p53 Regulates the Extent of Fibroblast Proliferation and Fibrosis in Left Ventricle Pressure Overload.

BACKGROUND: Cardiomyopathy is characterized by the pathological accumulation of resident cardiac fibroblasts that deposit ECM (extracellular matrix) and generate a fibrotic scar. However, the mechanisms that control the timing and extent of cardiac fibroblast proliferation and ECM production are not known, hampering the development of antifibrotic strategies to prevent heart failure. METHODS: We used the Tcf21 (transcription factor 21)MerCreMer mouse line for fibroblast-specific lineage tracing and p53 (tumor protein p53) gene deletion. We characterized cardiac physiology and used single-cell RNA-sequencing and in vitro studies to investigate the p53-dependent mechanisms regulating cardiac fibroblast cell cycle and fibrosis in left ventricular pressure overload induced by transaortic constriction. RESULTS: Cardiac fibroblast proliferation occurs primarily between days 7 and 14 following transaortic constriction in mice, correlating with alterations in p53-dependent gene expression. p53 deletion in fibroblasts led to a striking accumulation of Tcf21-lineage cardiac fibroblasts within the normal proliferative window and precipitated a robust fibrotic response to left ventricular pressure overload. However, excessive interstitial and perivascular fibrosis does not develop until after cardiac fibroblasts exit the cell cycle. Single-cell RNA sequencing revealed p53 null fibroblasts unexpectedly express lower levels of genes encoding important ECM proteins while they exhibit an inappropriately proliferative phenotype. in vitro studies establish a role for p53 in suppressing the proliferative fibroblast phenotype, which facilitates the expression and secretion of ECM proteins. Importantly, Cdkn2a (cyclin-dependent kinase inhibitor 2a) expression and the p16Ink4a-retinoblastoma cell cycle control pathway is induced in p53 null cardiac fibroblasts, which may eventually contribute to cell cycle exit and fulminant scar formation. CONCLUSIONS: This study reveals a mechanism regulating cardiac fibroblast accumulation and ECM secretion, orchestrated in part by p53-dependent cell cycle control that governs the timing and extent of fibrosis in left ventricular pressure overload.

A Novel Closed-Loop Electrical Brain Stimulation Device Featuring Wireless Low-Energy Ultrasound Power and Communication.

OBJECTIVES: This study aimed to indicate the feasibility of a prototype electrical neuromodulation system using a closed-loop energy-efficient ultrasound-based mechanism for communication, data transmission, and recharging. MATERIALS AND METHODS: Closed-loop deep brain stimulation (DBS) prototypes were designed and fabricated with ultrasonic wideband (UsWB) communication technology and miniaturized custom electronics. Two devices were implanted short term in anesthetized Göttingen minipigs (N = 2). Targeting was performed using preoperative magnetic resonance imaging, and locations were confirmed postoperatively by computerized tomography. DBS systems were tested over a wide range of stimulation settings to mimic minimal, typical, and/or aggressive clinical settings, and evaluated for their ability to transmit data through scalp tissue and to recharge the DBS system using UsWB. RESULTS: Stimulation, communication, reprogramming, and recharging protocols were successfully achieved in both subjects for amplitude (1V-6V), frequency (50-250 Hz), and pulse width (60-200 µs) settings and maintained for ≥six hours. The precision of pulse settings was verified with <5% error. Communication rates of 64 kbit/s with an error rate of 0.05% were shown, with no meaningful throughput degradation observed. Time to recharge to 80% capacity was <9 minutes. Two DBS systems also were implanted in the second test animal, and independent bilateral stimulation was successfully shown. CONCLUSIONS: The system performed at clinically relevant implant depths and settings. Independent bilateral stimulation for the duration of the study with a 4F energy storage and full rapid recharge were achieved. Continuous function extrapolates to six days of continuous stimulation in future design iterations implementing application specific integrated circuit level efficiency and 15F storage capacitance. UsWB increases energy efficiency, reducing storage requirements and thereby enabling device miniaturization. The device can enable intelligent closed-loop stimulation, remote system monitoring, and optimization and can serve as a power/data gateway to interconnect the intrabody network with the Internet of Medical Things.

Prevention of Fibrosis and Pathological Cardiac Remodeling by Salinomycin.

[Figure: see text].

Supervision during resistance training positively influences muscular adaptations in resistance-trained individuals.

This study compared the effects of supervised versus unsupervised resistance training (RT) on measures of muscle strength and hypertrophy in resistance-trained individuals. Thirty-six young men and women were randomly assigned to one of two experimental, parallel groups to complete an 8-week RT programme: One group received direct supervision for their RT sessions (SUP); the other group performed the same RT programme in an unsupervised manner (UNSUP). Programme variables were kept constant between groups. We obtained pre- and post-study assessments of body composition via multi-frequency bioelectrical impedance analysis (MF-BIA), muscle thickness of the upper and lower limbs via ultrasound, 1 repetition maximum (RM) in the back squat and bench press, isometric knee extension strength, and countermovement jump (CMJ) height. Results showed the SUP group generally achieved larger increases in muscle thickness for the triceps brachii, all sites of the rectus femoris, and the proximal region of the vastus lateralis. MF-BIA indicated increases in lean mass favoured SUP. Squat 1RM was greater for SUP; bench press 1RM and isometric knee extension were similar between conditions. CMJ increases modestly favoured UNSUP. In conclusion, our findings suggest that supervised RT promotes greater muscular adaptations and enhances exercise adherence in young, resistance-trained individuals.

The Value of Using a Quality Assurance Follow-Up Team to Address Incidental Findings After Emergency Department or Urgent Care Discharge: A Cost Analysis.

BACKGROUND: Incidental finding (IF) follow-up is of critical importance for patient safety and is a source of malpractice risk. Laboratory, imaging, or other types of IFs are often uncovered incidentally and are missed, not addressed, or only result after hospital discharge. Despite a growing IF notification literature, a need remains to study cost-effective non-electronic health record (EHR)-specific solutions that can be used across different types of IFs and EHRs. OBJECTIVE: The objective of this study was to evaluate the utility and cost-effectiveness of an EHR-independent emergency medicine-based quality assurance (QA) follow-up program in which an experienced nurse reviewed laboratory and imaging studies and ensured appropriate follow-up of results. METHODS: A QA nurse reviewed preceding-day abnormal studies from a tertiary care hospital, a community hospital, and an urgent care center. Laboratory values outside preset parameters or radiology over-reads resulting in clinically actionable changes triggered contact with an on-call emergency physician to determine an appropriate intervention and its implementation. RESULTS: Of 104,125 visits with 1,351,212 laboratory studies and 95,000 imaging studies, 6530 visits had IFs, including 2659 laboratory and 4004 imaging results. The most common intervention was contacting a primary care physician (5783 cases [88.6%]). Twenty-one cases resulted in a patient returning to the ED, at an average cost of $28,000 per potential life-/limb-saving intervention. CONCLUSIONS: Although abnormalities in laboratory results and imaging are often incidental to patient care, a dedicated emergency department QA follow-up program resulted in the identification and communication of numerous laboratory and imaging abnormalities and may result in changes to patients' subsequent clinical course, potentially increasing patient safety.

State-by-state estimates of avoidable trauma mortality with early and liberal versus delayed or restricted administration of tranexamic acid.

OBJECTIVE: Early administration of tranexamic acid (TXA) has been shown to save lives in trauma patients, and some U.S. emergency medical systems (EMS) have begun providing this therapy prehospital. Treatment protocols vary from state to state: Some offer TXA broadly to major trauma patients, others reserve it for patients meeting vital sign criteria, and still others defer TXA entirely pending a hospital evaluation. The purpose of this study is to compare the avoidable mortality achievable under each of these strategies, and to report on the various approaches used by EMS. METHODS: We used the National Center for Health Statistics Underlying Cause of Death data to identify a TXA-naïve population of trauma patients who died from 2007 to 2012 due to hemorrhage. We estimated the proportion of deaths where the patient was hypotensive or tachycardic using the National Trauma Data Bank. We used avoidable mortality risk ratios from the landmark CRASH 2 study to calculate lives saved had TXA been given within one hour of injury based on a clinician's gestalt the patient was at risk for significant hemorrhage; had it been reserved only for hypotensive or tachycardic patients; or had it been given between hours one to three of injury, considered here as a surrogate for deferring the question to the receiving hospital. RESULTS: Had TXA been given within 1 hour of injury, an average of 3409 deaths per year could have been averted nationally. Had TXA been given between one and three hours after injury, 2236 deaths per year could have been averted. Had TXA only been given to either tachycardic or hypotensive trauma patients, 1371 deaths per year could have been averted. Had TXA only been given to hypotensive trauma patients, 616 deaths per year could have been averted. Similar trends are seen at the individual state level. A review of EMS practices found 15 statewide protocols that allow EMS providers to administer TXA for trauma. CONCLUSION: Providing early TXA to persons at risk of significant hemorrhage has the potential to prevent many deaths from trauma, yet most states do not offer it in statewide prehospital treatment protocols.

Retrospective Review of Pregnant Patients Presenting for Evaluation of Acute Neurologic Complaints.

STUDY OBJECTIVE: Data suggest an increase in neurologic-related hospitalizations during pregnancy. It is crucial for health care providers to develop effective strategies to evaluate this young, generally healthy cohort of patients for whom missed neurologic diagnoses can have devastating results. We aim to describe the epidemiology of this high risk patient population by investigating exam findings, imaging studies, and clinical outcomes of pregnant women presenting to the emergency department (ED) with acute neurologic complaints. METHODS: We conducted a 7-year retrospective chart review of pregnant patients presenting with neurologic chief complaints to the emergency department of an urban tertiary academic medical center in the northeastern United States. We investigated examination findings, imaging studies, and clinical outcomes. RESULTS: Between January 1, 2010, and May 31, 2017, 205 pregnant patients presented to the ED with a neurologic chief complaint. The majority of patients had a normal neurologic examination result. Patients with an abnormal examination result were not more likely to have clinically significant imaging findings. Within our population, 28% underwent imaging, and noncontrast magnetic resonance imaging was the most common modality. Five patients had clinically significant imaging findings. Specifically, 3.3% of patients with abnormal examination result had significant findings and 2.3% of those with a normal examination result had significant findings. A minority of the patients with a visit resulting in discharge (9.8%) returned to the ED within a 7-day period. None required additional neuroimaging. CONCLUSION: To our knowledge, our study is unique in that it incorporated all neurologic complaints. Headache was the most common complaint, followed by dizziness and seizures. Most of the headaches were related to first-trimester migraines. There was a high incidence of imaging used in clinical practice even when there was a normal neurologic examination result. A normal examination result does not adequately exclude serious intracranial pathology, and diagnostic vigilance is justified.

Small proline-rich protein 2B drives stress-dependent p53 degradation and fibroblast proliferation in heart failure.

Heart disease is associated with the accumulation of resident cardiac fibroblasts (CFs) that secrete extracellular matrix (ECM), leading to the development of pathological fibrosis and heart failure. However, the mechanisms underlying resident CF proliferation remain poorly defined. Here, we report that small proline-rich protein 2b (Sprr2b) is among the most up-regulated genes in CFs during heart disease. We demonstrate that SPRR2B is a regulatory subunit of the USP7/MDM2-containing ubiquitination complex. SPRR2B stimulates the accumulation of MDM2 and the degradation of p53, thus facilitating the proliferation of pathological CFs. Furthermore, SPRR2B phosphorylation by nonreceptor tyrosine kinases in response to TGF-ß1 signaling and free-radical production potentiates SPRR2B activity and cell cycle progression. Knockdown of the Sprr2b gene or inhibition of SPRR2B phosphorylation attenuates USP7/MDM2 binding and p53 degradation, leading to CF cell cycle arrest. Importantly, SPRR2B expression is elevated in cardiac tissue from human heart failure patients and correlates with the proliferative state of patient-derived CFs in a process that is reversed by insulin growth factor-1 signaling. These data establish SPRR2B as a unique component of the USP7/MDM2 ubiquitination complex that drives p53 degradation, CF accumulation, and the development of pathological cardiac fibrosis.

The NLRP3 Inflammasome: Relevance in Solid Organ Transplantation.

The NOD, LRR, and pyrin domain-containing 3 (NLRP3) protein has been established as a central component of the inflammasome and regulates the inflammatory response to a myriad of environmental, microbial, and endogenous danger stimuli. Assembly of the NLRP3 inflammasome results in the cleavage and activation of caspase-1, in turn causing release of the pro-inflammatory interleukins 1-beta and 18. This activation response, while crucial to coordinated innate immune defense, can be aberrantly activated by the likes of cell-free DNA, and cause significant autoimmune pathology. Complications of autoimmunity induced by aberrant NLRP3 inflammasome activation have a great degree of mechanistic crossover with alloimmune injury in solid organ transplant, and stratagems to neutralize NLRP3 inflammasome activation may prove beneficial in solid organ transplant management. This article reviews NLRP3 inflammasome biology and the pathology associated with its hyperactivation, as well as the connections between NLRP3 inflammasome activation and allograft homeostasis.

The Influence of Medicare for All on Reimbursement for Emergency Care Treat-and-Release Visits.

STUDY OBJECTIVE: Single-payer health care is supported by most Americans, but the effect of single payer on any particular sector of the health care market has not been well explored. We examine the effect of 2 potential single-payer designs, Medicare for All and an alternative including Medicare and Medicaid, on total payments and out-of-pocket spending for treat-and-release emergency care (patients discharged after an emergency department [ED] visit). METHODS: We used the 2013 to 2016 Medical Expenditure Panel Survey to determine estimates of payments made for ED visits by insurance type, and the 2015 National Hospital Ambulatory Medical Care Survey to estimate the proportion of ED visits covered by each insurance type. RESULTS: We found that total payments were predicted to increase from $85.5 billion to $89.0 billion (range $81.3 to $99.8 billion) in the Medicare-only scenario and decrease to $79.4 billion (range $71.6 to $87.2 billion) under Medicare/Medicaid, whereas out-of-pocket costs were predicted to decrease from $116 per visit to $45 with Medicare and to $36 with Medicare/Medicaid. CONCLUSION: In this study of ED treat-and-release patients, a transition to a Medicare for All system may increase ED reimbursement and reduce consumer out-of-pocket costs, whereas a system that maintains Medicaid in addition to Medicare could reduce total payments for emergency care.

The Effect of a Rapid Assessment Zone on Emergency Department Operations and Throughput.

STUDY OBJECTIVE: We examine the effects of a front-end flow model designated the rapid assessment zone on multiple emergency department (ED) operational metrics. METHODS: This was a retrospective, before-after study of consecutive patient visits at an urban community ED. Six-month periods were compared before and after an intervention in 2017 that changed patient flow and the intake process. A lead nurse role splits patient flow immediately on patient arrival according to only age and chief complaint, allowing direct bedding without the bottlenecks of vital sign measurement, full triage assessment, or Emergency Severity Index assignment. A new patient care area (designated rapid assessment zone) preferentially expedites treatment of patients likely to remain ambulatory and serves as flexible acute care space when needed by individual cases and the ED. The outcomes measured were ED length of stay, arrival-to-provider time, the rate of leaving before treatment completion, and the rate of leaving before being seen. Data were analyzed with nonparametric testing, χ2 analysis, and multiple linear regression, controlling for patient visit characteristics, ED daily census volumes, and measurements of boarding patients. RESULTS: We analyzed 43,847 visits in the preintervention and 44,792 visits in the postintervention periods. The intervention was associated with the following changes: median ED length of stay from 203 to 171 minutes (-15.8%), median arrival-to-provider time from 28 to 13 minutes (-53.6%), leaving before treatment completion from 1.0% to 0.8% (-20%), and leaving before being seen from 3.1% to 0.5% (-84%). Regression analysis accounting for multiple confounders demonstrated that the reduced length of stay after rapid assessment zone implementation persisted across Emergency Severity Index levels 2 to 5 and all ED daily census levels. CONCLUSION: The rapid assessment zone model aims to decrease front-end bottlenecks and minimize serial intake assessments at a high-volume, urban ED. It was associated with improved patient throughput and decreased early patient departure. It may represent a useful model for similar centers.

Pre-existing fibroblasts of epicardial origin are the primary source of pathological fibrosis in cardiac ischemia and aging.

Serum response factor (SRF) and the SRF co-activators myocardin-related transcription factors (MRTFs) are essential for epicardium-derived progenitor cell (EPDC)-mobilization during heart development; however, the impact of developmental EPDC deficiencies on adult cardiac physiology has not been evaluated. Here, we utilize the Wilms Tumor-1 (Wt1)-Cre to delete Mrtfs or Srf in the epicardium, which reduced the number of EPDCs in the adult cardiac interstitium. Deficiencies in Wt1-lineage EPDCs prevented the development of cardiac fibrosis and diastolic dysfunction in aged mice. Mice lacking MRTF or SRF in EPDCs also displayed preservation of cardiac function following myocardial infarction partially due to the depletion of Wt1 lineage-derived cells in the infarct. Interestingly, depletion of Wt1-lineage EPDCs allows for the population of the infarct with a Wt1-negative cell lineage with a reduced fibrotic profile. Taken together, our study conclusively demonstrates the contribution of EPDCs to both ischemic cardiac remodeling and the development of diastolic dysfunction in old age, and reveals the existence of an alternative Wt1-negative source of resident fibroblasts that can populate the infarct.

Intravenous fluid resuscitation is associated with septic endothelial glycocalyx degradation.

BACKGROUND: Intravenous fluids, an essential component of sepsis resuscitation, may paradoxically worsen outcomes by exacerbating endothelial injury. Preclinical models suggest that fluid resuscitation degrades the endothelial glycocalyx, a heparan sulfate-enriched structure necessary for vascular homeostasis. We hypothesized that endothelial glycocalyx degradation is associated with the volume of intravenous fluids administered during early sepsis resuscitation. METHODS: We used mass spectrometry to measure plasma heparan sulfate (a highly sensitive and specific index of systemic endothelial glycocalyx degradation) after 6 h of intravenous fluids in 56 septic shock patients, at presentation and after 24 h of intravenous fluids in 100 sepsis patients, and in two groups of non-infected patients. We compared plasma heparan sulfate concentrations between sepsis and non-sepsis patients, as well as between sepsis survivors and sepsis non-survivors. We used multivariable linear regression to model the association between volume of intravenous fluids and changes in plasma heparan sulfate. RESULTS: Consistent with previous studies, median plasma heparan sulfate was elevated in septic shock patients (118 [IQR, 113-341] ng/ml 6 h after presentation) compared to non-infected controls (61 [45-79] ng/ml), as well as in a second cohort of sepsis patients (283 [155-584] ng/ml) at emergency department presentation) compared to controls (177 [144-262] ng/ml). In the larger sepsis cohort, heparan sulfate predicted in-hospital mortality. In both cohorts, multivariable linear regression adjusting for age and severity of illness demonstrated a significant association between volume of intravenous fluids administered during resuscitation and plasma heparan sulfate. In the second cohort, independent of disease severity and age, each 1 l of intravenous fluids administered was associated with a 200 ng/ml increase in circulating heparan sulfate (p = 0.006) at 24 h after enrollment. CONCLUSIONS: Glycocalyx degradation occurs in sepsis and septic shock and is associated with in-hospital mortality. The volume of intravenous fluids administered during sepsis resuscitation is independently associated with the degree of glycocalyx degradation. These findings suggest a potential mechanism by which intravenous fluid resuscitation strategies may induce iatrogenic endothelial injury.

Clinical differences between visits to adult freestanding and hospital-based emergency departments.

OBJECTIVE: Compare clinical characteristics for adult visits to freestanding emergency departments (FEDs) and a hospital-based ED (HBED). METHODS: Electronic health records were collected on adult ED visits from 7/1/14 to 6/30/15 from three FEDs and one level 1 trauma tertiary care HBED. RESULTS: There were 55,909 HBED visits; 44,108 FED visits. The FED population was slightly more female (61% vs 57%), younger (48 vs 46 years), white (86% vs 60%), and employed (67% vs 49%). A higher percent of FED visits had private insurance (43% vs 20%); a lower percent had Medicaid (25% vs 42%) and Medicare (23% vs 30%). The top three presenting problems were the same at the HBED and FEDs, but the order differed: gastrointestinal (HBED 19% vs FED 18%), cardiorespiratory (18% vs 16%), injury-pain-swelling of extremity (14% vs 17%). Differences were seen in primary ICD9 codes. One quarter of FED visits and only 18% of HBED visits were for injury/poisoning. A higher percent of FED visits were for respiratory diseases (12% vs 9%) but a lower percent were for circulatory system diseases (7% vs 11%) and visits for mental illness (2% vs 6%). Nearly 30% of HBED visits resulted in admission, compared to 8% of FED visits. ESI level differed significantly, with a lower percent of high acuity cases at FEDs (level 1: 0.1% vs 1.6%; level 2: 5% vs 26%). CONCLUSION: Differences were observed in clinical characteristics of adult HBED visits versus FEDs. Results of this study can help communities plan their emergency care system.

Nanosecond pulsed electric fields depolarize transmembrane potential via voltage-gated K+, Ca2+ and TRPM8 channels in U87 glioblastoma cells.

Nanosecond pulsed electric fields (nsPEFs) have a variety of applications in the biomedical and biotechnology industries. Cancer treatment has been at the forefront of investigations thus far as nsPEFs permeabilize cellular and intracellular membranes leading to apoptosis and necrosis. nsPEFs may also influence ion channel gating and have the potential to modulate cell physiology without poration of the membrane. This phenomenon was explored using live cell imaging and a sensitive fluorescent probe of transmembrane voltage in the human glioblastoma cell line, U87 MG, known to express a number of voltage-gated ion channels. The specific ion channels involved in the nsPEF response were screened using a membrane potential imaging approach and a combination of pharmacological antagonists and ion substitutions. It was found that a single 10ns pulsed electric field of 34kV/cm depolarizes the transmembrane potential of cells by acting on specific voltage-sensitive ion channels; namely the voltage and Ca2+ gated BK potassium channel, L- and T-type calcium channels, and the TRPM8 transient receptor potential channel.

Comparative primate obstetrics: Observations of 15 diurnal births in wild gelada monkeys (Theropithecus gelada) and their implications for understanding human and nonhuman primate birth evolution.

OBJECTIVES: The birth process has been studied extensively in many human societies, yet little is known about this essential life history event in other primates. Here, we provide the most detailed account of behaviors surrounding birth for any wild nonhuman primate to date. MATERIALS AND METHODS: Over a recent ∼10-year period, we directly observed 15 diurnal births (13 live births and 2 stillbirths) among geladas (Theropithecus gelada) at Guassa, Ethiopia. During each birth, we recorded the occurrence (or absence) of 16 periparturitional events, chosen for their potential to provide comparative evolutionary insights into the factors that shaped birth behaviors in humans and other primates. RESULTS: We found that several events (e.g., adopting standing crouched positions, delivering infants headfirst) occurred during all births, while other events (e.g., aiding the infant from the birth canal, licking infants following delivery, placentophagy) occurred during, or immediately after, most births. Moreover, multiparas (n = 9) were more likely than primiparas (n = 6) to (a) give birth later in the day, (b) isolate themselves from nearby conspecifics while giving birth, (c) aid the infant from the birth canal, and (d) consume the placenta. DISCUSSION: Our results suggest that prior maternal experience may contribute to greater competence or efficiency during the birth process. Moreover, face presentations (in which infants are born with their neck extended and their face appearing first, facing the mother) appear to be the norm for geladas. Lastly, malpresentations (in which infants are born in the occiput anterior position more typical of human infants) may be associated with increased mortality in this species. We compare the birth process in geladas to those in other primates (including humans) and discuss several key implications of our study for advancing understanding of obstetrics and the mechanism of labor in humans and nonhuman primates.

Thioredoxin-interacting protein is a biomechanical regulator of Src activity: key role in endothelial cell stress fiber formation.

RATIONALE: Fluid shear stress differentially regulates endothelial cell stress fiber formation with decreased stress fibers in areas of disturbed flow compared with steady flow areas. Importantly, stress fibers are critical for several endothelial cell functions including cell shape, mechano-signal transduction, and endothelial cell-cell junction integrity. A key mediator of steady flow-induced stress fiber formation is Src that regulates downstream signaling mediators such as phosphorylation of cortactin, activity of focal adhesion kinase, and small GTPases. OBJECTIVE: Previously, we showed that thioredoxin-interacting protein (TXNIP, also VDUP1 [vitamin D upregulated protein 1] and TBP-2 [thioredoxin binding protein 2]) was regulated by fluid shear stress; TXNIP expression was increased in disturbed flow compared with steady flow areas. Although TXNIP was originally characterized for its role in redox and metabolic cellular functions, recent reports show important scaffold functions related to its α-arrestin structure. Based on these findings, we hypothesized that TXNIP acts as a biomechanical sensor that regulates Src kinase activity and stress fiber formation. METHODS AND RESULTS: Using en face immunohistochemistry of the aorta and cultured endothelial cells, we show inverse relationship between TXNIP expression and Src activity. Specifically, steady flow increased Src activity and stress fiber formation, whereas it decreased TXNIP expression. In contrast, disturbed flow had opposite effects. We studied the role of TXNIP in regulating Src homology phosphatase-2 plasma membrane localization and vascular endothelial cadherin binding because Src homology phosphatase-2 indirectly regulates dephosphorylation of Src tyrosine 527 that inhibits Src activity. Using immunohistochemistry and immunoprecipitation, we found that TXNIP prevented Src homology phosphatase-2-vascular endothelial cadherin interaction. CONCLUSIONS: In summary, these data characterize a fluid shear stress-mediated mechanism for stress fiber formation that involves a TXNIP-dependent vascular endothelial cadherin-Src homology phosphatase-2-Src pathway.

Fitness impacts of tapeworm parasitism on wild gelada monkeys at Guassa, Ethiopia.

Parasitism is expected to impact host morbidity or mortality, although the fitness costs of parasitism have rarely been quantified for wildlife hosts. Tapeworms in the genus Taenia exploit a variety of vertebrates, including livestock, humans, and geladas (Theropithecus gelada), monkeys endemic to the alpine grasslands of Ethiopia. Despite Taenia's adverse societal and economic impacts, we know little about the prevalence of disease associated with Taenia infection in wildlife or the impacts of this disease on host health, mortality and reproduction. We monitored geladas at Guassa, Ethiopia over a continuous 6½ year period for external evidence (cysts or coenuri) of Taenia-associated disease (coenurosis) and evaluated the impact of coenurosis on host survival and reproduction. We also identified (through genetic and histological analyses) the tapeworms causing coenurosis in wild geladas at Guassa as Taenia serialis. Nearly 1/3 of adult geladas at Guassa possessed ≥1 coenurus at some point in the study. Coenurosis adversely impacted gelada survival and reproduction at Guassa and this impact spanned two generations: adults with coenuri suffered higher mortality than members of their sex without coenuri and offspring of females with coenuri also suffered higher mortality. Coenurosis also negatively affected adult reproduction, lengthening interbirth intervals and reducing the likelihood that males successfully assumed reproductive control over units of females. Our study provides the first empirical evidence that coenurosis increases mortality and reduces fertility in wild nonhuman primate hosts. Our research highlights the value of longitudinal monitoring of individually recognized animals in natural populations for advancing knowledge of parasite-host evolutionary dynamics and offering clues to the etiology and control of infectious disease.

Mental health care among low-income pregnant women with depressive symptoms: facilitators and barriers to care access and the effectiveness of financial incentives for increasing care.

Access to mental health care is suboptimal for low-income pregnant women. Using in-depth interviews, we examined barriers and facilitators to accessing care among 42 low income pregnant women with depressive symptoms. To pilot whether financial incentives would increase utilization during pregnancy, half the women were randomized to receive $10 gift cards after mental health visits. Women reported external and internal barriers to accessing mental health care, and internal and interpersonal facilitators. Financial incentives did not impact how often the women visited mental health providers, suggesting that small incentives are not sufficient to catalyze mental health care use for this population.