E-selectin targeted immunoliposomes for rapamycin delivery to activated endothelial cells

Activated endothelial cells play a pivotal role in the pathology of inflammatory disorders and thus present a target for therapeutic intervention by drugs that intervene in inflammatory signaling cascades, such as rapamycin (mammalian target of rapamycin (mTOR) inhibitor). In this study we developed anti-E-selectin immunoliposomes for targeted delivery to E-selectin over-expressing tumor necrosis factor-alpha (TNF-alpha) activated endothelial cells. Liposomes composed of 1,2-dipalmitoyl-sn-glycero-3.; hosphocholine (DPPC), Cholesterol, and 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000]-maleimide (DSPE-PEG- Mal) were loaded with rapamycin via lipid film hydration, after which they were further functionalized by coupling N-succinimidyl-S-acetylthioacetate (SATA)-modified mouse anti human E-selectin antibodies to the distal ends of the maleimidyl (Mal)-PEG groups. In cell binding assays, these immunoliposomes bound specifically to TNF-alpha activated endothelial cells. Upon internalization, rapamycin loaded immunoliposomes inhibited proliferation and migration of endothelial cells, as well as expression of inflammatory mediators. Our findings demonstrate that rapamycin-loaded immunoliposomes can specifically inhibit inflammatory responses in inflamed endothelial cells

Utility of Intravenous Curcumin Nanodelivery Systems for Improving In Vivo Pharmacokinetics and Anticancer Pharmacodynamics

Curcumin nanoformulations for intravenous injection have been developed to offset poor absorption, biotransformation, degradation, and excessive clearance associated with parenteral delivery. This review investigates (1) whether intravenous nanoformulations improve curcumin pharmacokinetics (PK) and (2) whether improved PK yields greater therapeutic efficacy. Standard PK parameters (measured maximum concentration [ C max], area under the curve [AUC], distribution volume [ V d], and clearance [CL]) of intravenously administered free curcumin in mice and rats were sourced from literature and compared to curcumin formulated in nanoparticles, micelles, and liposomes. The studies that also featured analysis of pharmacodynamics (PD) in murine cancer models were used to determine whether improved PK of nanoencapsulated curcumin resulted in improved PD. The distribution and clearance of free and nanoformulated curcumin were very fast, typically accounting for >80% curcumin elimination from plasma within 60 min. Case-matched analysis demonstrated that curcumin nanoencapsulation generally improved curcumin PK in terms of measured C max ( n = 27) and AUC ( n = 33), and to a lesser extent V d and CL. However, when the data were unpaired and clustered for comparative analysis, only 5 out of the 12 analyzed nanoformulations maintained a higher relative curcumin concentration in plasma over time compared to free curcumin. Quantitative analysis of the mean plasma concentration of free curcumin versus nanoformulated curcumin did not reveal an overall marked improvement in curcumin PK. No correlation was found between PK and PD, suggesting that augmentation of the systemic presence of curcumin does not necessarily lead to greater therapeutic efficacy

Tetrachloroethylene (PCE, Perc) Levels in Residential Dry Cleaner Buildings in Diverse Communities in New York City

Fugitive tetrachloroethylene (PCE, perc) emissions from dry cleaners operating in apartment buildings can contaminate residential indoor air. In 1997, New York State and New York City adopted regulations to reduce and contain perc emissions from dry cleaners located in residential and other buildings. As part of a New York State Department of Health (NYSDOH) study, indoor air perc levels were determined in 65 apartments located in 24 buildings in New York City where dry cleaners used perc on site. Sampling occurred during 2001–2003, and sampled buildings were dispersed across minority and nonminority as well as low-income and higher income neighborhoods. For the entire study area, the mean apartment perc level was 34 μg/m(3), 10-fold lower than mean apartment levels of 340–360 μg/m(3) documented before 1997. The maximum detected perc level was 5,000 μg/m(3), 5-fold lower than the maximum of 25,000 μg/m(3) documented before 1997. Despite these accomplishments, perc levels in 17 sampled apartments still exceeded the NYSDOH residential air guideline of 100 μg/m(3), and perc levels in 4 sampled apartments exceeded 1,000 μg/m(3). Moreover, mean indoor air perc levels in minority neighborhoods (75 μg/m(3)) were four times higher than in nonminority households (19 μg/m(3)) and were > 10 times higher in low-income neighborhoods (256 μg/m(3)) than in higher income neighborhoods (23 μg/m(3)). Logistic regression suitable for clustered data (apartments within buildings) indicated that perc levels on floors 1–4 were significantly more likely to exceed 100 μg/m(3) in buildings located in minority neighborhoods (odds ratio = 6.7; 95% confidence interval, 1.5–30.5) than in nonminority neighborhoods. Factors that may be contributing to the elevated perc levels detected, especially in minority and low-income neighborhoods, are being explored

Long-term mortality in HIV patients virally suppressed for more than three years with incomplete CD4 recovery: A cohort study

<p>Abstract</p> <p>Background</p> <p>The mortality in patients with persistent low CD4 count despite several years of HAART with sustained viral suppression is poorly documented. We aimed to identify predictors for inadequate CD4 cell recovery and estimate mortality in patients with low CD4 count but otherwise successful HAART.</p> <p>Method</p> <p>In a nationwide cohort of HIV patients we identified all individuals who started HAART before 1 January 2005 with CD4 cell count ≤ 200 cells/μL and experienced three years with sustained viral suppression. Patients were categorized according to CD4 cell count after the three years suppressed period (≤ 200 cells/μL; immunological non-responders (INRs), >200 cells/μL; immunological responders (IRs)). We used logistic regression and Kaplan-Meier analysis to estimated risk factors and mortality for INRs compared to IRs.</p> <p>Results</p> <p>We identified 55 INRs and 236 IRs. In adjusted analysis age > 40 years and > one year from first CD4 cell count ≤ 200 cells/μL to start of the virologically suppressed period were associated with increased risk of INR. INRs had substantially higher mortality compared to IRs. The excess mortality was mainly seen in the INR group with > one year of immunological suppression prior to viral suppression and injection drug users (IDUs).</p> <p>Conclusion</p> <p>Age and prolonged periods of immune deficiency prior to successful HAART are risk factors for incomplete CD4 cell recovery. INRs have substantially increased long-term mortality mainly associated with prolonged immunological suppression prior to viral suppression and IDU.</p

Lung cancer in HIV patients and their parents: A Danish cohort study

<p>Abstract</p> <p>Background</p> <p>HIV patients are known to be at increased risk of lung cancer but the risk factors behind this are unclear.</p> <p>Methods</p> <p>We estimated the cumulative incidence and relative risk of lung cancer in 1) a population of all Danish HIV patients identified from the Danish HIV Cohort Study (n = 5,053) and a cohort of population controls matched on age and gender (n = 50,530) (study period; 1995 - 2009) and 2) their parents (study period; 1969 - 2009). Mortality and relative risk of death after a diagnosis of lung cancer was estimated in both populations.</p> <p>Results</p> <p>29 (0.6%) HIV patients vs. 183 (0.4%) population controls were diagnosed with lung cancer in the observation period. HIV patients had an increased risk of lung cancer (adjusted incidence rate ratio (IRR); 2.38 (95% CI; 1.61 - 3.53)). The IRR was considerably increased in HIV patients who were smokers or former smokers (adjusted IRR; 4.06 (95% CI; 2.66 - 6.21)), male HIV patients with heterosexual route of infection (adjusted IRR; 4.19 (2.20 - 7.96)) and HIV patients with immunosuppression (adjusted IRR; 3.25 (2.01 - 5.24)). Both fathers and mothers of HIV patients had an increased risk of lung cancer (adjusted IRR for fathers; 1.31 (95% CI: 1.09 - 1.58), adjusted IRR for mothers 1.35 (95% CI: 1.07 - 1.70)). Mortality after lung cancer diagnose was increased in HIV patients (adjusted mortality rate ratio 2.33 (95%CI; 1.51 - 3.61), but not in the parents. All HIV patients diagnosed with lung cancer were smokers or former smokers.</p> <p>Conclusion</p> <p>The risk was especially increased in HIV patients who were smokers or former smokers, heterosexually infected men or immunosuppressed. HIV appears to be a marker of behavioural or family related risk factors that affect the incidence of lung cancer in HIV patients.</p

Measuring enteric methane emissions from individual ruminant animals in their natural environment

Ruminant livestock are an important source of meat, milk, fiber, and labor for humans. The process by which ruminants digest plant material through rumen fermentation into useful product results in the loss of energy in the form of methane gas from consumed organic matter. The animal removes the methane building up in its rumen by repeated eructations of gas through its mouth and nostrils. Ruminant livestock are a notable source of atmospheric methane, with an estimated 17% of global enteric methane emissions from livestock. Historically, enteric methane was seen as an inefficiency in production and wasted dietary energy. This is still the case, but now methane is seen more as a pollutant and potent greenhouse gas. The gold standard method for measuring methane production from individual animals is a respiration chamber, which is used for metabolic studies. This approach to quantifying individual animal emissions has been used in research for over 100 years; however, it is not suitable for monitoring large numbers of animals in their natural environment on commercial farms. In recent years, several more mobile monitoring systems discussed here have been developed for direct measurement of enteric methane emissions from individual animals. Several factors (diet composition, rumen microbial community, and their relationship with morphology and physiology of the host animal) drive enteric methane production in ruminant populations. A reliable method for monitoring individual animal emissions in large populations would allow (1) genetic selection for low emitters, (2) benchmarking of farms, and (3) more accurate national inventory accounting

SQUIDs in biomagnetism : A roadmap towards improved healthcare

This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 686865.Peer reviewedPublisher PD

Testing Developmental Pathways to Antisocial Personality Problems

This study examined the development of antisocial personality problems (APP) in young adulthood from disruptive behaviors and internalizing problems in childhood and adolescence. Parent ratings of 507 children’s (aged 6–8 years) symptoms of attention deficit hyperactivity disorder, oppositional defiant disorder, and anxiety, were linked to self-ratings of adolescents’ (aged 14–16 years) symptoms of depression, substance use, conduct problems, and somatic problems, to predict self-ratings of APP in young adulthood (age 20–22 years). The findings suggested a hierarchical development of antisocial behavior problems. Despite being positively associated with conduct problems in adolescence, neither internalizing problems nor substance use added to the prediction of APP in young adulthood from conduct problems in adolescence. The developmental pathways to APP in young adulthood did not differ by gender