6320 research outputs found
Sort by
In Vitro evaluation of viability, integrity and inflammation in genital epithelia upon exposure to pharmaceutical excipients and candidate microbicides
No full textMicrobicides are a promising approach for the prevention of HIV-1 transmission. Unfortunately, various candidates failed in clinical trials. In some cases, the candidate microbicide even resulted in enhanced virus transmission. Therefore, there is an urgent need to develop more predictive preclinical strategies to anticipate the in vivo efficiency/toxicity rate, including in vitro assays that evaluate effects on epithelial integrity and inflammation. The present study aims to identify potential safety issues concerning the use of microbicides and excipients commonly used in vaginal microbicide preparations. The toxicity of various active pharmaceutical ingredients (APIs) (TMC120, UC-781, PMPA, PRO2000 and GML) and excipients (preservatives, cosolvents, surfactants and cyclodextrins) was evaluated using an in vitro dual-chamber model and uterine cervical explants. Epithelial viability and permeability for fluorescent virus-sized beads, as well as induction of interleukin-8 (as a sensitive marker of an inflammatory response) were assessed. Surprisingly, cell viability and epithelial layer integrity were compromised by most excipients at concentrations near the typical concentration used in vaginal gels and a significant increase in the production of IL-8 was observed at sub-toxic concentrations. Within the API, TMC120, UC-781, PMPA showed a higher selectivity index compared to PRO2000 and GML. In conclusion, identification of safety issues concerning the use of pharmaceutical excipients could help to formulate less toxic vaginal microbicide preparation
Current status of vaccination against African trypanosomiasis
No full textAnti-trypanosomiasis vaccination still remains the best theoretical option in the fight against a disease that is continuously hovering between its wildlife reservoir and its reservoir in man and livestock. While antigentic variation of the parasite surface coat has been considered the major obstacle in the development of a functional vaccine, recent research into the biology of B cells has indicated that the problems might go further than that. This paper reviews past and current attempts to design both anti-trypanosome vaccines, as well as vaccines directed towards the inhibition of infection-associated patholog
Discovery and verification of osteopontin and beta-2-microglobulin as promising markers for staging human African trypanosomiasis
No full textHuman African trypanosomiasis (HAT), or sleeping sickness, is a parasitic disease endemic in sub-Saharan Africa, transmitted to humans through the bite of a tsetse fly. The first or haemolymphatic stage of the disease (S1) is associated with presence of parasites in the bloodstream, lymphatic system and body tissues. If patients are left untreated, parasites cross the blood-brain barrier (BBB) and invade the cerebrospinal fluid (CSF) and the brain parenchyma, giving rise to the second or meningoencephalitic stage (S2). Stage determination is a crucial step in guiding the choice of treatment, as drugs used for S2 are potentially dangerous. Current staging methods, based on counting white blood cells (WBC) and demonstrating trypanosomes in CSF, lack specificity and/or sensitivity. In the present study, we used a number of proteomic strategies to discover new markers with potential for staging HAT. CSF samples were collected from patients infected with Trypanosoma brucei gambiense in the Democratic Republic of Congo. The stage was determined following the guidelines of the national control program. The proteome of the samples was analysed by two-dimensional gel electrophoresis (n=9), and by sixplex tandem mass tag (TMT) isobaric labeling (n=6) quantitative mass spectrometry. Overall, 73 proteins were over-expressed in patients presenting the second stage of disease. Two of these, osteopontin and beta-2-microglobulin, were confirmed to be potential markers for staging HAT by Western blot and ELISA. The two proteins significantly discriminated between S1 and S2 patients with high sensitivity (68% and 78%, respectively) for 100% specificity, and a combination of both improved the sensitivity to 91%. The levels of osteopontin and beta-2-microglobulin in CSF of S2 patients (microg/ml range), as well as the fold increased concentration in S2 compared to S1 (3.8 and 5.5 respectively) make the two markers good candidates for the development of a test for staging HAT patient
Prioritizing emerging zoonoses in The Netherlands
No full textBACKGROUND: To support the development of early warning and surveillance systems of emerging zoonoses, we present a general method to prioritize pathogens using a quantitative, stochastic multi-criteria model, parameterized for the Netherlands. METHODOLOGY/PRINCIPAL FINDINGS: A risk score was based on seven criteria, reflecting assessments of the epidemiology and impact of these pathogens on society. Criteria were weighed, based on the preferences of a panel of judges with a background in infectious disease control. CONCLUSIONS/SIGNIFICANCE: Pathogens with the highest risk for the Netherlands included pathogens in the livestock reservoir with a high actual human disease burden (e.g. Campylobacter spp., Toxoplasma gondii, Coxiella burnetii) or a low current but higher historic burden (e.g. Mycobacterium bovis), rare zoonotic pathogens in domestic animals with severe disease manifestations in humans (e.g. BSE prion, Capnocytophaga canimorsus) as well as arthropod-borne and wildlife associated pathogens which may pose a severe risk in future (e.g. Japanese encephalitis virus and West-Nile virus). These agents are key targets for development of early warning and surveillanc
Gezondheidsadviezen voor reizigers 2010-2011 (uitgave bestemd voor het medisch korps); Conseils de santé pour voyageurs 2010-2011 (édition destinée au corps médical) [CDROM
No full textTurning around an ailing district hospital: a realist evaluation of strategic changes at Ho Municipal Hospital (Ghana)
No full textBACKGROUND: There is a growing consensus that linear approaches to improving the performance of health workers and health care organisations may only obtain short-term results. 'High commitment management' is an alternative approach, premised on the principle of bundles of balanced practices. This has been shown to contribute to better organisational performance. This paper illustrates an intervention and outcome of high commitment management (HiCom) at an urban hospital in Ghana. Few studies have shown how HiCom management might contribute to better performance of health services and in particular of hospitals in low and middle-income settings. METHODS: A realist case study design was used to analyse how specific management practices might contribute to improving the performance of an urban district hospital in Ho, Volta Region, in Ghana. Mixed methods were used to collect data, including document review, in-depth interviews, group discussions, observations and a review of routine health information. RESULTS: At Ho Municipal Hospital, the management team dealt with the crisis engulfing the ailing urban district hospital by building an alliance between hospital staff to generate a sense of ownership with a focus around participative problem analysis. The creation of an alliance led to improving staff morale and attitude, and contributed also to improvements in the infrastructure and equipment. This in turn had a positive impact on the revenue generating capacity of the hospital. The quick turn around in the state of this hospital showed that change was indeed possible, a factor that greatly motivated the staff. In a second step, the management team initiated the development of a strategic plan for the hospital to maintain the dynamics of change. This was undertaken through participative methods and sustained earlier staff involvement, empowerment and feelings of reciprocity. We found that these factors acted as the core mechanisms underlying the changes taking place at Ho Municipal Hospital. CONCLUSIONS: This study shows how a hospital management team in Ghana succeeded in resuscitating an ailing hospital. Their high commitment management approach led to the active involvement and empowerment of staff. It also showed how a realist evaluation approach could be used in the research of the management of health care organisations to explain how management interventions may or may not work
Metabolomics to unveil and understand phenotypic diversity between pathogen populations
No full textLeishmaniasis is a debilitating disease caused by the parasite Leishmania. There is extensive clinical polymorphism, including variable responsiveness to treatment. We study Leishmania donovani parasites isolated from visceral leishmaniasis patients in Nepal that responded differently to antimonial treatment due to differing intrinsic drug sensitivity of the parasites. Here, we present a proof-of-principle study in which we applied a metabolomics pipeline specifically developed for L. donovani to characterize the global metabolic differences between antimonial-sensitive and antimonial-resistant L. donovani isolates. Clones of drug-sensitive and drug-resistant parasite isolates from clinical samples were cultured in vitro and harvested for metabolomics analysis. The relative abundance of 340 metabolites was determined by ZIC-HILIC chromatography coupled to LTQ-Orbitrap mass spectrometry. Our measurements cover approximately 20% of the predicted core metabolome of Leishmania and additionally detected a large number of lipids. Drug-sensitive and drug-resistant parasites showed distinct metabolic profiles, and unsupervised clustering and principal component analysis clearly distinguished the two phenotypes. For 100 metabolites, the detected intensity differed more than three-fold between the 2 phenotypes. Many of these were in specific areas of lipid metabolism, suggesting that the membrane composition of the drug-resistant parasites is extensively modified. Untargeted metabolomics has been applied on clinical Leishmania isolates to uncover major metabolic differences between drug-sensitive and drug-resistant isolates. The identified major differences provide novel insights into the mechanisms involved in resistance to antimonial drugs, and facilitate investigations using targeted approaches to unravel the key changes mediating drug resistance