The overall aim of this dissertation was to study the contribution of a syndemics framework to understanding and addressing persistent health disparities. Departing from an interdisciplinary... Show moreThe overall aim of this dissertation was to study the contribution of a syndemics framework to understanding and addressing persistent health disparities. Departing from an interdisciplinary approach, the dissertation attends to research questions on syndemics indicators, contextual drivers for syndemics, the intergenerational nature of syndemics, and possibilities for early public health interventions in Katwijk, a former fishing town in the Netherlands. An epidemiological study described the three most prevalent disease clusters in Katwijk. A qualitative life course study found a first indication that syndemic vulnerability is potentially intergenerational, and that syndemic processes can be countered. A mixed method study showed that while challenging, a family-engagement approach can elicit positive effects on families’ health and wellbeing. The ethnographic study described the hurdles for implementing family-focused health promotion for multifaceted health conditions, such as childhood obesity. This dissertation establishes that the syndemics framework provides tools to identify past and present factors on the complex pathways to persistent poor health, which in turn point at directions for breaking patterns of generational health. The findings highlight a need for multisystem approaches in which stakeholders develop a thorough understanding of a community’s history and past legacies with institutions, and professionals are equipped with the necessary knowledge, attitudes and skills for community-based and family-focused interventions. Show less
Clostridioides difficile infection (CDI) remains a significant healthcare burden. Non-toxigenic C. difficile (NTCD) strains have shown a benefit in preventing porcine enteritis and in human... Show moreClostridioides difficile infection (CDI) remains a significant healthcare burden. Non-toxigenic C. difficile (NTCD) strains have shown a benefit in preventing porcine enteritis and in human recurrent CDI. In this study, we evaluated the efficacy of metronidazole-resistant NTCD-E4 in preventing CDI facilitated by a range of antimicrobials in an in vitro human gut model. NTCD-E4 spores (at a dose of 10(7)) were instilled 7 days before a clinical ribotype (RT) 027 (at the same dose) strain (210). In separate experiments, four different antimicrobials were used to perturb gut microbiotas; bacterial populations and cytotoxin production were determined using viable counting and Vero cell cytotoxicity, respectively. RT027 and NTCD-E4 proliferated in the in vitro model when inoculated singly, with RT027 demonstrating high-level cytotoxin (3-5-log(10)-relative units) production. In experiments where the gut model was pre-inoculated with NTCD-E4, RT027 was remained quiescent and failed to produce cytotoxins. NTCD-E4 showed mutations in hsmA and a gene homologous to CD196-1331, previously linked to medium-dependent metronidazole resistance, but lacked other metronidazole resistance determinants. This study showed that RT027 was unable to elicit simulated infection in the presence of NTCD-E4 following stimulation by four different antimicrobials. These data complement animal and clinical studies in suggesting NTCD offer prophylactic potential in the management of human CDI. Show less
Clostridioides difficile infection (CDI) remains a significant healthcare burden. Non-toxigenicC. difficile (NTCD) strains have shown a benefit in preventing porcine enteritis and in human... Show moreClostridioides difficile infection (CDI) remains a significant healthcare burden. Non-toxigenicC. difficile (NTCD) strains have shown a benefit in preventing porcine enteritis and in human recurrentCDI. In this study, we evaluated the efficacy of metronidazole-resistant NTCD-E4 in preventingCDI facilitated by a range of antimicrobials in an in vitro human gut model. NTCD-E4 spores (ata dose of 107) were instilled 7 days before a clinical ribotype (RT) 027 (at the same dose) strain(210). In separate experiments, four different antimicrobials were used to perturb gut microbiotas;bacterial populations and cytotoxin production were determined using viable counting and Vero cellcytotoxicity, respectively. RT027 and NTCD-E4 proliferated in the in vitro model when inoculatedsingly, with RT027 demonstrating high-level cytotoxin (3-5-log10-relative units) production. Inexperiments where the gut model was pre-inoculated with NTCD-E4, RT027 was remained quiescentand failed to produce cytotoxins. NTCD-E4 showed mutations in hsmA and a gene homologous toCD196-1331, previously linked to medium-dependent metronidazole resistance, but lacked othermetronidazole resistance determinants. This study showed that RT027 was unable to elicit simulatedinfection in the presence of NTCD-E4 following stimulation by four different antimicrobials. Thesedata complement animal and clinical studies in suggesting NTCD offer prophylactic potential in themanagement of human CDI. Show less
Clostridioides difficile infection (CDI) remains a significant healthcare burden. Non-toxigenic C. difficile (NTCD) strains have shown a benefit in preventing porcine enteritis and in human... Show moreClostridioides difficile infection (CDI) remains a significant healthcare burden. Non-toxigenic C. difficile (NTCD) strains have shown a benefit in preventing porcine enteritis and in human recurrent CDI. In this study, we evaluated the efficacy of metronidazole-resistant NTCD-E4 in preventing CDI facilitated by a range of antimicrobials in an in vitro human gut model. NTCD-E4 spores (at a dose of 107) were instilled 7 days before a clinical ribotype (RT) 027 (at the same dose) strain (210). In separate experiments, four different antimicrobials were used to perturb gut microbiotas; bacterial populations and cytotoxin production were determined using viable counting and Vero cell cytotoxicity, respectively. RT027 and NTCD-E4 proliferated in the in vitro model when inoculated singly, with RT027 demonstrating high-level cytotoxin (3-5-log10-relative units) production. In experiments where the gut model was pre-inoculated with NTCD-E4, RT027 was remained quiescent and failed to produce cytotoxins. NTCD-E4 showed mutations in hsmA and a gene homologous to CD196-1331, previously linked to medium-dependent metronidazole resistance, but lacked other metronidazole resistance determinants. This study showed that RT027 was unable to elicit simulated infection in the presence of NTCD-E4 following stimulation by four different antimicrobials. These data complement animal and clinical studies in suggesting NTCD offer prophylactic potential in the management of human CDI. Show less
From the Palestinian struggle against Israeli Apartheid, to First Nations' mass campaigns against pipeline construction in North America, Indigenous peoples are at the forefront of some of the... Show moreFrom the Palestinian struggle against Israeli Apartheid, to First Nations' mass campaigns against pipeline construction in North America, Indigenous peoples are at the forefront of some of the crucial struggles of our age. Rich with their unique histories, characteristics, and social relations, they are connected by the shared enemy they face: settler colonialism.In this introduction, Sai Englert highlights the ways in which it has, and continues to shape our global economic and political order. From the rapacious accumulation of resources, land, and labour, through Indigenous dispossession and genocide, to the development of racism as a form of social control, settler colonialism is deeply connected to many of the social ills we continue to face today.To understand settler colonialism as an ongoing process, is therefore also to start engaging with contemporary social movements and solidarity campaigns differently. It is to start seeing how distinct struggles for justice and liberation are intertwined. Show less
Chikungunya virus (CHIKV) nonstructural protein 1 (nsP1) harbors the methyltransferase (MTase) and guanylyltransferase (GTase) activities needed for viral RNA capping and represents a promising... Show moreChikungunya virus (CHIKV) nonstructural protein 1 (nsP1) harbors the methyltransferase (MTase) and guanylyltransferase (GTase) activities needed for viral RNA capping and represents a promising antiviral drug target. We compared the antiviral efficacies of nsP1 inhibitors belonging to the MADTP, CHVB, and FHNA series (6'-fluoro-homoneplanocin A [FHNA], its 3'-keto form, and 6'-beta-fluoro-homoaristeromycin). Cell-based phenotypic cross-resistance assays revealed that the CHVB and MADTP series had similar modes of action that differed from that of the FHNA series. In biochemical assays with purified Semliki Forest virus and CHIKV nsP1, CHVB compounds strongly inhibited MTase and GTase activities, while MADTP-372 had a moderate inhibitory effect. FHNA did not directly inhibit the enzymatic activity of CHIKV nsP1. The first-of-their-kind molecular-docking studies with the cryo-electron microscopy (cryo-EM) structure of CHIKV nsP1, which is assembled into a dodecameric ring, revealed that the MADTP and CHVB series bind at the S-adenosylmethionine (SAM)-binding site in the capping domain, where they would function as competitive or noncompetitive inhibitors. The FHNA series was predicted to bind at the secondary binding pocket in the ring-aperture membrane-binding and oligomerization (RAMBO) domain, potentially interfering with the membrane binding and oligomerization of nsP1. Our cell-based and enzymatic assays, in combination with molecular docking and mapping of compound resistance mutations to the nsP1 structure, allowed us to group nsP1 inhibitors into functionally distinct classes. This study identified druggable pockets in the nsP1 dodecameric structure and provides a basis for the rational design, optimization, and combination of inhibitors of this unique and promising antiviral drug target. Show less
Simple SummaryThe insulin-like growth factor-1 receptor (IGF1R) is a receptor commonly overexpressed and overactivated in a variety of cancers, including Ewing sarcoma, and promotes cell growth and... Show moreSimple SummaryThe insulin-like growth factor-1 receptor (IGF1R) is a receptor commonly overexpressed and overactivated in a variety of cancers, including Ewing sarcoma, and promotes cell growth and survival. After promising results with targeting and inhibiting the receptor in vitro, multiple different IGF1R targeting compounds have been clinically tried but showed limited efficacy. Here we discuss several possible resistance mechanisms which could explain why IGF1R targeting fails in the clinic and discuss possible ways to overcome these resistances.Insulin-like growth factor-1 receptor (IGF1R) inhibitors are effective in preclinical studies, but so far, no convincing benefit in clinical studies has been observed, except in some rare cases of sustained response in Ewing sarcoma patients. The mechanism of resistance is unknown, but several hypotheses are proposed. In this review, multiple possible mechanisms of resistance to IGF-targeted therapies are discussed, including activated insulin signaling, pituitary-driven feedback loops through growth hormone (GH) secretion and autocrine loops. Additionally, the outcomes of clinical trials of IGF1-targeted therapies are discussed, as well as strategies to overcome the possible resistance mechanisms. In conclusion, lowering the plasma insulin levels or blocking its activity could provide an additional target in cancer therapy in combination with IGF1 inhibition. Furthermore, because Ewing sarcoma cells predominantly express the insulin receptor A (IRA) and healthy tissue insulin receptor B (IRB), it may be possible to synthesize a specific IRA inhibitor. Show less
This book explores the relationship between plantation labour and gender in Africa, particularly Cameroon. It demonstrates that the introduction of plantation labour during colonial rule has had... Show moreThis book explores the relationship between plantation labour and gender in Africa, particularly Cameroon. It demonstrates that the introduction of plantation labour during colonial rule has had significant consequences for gender roles and relations within and beyond the capitalist labour process. These effects have been quite ambivalent, being marked by both profound changes and remarkable continuities. The book focuses on two tea estates established in anglophone Cameroon in the 1950s, the Tole Estate and the Ndu Estate, the first employing mainly female pluckers, the second mainly male pluckers. This allows for an examination of the variations in male and female workers' modes of resistance to the control and exploitation they meet in the labour process. [ASC Leiden abstract] Show less
The colonial conquest of Namibia was extremely brutal. Repressive controls continued in the decades that followed as exemplified by the South African colonial administration's regulation of the... Show moreThe colonial conquest of Namibia was extremely brutal. Repressive controls continued in the decades that followed as exemplified by the South African colonial administration's regulation of the production and consumption of alcohol by the territory's black African inhabitants. Nonetheless, the colonial State's policies were inconsistent and vigorously opposed at every turn by differing sections of the black population. In this chapter, the unlikely alliance of two of the territory's Herero urban groups, the 'Otruppe', illiterate Herero men, and the female 'khari' beer brewers, is examined. During the 1920s and 1930s, they faced the colonial State's attempts to undercut and ultimately eradicate the illicit production of alcohol through the establishment of a Location Advisory Board. In so doing, they were pitted against the colonial State and a newly emerging Herero political elite. The 'angry young men' of the 'Otruppe' and the Herero women brewers proved to be an invincible alliance that managed to evade colonial regulations on alcohol. Bibliogr., notes, ref. [ASC Leiden abstract] Show less
