Purpose
This work investigated the endocytic pathways taken by poly(isobutylcyanoacrylate) (PIBCA) nanoparticles differing in their surface composition and architecture, assuming that this might ...determine their efficiency of intracellular drug delivery.
Methods
Nanoparticles (A0, A25, A100, R0, R25 ) were prepared by anionic or redox radical emulsion polymerization using mixtures of dextran and fucoidan (0, 25, 100 % in fucoidan). Cell uptake was evaluated by incubating J774A.1 macrophages with nanoparticles. Endocytic pathways were studied by incubating cells with endocytic pathway inhibitors (chlorpromazine, genistein, cytochalasin D, methyl-ß-cyclodextrin and nocodazole) and nanoparticle uptake was evaluated by flow cytometry and confocal microscopy.
Results
The fucoidan-coated PIBCA nanoparticles A
25
were internalized 3-fold more efficiently than R
25
due to the different architecture of the fucoidan chains presented on the surface. Different fucoidan density and architecture led to different internalization pathway preferred by the cells. Large A
100
nanoparticles with surface was covered with fucoidan chains in a loop and train configuration were internalized the most efficiently, 47-fold compared with A
0
, and 3-fold compared with R
0
and R
25
through non-endocytic energy-independent pathways and reached the cell cytoplasm.
Conclusion
Internalization pathways of PIBCA nanoparticles by J774A.1 macrophages could be determined by nanoparticle fucoidan surface composition and architecture. In turn, this influenced the extent of internalization and localization of accumulated nanoparticles within cells. The results are of interest for rationalizing the design of nanoparticles for potential cytoplamic drug delivery by controlling the nature of the nanoparticle surface.
Graphical abstract
Diabetic Retinopathy Hendrick, Andrew M; Gibson, Maria V; Kulshreshtha, Ambar
Primary care,
09/2015, Letnik:
42, Številka:
3
Journal Article
Recenzirano
The prevalence of diabetes is on the rise globally as are the consequences, such as diabetic retinopathy. Diabetic retinopathy is a leading cause of vision loss in working-age adults in developed ...countries. Visual impairment as a result of diabetic retinopathy has a significant negative impact on the patient's quality of life and their ability to successfully manage their disease. Glycemic control, blood pressure normalization, and lipid management form the basis for long-term diabetes management and protection from worsening eye disease.
Fragility fractures are a strong indicator of underlying osteoporosis (OP). With the risk of future fracture being increased 1.5- to 9.5-fold following a fragility fracture, the diagnosis and ...treatment of OP in men and women with fragility fractures provides the opportunity to prevent future fragility fractures. This review describes the current status of practice in investigation and diagnosis of OP in men and women with fragility fractures, the rates and types of postfracture treatment in patients with fragility fractures and OP, interventions undertaken in this population, and the barriers to OP identification and treatment. A literature search performed in Medline, Healthstar, CINAHL, EMBASE, PreMedline, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews identified 37 studies on OP diagnosis, treatment, and interventions. The studies varied in design methodology, study facilities, types of fractures, and pharmacological treatments. Some studies revealed that no patients with fragility fractures received investigation or treatment for underlying OP. Investigation of OP by bone mineral density was low: 14 of 16 studies reported investigation of less than 32% of patients. Investigation by bone mineral density resulted in high rates of OP diagnosis (35-100%), but only moderate use of calcium and vitamin D (8-62%, median 18%) and bisphosphates (0.5-38%) in patients investigated postfracture. Studies on barriers to OP identification and treatment focused on various groups of health practitioners. Barriers included the cost of therapies, time and cost of resources for diagnosis, concerns about medications, and the lack of clarity regarding the responsibility to undertake this care.
Adolescents commonly experience loss due to death, and perceived closeness to the deceased can often increase the intensity of bereavement. Adolescents and early young adult (AeYA) oncology patients ...may recall previous losses or experience new losses, possibly of other children with cancer, while coping with their own increased risk of mortality. The bereavement experiences of AeYA patients are not well described in the literature.
This analysis of bereavement sought to describe the prevalence and types of losses, the support following a death, and the impact of loss on AeYAs aged 13-21 years with malignant disease (or a hematologic disorder requiring allogeneic transplant). Participants were receiving active oncologic therapy or had completed therapy within the past 3 years. Participants completed a bereavement questionnaire and inventories on depression, anxiety, and somatization. The cross-sectional study enrolled 153 AeYAs (95% participation), most (88%) of whom had experienced a loss due to death. The most commonly reported losses were of a grandparent (58%) or friend (37%). Peer deaths were predominantly cancer related (66%). Many participants (39%) self-identified a loss as "very significant." As loss significance increased, AeYAs were more likely to report that it had changed their life "a lot/enormously" (P<0.0001), that they were grieving "slowly or never got over it" (P<0.0001), and that they felt a need for more professional help (P = 0.026). Peer loss was associated with increased risk of adverse psychological outcomes (P = 0.029), as was parental loss (P = 0.018).
Most AeYAs with serious illness experience the grief process as slow or ongoing. Peer or parental loss was associated with increased risk of negative mental health outcomes. Given the high prevalence of peer loss, screening for bereavement problems is warranted in AeYAs with cancer, and further research on grief and bereavement is needed in AeYAs with serious illness.
Summary
Peptide immunotherapy (PIT) is a targeted therapeutic approach, involving administration of disease‐associated peptides, with the aim of restoring antigen‐specific immunological tolerance ...without generalized immunosuppression. In type 1 diabetes, proinsulin is a primary antigen targeted by the autoimmune response, and is therefore a strong candidate for exploitation via PIT in this setting. To elucidate the optimal conditions for proinsulin‐based PIT and explore mechanisms of action, we developed a preclinical model of proinsulin autoimmunity in a humanized HLA‐DRB1*0401 transgenic HLA‐DR4 Tg mouse. Once proinsulin‐specific tolerance is broken, HLA‐DR4 Tg mice develop autoinflammatory responses, including proinsulin‐specific T cell proliferation, interferon (IFN)‐γ and autoantibody production. These are preventable and quenchable by pre‐ and post‐induction treatment, respectively, using intradermal proinsulin‐PIT injections. Intradermal proinsulin‐PIT enhances proliferation of regulatory forkhead box protein 3 (FoxP3+)CD25high CD4 T cells, including those capable of proinsulin‐specific regulation, suggesting this as its main mode of action. In contrast, peptide delivered intradermally on the surface of vitamin D3‐modulated (tolerogenic) dendritic cells, controls autoimmunity in association with proinsulin‐specific IL‐10 production, but no change in regulatory CD4 T cells. These studies define a humanized, translational model for in vivo optimization of PIT to control autoimmunity in type 1 diabetes and indicate that dominant mechanisms of action differ according to mode of peptide delivery.
Pregnant women are at increased risk of venous thrombosis compared to non-pregnant women. Epidemiological and laboratory data suggest that hypercoagulability begins in the first trimester but it is ...unknown exactly how early in pregnancy this develops. The mechanisms that result in a prothrombotic state may involve oestrogens and progestogens.
Plasma samples were taken prior to conception and five times in early pregnancy, up to Day 59 gestation, from 22 women undergoing natural cycle in vitro fertilization, who subsequently gave birth at term following a normal pregnancy.
Thrombin generation, free Protein S, Ddimer, Fibrinogen, factor VIII, estradiol and progesterone were measured. To counter inter-individual variability, the change in laboratory measurements between the pre-pregnant and pregnant state were measured over time.
Peak thrombin, Endogenous Thrombin Potential, Velocity Index and fibrinogen significantly increased, and free Protein S significantly decreased, from pre-pregnancy levels, by 32 days gestation. Ddimer and VIII significantly increased from pre-pregnancy levels by 59 days gestation. Estradiol significantly increased by Day 32 gestation with a non-significant increase of 67% by Day 24 gestation. Progesterone significantly increased by Day 32 gestation. Almost all laboratory markers of thrombosis correlated significantly with estradiol and progesterone.
Our work is the first to demonstrate that the prothrombotic state develops very early in the first trimester. Laboratory markers of hypercoagulability correlate significantly with estradiol and progesterone suggesting these are linked to the prothrombotic state of pregnancy. Clinicians should consider commencing thromboprophylaxis early in the first trimester in women at high thrombotic risk.
•It is unclear how early in pregnancy women become hypercoagulable•This study measured markers of hypercoagulability during very early pregnancy•Laboratory hypercoagulability begins to develop during the fifth week of pregnancy•Estradiol and progesterone may be linked to the prothrombotic state of pregnancy•Consider starting thromboprophylaxis very early in high risk pregnant women
Research Priorities in Pediatric Palliative Care Baker, Justin N., MD; Levine, Deena R., MD; Hinds, Pamela S., PhD, RN, FAAN ...
The Journal of pediatrics,
08/2015, Letnik:
167, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Objective To synthesize the perspectives of a broad range of pediatric palliative care (PPC) clinicians and parents, to formulate a consensus on prioritization of the PPC research agenda. Study ...design A 4-round modified Delphi online survey was administered to PPC experts and to parents of children who had received PPC. In round 1, research priorities were generated spontaneously. Rounds 2 and 3 then served as convergence rounds to synthesize priorities. In round 4, participants were asked to rank the research priorities that had reached at least 80% consensus. Results A total of 3093 concepts were spontaneously generated by 170 experts and 72 parents in round 1 (65.8% response rate RR). These concepts were thematically organized into 78 priorities and recirculated for round 2 ratings (n = 130; 53.7% RR). Round 3 achieved response stability, with 31 consensus priorities oscillating within 10% of the mode (n = 98; 75.4% RR). Round 4 resulted in consensus recognition of 20 research priorities, which were thematically grouped as decision making, care coordination, symptom management, quality improvement, and education. Conclusions This modified Delphi survey used professional and parental consensus to identify preeminent PPC research priorities. Attentiveness to these priorities may help direct resources and efforts toward building a formative evidence base. Investigating PPC implementation approaches and outcomes can help improve the quality of care services for children and families.
This study aims to determine osteoporosis (OP) investigation and treatment within post-fracture initiatives conducted in fracture clinics and other orthopedic environments. A systematic review was ...conducted. Eligibility criteria were: hip fracture patients plus all other fracture patients presenting with a fragility fracture, orthopedic setting where orthopedic physicians/staff were involved, intervention to improve OP management, primary data on ≥20 patients from randomized controlled trials (RCTs) and other study designs. We calculated outcome data within 6 months of screening from an intention-to-treat principle to derive an equated proportion (EP) across interventions. Outcomes were: (1) proportion of patients investigated with bone densitometry, (2) proportion of patients initiating OP medication, and (3) proportion of patients taking OP medication. We identified 2,259 citations, of which 57 articles that included 64 intervention groups were eligible. The median EP for patients investigated was 43% and the 75th percentile was 71%. The median EP for medication initiation was 22% and the 75th percentile was 34%. The median EP for medication taking was 27.5% and the 75th percentile was 43%. The EPs for all outcomes were higher for interventions with dedicated personnel to implement the intervention and those within which bone mineral density testing and/or treatment were included. In studies with an EP, up to 71% of patients were investigated for OP, but <35% initiated medication, and <45% were taking medication within 6 months of screening. Calculating an EP allowed us to compare outcomes across the studies, therefore capturing both RCTs and other study designs typical of real-world settings.
Summary
We examined the demographic characteristics and risk factors of FLS fragility fracture patients who had sustained prior fragility fracture(s) and found that this is an important high-risk ...subgroup that warrants further attention within FLS priority pathways in order to disrupt their fragility fracture cycle.
Purpose
Our primary objective was to examine whether fragility fracture patients presenting to a provincial fracture liaison service (FLS) having a history of prior fractures, versus those without, differ in demographic characteristics and risk factors for future fracture. A secondary objective was to understand if those who report two or more prior fractures differ from those reporting one prior fracture.
Methods
This cohort study included fragility fracture patients aged 50 + enrolled in the Ontario FLS between July 2017 and September 2019. Patients with versus those without prior fractures were compared on age, sex, index fracture site, biological parents’ history of hip fracture, current fracture due to a fall, history of feeling unsteady when walking, history of falls in the past year, smoking, oral steroid use, and comorbid chronic conditions. Pearson’s chi-square, Fischer’s exact, and analysis of variance tests were used to assess differences.
Results
Among 14,454 patients, 16.8% (
n
= 2428) reported a history of one or more prior fractures after the age of 40. They were significantly more likely to be older, female, with a higher number of comorbidities, with greater incidence of falls, and feel unsteady when walking. Compared to those with one prior fracture, patients with greater than one prior fracture were more likely to report falls in the past year and feel unsteady when walking.
Conclusion
Findings suggest that FLS fragility fracture patients who had sustained prior fragility fracture are an important high-risk subgroup that warrants further attention within FLS priority pathways in order to disrupt their fragility fracture cycle.
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