Water and sanitation services are critical for public health. The importance of these services is reflected in SDG 6 and the associated targets 6.1, 6.2 and 6.3. Much progress remains to be made to ...achieve these targets, but it is already becoming clear that greater ambition is needed. This paper looks at three global challenges: the need to increase the level of service to protect public health including infectious respiratory diseases; the role of sanitation in combatting anti-microbial resistance (AMR); and the urgent need to build more climate-resilient services. We need to upgrade the SDG targets to focus on universal access to piped water on premises, to incorporate action on AMR in definitions of safe sanitation and to embed actions to improve resilience, which take into account the greater ambition called for in the SDG 6 targets. This requires a shift in thinking in the sector, away from relying on households and communities to manage their services to properly funded, professional services staffed by trained technical, managerial and finance staff. This will require more public finance and better use of financial instruments that have proved effective in other sectors. Increasing our ambition will mean the world can achieve the aim of universal access to safe, sustainable, and resilient services and protect public health. HIGHLIGHTS Protecting public health requires higher levels of water and sanitation service.; Tackling anti-microbial resistance should become a key element of safe sanitation.; Climate change poses challenges for water and sanitation, investing in resilience is critical.; Greater professionalisation is needed to provide safe, sustainable and resilient services.; More and better use of public finance is needed for services.;
Climate change represents the most significant challenge of the twenty-first century and poses risks to water and sanitation services. Concerns for water supply include damage to infrastructure from ...flooding, loss of water sources due to declining rainfall and increasing demand, and changes in the water quality of water sources and within distribution of water. Sanitation concerns include damage and loss of services from floods and reduced carrying capacity of waters receiving wastewater. Key actions to reduce climate risks include the integration of measures of climate resilience into water safety plans, as well as improved accounting and management of water resources. Policy prescriptions on technologies for service delivery and changes in management models offer potential to reduce risks, particularly in low-income settings. Water and sanitation services contribute to greenhouse gas emissions. Choice of wastewater treatment technologies, improved pumping efficiency, use of renewable sources of energy, and within-system generation of energy offer potential for reducing emissions. Overall, greater attention and research are required to understand, plan for, and adapt to climate change in water and sanitation services. As with many other climate change adaptations, the likely benefits from no-regrets solutions are likely to outweigh the costs of investment.
Consequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. Obesity is a risk factor for many cancers, but the mechanisms by which it contributes to cancer ...development and patient outcome have yet to be fully elucidated. Here, we examined the effects of coculturing human-derived adipocytes with established and primary breast cancer cells on tumorigenic potential. We found that the interaction between adipocytes and cancer cells increased the secretion of proinflammatory cytokines. Prolonged culture of cancer cells with adipocytes or cytokines increased the proportion of mammosphere-forming cells and of cells expressing stem-like markers in vitro. Furthermore, contact with immature adipocytes increased the abundance of cancer cells with tumor-forming and metastatic potential in vivo. Mechanistic investigations demonstrated that cancer cells cultured with immature adipocytes or cytokines activated Src, thus promoting Sox2, c-Myc, and Nanog upregulation. Moreover, Sox2-dependent induction of miR-302b further stimulated cMYC and SOX2 expression and potentiated the cytokine-induced cancer stem cell-like properties. Finally, we found that Src inhibitors decreased cytokine production after coculture, indicating that Src is not only activated by adipocyte or cytokine exposures, but is also required to sustain cytokine induction. These data support a model in which cancer cell invasion into local fat would establish feed-forward loops to activate Src, maintain proinflammatory cytokine production, and increase tumor-initiating cell abundance and metastatic progression. Collectively, our findings reveal new insights underlying increased breast cancer mortality in obese individuals and provide a novel preclinical rationale to test the efficacy of Src inhibitors for breast cancer treatment.
Three large new trials of unprecedented scale and cost, which included novel factorial designs, have found no effect of basic water, sanitation and hygiene (WASH) interventions on childhood stunting, ...and only mixed effects on childhood diarrhea. Arriving at the inception of the United Nations' Sustainable Development Goals, and the bold new target of safely managed water, sanitation and hygiene for all by 2030, these results warrant the attention of researchers, policy-makers and practitioners.
Here we report the conclusions of an expert meeting convened by the World Health Organization and the Bill and Melinda Gates Foundation to discuss these findings, and present five key consensus messages as a basis for wider discussion and debate in the WASH and nutrition sectors. We judge these trials to have high internal validity, constituting good evidence that these specific interventions had no effect on childhood linear growth, and mixed effects on childhood diarrhea. These results suggest that, in settings such as these, more comprehensive or ambitious WASH interventions may be needed to achieve a major impact on child health.
These results are important because such basic interventions are often deployed in low-income rural settings with the expectation of improving child health, although this is rarely the sole justification. Our view is that these three new trials do not show that WASH in general cannot influence child linear growth, but they do demonstrate that these specific interventions had no influence in settings where stunting remains an important public health challenge. We support a call for transformative WASH, in so much as it encapsulates the guiding principle that - in any context - a comprehensive package of WASH interventions is needed that is tailored to address the local exposure landscape and enteric disease burden.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study set out to determine the sanitary risk scores and microbial health risks associated with wells and boreholes in Ilara-Mokin and Ibule-Soro, Nigeria. Water samples (n = 96) were collected ...over a period of five months to determine the levels of enteric bacteria and to perform a Quantitative Microbial Risk Assessment (QMRA) of drinking water quality. Sanitary risk scores revealed `medium' and `low' overall risks for the wells and boreholes, respectively. Three risk factors (faulty fence; small apron; pollution sources) exhibited high significant (p < 0.01) association with the presence of E. coli and thermotolerant coliforms in water samples from the wells. E. coli and Salmonella ranged from 1.82 to 2.28 and 2.15 to 2.63 log
CFU/100 ml respectively in water from the wells, but were below detection limit in water from the boreholes. Shigella and Campylobacter were detected in all water samples. Estimated risks of infection associated with Shigella (2.1 × 10
to 2.3 × 10
) were higher than those of Campylobacter (6.7 × 10
to 1.9 × 10
) and Salmonella (1.9×10
to 5.6×10
). Adaption of water safety plans may be advantageous in these settings, since intentional ingestion of water from the wells and boreholes may pose potential risks of diarrheal illness to humans.
Abstract
The COVID-19 pandemic placed hygiene at the centre of disease prevention. Yet, access to the levels of water supply that support good hand hygiene and institutional cleaning, our ...understanding of hygiene behaviours, and access to soap are deficient in low-, middle- and high-income countries. This paper reviews the role of water, sanitation and hygiene (WaSH) in disease emergence, previous outbreaks, combatting COVID-19 and in preparing for future pandemics. We consider settings where these factors are particularly important and identify key preventive contributions to disease control and gaps in the evidence base. Urgent substantial action is required to remedy deficiencies in WaSH, particularly the provision of reliable, continuous piped water on-premises for all households and settings. Hygiene promotion programmes, underpinned by behavioural science, must be adapted to high-risk populations (such as the elderly and marginalised) and settings (such as healthcare facilities, transport hubs and workplaces). WaSH must be better integrated into preparation plans and with other sectors in prevention efforts. More finance and better use of financing instruments would extend and improve WaSH services. The lessons outlined justify no-regrets investment by government in response to and recovery from the current pandemic; to improve day-to-day lives and as preparedness for future pandemics.
The transcription factor p63 is required for skeletal formation, and is important for the regulation of 1α,25(OH)2D3 receptor (VDR) in human mesenchymal stem cells (hMSC). Herein we report that ...TAp63γ and ΔNp63β appear to be an integral part of the osteoblastic differentiation of hMSC and are differentially regulated by the vitamin D3 metabolites 1α,25(OH)2D3 and 24R,25(OH)2D3. We compared the endogenous expression of p63 isoforms (TA- and ΔNp63) and splice variants (p63α, -β, -γ), in naive hMSC and during osteoblastic differentiation of hMSC. TAp63α and -β were the predominant p63 variants in naive, proliferating hMSC. In contrast, under osteoblastic differentiation conditions, expression of p63 changed from the TAp63α and -β to the TAp63γ and ΔNp63β variants. Transient overexpression of the p63 variants demonstrated that TAp63β, ΔNp63β, and ΔNp63γ increased alkaline phosphatase activity and ΔNp63α and -γ increased the expression of mRNA for osteocalcin and osterix. Our results support the hypothesis that TAp63α and -β promote a naive state in hMSC. Moreover, TAp63γ is increased during and promotes early osteoblastic differentiation through the expression of pro-osteogenic genes; VDR, Osterix, Runx2 and Osteopontin. ΔNp63β also appears to support osteogenic maturation through increased alkaline phosphatase activity. Treatment with 1α,25(OH)2D3 increased the expression of mRNA for ΔNp63, while addition of 24R,25(OH)2D3 increased the expression of TA- and ΔNp63γ variants. These novel findings demonstrate for the first time that p63 variants are differentially expressed in naive hMSC (TAp63α,β), are important during the osteoblastic differentiation of hMSC (TAp63γ and ΔNp63β), and are differentially regulated by the vitamin D3 metabolites, 1α,25(OH)2D3 and 24R,25(OH)2D3. The molecular nuances and mechanisms of osteoblastic differentiation presented here will hopefully improve our understanding of bone development, complications in bone repair (mal- and non-union fractures), osteoporosis and possibly lead to new modalities of treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We recently reported the isolation of a unique subpopulation of human stromal cells from bone marrow (BM) termed marrow-isolated adult multilineage inducible (MIAMI) cells, capable of differentiating ...in vitro into mature-like cells from all three germ layers. The oxygen tension (pO
2) in BM ranges from 1 to 7%, which prompted us to examine the role of pO
2 in regulating the capacity of MIAMI cells both to self-renew and maintain their pluripotentiality (stemness) or to progress toward osteoblastic differentiation. MIAMI cells were grown under low-pO
2 conditions (1, 3, 5, and 10% oxygen) or air (21% oxygen). The proliferation rate of cells exposed to 3% oxygen (3 days) increased, resulting in cell numbers more than threefold higher than those of cells exposed to air (at 7 days). In cells grown under osteoblastic differentiation conditions, the expression of the osteoblastic markers osteocalcin, bone sialoprotein, osterix, and Runx2 and alkaline phosphatase activity was upregulated when incubated in air; however, it was blocked at low (3%) pO
2. Similarly, biomineralization of long-term cell cultures was high under osteoblastic differentiation conditions in air but was undetectable at low (3%) pO
2. In contrast, low pO
2 upregulated mRNAs for OCT-4, REX-1, telomerase reverse transcriptase, and hypoxia-inducible factor-1α, and increased the expression of SSEA-4 compared to air. Moreover, the expression of embryonic stem cell markers was sustained even under osteogenic culture conditions. Similar results were obtained using commercially available marrow stromal cells. We hypothesize a physiological scenario in which primitive MIAMI cells self-renew while localized to areas of low pO
2 in the bone marrow, but tend to differentiate toward osteoblasts when they are located closer to blood vessels and exposed to higher pO
2. Our results strongly suggest that maintaining developmentally primitive human cells in vitro at low pO
2 would be more physiological and favor stemness over differentiation.
Hepatocyte growth factor (HGF) is a paracrine factor involved in organogenesis, tissue repair, and wound healing. We report here that HGF promotes osteogenic differentiation through the transcription ...of key osteogenic markers, including osteocalcin, osterix, and osteoprotegerin in human mesenchymal stem cells and is a necessary component for the establishment of osteoblast mineralization. Blocking endogenous HGF using PHA665752, a c-Met inhibitor (the HGF receptor), or an HGF-neutralizing antibody attenuates mineralization, and PHA665752 markedly reduced alkaline phosphatase activity. Moreover, we report that HGF promotion of osteogenic differentiation involves the rapid phosphorylation of p38 and differential regulation of its isoforms, p38α and p38β. Western blot analysis revealed a significantly increased level of p38α and p38β protein, and reverse transcription quantitative PCR revealed that HGF increased the transcriptional level of both p38α and p38β. Using small interfering RNA to reduce the transcription of p38α and p38β, we saw differential roles for p38α and p38β on the HGF-induced expression of key osteogenic markers. In summary, our data demonstrate the importance of p38 signaling in HGF regulation of osteogenic differentiation.
PDF
