maakia amuriensis, Datura stramonium or Peanut agglutinin. Deglycosylation of arylsulfatase A with peptide N-glycosidase F and endo-beta-N-acetylglucosaminidase F resulted in complete cleavage of its carbohydrate component from each subunit. Their molecular weights decreased by 3 kDa. Neuraminidase treatment of the enzyme from liver and placenta followed by isoelectrofocusing separation showed the presence of sialylated forms which constituted a small percentage of total enzyme activity. Placental arylsulfatase A became bound to Lens culinaris agglutinin agarose, while no interaction with Ricinus communis or Griffonia simplicifolia agglutinin agarose was observed. The study shows that both subunits of arylsulfatase A from human placenta possess two high mannose/hybrid type glycans as major structures, with at least one 6-O-L-fucose bound to the innermost N-acetylglucosamine on each.(ABSTRACT TRUNCATED AT 250 WORDS)