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Yalka Dayanand,1 Reveshni Pather,1 Nombuso Xulu,1 Irvin Booysen,2 Ntethelelo Sibiya,3 Andile Khathi,1 Phikelelani Ngubane1 1School of Laboratory Medicine and Medical Science, University of Kwazulu-Natal, Durban, South Africa; 2School of Chemistry and Physics, University of Kwazulu-Natal, Pietermaritzburg, South Africa; 3Pharmacology Division, Faculty of Pharmacy, Rhodes University, Grahamstown, South AfricaCorrespondence: Reveshni Pather, Department of Human Physiology School of Laboratory Medicine and Medical Sciences College of Health Sciences, University of KwaZulu-Natal, E-Block, Level 4, University Road, Chiltern Hills, Westville Campus, Private Bag X54001, Westville, Durban, 4000, South Africa, Tel +27826570642, Email reveshnipather1@gmail.comAbstract: The prevalence of diabetes mellitus and diabetes-related complications is rapidly increasing worldwide, placing a substantial financial burden on healthcare systems. Approximately 537 million adults are currently diagnosed with type 1 or type 2 diabetes globally. However, interestingly, the increasing morbidity rate is primarily influenced by the effects of long-term hyperglycemia on vital organs such as the brain, the liver and the heart rather than the ability of the body to use glucose effectively. This can be attributed to the summation of the detrimental effects of excessive glucose on major vascular systems and the harmful side effects attributed to the current treatment associated with managing the disease. These drugs have been implicated in the onset and progression of cardiovascular disease, hepatocyte injury and cognitive dysfunction, thereby warranting extensive research into alternative treatment strategies. Literature has shown significant progress in utilizing metal-based compounds, specifically those containing transition metals such as zinc, magnesium and vanadium, in managing hyperglycaemia. Amongst these metals, research carried out on vanadium reflected the most promising anti-diabetic efficacy in cell culture and animal studies. This was attributed to the ability to improve glucose management in the bloodstream by enhancing its uptake and metabolism in the kidney, brain, skeletal muscle, heart and liver. Despite this, organic vanadium was considered toxic due to its accumulative characteristics. To alleviate vanadium’s toxic nature while subsequently manipulating its therapeutic properties, vanadium complexes were synthesized using either vanadate or vanadyl as a base compound. This review attempts to evaluate organic vanadium salts’ therapeutic and toxic effects, highlight vanadium complexes’ research and provide insight into the novel dioxidovanadium complex synthesized in our laboratory to alleviate hyperglycaemia-associated macrovascular complications in the brain, heart and liver.Keywords: diabetes mellitus, hyperglycaemia, dioxidovanadium, toxicity

Nombuso Xulu,1 Phikelelani Ngubane,1 Andile Khathi,1 Irvin Booysen,2 Ntethelelo Sibiya3 1School of Laboratory Medicine and Medical Sciences, University of KwaZulu Natal, Durban, South Africa; 2School of Chemistry and Physics, College of Agriculture, Engineering and Sciences, University of KwaZulu-Natal, Pietermaritzburg, South Africa; 3Pharmacology Division, Faculty of Pharmacy, Rhodes University, Grahamstown, South AfricaCorrespondence: Phikelelani NgubaneDepartment of Human Physiology University of KwaZulu Natal, E-Block, Level 4, University Road, Chiltern Hills, Westville Campus, 3629 Private Bag X54001, Westville, Durban, 4000, South AfricaEmail ngubanep1@ukzn.ac.zaBackground: Despite the effective maintenance of glucose homeostasis by insulin in type 1 diabetes mellitus, the drug has been implicated as one of the causes of haematological disturbances, which give rise to cardiovascular complications. As a result, research into alternative therapies for diabetes is needed. In our laboratory, an anti-hyperglycaemic novel vanadium complex has been synthesized using organic heterocyclic ligands. The complex has been shown and improve glycaemic control. The effects of this complex on haematological function, however, have not yet been established. Therefore, this study sought to investigate the haematological effects of dioxidovanadium(V) complex in (STZ)-induced diabetic rats.Methods: Diabetic rats received vanadium complex (40 mg kg − 1 p.o), diabetic untreated (H2O) and insulin treated (0.175 mg kg− 1 s.c), groups acted as a negative and positive control, respectively. Vanadium complex was administered twice daily, and blood glucose concentration was monitored weekly for 5 weeks. Thereafter, the animals were sacrificed followed by blood and kidneys collection for haematological (full blood count and Annexin V), hormonal (EPO) and oxidative status (SOD and GPx) analysis.Results: After 5 weeks, untreated diabetic rats presented with hyperglycaemia compared to non-diabetic rats which was attenuated by vanadium complex administration. Furthermore, vanadium treated groups presented with an augmented RBC count, haematocrit, haemoglobin concentration, MCHC, MCV, and (EPO) levels compared to diabetic control. An increase in annexin V expression hence cell survival was observed in vanadium complex treated rats. Lastly, the administration of the complex improved antioxidant status as evidenced by increases in SOD and GPx concentration in plasma and in the kidneys.Conclusion: The administration of the anti-hyperglycaemic dioxidovanadium(V) complex improved haematological parameters, cell survival and the antioxidant status displayed by the diabetic rats. These results give an indication that the complex might be an effective alternative therapeutic drug for the treatment of hyperglycaemia in DM.Keywords: hyperglycaemia, vanadium complex, haematological, cardiovascular

Background: Injectable progestin-only contraceptives (IPCs), including Depo-Provera (DMPA), have been associated with HIV acquisition risk in some epidemiological studies and in animal models. This risk has not been consistently observed and the risk of IPCs must be weighed against the known benefits of effective contraception. Regardless, understanding how IPCs shape the mucosal environment of the female genital tract can help elucidate biological mechanisms underlying their potential impact on HIV acquisition risk and may lead to new HIV prevention strategies. Methods: Cervical cytobrushes were collected from HIV-uninfected women aged 18 to 23 years through the FRESH (Females Rising through Education, Support, and Health) study in Umlazi, South Africa, and cervical epithelial and CD4+ T cells were FACS-sorted. RNAseq was performed on the sorted cells and data was analyzed using STAR, HTSeq, DESeq2, and GSEA. Results: Cervical epithelial cells were compared between women who reported using DMPA (n = 6) and women in the follicular phase of the menstrual cycle by reported last menstrual period (n = 6). tSNE clustering showed clear segregation between groups, and 369 genes were significantly differentially expressed. Of these genes, two of the most highly expressed in DMPA users were CCL3 and CCL3L3, mediators of T cell homing. GSEA analysis demonstrated that the epithelial gene sets most significantly over-expressed in DMPA-using women were keratinization, cellular response to IFNg, and keratinocyte differentiation (FDR q < 0.05). Parallel analysis of cervical CD4+ T cells identified 5 significantly differentially expressed genes (fold change >90) and a significantly enriched gene set in DMPA users, 'positive regulation of T cell mediated immunity' (FDR q-val 0.087). Conclusions: In DMPA users, cervical epithelial cells express higher levels of the T cell homing cytokines CCL3 and CCL3L3, while cervical CD4+ T cells exhibit inflammatory gene set enrichment. At the same time, keratinization pathways may be altered in DMPA users, as suggested in previous literature. Together, these results suggest possible mechanisms by which progestins may contribute to genital inflammation and/or differential barrier function in the genital mucosa. These findings may point towards potential biological approaches to reduce HIV acquisition risk in women., OA19.03 E.H. Byrne (1); M. Farcasanu (2); S. Bloom (3); N. Xulu (4); J. Xu (2); S. Handley (5); J. Bramante (2); C. Mitchell (6); A.-C. Villani (7) and D.S. [...]

Background: Milk is one of the most nutritious foods providing a variety of proteins, fats, minerals, and vitamins needed to maintain, grow, and develop the body. The aim of this study was to assess microbial and chemical adulterants of raw cow milk collected from dairy farms of Hlabisa villages, KwaZulu-Natal Province, South Africa. Methods: A total of 68 raw cow milk samples were obtained from teats sampling points, milking buckets, and communal pooling buckets. The bacteriological analysis was conducted for the detection of various bacteria in milk samples. Biochemical tests were also done to detect some chemical adulterants in milk samples. Results: Total bacterial count of teats, milking buckets, and communal milk pooling buckets were 6.91, 6.06, and 6.06 log Colony Forming Unit (CFU)/ml, respectively. The most found chemical adulterant was urea detected in 23 out of 68 (33.8%) samples, followed by hydrogen peroxide showed in 22 out of 68 (32.3%) samples. However, none of the samples were contaminated with formalin, starch, and neutralizer. Conclusion: The present study revealed high microbial contamination of raw cow milk produced by rural small-scale dairy farmers of Hlabisa villages, KwaZulu-Natal Province, South Africa, indicating the lack of standard operating sanitation. It was also stated that raw milk samples contained various types of chemical adulterants that may lead to severe health problems. Good hygiene practices must be adopted by small-scale dairy farmers at every stage of their milk handling and processing. [ABSTRACT FROM AUTHOR]

Bacterial vaginosis (BV), a common syndrome characterized by Lactobacillus-deficient vaginal microbiota, is associated with adverse health outcomes. BV often recurs after standard antibiotic therapy in part because antibiotics promote microbiota dominance by Lactobacillus iners instead of Lactobacillus crispatus, which has more beneficial health associations. Strategies to promote L. crispatus and inhibit L. iners are thus needed. We show that oleic acid (OA) and similar long-chain fatty acids simultaneously inhibit L. iners and enhance L. crispatus growth. These phenotypes require OA-inducible genes conserved in L. crispatus and related lactobacilli, including an oleate hydratase (ohyA) and putative fatty acid efflux pump (farE). FarE mediates OA resistance, while OhyA is robustly active in the vaginal microbiota and enhances bacterial fitness by biochemically sequestering OA in a derivative form only ohyA-harboring organisms can exploit. OA promotes L. crispatus dominance more effectively than antibiotics in an in vitro BV model, suggesting a metabolite-based treatment approach., Competing Interests: Declaration of interests M.Z., S.M.B., P.C.B., and D.S.K. are co-inventors on a patent related to this work. P.C.B. serves as a consultant and equity holder of companies in the microfluidics and life sciences industries, including 10x Genomics, GALT/Isolation Bio, Celsius Therapeutics, Next Gen Diagnostics, Cache DNA, Concerto Biosciences, Amber Bio, Stately, Ramona Optics, and Bifrost Biosystems. D.S.K. serves as an equity holder of Day Zero Diagnostics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Despite antiretroviral therapy (ART), human immunodeficiency virus (HIV)-associated neurocognitive impairment persists. We investigated the association between serum levels of mature brain-derived neurotrophic factor (mBDNF), precursor brain-derived neurotrophic factor (proBDNF), and neurocognitive changes over time among adults with HIV in sub-Saharan Africa, seeking to elucidate the interplay between neurotrophic factors and neurocognitive outcomes post-ART., Methods: Utilizing data from the ACTG 5199 study in Johannesburg and Harare, serum mBDNF and proBDNF levels were measured via enzyme-linked immunosorbent assay. Neurocognitive performance was assessed at baseline and 24, 48, and 96 weeks using neuropsychological tests. The Friedman test and linear mixed-effects models were used to assess changes in mBDNF, proBDNF, and neurocognitive performance over time, accounting for individual variability and adjusting for multiple comparisons., Results: Among 155 participants, there were significant cognitive improvements ( P < .001) and a rise in mBDNF levels from baseline to 96 weeks. The proBDNF levels initially remained stable ( P = .57) but notably increased by 48 weeks ( P = .04). Higher mBDNF levels were positively associated with enhanced neurocognitive performance at 48 weeks (β = .16, P = .01) and 96 weeks (β = .32, P < .001). Similarly, higher proBDNF levels were positively associated with neurocognitive performance at 96 weeks (β = .25, P < .001)., Conclusions: This study highlights the significant association between serum BDNF levels and neurocognitive improvement post-ART in adults with HIV. However, more research is needed to replicate these findings, establish causal relationships, and explore whether BDNF-enhancing activities can improve neurocognitive outcomes in people with HIV., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Vaginal microbiota composition affects many facets of reproductive health. Lactobacillus iners-dominated microbial communities are associated with poorer outcomes, including higher risk of bacterial vaginosis (BV), compared with vaginal microbiota rich in L. crispatus. Unfortunately, standard-of-care metronidazole therapy for BV typically results in dominance of L. iners, probably contributing to post-treatment relapse. Here we generate an L. iners isolate collection comprising 34 previously unreported isolates from 14 South African women with and without BV and 4 previously unreported isolates from 3 US women. We also report an associated genome catalogue comprising 1,218 vaginal Lactobacillus isolate genomes and metagenome-assembled genomes from >300 women across 4 continents. We show that, unlike L. crispatus, L. iners growth is dependent on L-cysteine in vitro and we trace this phenotype to the absence of canonical cysteine biosynthesis pathways and a restricted repertoire of cysteine-related transport mechanisms. We further show that cysteine concentrations in cervicovaginal lavage samples correlate with Lactobacillus abundance in vivo and that cystine uptake inhibitors selectively inhibit L. iners growth in vitro. Combining an inhibitor with metronidazole promotes L. crispatus dominance of defined BV-like communities in vitro by suppressing L. iners growth. Our findings enable a better understanding of L. iners biology and suggest candidate treatments to modulate the vaginal microbiota to improve reproductive health for women globally., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The microbiome of the female genital tract (FGT) is closely linked to reproductive health outcomes. Diverse, anaerobe-dominated communities with low Lactobacillus abundance are associated with a number of adverse reproductive outcomes, such as preterm birth, cervical dysplasia, and sexually transmitted infections (STIs), including HIV. Vaginal dysbiosis is associated with local mucosal inflammation, which likely serves as a biological mediator of poor reproductive outcomes. Yet the precise mechanisms of this FGT inflammation remain unclear. Studies in humans have been complicated by confounding demographic, behavioral, and clinical variables. Specifically, hormonal contraception is associated both with changes in the vaginal microbiome and with mucosal inflammation. In this study, we examined the transcriptional landscape of cervical cell populations in a cohort of South African women with differing vaginal microbial community types. We also investigate effects of reproductive hormones on the transcriptional profiles of cervical cells, focusing on the contraceptive depot medroxyprogesterone acetate (DMPA), the most common form of contraception in sub-Saharan Africa. We found that antigen presenting cells (APCs) are key mediators of microbiome associated FGT inflammation. We also found that DMPA is associated with significant transcriptional changes across multiple cell lineages, with some shared and some distinct pathways compared to the inflammatory signature seen with dysbiosis. These results highlight the importance of an integrated, systems-level approach to understanding host-microbe interactions, with an appreciation for important variables, such as reproductive hormones, in the complex system of the FGT mucosa., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Byrne, Farcasanu, Bloom, Xulu, Xu, Hykes, Mafunda, Hayward, Dong, Dong, Gumbi, Ceasar, Ismail, Ndung’u, Gosmann, Ghebremichael, Handley, Mitchell, Villani and Kwon.)

Background: Cervicovaginal bacterial communities composed of diverse anaerobes with low Lactobacillus abundance are associated with poor reproductive outcomes such as preterm birth, infertility, cervicitis, and risk of sexually transmitted infections (STIs), including human immunodeficiency virus (HIV). Women in sub-Saharan Africa have a higher prevalence of these high-risk bacterial communities when compared to Western populations. However, the transition of cervicovaginal communities between high- and low-risk community states over time is not well described in African populations., Results: We profiled the bacterial composition of 316 cervicovaginal swabs collected at 3-month intervals from 88 healthy young Black South African women with a median follow-up of 9 months per participant and developed a Markov-based model of transition dynamics that accurately predicted bacterial composition within a broader cross-sectional cohort. We found that Lactobacillus iners-dominant, but not Lactobacillus crispatus-dominant, communities have a high probability of transitioning to high-risk states. Simulating clinical interventions by manipulating the underlying transition probabilities, our model predicts that the population prevalence of low-risk microbial communities could most effectively be increased by manipulating the movement between L. iners- and L. crispatus-dominant communities., Conclusions: The Markov model we present here indicates that L. iners-dominant communities have a high probability of transitioning to higher-risk states. We additionally identify transitions to target to increase the prevalence of L. crispatus-dominant communities. These findings may help guide future intervention strategies targeted at reducing bacteria-associated adverse reproductive outcomes among women living in sub-Saharan Africa. Video Abstract., (© 2021. The Author(s).)