Type III interferon signaling restricts enterovirus 71 infection of goblet cells.

Recent worldwide outbreaks of enterovirus 71 (EV71) have caused major epidemics of hand, foot, and mouth disease with severe neurological complications, including acute flaccid paralysis. EV71 is transmitted by the enteral route, but little is known about the mechanisms it uses to cross the human gastrointestinal tract. Using primary human intestinal epithelial monolayers, we show that EV71 infects the epithelium from the apical surface, where it preferentially infects goblet cells. We found that EV71 infection did not alter epithelial barrier function but did reduce the expression of goblet cell-derived mucins, suggesting that it alters goblet cell function. We also show that the intestinal epithelium responds to EV71 infection through the selective induction of type III interferons (IFNs), which restrict EV71 replication. Collectively, these findings define the early events associated with EV71 infections of the human intestinal epithelium and show that host IFN signaling controls replication in an IFN-specific manner.

Organotypic models of type III interferon-mediated protection from Zika virus infections at the maternal-fetal interface.

Protecting the fetus from the hematogenous spread of viruses requires multifaceted layers of protection and relies heavily on trophoblasts, the fetal-derived cells that comprise the placental barrier. We showed previously that trophoblasts isolated from full-term placentas resist infection by diverse viruses, including Zika virus (ZIKV), and transfer this resistance to nonplacental cells through the activity of paracrine effectors, including the constitutive release of type III interferons (IFNs). Here, we developed 3D cell-line-based models of human syncytiotrophoblasts, cells that lie in direct contact with maternal blood, and show that these cells recapitulate the antiviral properties of primary trophoblasts through the constitutive release of type III IFNs (IFNλ1 and IFNλ2) and become resistant to ZIKV infection. In addition, using organotypic human midgestation chorionic villous explants, we show that syncytiotrophoblasts isolated from the second trimester of pregnancy also constitutively release type III IFNs and use these IFNs in autocrine and paracrine manners to restrict ZIKV infection. Collectively, these data provide important insights into the defense mechanisms used by syncytiotrophoblasts at various stages of human gestation to resist ZIKV infection and new human models to study the role of type III IFNs in the vertical transmission of ZIKV and other viruses associated with congenital disease.

A Three-Dimensional Cell Culture System To Model RNA Virus Infections at the Blood-Brain Barrier.

The blood-brain barrier (BBB) comprises the foremost protective barrier in the brain and is composed in part of a layer of microvascular endothelial cells that line the capillaries surrounding the brain. Here, we describe a human three-dimensional (3-D) cell-based model of the BBB microvascular endothelium that recapitulates properties of these cells in vivo, including physiologically relevant transcriptional profiles, the capacity to induce potent antimicrobial innate immune signaling, and the ability to resist infection by diverse RNA viruses, including members of the enterovirus (coxsackievirus B, echovirus 11, enterovirus 71, poliovirus) and flavivirus (dengue virus, Zika virus [ZIKV]) families. We show that disruption of apical tight junctions by proinflammatory cytokine tumor necrosis factor alpha (TNF-α) sensitizes 3-D-cultured BBB cells to ZIKV infection and that 3-D derived BBB cells can be used to model the transmigration of ZIKV-infected monocytes across the endothelial barrier to access underlying astrocytes. Taken together, our findings show that human BBB microvascular endothelial cells cultured in 3-D can be used to model the mechanisms by which RNA viruses access the central nervous system (CNS), which could be used for the development and screening of therapeutics to limit this event. IMPORTANCE Neurotropic viral infections are significant sources of global morbidity and mortality. The blood-brain barrier (BBB) is composed in part of a layer of microvascular endothelial cells and functions to restrict viral access to the brain. In vitro models that recapitulate many of the properties of the human BBB endothelium are lacking, particularly with respect to the unique cellular and immunological mechanisms by which these cells restrict viral infections of the brain. Here, we developed a three-dimensional cell culture model that recapitulates many of the morphological and functional properties of the BBB microvasculature and apply this model to the study of RNA virus infections. The model we describe can therefore be used to study a variety of aspects of BBB physiology, including the mechanisms by which viruses might access the CNS, and could be used for the development and screening of antiviral therapeutics to limit this important step in viral pathogenesis.

Time until incident dementia among Medicare beneficiaries using centrally acting or non-centrally acting ACE inhibitors.

BACKGROUND: Centrally active (CA) angiotensin-converting enzyme inhibitors (ACEIs) are able to cross the blood­brain barrier. Small observational studies and mouse models suggest that use of CA versus non-CA ACEIs is associated with a reduced incidence of Alzheimer's disease and related dementias (ADRD). OBJECTIVE: The aim of this research was to assess the effect of CA versus non-CA ACEI use on incident ADRD. DESIGN: This is a retrospective cohort study with a non-equivalent control group. SETTING AND PATIENTS" This study used a national random sample of Medicare beneficiaries enrolled in Part D with an ACEI prescription. A prevalent ACEI user cohort included beneficiaries (n = 107 179) with an ACEI prescription prior to 30 April 2007; beneficiaries without an ACEI prescription before this date were defined as incident ACEI users (n = 9840). MEASUREMENTS: The main outcome was time until first diagnosis of ADRD in Medicare claims. RESULTS: The unadjusted, propensity-matched and instrumental variable analyses of both the prevalent and incident ACEI user cohorts consistently showed similar time until incident ADRD in those taking CA ACEIs compared with those who took non-CA ACEIs. LIMITATIONS: The limitations of this study include the use of observational data, relatively short follow-up time and claims-based measure of cognitive decline. CONCLUSIONS: In this analysis of Medicare beneficiaries who were prevalent or incident users of ACEIs in 2007­2009, the use of CA ACEIs was unrelated to cognitive decline within 3 years of index prescription. Continued follow-up of these patients and more sensitive measures of cognitive decline are necessary to determine whether a cognitive benefit of CA ACEIs is realized in the long term.

Nurses' voices: policy, practice and ethics.

This article deals with nurses' ethical concerns raised by the consequences of changes in governmental and institutional policies on nursing practice and patient care. The aims of this project were to explore perspectives of registered nurses who provide or manage direct patient care on policies that affect nursing and patient care, and to provide input to policy makers for the development of more patient-centred policies. Four focus groups were conducted with a total of 36 registered nurse participants. The project team identified major themes that emerged in the analysis of transcripts of the focus group discussions. The four major themes were: effects of policy focused on cost containment, effects on quality of care, effects on patient education and access to needed services, and effects on nurses and nursing. The participants identified primarily negative effects of changes in national health policy and legislation that influence institutional policies on patient care and nursing practice. The effects of identified policy changes raised concerns about meeting nurses' ethical obligations to patients and families. Participants specified key points for consideration by legislators and other policy makers. They viewed nurses who are involved in direct patient care as a critical resource for legislators and other policy makers in the development of public and institutional policies that affect nursing and patient care.

State laws mandating or promoting training programs for alcohol servers and establishment managers: an assessment of statutory and administrative procedures.

We conducted a qualitative analysis of 23 state Responsible Beverage Service (RBS) laws to determine how effective the laws are in mandating or encouraging high-quality RBS programs. As of January, 2001, 12 states at least partially mandate RBS training for alcohol establishments and 11 states offer incentives to encourage participation in RBS training. We collected information regarding state RBS laws from two sources: (1) RBS statutes and associated regulatory provisions, and (2) telephone surveys of Alcoholic Beverage Control agency staff. We identified and evaluated five components of RBS laws: program requirements, administrative requirements, enforcement provisions, penalties for lack of compliance with law, and benefits for participation in training programs. Comprehensiveness of RBS laws varied by state; however, RBS legislation was weak across all states overall. While some states were strong in one or two of the RBS components, almost all states were weak in at least one component.