Using Extracellular Vesicles Released by GDNF-Transfected Macrophages for Therapy of Parkinson Disease

Extracellular vesicles (EVs) are cell-derived nanoparticles that facilitate transport of proteins, lipids, and genetic material, playing important roles in intracellular communication. They have remarkable potential as non-toxic and non-immunogenic nanocarriers for drug delivery to unreachable organs and tissues, in particular, the central nervous system (CNS). Herein, we developed a novel platform based on macrophage-derived EVs to treat Parkinson disease (PD). Specifically, we evaluated the therapeutic potential of EVs secreted by autologous macrophages that were transfected ex vivo to express glial-cell-line-derived neurotrophic factor (GDNF). EV-GDNF were collected from conditioned media of GDNF-transfected macrophages and characterized for GDNF content, size, charge, and expression of EV-specific proteins. The data revealed that, along with the encoded neurotrophic factor, EVs released by pre-transfected macrophages carry GDNF-encoding DNA. Four-month-old transgenic Parkin Q311(X)A mice were treated with EV-GDNF via intranasal administration, and the effect of this therapeutic intervention on locomotor functions was assessed over a year. Significant improvements in mobility, increases in neuronal survival, and decreases in neuroinflammation were found in PD mice treated with EV-GDNF. No offsite toxicity caused by EV-GDNF administration was detected. Overall, an EV-based approach can provide a versatile and potent therapeutic intervention for PD

Evidence-based beta blocker use associated with lower heart failure readmission and mortality, but not all-cause readmission, among Medicare beneficiaries hospitalized for heart failure with reduced ejection fraction.

The beta blockers carvedilol, bisoprolol, and sustained-release metoprolol succinate reduce readmissions and mortality among patients with heart failure with reduced ejection fraction (HFrEF), based upon clinical trial and registry studies. Results from these studies may not generalize to the typical patient with HFrEF. We conducted a retrospective cohort study of beneficiaries in the Medicare 5% sample hospitalized for HFrEF between 2007 and 2013 and were discharged alive. We compared the 30-day and 365-day heart failure (HF) readmission, all-cause readmission, and mortality rates between beneficiaries who filled a prescription for an evidence-based beta blocker and those who did not after being hospitalized for HFrEF. Out of 12,127 beneficiaries hospitalized for HFrEF, 20% were readmitted for HF, 62% were readmitted for any cause, and 27% died within 365 days. In competing risk models adjusted for demographics, healthcare utilization, and comorbidities, beta blocker use was associated with a lower risk of HF readmission between 8-365 days post discharge (hazard ratio 0.79 [95% confidence interval 0.76, 0.82]), but was not significantly associated with all-cause readmission (1.02 [0.97-1.07]). In Cox models adjusted for the same covariates, beta blocker use was associated with lower mortality 8-365 days post discharge (0.65 [0.60-0.71]). Results were similar when follow up was truncated at 30 days post discharge. Increasing the use of beta blockers following HFrEF hospitalization may not decrease all-cause readmissions among Medicare beneficiaries, but may reduce HF-specific readmissions and mortality

Using Extracellular Vesicles Released by GDNF-Transfected Macrophages for Therapy of Parkinson Disease

Extracellular vesicles (EVs) are cell-derived nanoparticles that facilitate transport of proteins, lipids, and genetic material, playing important roles in intracellular communication. They have remarkable potential as non-toxic and non-immunogenic nanocarriers for drug delivery to unreachable organs and tissues, in particular, the central nervous system (CNS). Herein, we developed a novel platform based on macrophage-derived EVs to treat Parkinson disease (PD). Specifically, we evaluated the therapeutic potential of EVs secreted by autologous macrophages that were transfected ex vivo to express glial-cell-line-derived neurotrophic factor (GDNF). EV-GDNF were collected from conditioned media of GDNF-transfected macrophages and characterized for GDNF content, size, charge, and expression of EV-specific proteins. The data revealed that, along with the encoded neurotrophic factor, EVs released by pre-transfected macrophages carry GDNF-encoding DNA. Four-month-old transgenic Parkin Q311(X)A mice were treated with EV-GDNF via intranasal administration, and the effect of this therapeutic intervention on locomotor functions was assessed over a year. Significant improvements in mobility, increases in neuronal survival, and decreases in neuroinflammation were found in PD mice treated with EV-GDNF. No offsite toxicity caused by EV-GDNF administration was detected. Overall, an EV-based approach can provide a versatile and potent therapeutic intervention for PD

Alterations in zonal distribution and plasma membrane localization of hepatocyte bile acid transporters in patients with NAFLD

Background:. NAFLD is highly prevalent with limited treatment options. Bile acids (BAs) increase in the systemic circulation and liver during NAFLD progression. Changes in plasma membrane localization and zonal distribution of BA transporters can influence transport function and BA homeostasis. However, a thorough characterization of how NAFLD influences these factors is currently lacking. This study aimed to evaluate the impact of NAFLD and the accompanying histologic features on the functional capacity of key hepatocyte BA transporters across zonal regions in human liver biopsies. Methods:. A novel machine learning image classification approach was used to quantify relative zonal abundance and plasma membrane localization of BA transporters (bile salt export pump [BSEP], sodium-taurocholate cotransporting polypeptide, organic anion transporting polypeptides [OATP] 1B1 and OATP1B3) in non-diseased (n = 10), NAFL (n = 9), and NASH (n = 11) liver biopsies. Based on these data, membrane-localized zonal abundance (MZA) measures were developed to estimate transporter functional capacity. Results:. NAFLD diagnosis and histologic scoring were associated with changes in transporter membrane localization and zonation. Increased periportal BSEPMZA (mean proportional difference compared to non-diseased liver of 0.090) and decreased pericentral BSEPMZA (−0.065) were observed with NASH and also in biopsies with higher histologic scores. Compared to Non-diseased Liver, periportal OATP1B3MZA was increased in NAFL (0.041) and NASH (0.047). Grade 2 steatosis (mean proportional difference of 0.043 when compared to grade 0) and grade 1 lobular inflammation (0.043) were associated with increased periportal OATP1B3MZA. Conclusions:. These findings provide novel mechanistic insight into specific transporter alterations that impact BA homeostasis in NAFLD. Changes in BSEPMZA likely contribute to altered BA disposition and pericentral microcholestasis previously reported in some patients with NAFLD. BSEPMZA assessment could inform future development and optimization of NASH-related pharmacotherapies

Occupational Exposures and Cardiac Structure and Function: ECHO-SOL (Echocardiographic Study of Latinos)

Background Our objective was to determine associations of occupational exposures with cardiac structure and function in Hispanic/Latino adults. Methods and Results Employed participants were included (n=782; 52% women, mean age 52.9 years). Occupational exposures to burning wood, vehicle exhaust, solvents, pesticides, and metals at the current and longest-held job were assessed by questionnaire. Survey multivariable linear regression analyses were used to model the relationship of each self-reported exposure with echocardiographic measures of cardiac structure and function. Exposure to burning wood at the current job was associated with decreased left ventricular (LV) ejection fraction (-3.1%; standard error [SE], 1.0 [ =0.002]). When the analysis was restricted to exposure at the longest-held job, occupational exposure to burning wood was associated with increased LV diastolic volume (6.7 mL; SE, 1.6 [ <0.0001]), decreased LV ejection fraction (-2.7%; SE, 0.6 [ <0.0001]), worse LV global longitudinal strain (1.0%; SE, 0.3 [ =0.0009]), and decreased right ventricular fractional area change (-0.02; SE, 0.004 [ <0.001]). Exposure to pesticides was associated with worse average global longitudinal strain (0.8%; SE, 0.2 [ <0.0001]). Exposure to metals was associated with worse global longitudinal strain in the 2-chamber view (1.0%; SE, 0.5 [ =0.04]), increased stroke volume (3.6 mL; SE, 1.6 [ =0.03]), and increased LV mass indexed to BSA (9.2 g/m ; SE, 3.8 [ =0.01]) or height (4.4 g/m ; SE, 1.9 [ =0.02]). Conclusions Occupational exposures to burning wood, vehicle exhaust, pesticides, and metals were associated with abnormal parameters of LV and right ventricular systolic function. Reducing exposures to toxic chemicals and particulates in the workplace is a potential opportunity to prevent cardiovascular disease in populations at risk

Factors associated with undiagnosed diabetes among adults with diabetes: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

AimsTo investigate sociodemographic and health factors associated with undiagnosed diabetes among adults with diabetes in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).MethodsAmong 3384 adults with self-reported diabetes or undiagnosed diabetes in the baseline HCHS/SOL, we estimated odds ratios (OR) of being undiagnosed for demographic, cultural, access to care, and health factors.ResultsAmong individuals with diabetes, 37.0% were undiagnosed. After adjustment and compared to people of Mexican heritage, people of Cuban and South American heritage had 60% (OR = 1.60, 95% CI = 1.02-2.50) and 91% (OR = 1.91, 1.16-3.14) higher odds of being undiagnosed, respectively. Individuals with a higher odds of being undiagnosed were women (OR = 1.64, 1.26-2.13), those with no health insurance (OR = 1.31, 1.00-1.71), individuals who received no healthcare in the past year (OR = 3.59, 2.49-5.16), those who were overweight (vs. normal weight) (OR = 1.60, 1.02-2.50), and those with dyslipidemia (OR = 1.38, 1.10-1.74). Individuals with lower odds of being undiagnosed were those with a family history of diabetes (OR = 0.54, 0.43-0.68), and those with hypertension (OR = 0.46, 0.36-0.58).ConclusionsVariation by Hispanic heritage group, sex, and access to medical care highlight where concentrated efforts are need to improve diabetes awareness. Our findings will inform clinical and public health practices to improve diabetes awareness among vulnerable populations

Factors associated with undiagnosed diabetes among adults with diabetes: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

AimsTo investigate sociodemographic and health factors associated with undiagnosed diabetes among adults with diabetes in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).MethodsAmong 3384 adults with self-reported diabetes or undiagnosed diabetes in the baseline HCHS/SOL, we estimated odds ratios (OR) of being undiagnosed for demographic, cultural, access to care, and health factors.ResultsAmong individuals with diabetes, 37.0% were undiagnosed. After adjustment and compared to people of Mexican heritage, people of Cuban and South American heritage had 60% (OR = 1.60, 95% CI = 1.02-2.50) and 91% (OR = 1.91, 1.16-3.14) higher odds of being undiagnosed, respectively. Individuals with a higher odds of being undiagnosed were women (OR = 1.64, 1.26-2.13), those with no health insurance (OR = 1.31, 1.00-1.71), individuals who received no healthcare in the past year (OR = 3.59, 2.49-5.16), those who were overweight (vs. normal weight) (OR = 1.60, 1.02-2.50), and those with dyslipidemia (OR = 1.38, 1.10-1.74). Individuals with lower odds of being undiagnosed were those with a family history of diabetes (OR = 0.54, 0.43-0.68), and those with hypertension (OR = 0.46, 0.36-0.58).ConclusionsVariation by Hispanic heritage group, sex, and access to medical care highlight where concentrated efforts are need to improve diabetes awareness. Our findings will inform clinical and public health practices to improve diabetes awareness among vulnerable populations