Search

The gastrointestinal tract may be a site of origin for α-synuclein pathology in idiopathic Parkinson’s disease (PD). Disruption of the autophagy-lysosome pathway (ALP) may contribute to α-synuclein aggregation. Here we examined epigenetic alterations in the ALP in the appendix by deep sequencing DNA methylation at 521 ALP genes. We identified aberrant methylation at 928 cytosines affecting 326 ALP genes in the appendix of individuals with PD and widespread hypermethylation that is also seen in the brain of individuals with PD. In mice, we find that DNA methylation changes at ALP genes induced by chronic gut inflammation are greatly exacerbated by α-synuclein pathology. DNA methylation changes at ALP genes induced by synucleinopathy are associated with the ALP abnormalities observed in the appendix of individuals with PD specifically involving lysosomal genes. Our work identifies epigenetic dysregulation of the ALP which may suggest a potential mechanism for accumulation of α-synuclein pathology in idiopathic PD., Dysfunction of the gastrointestinal system, and to the autophagy lysososmal pathway (ALP) have been reported in Parkinson’s disease. Here the authors report epigenetic disruption of ALP related genes in the appendix of individuals with Parkinson’s disease.

Non-invasive imaging markers in patients with repaired tetralogy of Fallot (rTOF) are still being investigated to inform clinical decision making. Atrial function is a prognostic indicator in many acquired and congenital heart diseases. We sought to examine the relationship between cardiac MRI (CMR)-derived indices of left atrial (LA) function, native left ventricular (LV) T1 values, biventricular systolic function, and exercise capacity in rTOF. Sixty-six patients with rTOF without prior pulmonary valve replacement who underwent CMR (median age 18.5 years) were identified. Twenty-one adult rTOF patients (age range 19–32 years) were compared with 20 age-matched healthy volunteers (age range 19–34 years). LA reservoir, conduit, and pump global longitudinal strain (GLS) and strain rate (SR) were determined by tissue tracking. Native LV T1 values were measured on rTOF patients. Pearson correlations were performed to determine bivariate associations. Adult rTOF patients had higher pump GLS, pump:conduit, and pump:reservoir GLS ratios, and lower conduit:reservoir GLS ratio, LV ejection fraction (EF), and right ventricular EF compared to controls (p

Data on medium-term outcomes in indivduals with myocarditis after mRNA COVID-19 vaccination are scarce. We aimed to assess clinical outcomes and quality of life at least 90 days since onset of myocarditis after mRNA COVID-19 vaccination in adolescents and young adults.In this follow-up surveillance study, we conducted surveys in US individuals aged 12-29 years with myocarditis after mRNA COVID-19 vaccination, for whom a report had been filed to the Vaccine Adverse Event Reporting System between Jan 12 and Nov 5, 2021. A two-component survey was administered, one component to patients (or parents or guardians) and one component to health-care providers, to assess patient outcomes at least 90 days since myocarditis onset. Data collected were recovery status, cardiac testing, and functional status, and EuroQol health-related quality-of-life measures (dichotomised as no problems or any problems), and a weighted quality-of-life measure, ranging from 0 to 1 (full health). The EuroQol results were compared with published results in US populations (aged 18-24 years) from before and early on in the COVID-19 pandemic.Between Aug 24, 2021, and Jan 12, 2022, we collected data for 519 (62%) of 836 eligible patients who were at least 90 days post-myocarditis onset: 126 patients via patient survey only, 162 patients via health-care provider survey only, and 231 patients via both surveys. Median patient age was 17 years (IQR 15-22); 457 (88%) patients were male and 61 (12%) were female. 320 (81%) of 393 patients with a health-care provider assessment were considered recovered from myocarditis by their health-care provider, although at the last health-care provider follow-up, 104 (26%) of 393 patients were prescribed daily medication related to myocarditis. Of 249 individuals who completed the quality-of-life portion of the patient survey, four (2%) reported problems with self-care, 13 (5%) with mobility, 49 (20%) with performing usual activities, 74 (30%) with pain, and 114 (46%) with depression. Mean weighted quality-of-life measure (0·91 [SD 0·13]) was similar to a pre-pandemic US population value (0·92 [0·13]) and significantly higher than an early pandemic US population value (0·75 [0·28]; p0·0001). Most patients had improvements in cardiac diagnostic marker and testing data at follow-up, including normal or back-to-baseline troponin concentrations (181 [91%] of 200 patients with available data), echocardiograms (262 [94%] of 279 patients), electrocardiograms (240 [77%] of 311 patients), exercise stress testing (94 [90%] of 104 patients), and ambulatory rhythm monitoring (86 [90%] of 96 patients). An abnormality was noted among 81 (54%) of 151 patients with follow-up cardiac MRI; however, evidence of myocarditis suggested by the presence of both late gadolinium enhancement and oedema on cardiac MRI was uncommon (20 [13%] of 151 patients). At follow-up, most patients were cleared for all physical activity (268 [68%] of 393 patients).After at least 90 days since onset of myocarditis after mRNA COVID-19 vaccination, most individuals in our cohort were considered recovered by health-care providers, and quality of life measures were comparable to those in pre-pandemic and early pandemic populations of a similar age. These findings might not be generalisable given the small sample size and further follow-up is needed for the subset of patients with atypical test results or not considered recovered.US Centers for Disease Control and Prevention.

The objective of the study was to determine normal global left ventricular reference values for T1 and T2 in children. This is a retrospective study that included healthy subjects, age 5-19 years, who underwent CMR for the indication of pectus excavatum from 2018 to 2019. Linear regression models were used to determine associations of native T1 and T2 values to heart rate, age, and other CMR parameters. 102 patients with a mean age of 14.0 ± 2.4 years were included (range 5.4-18.8). 87 (85%) were males and 15 (15%) were females. The mean global T1 was 1018 ± 25 ms and the mean T2 was 53 ± 3 ms. T1 was negatively correlated with age (r = - 0.39, p < 0.001) and positively correlated with heart rate (r = 0.32, p < 0.001) by univariate analysis. Multivariable analysis showed that age and heart rate were independently associated with T1. T2 demonstrated a weak negative correlation with age (r = - 0.20, p = 0.047) and no correlation with heart rate. There was no difference in T1 (p = 0.23) or T2 (p = 0.52) between genders. This study reports normal pediatric T1 and T2 values at a 1.5 Tesla scanner. T1 was dependent on age and heart rate, while T2 was less dependent on age with no correlation with heart rate.

This article investigates the effects of long-term bilingualism on the production of filled pauses (FPs; e.g., uh, um, eh, em) in the speech of Afrikaans-Spanish bilinguals from Patagonia, Argentina. The instrumental analysis draws from a corpus of sociolinguistic interviews obtained from three speaker groups: L1-Afrikaans/L2-Spanish bilinguals; L1-Spanish-comparison speakers, also from Patagonia; and L1-Afrikaans-comparison speakers from South Africa. In the data analysis, we examined relative FP usage (categorical outcomes), as well as phonetic measures of vowel quality and segmental duration (continuous outcomes). The results allude to multiple patterns of cross-language influence (e.g., L1-to-L2 influence, L2-to-L1 influence, bidirectional influence), which depend on the phonetic measure explored. Overall, the findings suggest that the patterns of cross-language phonetic influence observed in the L2 learning of traditionally understood lexical items likewise hold in the L2 learning of hesitation markers such as FPs.

Introduction: To promote the rational use of cardiovascular imaging in the delivery of high-quality and cost-effective care to patients with congenital heart disease (CHD), the American College of Cardiology developed Appropriate Use Criteria (AUC). We aimed to evaluate the appropriateness of indications for cardiac CT and MRI in patients with conotruncal defects and to identify factors associated with Maybe or Rarely Appropriate (M/R) indications. Methods: Twelve US centers contributed a median of 147 studies performed prior to AUC publication (01/2020) on patients with conotruncal defects. Studies were excluded if the patient did not receive primary cardiac care at the center or were not seen > 5 years prior to study date. To account for the nesting of physicians within center, a hierarchical generalized linear mixed model was used to account for center-level variation with physicians nested within center. Results: Of the 1,753 studies (20% CT, 80% MRI) from 12 centers, 16% (range 4-39%) were rated M/R and 2.4% were unclassifiable (Figure 1). Patients age Conclusions: Most cardiac CTs and MRIs ordered for the follow-up care of patients with conotruncal defects were rated Appropriate and nearly all were able to be classified. However, there was significant center-level variation and higher annual MRI volume was independently associated with lower odds of M/R rating. These findings inform future quality improvement initiatives.

Non-invasive imaging markers in patients with repaired tetralogy of Fallot (rTOF) are still being investigated to inform clinical decision making. Atrial function is a prognostic indicator in many acquired and congenital heart diseases. We sought to examine the relationship between cardiac MRI (CMR)-derived indices of left atrial (LA) function, native left ventricular (LV) T1 values, biventricular systolic function, and exercise capacity in rTOF.Sixty-six patients with rTOF without prior pulmonary valve replacement who underwent CMR (median age 18.5 years) were identified. Twenty-one adult rTOF patients (age range 19-32 years) were compared with 20 age-matched healthy volunteers (age range 19-34 years). LA reservoir, conduit, and pump global longitudinal strain (GLS) and strain rate (SR) were determined by tissue tracking. Native LV T1 values were measured on rTOF patients. Pearson correlations were performed to determine bivariate associations.Adult rTOF patients had higher pump GLS, pump:conduit, and pump:reservoir GLS ratios, and lower conduit:reservoir GLS ratio, LV ejection fraction (EF), and right ventricular EF compared to controls (p 0.001 for each comparison). LA conduit:reservoir GLS and pump:reservoir GLS had correlations to native LV T1 (ρ = 0.26, p = 0.03 and ρ = - 0.26, p = 0.03, respectively). LA reservoir SR had positive correlation to RV EF (ρ = 0.27, p = 0.03). There were no statistically significant correlations between LA function and exercise capacity.LA function is altered in adolescent and young adult patients with rTOF indicating worse diastolic function and relates to increasing native LV T1 values. Future studies are indicated to investigate the progression of adverse atrial-ventricular interactions and poor outcomes in this population.

Introduction: Variation in aortic root (AoR) rotational position affects flow dynamics in normal patients. Complications of arterial switch operation (ASO) for transposition of the great arteries (TGA) include aortic dilation and neo-aortic regurgitation (AR). We sought to assess the association of neo-AoR rotational position with neo-AoR and ascending aorta (AA) dilation and neo-AR in TGA after ASO. Methods: Patients after ASO for TGA who underwent cardiac magnetic resonance (CMR) from 2005-2020 were retrospectively reviewed. Neo-AoR rotational angle, indexed (to height) neo-AoR and AA dimensions, indexed left ventricular end diastolic volume (LVEDVi), and neo-aortic regurgitant fraction (RF) were obtained from CMR. Multivariable regression analysis for neo-AoR and AA dilation, RF, and LVEDVi were performed. Results: A total of 36 patients (78% male) were included. Median age at ASO was 5 days (3, 7) and at CMR was 17.1 years (12.3, 21.9). Rotational angle was 25% counterclockwise (+15°). There was no material association of neo-AoR and AA size with sex, age, and coronary artery anatomy. A quadratic term for neo-AoR rotational angle - increasing extremes of counterclockwise and clockwise angles - was significantly associated with neo-AoR dilation (p=0.03), AA dilation (p Conclusions: In conclusion, both clockwise and counterclockwise neo-AoR rotational position in TGA after ASO are associated with neo-AoR and AA dilation and LVEDVi. Counterclockwise rotational angle was associated with RF. Neo-AoR rotational position likely affects valve function and hemodynamics, leading to risk of neo-AR and aortic dilation.

The objective of the study was to determine normal global left ventricular reference values for T1 and T2 in children. This is a retrospective study that included healthy subjects, age 5-19 years, who underwent CMR for the indication of pectus excavatum from 2018 to 2019. Linear regression models were used to determine associations of native T1 and T2 values to heart rate, age, and other CMR parameters. 102 patients with a mean age of 14.0 ± 2.4 years were included (range 5.4-18.8). 87 (85%) were males and 15 (15%) were females. The mean global T1 was 1018 ± 25 ms and the mean T2 was 53 ± 3 ms. T1 was negatively correlated with age (r = - 0.39, p0.001) and positively correlated with heart rate (r = 0.32, p0.001) by univariate analysis. Multivariable analysis showed that age and heart rate were independently associated with T1. T2 demonstrated a weak negative correlation with age (r = - 0.20, p = 0.047) and no correlation with heart rate. There was no difference in T1 (p = 0.23) or T2 (p = 0.52) between genders. This study reports normal pediatric T1 and T2 values at a 1.5 Tesla scanner. T1 was dependent on age and heart rate, while T2 was less dependent on age with no correlation with heart rate.

Miscarriage and intrauterine growth restriction (IUGR) are devastating complications in fetal/neonatal alloimmune thrombocytopenia (FNAIT). We previously reported the mechanisms for bleeding diatheses, but it is unknown whether placental, decidual immune cells or other abnormalities at the maternal–fetal interface contribute to FNAIT. Here we show that maternal immune responses to fetal platelet antigens cause miscarriage and IUGR that are associated with vascular and immune pathologies in murine FNAIT models. Uterine natural killer (uNK) cell recruitment and survival beyond mid-gestation lead to elevated NKp46 and CD107 expression, perforin release and trophoblast apoptosis. Depletion of NK cells restores normal spiral artery remodeling and placental function, prevents miscarriage, and rescues hemorrhage in neonates. Blockade of NK activation receptors (NKp46, FcɣRIIIa) also rescues pregnancy loss. These findings shed light on uNK antibody-dependent cell-mediated cytotoxicity of invasive trophoblasts as a pathological mechanism in FNAIT, and suggest that anti-NK cell therapies may prevent immune-mediated pregnancy loss and ameliorate FNAIT., Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a gestational disease caused by maternal immune responses against fetal platelets. Using a FNAIT mouse model and human trophoblast cell lines, here the authors show that uterine natural killer cell-mediated trophoblast apoptosis contributes to FNAIT pathogenesis.

Hemispheric asymmetry in neuronal processes is a fundamental feature of the human brain and drives symptom lateralization in Parkinson’s disease (PD), but its molecular determinants are unknown. Here, we determine epigenetic differences involved in hemispheric asymmetry in the healthy and the PD brain. Neurons of the healthy brain exhibit numerous hemispheric differences in DNA methylation, which affect genes implicated in neurodegenerative diseases. In PD patients, hemispheric asymmetry in DNA methylation is even greater and involves many PD risk genes. The lateralization of clinical PD symptoms involves epigenetic, transcriptional, and proteomic differences across hemispheres that affect neurodevelopment, immune activation, and synaptic transmission. During aging, healthy neurons show a progressive loss of hemispheric asymmetry in the epigenome, which is amplified in PD. For PD patients, a long disease course is associated with greater hemispheric asymmetry in neuronal epigenomes than a short disease course. Hemispheric differences in epigenetic gene regulation are prevalent in neurons and may affect the progression and symptoms of PD.

IMPORTANCE: Many clinicians do not discuss long-term prognosis with their patients due to uncertainty associated with the prognostic estimate and fear of causing psychological harm. For clinicians with experience discussing long-term prognosis, there are limited descriptions of the perceived benefits of having these conversations, as well as of preferred communication strategies. OBJECTIVE: To characterize the goals and approaches of clinicians with experience discussing long-term prognostic information with older adults. DESIGN: We used a semi-structured interview guide containing two key domains of perceived benefits and strategies to explore why and how clinicians choose to discuss long-term prognosis with patients. Long-term prognosis was defined as life expectancy on the scale of years. Clinician responses were analyzed qualitatively using the constant comparisons approach. SETTING: Clinicians from home-based primary care practices, community-based clinics, and academic medical centers across San Francisco. PARTICIPANTS: Fourteen physicians, including eleven geriatricians, and one geriatric nurse practitioner with a mean age of 40 years and mean 9 years in practice. RESULTS: Perceived benefits of discussing long-term prognosis included (1) establishing realistic expectations for patients, (2) encouraging conversations about future planning, and (3) promoting shared decision-making through understanding of patient goals of care. Communication strategies included (1) adapting discussions to individual patient preferences and (2) engaging in multiple conversations over time. Clinicians preferred to communicate prognosis both in words and with a visual aid, though most did not know of a suitable visual aid. CONCLUSION: Engaging in tailored, longitudinal discussions of long-term prognosis aids clinicians in anchoring conversations about future planning and preparing patients for the end of life.

In this chapter, the authors trace the development of non-profit organizations in China. They then identify the context to, and characteristics of communications in the NGO sector focusing on advocacy INGOs and national NGOs. The importance of using a variety of tactics to influence change, from an in-depth case report to digital communications, is illustrated through the case study about Greenpeace’s Hungry Coal campaign. Some challenges of INGO communications are further explored in an interview with an anonymous campaigner.

This retrospective cohort study examines whether patients with type 2 diabetes on hospice are assessed for dysglycemia, receive insulin or oral hypoglycemic medications, or experience hypoglycemia and hyperglycemia in the nursing home setting.

Right ventricular (RV) end-diastolic volume measured by cardiovascular magnetic resonance imaging (CMR) is a criterion for pulmonary valve replacement in patients with tetralogy of Fallot (TOF). We sought to determine if the ratio of echocardiographic, short-axis RV-to-left ventricular (LV) end-diastolic areas (EDA) could be used to predict RV volume on CMR. We retrospectively reviewed the echocardiograms of all patients with repaired TOF who underwent CMR at our institution from 2011 to 2015 and also had an echocardiogram within 6 months of the CMR. The short-axis RV and LV EDAs were measured and the ratio of the two was calculated. Results were compared with CMR RV end-diastolic volume index (RVEDVi) and RV:LV end-diastolic volume ratio. The sensitivity and specificity values predicting RV volumes > 150 ml/m2 were calculated. Fifty-eight studies met inclusion criteria. There were 47 studies with RVEDVi 150 ml/m2. RV:LV EDA and CMR RV:LV end-diastolic volume ratio correlated strongly (r = 0.76, p 150 ml/m2 (area under the curve = 0.74, 95% CI 1.5-27.9; p = 0.012). An RV:LV EDA ≥ 1.88 had an 81% specificity to detect RV volume index > 150 ml/m2. Short-axis RV:LV EDA correlates well with an increased RVEDVi as measured by CMR. This new and simple measure can be used to predict optimal timing for CMR in anticipation of pulmonary valve replacement in repaired TOF.

Importance Long-term prognosis informs clinical and personal decisions for older adults with late-life disability. However, many clinicians worry that telling patients their prognosis may cause harm. Objective To explore the safety of and reactions to prognosis communication in late-life disability. Design Participants estimated their own life expectancy and were then presented their calculated life expectancy using a validated prognostic index. We used a semi-structured interview guide to ask for their reactions. Qualitative data were analyzed using constant comparative analysis. Potential psychological and behavioral outcomes in response to receiving one's calculated prognosis were recorded and re-assessed 2–4 weeks later. Setting Community-dwelling older adults age 70+ residing in the San Francisco Bay Area. Participants Thirty five older adults with a median age of 80 requiring assistance with ≥1 Activity of Daily Living. Results Self-estimates of life expectancy were similar to calculated results for 16 participants. 15 estimated their life expectancy to be longer than their calculated life expectancy by >2 years, while 4 shorter by >2 years. An overarching theme of, “fitting life expectancy into one's narrative” emerged from qualitative analysis. Discussing life expectancy led participants to express how they could alter their life expectancy (subtheme “locus of control”), how they saw their present health (subtheme “perceived health”), and their hopes and fears for the remaining years of their lives (subtheme “outlook on remaining years”). Feelings of anxiety and sadness in reaction to receiving calculated prognosis were rare. Conclusions and Relevance About half of the disabled older adults' self-estimates of prognosis were similar to calculated estimates. Evidence of sadness or anxiety was rare. These data suggest that in most cases, clinicians may offer to discuss prognosis.

Low income is strongly associated with adverse health outcomes. Wealth may be a better marker of resources in late life than income. Our objective was to determine the relationship of wealth with mortality and disability (defined as activity of daily living difficulty) among older adults in the US and England. The US Health and Retirement Study (HRS) and English Longitudinal Study on Ageing (ELSA) are nationally representative cohorts of community-dwelling older adults. We examined participants enrolled in HRS (N = 13,533) and ELSA (N = 8,886) in 2002, stratifying our analyses by age (50–64 vs 66–80) as many safety-net programs commence around age 65. Wealth quintile was based on total net-worth in 2002. Participants were followed until 2012 for mortality and disability. We found increased risk of both death and disability as wealth decreased. In the US, participants age 50–64 in the lowest wealth quintile (Q1) ($553,000) had a 6% risk of mortality and 15% risk of disability. In England, 50–64 year olds in Q1 (£303,000) had a 4% risk of mortality and 11% risk of disability. In 66–80 year olds, the absolute risks of mortality and disability were higher, but the risk gradient across wealth quintiles did not differ. Low wealth was similarly associated with death and disability in both the US and England.

We sought to determine the relationship between aortic valve morphology and left ventricular (LV) systolic function in children with aortic stenosis (AS) prior to balloon aortic valvuloplasty (BAV).Both aortic valve morphology and LV systolic function have been linked with outcomes in children with congenital AS undergoing BAV. The relationship between aortic valve morphology and LV function is poorly defined despite their importance in regard to outcomes.We performed a retrospective multicenter cohort study of 89 AS patients who underwent BAV between 2007-2013. Pre-BAV echocardiograms were analyzed for: aortic valve opening (AVO); aortic valve type (true bicuspid, functionally bicuspid, or unicuspid); maximal raphe length; aortic valve leaflet symmetry; and valve angle of excursion. The primary endpoint was low function, defined as LV shortening fraction (LVSF)28%.Median patient age was 0.17 years (interquartile range [IQR], 0.10-10.74 years) and the median aortic valve mean gradient was 47.00 mm Hg (IQR, 36.75-56.00 mm Hg). Multivariate analysis demonstrated that low AVO (P=.03) was associated with reduced LV function, independent of age or aortic valve gradient (R² = .652). Bicuspid aortic valve (P=.07) was associated with improved LV function compared with functionally unicuspid aortic valve. Low AVO0.10 was associated with higher adverse outcome.LV systolic function is most significantly influenced by degree of valve stenosis. Qualitative aspects such as valve type may also affect LV systolic function. Further study may elucidate whether aortic valve morphology or LV function is the principal predictor of response to BAV and of late outcomes after BAV.

148 Background: Although radiation therapy (RT) for prostate cancer is generally well tolerated, frail older adults with less functional reserve may experience more toxicity and loss of independence. Our objective was to determine trajectories of activities of daily living (ADL) for prostate cancer patients admitted to a nursing home for RT. Methods: We used the Veterans Affairs (VA) Minimum Data Set (MDS) to identify men age ≥65 with an ICD9 diagnosis of prostate cancer living in a VA nursing facility (CLC) 1/2005-12/2015, an MDS evaluation reporting RT and no ICD9 code for bone metastasis. Functional status was assessed using MDS-ADL score (range 0-28, higher scores = greater disability). A piecewise linear mixed effects model (nodes at months 1 and 3) modeled the relationship between baseline characteristics and MDS-ADL score. Results: 645 patients were identified, of whom 585 (90.7%) had not resided in a CLC prior to RT. Median age 74 (range 65-94), median baseline PSA 5.33 ng/mL (IQR 1-14.57), and median Charlson Comorbidity Index (CCI) 5 (30.5% CCl ≥8). Baseline median MDS-ADL score was 1 (range 0-28). Patients with CCI 2-3 did not have appreciable change in functional status in 6 months following start of RT, while patients with CCI 4-7 had an increase months 1-3, followed by improvement (Table). Compared to patients with CCI 2-3, those with CCl ≥8 had an increase in MDS-ADL score of 1.8 points/month months 1-3 after starting RT (p = 0.008), and increase in MDS-ADL score of 3 points/month from 3 months onward (p < 0.001). Older age and higher CCI were associated with increase in MDS-ADL score (p < 0.05). Conclusions: In a cohort of elderly prostate cancer patients with significant comorbidity, RT led to different functional trajectories depending on comorbidity burden. While patients with moderate comorbidity had an initial decline in functional status followed by improvement, patients with high comorbidity had continued functional decline. [Table: see text]

Platelet P-selectin plays important roles in inflammation and contributes to thrombosis and hemostasis. Although it has been reported that von Willebrand factor (VWF) affects P-selectin expression on endothelial cells, little information is available regarding regulation of platelet P-selectin expression. Here, we first observed that P-selectin expression was significantly decreased on platelets of fibrinogen and VWF double-deficient mice. Subsequently, we identified this was due to fibrinogen deficiency. Impaired P-selectin expression on fibrinogen-deficient platelets was further confirmed in human hypofibrinogenemic patients. We demonstrated that this impairment is unlikely due to excessive P-selectin shedding, deficient fibrinogen-mediated cell surface P-selectin binding, or impaired platelet granule release, but rather is due to decreased platelet P-selectin content. Fibrinogen transfusion completely recovered this impairment in fibrinogen-deficient (Fg−/−) mice, and engagement of the C-terminus of the fibrinogen γ chain with β3 integrin was required for this process. Furthermore, Fg−/− platelets significantly increased P-selectin expression following transfusion into β3 integrin–deficient mice and when cultured with fibrinogen. These data suggest fibrinogen may play important roles in inflammation, thrombosis, and hemostasis via enhancement of platelet P-selectin expression. Since human fibrinogen levels vary significantly in normal and diseased populations, P-selectin as an activation marker on platelets should be used with caution.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening disease in which intracranial hemorrhage (ICH) is the major risk. Although thrombocytopenia, which is caused by maternal antibodies against β3 integrin and occasionally by maternal antibodies against other platelet antigens, such as glycoprotein GPIbα, has long been assumed to be the cause of bleeding, the mechanism of ICH has not been adequately explored. Utilizing murine models of FNAIT and a high-frequency ultrasound imaging system, we found that ICH only occurred in fetuses and neonates with anti-β3 integrin-mediated, but not anti-GPIbα-mediated, FNAIT, despite similar thrombocytopenia in both groups. Only anti-β3 integrin-mediated FNAIT reduced brain and retina vessel density, impaired angiogenic signaling, and increased endothelial cell apoptosis, all of which were abrogated by maternal administration of intravenous immunoglobulin (IVIG). ICH and impairment of retinal angiogenesis were further reproduced in neonates by injection of anti-β3 integrin, but not anti-GPIbα antisera. Utilizing cultured human endothelial cells, we found that cell proliferation, network formation, and AKT phosphorylation were inhibited only by murine anti-β3 integrin antisera and human anti-HPA-1a IgG purified from mothers with FNAIT children. Our data suggest that fetal hemostasis is distinct and that impairment of angiogenesis rather than thrombocytopenia likely causes FNAIT-associated ICH. Additionally, our results indicate that maternal IVIG therapy can effectively prevent this devastating disorder.

Low income has been associated with poor health outcomes. Owing to retirement, wealth may be a better marker of financial resources among older adults.To determine the association of wealth with mortality and disability among older adults in the United States and England.The US Health and Retirement Study (HRS) and English Longitudinal Study of Aging (ELSA) are nationally representative cohorts of community-dwelling older adults. We examined 12 173 participants enrolled in HRS and 7599 enrolled in ELSA in 2002. Analyses were stratified by age (54-64 years vs 66-76 years) because many safety-net programs commence around age 65 years. Participants were followed until 2012 for mortality and disability.Wealth quintile, based on total net worth in 2002.Mortality and disability, defined as difficulty performing an activity of daily living.A total of 6233 US respondents and 4325 English respondents aged 54 to 64 years (younger cohort) and 5940 US respondents and 3274 English respondents aged 66 to 76 years (older cohort) were analyzed for the mortality outcome. Slightly over half of respondents were women (HRS: 6570, 54%; ELSA: 3974, 52%). A higher proportion of respondents from HRS were nonwhite compared with ELSA in both the younger (14% vs 3%) and the older (13% vs 3%) age cohorts. We found increased risk of death and disability as wealth decreased. In the United States, participants aged 54 to 64 years in the lowest wealth quintile (Q1) (≤$39 000) had a 17% mortality risk and 48% disability risk over 10 years, whereas in the highest wealth quintile (Q5) ($560 000) participants had a 5% mortality risk and 15% disability risk (mortality hazard ratio [HR], 3.3; 95% CI, 2.0-5.6; P .001; disability subhazard ratio [sHR], 4.0; 95% CI, 2.9-5.6; P .001). In England, participants aged 54 to 64 years in Q1 (≤£34,000) had a 16% mortality risk and 42% disability risk over 10 years, whereas Q5 participants (£310,550) had a 4% mortality risk and 17% disability risk (mortality HR, 4.4; 95% CI, 2.7-7.0; P .001; disability sHR, 3.0; 95% CI, 2.1-4.2; P .001). In 66- to 76-year-old participants, the absolute risks of mortality and disability were higher, but risk gradients across wealth quintiles were similar. When adjusted for sex, age, race, income, and education, HR for mortality and sHR for disability were attenuated but remained statistically significant.Low wealth was associated with death and disability in both the United States and England. This relationship was apparent from age 54 years and continued into later life. Access to health care may not attenuate wealth-associated disparities in older adults.

SummaryFetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder caused by maternal antibodies against fetal/neonatal platelets. FNAIT is also linked with miscarriages, although the incidence and mechanisms of fetal death have not been well studied. Integrin αIIbβ3 (GPIIbIIIa) and the GPIbα complex are major glycoproteins expressed on platelets and are also major antigens targeted in autoimmune thrombocytopenia (ITP), but reported cases of anti-GPIb-mediated FNAIT are rare. Bacterial and viral infections have been causally linked with the pathogenesis of immune-mediated thrombocytopenia (ITP); however, it is unknown whether these infections contribute to the severity of FNAIT. Here, immune responses against platelet antigens were examined by transfusing wild-type (WT) mouse platelets into β3-/- or GPIbα-/- mice. To mimic bacterial or viral infections, lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (Poly I:C) were injected intraperitoneally following platelet transfusions. The FNAIT model was established by breeding the immunised female mice with WT male mice. We demonstrated for the first time that the platelet GPIbα has lower immunogenicity compared to β3 integrin. Interestingly, co-stimulation with LPS or Poly I:C markedly enhanced the immune response against platelet GPIbα and caused severe pathology of FNAIT (i.e. miscarriages). LPS or Poly I:C also enhanced the immune response against platelet β3 integrin. Our data suggest that bacterial and viral infections facilitate the anti-platelet GPIbα response, which may lead to a severe non-classical FNAIT (i.e. miscarriage but not neonatal bleeding) that has not been adequately reported in humans.

Phagocytes were first described by Dr. Metchnikoff in 1873. The roles of phagocytes in innate and adaptive immunity have been well established to date, although the molecular mechanisms involved in initiating phagocytosis (through Fc or other receptors) remain to be further explored. Phagocytes in the reticuloendothelial system, particularly macrophages, have been implicated in the clearance of senescent blood cells. The destruction of these cells may be primarily mediated via an Fc-independent pathway. Fc-independent phagocytosis may also play an important role in platelet clearance, including in autoimmune thrombocytopenia (ITP), and in clearance of platelet-rich emboli detached from sites of vascular injury. In ITP, the two major platelet auto-antigens have been located on glycoprotein (GP)IIbIIIa and the GPIb complex. It has been demonstrated that anti-GPIb antibodies, in contrast to anti-GPIIbIIIa, can induce thrombocytopenia in an Fc-independent manner. We further demonstrated in an animal model that intravenous IgG (IVIG) is unable to ameliorate thrombocytopenia caused by most anti-GPIb antibodies, despite its efficacy in anti- GPIIbIIIa-mediated thrombocytopenia. Our data was supported by subsequent retrospective studies with ITP patients by several independent groups. Most recently, we found that anti-GPIb-mediated ITP was also resistant to steroid therapy and that platelet activation and apoptosis induced by anti-GPIb antibodies may be involved in the Fc-independent platelet clearance. Therefore, identification of antibody specificity in patients, e.g. anti-GPIIbIIIa (Fc-dependent) versus anti-GPIb (Fc-independent), may be important for therapies against ITP, as well as other immune-mediated thrombocytopenias.

Platelets are small anucleate cells circulating in the blood. It has been recognized for more than 100 years that platelet adhesion and aggregation at the site of vascular injury are critical events in hemostasis and thrombosis; however, recent studies demonstrated that, in addition to these classic roles, platelets also have important functions in inflammation and the immune response. Platelets contain many proinflammatory molecules and cytokines (e.g., P-selectin, CD40L, IL-1β, etc.), which support leukocyte trafficking, modulate immunoglobulin class switch, and germinal center formation. Platelets express several functional Toll-like receptors (TLRs), such as TLR-2, TLR-4, and TLR-9, which may potentially link innate immunity with thrombosis. Interestingly, platelets also contain multiple anti-inflammatory molecules and cytokines (e.g., transforming growth factor-βand thrombospondin-1). Emerging evidence also suggests that platelets are involved in lymphatic vessel development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2. Besides the active contributions of platelets to the immune system, platelets are passively targeted in several immune-mediated diseases, such as autoimmune thrombocytopenia, infection-associated thrombocytopenia, and fetal and neonatal alloimmune thrombocytopenia. These data suggest that platelets are important immune cells and may contribute to innate and adaptive immunity under both physiological and pathological conditions.

Fetal and neonatal immune thrombocytopenia (FNIT) is a severe bleeding disorder caused by maternal antibody–mediated destruction of fetal/neonatal platelets. It is the most common cause of severe thrombocytopenia in neonates, but the frequency of FNIT-related miscarriage is unknown, and the mechanism(s) underlying fetal mortality have not been explored. Furthermore, although platelet αIIbβ3 integrin and GPIbα are the major antibody targets in immune thrombocytopenia, the reported incidence of anti-GPIbα–mediated FNIT is rare. Here, we developed mouse models of FNIT mediated by antibodies specific for GPIbα and β3 integrin and compared their pathogenesis. We found, unexpectedly, that miscarriage occurred in the majority of pregnancies in our model of anti-GPIbα–mediated FNIT, which was far more frequent than in anti-β3–mediated FNIT. Dams with anti-GPIbα antibodies exhibited extensive fibrin deposition and apoptosis/necrosis in their placentas, which severely impaired placental function. Furthermore, anti-GPIbα (but not anti-β3) antiserum activated platelets and enhanced fibrin formation in vitro and thrombus formation in vivo. Importantly, treatment with either intravenous IgG or a monoclonal antibody specific for the neonatal Fc receptor efficiently prevented anti-GPIbα–mediated FNIT. Thus, the maternal immune response to fetal GPIbα causes what we believe to be a previously unidentified, nonclassical FNIT (i.e., spontaneous miscarriage but not neonatal bleeding) in mice. These results suggest that a similar pathology may have masked the severity and frequency of human anti-GPIbα–mediated FNIT, but also point to possible therapeutic interventions.

Platelets are small anucleate cells generated from megakaryocytes in the bone marrow. After being released into the circulation, platelets play key roles in the surveillance of vascular injury, and can quickly adhere and aggregate at the site of injury, which are critical events for vascular repair and hemostasis. However, the same biological processes of platelet adhesion and aggregation may also cause thrombotic disorders. The formation of a platelet plug at sites of atherosclerotic lesion rupture is the most common mechanism leading to myocardial or cerebral infarction. Platelet-related deep vein thrombosis is also one of the leading causes of mortality worldwide. The contribution of several platelet receptors and their ligands has been highlighted in these processes. In platelet adhesion, particularly at high shear stress, GPIbα-von Willebrand factor (VWF) interaction may initiate this event, which is followed by GPVI signalling and firm platelet adhesion mediated by members of the integrin family, such as β3 (αIIbβ3) and β1 (α2β1, α5β1) integrins. In platelet aggregation, although GPIbα-VWF, P selectin-sulfatides, and other molecules, may be involved, the process is mainly mediated by β3 (αIIbβ3) integrin and its ligands, such as fibrinogen and VWF. It is intriguing that platelet adhesion and aggregation still occur in mice lacking both fibrinogen and VWF, suggesting that other unforeseen molecule(s) may also be important in these processes. Identification and characterization of these molecules will enrich our knowledge in the basic science of hemostasis and thrombosis, and may lead to the development of new therapies against bleeding disorders and thrombotic diseases.