P-glycoprotein (ABCB1) and oxidative stress: Focus on Alzheimer's disease

ATP-binding cassette (ABC) transporters, in particular P-glycoprotein (encoded by ABCB1), are important and selective elements of the blood-brain barrier (BBB), and they actively contribute to brain homeostasis. Changes in ABCB1 expression and/or function at the BBB may not only alter the expression and function of other molecules at the BBB but also affect brain environment. Over the last decade, a number of reports have shown that ABCB1 actively mediates the transport of beta amyloid (A\u3b2) peptide. This finding has opened up an entirely new line of research in the field of Alzheimer's disease (AD). Indeed, despite intense research efforts, AD remains an unsolved pathology and effective therapies are still unavailable. Here, we review the crucial role of ABCB1 in the A\u3b2 transport and how oxidative stress may interfere with this process. A detailed understanding of ABCB1 regulation can provide the basis for improved neuroprotection in AD and also enhanced therapeutic drug delivery to the brain

Sulforaphane causes cell cycle arrest and apoptosis in human glioblastoma u87mg and u373mg cell lines under hypoxic conditions

Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor. The median survival rate from diagnosis ranges from 15 to 17 months because the tumor is resistant to most therapeutic strategies. GBM exhibits microvascular hyperplasia and pronounced necrosis triggered by hypoxia. Sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables, has already demonstrated the ability to inhibit cell proliferation, by provoking cell cycle arrest, and leading to apoptosis in many cell lines. In this study, we investigated the antineoplastic effects of SFN [20–80 µM for 48 h] in GBM cells under normoxic and hypoxic conditions. Cell viability assays, flow cytometry, and Western blot results revealed that SFN could induce apoptosis of GBM cells in a dose-dependent manner, under both conditions. In particular, SFN significantly induced caspase 3/7 activation and DNA fragmentation. Moreover, our results demonstrated that SFN suppressed GBM cells proliferation by arresting the cell cycle at the S-phase, also under hypoxic condition, and that these effects may be due in part to its ability to induce oxidative stress by reducing glutathione levels and to increase the phosphorylation of extracellular signal-regulated kinases (ERKs). Overall, we hypothesized that SFN treatment might serve as a potential therapeutic strategy, alone or in combination, against GBM

Antimicrobial activity of aztreonam in combination with old and new β-lactamase inhibitors against mbl and esbl co-producing gram-negative clinical isolates: Possible options for the treatment of complicated infections

none14noMetallo-β-lactamases (MBLs) are among the most challenging bacterial enzymes to over-come. Aztreonam (ATM) is the only β-lactam not hydrolyzed by MBLs but is often inactivated by co-produced extended-spectrum β-lactamases (ESBL). We assessed the activity of the combination of ATM with old and new β-lactamases inhibitors (BLIs) against MBL and ESBL co-producing Gram-negative clinical isolates. Six Enterobacterales and three non-fermenting bacilli co-producing MBL and ESBL determinants were selected as difficult-to-treat pathogens. ESBLs and MBLs genes were characterized by PCR and sequencing. The activity of ATM in combination with seven different BLIs (clavulanate, sulbactam, tazobactam, vaborbactam, avibactam, relebactam, zidebactam) was assessed by microdilution assay and time–kill curve. ATM plus avibactam was the most effective combination, able to restore ATM susceptibility in four out of nine tested isolates, reaching in some cases a 128-fold reduction of the MIC of ATM. In addition, relebactam and zidebactam showed to be effective, but with lesser reduction of the MIC of ATM. E. meningoseptica and C. indologenes were not inhibited by any ATM–BLI combination. ATM–BLI combinations demonstrated to be promising against MBL and ESBL co-producers, hence providing multiple options for treatment of related infections. However, no effective combination was found for some non-fermentative bacilli, suggesting the presence of additional resistance mechanisms that complicate the choice of an active therapy.openMorroni G.; Bressan R.; Fioriti S.; D'Achille G.; Mingoia M.; Cirioni O.; Di Bella S.; Piazza A.; Comandatore F.; Mauri C.; Migliavacca R.; Luzzaro F.; Principe L.; Lagatolla C.Morroni, G.; Bressan, R.; Fioriti, S.; D'Achille, G.; Mingoia, M.; Cirioni, O.; Di Bella, S.; Piazza, A.; Comandatore, F.; Mauri, C.; Migliavacca, R.; Luzzaro, F.; Principe, L.; Lagatolla, C

Improving health-care quality in resource-poor settings

Improvements in health-care quality can contribute to healthier populations. However, many global and national health strategies are not sufficiently considering the issues of measuring and improving health-care quality in low-resource settings.1 The barriers to delivering high-quality care are often similar across different health systems. However, the extent and mechanisms through which these barriers affect quality improvement interventions may be different in resource-poor settings.2 Investments in health systems strengthening without continuous quality improvement is thought to be a useless effort.3 Conversely, only focusing on quality improvement in a resource-poor context without engaging the broader health system for support is of limited value. Hence, both areas must be improved simultaneously

Gaps in monitoring systems for Implanon NXT services in South Africa: An assessment of 12 facilities in two districts

Background. Implanon NXT, a long-acting subdermal contraceptive implant, was introduced in South Africa (SA) in early 2014 as part of an expanded contraceptive method mix. After initial high levels of uptake, reports emerged of frequent early removals and declines in use. Monitoring of progress and challenges in implant service delivery could identify aspects of the programme that require strengthening.Objectives. To assess data management and record keeping within implant services at primary care facilities.Methods. We developed a checklist to assess the tools used for monitoring implant services and data reporting to district offices. The checklist was piloted in seven facilities. An additional six high-volume and six low-volume implant insertion clinics in the City of Johannesburg (CoJ), Gauteng Province, and the Dr Kenneth Kaunda District, North West Province, were selected for assessment.Results. All 12 facilities completed a Daily Head Count Register, which tallied the number of clients attending the clinic, but not information about implant use. A more detailed Tick Register recorded services that clinic attendees received, with nine documenting number of implant insertions and six implant removals. A more specific tool, an Insertion Checklist, collected data on insertion procedures and client characteristics, but was only used in CoJ (five of six facilities). Other registers, which were developed de novo by staff at individual facilities, captured more detailed information about insertions and removals, including reasons. Five of six low-volume insertion facilities used these registers, but only three of six high-volume facilities. No facilities used the form specifically developed by the National Department of Health for implant pharmacovigilance. Nine of 12 clinics reported data on numbers of insertions to the district office, six reported removals and none provided data on reasons for removals.Conclusion. For data to inform effective decision-making and quality improvement in implant services in SA, standardised reporting guidelines and data collection tools are needed, reinforced by staff training and quality assessment of data collection. Staff often took the initiative to fill gaps in reporting systems. Current systems are unable to accurately monitor uptake or discontinuation, or identify aspects of services requiring strengthening. Lack of pharmacovigilance data is especially concerning. Deficiencies noted in these monitoring systems may be common to family planning services more broadly, which warrants investigation

Uptake and early removals of Implanon NXT in South Africa: Perceptions and attitudes of healthcare workers

Background. The South African (SA) government introduced Implanon NXT, a long-acting subdermal contraceptive implant, in 2014 to expand contraceptive choice. Following an initial high uptake, its use declined considerably amid reports of early removals and frequent side-effects. We examine providers’ perceptions of training and attitudes towards Implanon NXT, as well as their views on the causes of early removals and the impact on the implant service. Objective. To assess healthcare providers’ perceptions and attitudes towards implant services in SA. Methods. In-depth interviews were conducted with eight nurses providing implant services in public facilities in Gauteng and North West Province. Emerging themes were identified, manually coded and thematically analysed following an interpretivism approach. Results. Nurses lacked confidence in providing implant services effectively, particularly removals, which they ascribed to the brief, cascade-type training received. Nurses generally held negative views towards the method. They also reported that side-effects are the most common reason for early removals – particularly irregular bleeding – and that men often do not support their partners who use the method. Lastly, it was found that providers require guidance on counselling regarding the method and standardised guidelines on the management of side-effects. Conclusion. Retraining and support of providers are needed to address competency gaps and negative attitudes towards the method. Assessment of providers’ readiness to perform removal procedures is also important. Finally, effective plans are necessary to improve implant continuation rates, especially among women whose partners are unsupportive

Uptake and early removals of Implanon NXT in South Africa: Perceptions and attitudes of healthcare workers

Background. The South African (SA) government introduced Implanon NXT, a long-acting subdermal contraceptive implant, in 2014 to expand contraceptive choice. Following an initial high uptake, its use declined considerably amid reports of early removals and frequent side-effects. We examine providers’ perceptions of training and attitudes towards Implanon NXT, as well as their views on the causes of early removals and the impact on the implant service.Objective. To assess healthcare providers’ perceptions and attitudes towards implant services in SA.Methods. In-depth interviews were conducted with eight nurses providing implant services in public facilities in Gauteng and North West Province. Emerging themes were identified, manually coded and thematically analysed following an interpretivism approach.Results. Nurses lacked confidence in providing implant services effectively, particularly removals, which they ascribed to the brief, cascade-type training received. Nurses generally held negative views towards the method. They also reported that side-effects are the most common reason for early removals – particularly irregular bleeding – and that men often do not support their partners who use the method. Lastly, it was found that providers require guidance on counselling regarding the method and standardised guidelines on the management of side-effects.Conclusion. Retraining and support of providers are needed to address competency gaps and negative attitudes towards the method. Assessment of providers’ readiness to perform removal procedures is also important. Finally, effective plans are necessary to improve implant continuation rates, especially among women whose partners are unsupportive

User perspectives on Implanon NXT in South Africa: A survey of 12 public-sector facilities

Background. Implanon NXT, a long-acting reversible contraceptive, was introduced in South Africa (SA) in early 2014, aiming to expand the method mix and increase its effectiveness. Initial uptake was high, but has since declined considerably. In these early years after the implant’s introduction, it is important to identify reasons for the decline, and remedy gaps in services.Objectives. To determine periods of use, reasons for the use and early removal of the implant Implanon NXT.Methods. In 2016, we recruited 152 women from six clinics in the City of Johannesburg, and six in North West Province, SA. A semistructured interview was administered to 91 women currently using the implant and 61 previous users. We examined user perspectives, factors influencing women’s experiences with the implant and reasons for discontinuation.Results. The participants’ mean age was 30 years, with only 15% aged <25. Implant uptake was motivated by convenience (less frequent visits required than for short-acting methods) and by favourable views of the method among friends, family and healthcare providers. Only about a quarter of women recalled being counselled pre-insertion about implant effectiveness, and half about side-effects pre-insertion. Among discontinuers, the median time to device removal was 8 months (interquartile range 6 - 12), and this was primarily as a result of side-effects (90%), especially bleeding-pattern changes and headaches. Removals were most common among married and cohabiting women, often ascribed to the effects of bleeding on their sexual relationships. Rumours and misinformation contributed to some removals. Overall, women’s experiences with the implant were rated ‘good’ or ‘very good’ by 74% of those continuing use, many of whom reported not having experienced any side-effects or that these had diminished over time.Conclusion. Levels of acceptability among continuing users were high, mainly linked to the method’s convenience. While early favourable views drove uptake, negative perceptions, if unaddressed, may now undermine services. Deficiencies in counselling around effectiveness and side-effects may extend to contraceptive services more generally. Women require more intensive support when experiencing sideeffects, including effective systematic approaches to ameliorating bleeding and headaches. Implant services could specifically target young women and first-time contraceptive users. These actions together could reverse the persistent decline in implant use in SA

Lessons learnt from the introduction of the contraceptive implant in South Africa

In 2014, South Africa (SA) introduced the subdermal contraceptive implant with the aim of expanding the contraceptive method mix and availability of long-acting reversible methods in the public sector. Three years on, concerns have been raised about the decline in uptake, early implant removals and challenges in service delivery. This article explores the lessons learnt from the introduction of contraceptive technologies elsewhere and applies these to the SA context. Drawing on the World Health Organization’s conceptual framework for the introduction of new contraceptive methods, and subsequent literature on the topic, lessons are classified into six cross-cutting themes. Recommendations highlight the need for SA to review and explore strategies to strengthen current implant services, including the provision of improved provider training aimed at sensitive, client-centred approaches; increased community engagement; and improved systems for programmatic monitoring and evaluation. With implementation of these recommendations, worrying trends in the provision of implants could be reversed