The high selectivity of the human blood-brain barrier (BBB) restricts delivery of many pharmaceuticals and therapeutic antibodies to the central nervous system. Here, we describe an in vitro ...microfluidic organ-on-a-chip BBB model lined by induced pluripotent stem cell-derived human brain microvascular endothelium interfaced with primary human brain astrocytes and pericytes that recapitulates the high level of barrier function of the in vivo human BBB for at least one week in culture. The endothelium expresses high levels of tight junction proteins and functional efflux pumps, and it displays selective transcytosis of peptides and antibodies previously observed in vivo. Increased barrier functionality was accomplished using a developmentally-inspired induction protocol that includes a period of differentiation under hypoxic conditions. This enhanced BBB Chip may therefore represent a new in vitro tool for development and validation of delivery systems that transport drugs and therapeutic antibodies across the human BBB.
Food insecurity is associated with poor mental health among people living with HIV (PLHIV). This qualitative study explored the mental health experiences of PLHIV participating in a medically ...appropriate food support program.
Semi-structured interviews were conducted post-intervention (n = 34). Interview topics included changes, or lack thereof, in mental health and reasons for changes. Interviews were audio-recorded, transcribed, and double-coded. Salient themes were identified using an inductive-deductive method.
Positive changes in mental health self-reported by PLHIV included improved mood and reduced stress, worry, and anxiety. Participants attributed these changes to: 1) increased access to sufficient and nutritious foods, 2) increased social support, 3) reduced financial hardship, 4) increased sense of control and self-esteem, and 5) reduced functional barriers to eating.
Medically appropriate food support may improve mental health for some PLHIV. Further work is needed to understand and prevent possible adverse consequences on mental health after programs end.
Apolipoprotein B (apoB) is the essential protein required for the assembly and secretion of chylomicrons from the small intestine and VLDLs from the liver. These lipoproteins, as well as their ...remnants and LDL, play key roles in the transport of dietary and endogenously synthesized lipids throughout the body. However, they can be involved in the initiation of atherosclerotic lesions in the vessel wall. Therefore, it is not surprising that the assembly of apoB-containing lipoproteins in the small intestine and liver is a highly regulated process. In particular, cotranslational and posttranslational targeting of apoB for degradation, regulated largely by the availability of the core lipids carried in the lipoprotein, by the types of dietary fatty acids consumed, and by the hormonal milieu, determines the number of chylomicrons or VLDL that are secreted. In this review, we summarize both older and more recent findings on the pathways of apoB degradation, focusing on events in the liver.
Procedural sedation is frequently performed in spontaneously breathing patients, but hypnotics and opioids decrease respiratory drive and place the upper airway at risk for collapse.
In a randomized, ...controlled, cross-over, pharmaco-physiologic study in 12 rats, we conducted acute experiments to compare breathing and genioglossus electromyogram activity at equianesthetic concentrations of ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist that combines potent analgesic with hypnotic action effects, versus propofol. In 10 chronically instrumented rats resting in a plethysmograph, we measured these variables as well as electroencephalography during five conditions: quiet wakefulness, nonrapid-eye-movement sleep, rapid eye movement sleep, and low-dose (60 mg/kg intraperitoneally) and high-dose ketamine anesthesia (125 mg/kg intraperitoneally).
Ketamine anesthesia was associated with markedly increased genioglossus activity (1.5 to fivefold higher values of genioglossus electromyogram) compared with sleep- and propofol-induced unconsciousness. Plethysmography revealed a respiratory stimulating effect: higher values of flow rate, respiratory rate, and duty-cycle (effective inspiratory time, 1.5-to-2-fold higher values). During wakefulness and normal sleep, the δ (f = 6.51, P = 0.04) electroencephalogram power spectrum was an independent predictor of genioglossus activity, indicating an association between electroencephalographic determinants of consciousness and genioglossus activity. Following ketamine administration, electroencephalogram power spectrum and genioglossus electroencephalogram was dissociated (P = 0.9 for the relationship between δ/θ power spectrum and genioglossus electromyogram).
Ketamine is a respiratory stimulant that abolishes the coupling between loss-of-consciousness and upper airway dilator muscle dysfunction in a wide dose-range. Ketamine compared with propofol might help stabilize airway patency during sedation and anesthesia.
Food-insecure people living with HIV/AIDS (PLHIV) consistently exhibit worse clinical outcomes than their food-secure counterparts. This relationship is mediated in part through non-adherence to ...antiretroviral therapy (ART), sub-optimal engagement in HIV care, and poor mental health. An in-depth understanding of how these pathways operate in resource-rich settings, however, remains elusive.
We aimed to understand the relationship between food insecurity and HIV health among low-income individuals in the San Francisco Bay Area using qualitative methods.
Semi-structured in-depth interviews were conducted with 34 low-income PLHIV receiving food assistance from a non-profit organization. Interviews explored experiences with food insecurity and its perceived effects on HIV-related health, mental health, and health behaviors including taking ART and attending clinics. Thematic content analysis of transcripts followed an integrative inductive-deductive approach.
Food insecurity was reported to contribute to poor ART adherence and missing scheduled clinic visits through various mechanisms, including exacerbated ART side effects in the absence of food, physical feelings of hunger and fatigue, and HIV stigma at public free-meal sites. Food insecurity led to depressive symptoms among participants by producing physical feelings of hunger, aggravating pre-existing struggles with depression, and nurturing a chronic self-perception of social failure. Participants further explained how food insecurity, depression, and ART non-adherence could reinforce each other in complex interactions.
Our study demonstrates how food insecurity detrimentally shapes HIV health behavior and outcomes through complex and interacting mechanisms, acting via multiple socio-ecological levels of influence in this setting. The findings emphasize the need for broad, multisectoral approaches to tackling food insecurity among urban poor PLHIV in the United States.
•Provides insight into link between food insecurity and poor HIV health outcomes.•Uses socio-ecological model to analyse complex and interacting mechanisms.•Demonstrates in detail how food insecurity compromises adherence to HIV care.•Provides evidence for how food insecurity contributes to development of depression.
Food insecurity continues to be a major challenge in the United States, affecting 49 million individuals. Quantitative studies show that food insecurity has serious negative health impacts among ...individuals suffering from chronic illnesses, including people living with HIV/AIDS (PLHIV). Formulating effective interventions and policies to combat these health effects requires an in-depth understanding of the lived experience and structural drivers of food insecurity. Few studies, however, have elucidated these phenomena among people living with chronic illnesses in resource-rich settings, including in the United States. Here we sought to explore the experiences and structural determinants of food insecurity among a group of low-income PLHIV in the San Francisco Bay Area. Thirty-four semi-structured in-depth interviews were conducted with low-income PLHIV receiving food assistance from a local non-profit in San Francisco and Alameda County, California, between April and June 2014. Interview transcripts were coded and analysed according to content analysis methods following an inductive–deductive approach. The lived experience of food insecurity among participants included periods of insufficient quantity of food and resultant hunger, as well as long-term struggles with quality of food that led to concerns about the poor health effects of a cheap diet. Participants also reported procuring food using personally and socially unacceptable strategies, including long-term dependence on friends, family, and charity; stealing food; exchanging sex for food; and selling controlled substances. Food insecurity often arose from the need to pay high rents exacerbated by gentrification while receiving limited disability income–a situation resulting in large part from the convergence of long-standing urban policies amenable to gentrification and an outdated disability policy that constrains financial viability. The experiences of food insecurity described by participants in this study can be understood as a form of structural violence, motivating the need for structural interventions at the policy level that extend beyond food-specific solutions.
•Unique focus on prominent current issue of gentrification.•Elucidates novel link between food insecurity, chronic illness, and gentrification.•Analyses gentrification in the United States from a structural perspective.•Argues for reconsideration of disability benefits and provision for chronically ill.
Machado-Joseph disease (MJD), the most common dominantly inherited ataxia worldwide, is caused by a polyglutamine (polyQ) expansion in the deubiquitinating (DUB) enzyme ataxin-3. Interestingly, MJD ...can present clinically with features of Parkinsonism. In this study, we identify parkin, an E3 ubiquitin-ligase responsible for a common familial form of Parkinson's disease, as a novel ataxin-3 binding partner. The interaction between ataxin-3 and parkin is direct, involves multiple domains and is greatly enhanced by parkin self-ubiquitination. Moreover, ataxin-3 deubiquitinates parkin directly in vitro and in cells. Compared with wild-type ataxin-3, MJD-linked polyQ-expanded mutant ataxin-3 is more active, possibly owing to its greater efficiency at DUB K27- and K29-linked Ub conjugates on parkin. Remarkably, mutant but not wild-type ataxin-3 promotes the clearance of parkin via the autophagy pathway. The finding is consistent with the reduction in parkin levels observed in the brains of transgenic mice over-expressing polyQ-expanded but not wild-type ataxin-3, raising the intriguing possibility that increased turnover of parkin may contribute to the pathogenesis of MJD and help explain some of its parkinsonian features.
Here we report the structural characterization of the product formed from the reaction between hydroethidine (HE) and superoxide ( O2
· -). By using mass spectral and NMR techniques, the chemical ...structure of this product was determined as 2-hydroxyethidium (2- OH- E+). By using an authentic standard, we developed an HPLC approach to detect and quantitate the reaction product of HE and O2
· -formed in bovine aortic endothelial cells after treatment with menadione or antimycin A to induce intracellular reactive oxygen species. Concomitantly, we used a spin trap, 5-tert-butoxycarbonyl-5-methyl-1-pyrroline N-oxide (BMPO), to detect and identify the structure of reactive oxygen species formed. BMPO trapped the O2
· -that formed extracellularly and was detected as the BMPO-OH adduct during use of the EPR technique. BMPO, being cell-permeable, inhibited the intracellular formation of 2- OH- E+. However, the intracellular BMPO spin adduct was not detected. The definitive characterization of the reaction product of O2
· -with HE described here forms the basis of an unambiguous assay for intracellular detection and quantitation of O2
· -. Analysis of the fluorescence characteristics of ethidium ( E+) and 2- OH- E+strongly suggests that the currently available fluorescence methodology is not suitable for quantitating intracellular O2
· -. We conclude that the HPLC/fluorescence assay using HE as a probe is more suitable reactive oxygen species for detecting intracellular O2
· -.
Food insecurity, which disproportionately affects marginalized women in the United States, is associated with depressive symptoms. Few studies have examined relations of food insecurity with other ...mental health outcomes.
The aim of this study was to investigate the associations of food insecurity with symptoms of generalized anxiety disorder (GAD), stress, and posttraumatic stress disorder (PTSD) in the Women's Interagency HIV Study (WIHS), a prospective cohort study of women with or at risk of HIV in the United States.
Participants were 2553 women with or at risk of HIV, predominantly African American/black (71.6%). Structured questionnaires were conducted during April 2013–March 2016 every 6 mo. Food security (FS) was the primary predictor, measured using the Household Food Security Survey Module. We measured longitudinal outcomes for GAD (GAD-7 score and a binary GAD-7 screener for moderate-to-severe GAD). Only cross-sectional data were available for outcomes measuring perceived stress (PSS-10 score) and PTSD (PCL-C score and a binary PCL-C screener for PTSD). We examined associations of FS with the outcomes through use of multivariable linear and logistic regression, including lagged associations with GAD outcomes.
After adjusting for sociodemographic and health-related factors including HIV serostatus, current marginal, low, and very low FS were associated with increasingly higher GAD-7 scores, and with 1.41 (95% CI: 1.10, 1.80; P < 0.01), 2.03 (95% CI: 1.59, 2.61; P < 0.001), and 3.23 (95% CI: 2.43, 4.29; P < 0.001) times higher odds of screening positive for moderate-to-severe GAD, respectively. Low and very low FS at the previous visit (6 mo earlier) were independently associated with GAD outcomes at current visit. Associations of FS with PSS-10 and PCL-C scores exhibited similar dose-response relations. Very low FS was associated with 1.93 (95% CI: 1.15, 3.24; P < 0.05) times higher odds of screening positive for PTSD.
Food insecurity may be associated with a range of poor mental health outcomes among women in the United States with or at risk of HIV.
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