Synthesis and characterisation of cationic quaternary ammonium-modified polyvinyl alcohol hydrogel beads as a drug delivery embolisation system

To extend the platform of clinically utilised chemoembolic agents based on ion-exchange systems to support the delivery of anionic drugs, a series of PVA-based beads was produced with different levels of (3-acrylamidopropyl)trimethylammonium chloride (APTA) in their formulation. The beads were characterised to confirm composition and the effect of formulation variation on physical properties was assessed. Suspension polymerisation was shown to successfully produce uniformly spherical copolymer beads with APTA content up to 60 wt%. Equilibrium water content and resistance to compression both increased with increasing APTA content in the formulation. Confocal laser scanning microscopy was used with model drugs to demonstrate that by increasing APTA content, compounds between the molecular weight range 70–250 kDa could permeate the microsphere structures. Interaction with anionic drugs was modelled using multivalent dyes. Dyes with multi-binding sites had increased interaction with the polymer, slowing the release and also demonstrating a reduced rate of elution from beads with higher charge density. The model drug release studies demonstrate that these systems can be engineered for different potential anionic drugs for local therapeutic delivery in the clinic

Psychosocial and physiologic correlates of perceived health among HIV-infected women

The purpose of this study was to identify factors related to perception of physical health in a cohort of HIV-infected women. A descriptive correlational design was used to identify factors influencing perceived physical health in a sample of 275 HIV-infected women in Georgia, South Carolina, and North Carolina. Participants were predominantly single African-American women with household incomes of less than $10,000 per year. Using Spearman’s rho, statistically significant positive correlations (p \u3c .05) were found between perceived physical health and T helper cell count, hope, present life satisfaction, education, and income. Statistically significant positive correlations (p \u3c.05) were observed between perceived physical health and three HIV-specific active coping styles (managing the illness, focusing on others, and positive thinking). Inverse relationships were observed between perceived physical health and HIVrelated symptoms, stage of illness, depression, physical and sexual violence experienced since becoming HIV-infected, history of drug use since becoming HIV-infected, and age. Using backward stepwise selection, 9 of 14 variables were retained in the final model that explained 60% of the variance in physical health at the p \u3c .10 level of significance (R2 = .60). Variables that demonstrated a significant relationship with perceived physical health were HIV-related symptoms, depression, present life satisfaction, age, education, coping by managing the illness, coping through positive thinking, and coping by focusing on the present. These findings support the need to address the psychosocial as well as the physiologic factors associated with HIV/AIDS in developing comprehensive plans of nursing care

A 31-day time to surgery compliant exercise training programme improves aerobic health in the elderly

Background: Over 41,000 people were diagnosed with colorectal cancer (CRC) in the UK in 2011. The incidence of CRC increases with age. Many elderly patients undergo surgery for CRC, the only curative treatment. Such patients are exposed to risks, which increase with age and reduced physical fitness. Endurance-based exercise training programmes can improve physical fitness, but such programmes do not comply with the UK, National Cancer Action Team 31-day time-to-treatment target. High-intensity interval training (HIT) can improve physical performance within 2–4 weeks, but few studies have shown HIT to be effective in elderly individuals, and those who do employ programmes longer than 31 days. Therefore, we investigated whether HIT could improve cardiorespiratory fitness in elderly volunteers, age-matched to a CRC population, within 31 days. Methods: This observational cohort study recruited 21 healthy elderly participants (8 male and 13 female; age 67 years (range 62–73 years)) who undertook cardiopulmonary exercise testing before and after completing 12 sessions of HIT within a 31-day period. Results: Peak oxygen consumption (VO2 peak) (23.9 ± 4.7 vs. 26.2 ± 5.4 ml/kg/min, p = 0.0014) and oxygen consumption at anaerobic threshold (17.86 ± 4.45 vs. 20.21 ± 4.11 ml/kg/min, p = 0.008) increased after HIT. Conclusions: It is possible to improve cardiorespiratory fitness in 31 days in individuals of comparable age to those presenting for CRC surgery

Towards Hypoxia-responsive Drug-eluting Embolization Beads

Drug release from chemoembolization microspheres stimulated by the presence of a chemically reducing environment may provide benefits for targeting drug resistant and metastatic hypoxic tumours. A water-soluble disulfide-based bifunctional cross-linker bis(acryloyl)-(l)-cystine (BALC) was synthesised, characterised and incorporated into a modified poly(vinyl) alcohol (PVA) hydrogel beads at varying concentrations using reverse suspension polymerisation. The beads were characterised to confirm the amount of cross-linker within each formulation and its effects on the bead properties. Elemental and UV/visible spectroscopic analysis confirmed the incorporation of BALC within the beads and sizing studies showed that in the presence of a reducing agent, all bead formulations increased in mean diameter. The BALC beads could be loaded with doxorubicin hydrochloride and amounts in excess of 300mg of drug per mL of hydrated beads could be achieved but required conversion of the carboxylic acid groups of the BALC to their sodium carboxylate salt forms. Elution of doxorubicin from the beads demonstrated a controlled releaseviaionic exchange. Some formulations exhibited an increase in size and release of drug in the presence of a reducing agent, and therefore demonstrated the ability to respond to anin vitroreducing environment

Calpain-mediated proteolysis of vimentin filaments is augmented in giant axonal neuropathy fibroblasts exposed to hypotonic stress

Giant Axonal Neuropathy (GAN) is a pediatric neurodegenerative disease caused by loss-of-function mutations in the E3 ubiquitin ligase adaptor gigaxonin, which is encoded by the KLHL16 gene. Gigaxonin regulates the degradation of multiple intermediate filament (IF) proteins, including neurofilaments, GFAP, and vimentin, which aggregate in GAN patient cells. Understanding how IFs and their aggregates are processed under stress can reveal new GAN disease mechanisms and potential targets for therapy. Here we tested the hypothesis that hypotonic stress-induced vimentin proteolysis is impaired in GAN. In both GAN and control fibroblasts exposed to hypotonic stress, we observed time-dependent vimentin cleavage that resulted in two prominent ∼40–45 kDa fragments. However, vimentin proteolysis occurred more rapidly and extensively in GAN cells compared to unaffected controls as both fragments were generated earlier and at 4-6-fold higher levels. To test enzymatic involvement, we determined the expression levels and localization of the calcium-sensitive calpain proteases-1 and -2 and their endogenous inhibitor calpastatin. While the latter was not affected, the expression of both calpains was 2-fold higher in GAN cells compared to control cells. Moreover, pharmacologic inhibition of calpains with MDL-28170 or MG-132 attenuated vimentin cleavage. Imaging analysis revealed striking colocalization between large perinuclear vimentin aggregates and calpain-2 in GAN fibroblasts. This colocalization was dramatically altered by hypotonic stress, where selective breakdown of filaments over aggregates occurred rapidly in GAN cells and coincided with calpain-2 cytoplasmic redistribution. Finally, mass spectrometry-based proteomics revealed that phosphorylation at Ser-412, located at the junction between the central “rod” domain and C-terminal “tail” domain on vimentin, is involved in this stress response. Over-expression studies using phospho-deficient and phospho-mimic mutants revealed that Ser-412 is important for filament organization, solubility dynamics, and vimentin cleavage upon hypotonic stress exposure. Collectively, our work reveals that osmotic stress induces calpain- and proteasome-mediated vimentin degradation and IF network breakdown. These effects are significantly augmented in the presence of disease-causing KLHL16 mutations that alter intermediate filament organization. While the specific roles of calpain-generated vimentin IF fragments in GAN cells remain to be defined, this proteolytic pathway is translationally-relevant to GAN because maintaining osmotic homeostasis is critical for nervous system function

Renal crystal deposits and histopathology in patients with cystine stones

We have biopsied the papillae of patients who have cystine stones asking if this stone type is associated with specific tissue changes. We studied seven cystine stone formers (SF) treated with percutaneous nephrolithotomy using digital video imaging of renal papillae for mapping and obtained papillary biopsies. Biopsies were analyzed by routine light and electron microscopy, infrared spectroscopy, electron diffraction, and micro-CT. Many ducts of Bellini (BD) had an enlarged ostium, and all such were plugged with cystine crystals, and had injured or absent lining cells with a surrounding interstitium that was inflamed to fibrotic. Crystal plugs often projected into the urinary space. Many inner medullary collecting ducts (IMCD) were dilated with or without crystal plugging. Apatite crystals were identified in the lumens of loops of Henle and IMCD. Abundance of interstitial Randall's plaque was equivalent in amount to that of non-SF. In the cortex, glomerular obsolescence and interstitial fibrosis exceeded normal. Cystine crystallizes in BD with the probable result of cell injury, interstitial reaction, nephron obstruction, and with the potential of inducing cortical change and loss of IMCD tubular fluid pH regulation, resulting in apatite formation. The pattern of IMCD dilation, and loss of medullary structures is most compatible with such obstruction, either from BD lumen plugs or urinary tract obstruction from stones themselves

It Is Not Just About Enrollment: Recognizing the Impact of RCT Recruitment Approaches on Prediabetes Awareness, Screening, and Capacity Building in African American Communities

Diabetes is a growing epidemic in the USA. Compared to white Americans, African Americans are 1.8 times more likely to have diabetes [1]. Additionally, African Americans with diabetes experience higher rates of morbidity and mortality than other racial groups. Compared to whites, African Americans are twice as likely to suffer from diabetes-related blindness, 1.5 to 2.5 times more likely to suffer from lower limb amputations and 2.6 to 5.6 times more likely to suffer from kidney disease [1, 2]. Prediabetes is a common precursor to diabetes and characterized by blood glucose levels that are above normal but below the criteria for a diagnosis of diabetes [3]. Approximately 30% or 88 million US adults have prediabetes [4] with African Americans disproportionately affected. During the average 3 years of follow-up of the landmark Diabetes Prevention Program, prediabetes developed into type 2 diabetes in approximately 11% of the subjects who participated in the standard care or control group [5]. Other estimates show that if prevention strategies are not implemented, individuals with prediabetes will be diagnosed with type 2 diabetes within 10 years [6]. While African Americans with prediabetes are at significant risk for developing diabetes, this outcome is not inevitable. Diagnosis of prediabetes is an example of secondary prevention, screening to identify diseases at an early stage, before symptoms begin [7]. The identification of pre-diabetes, and subsequent secondary prevention efforts to thwart or delay transition to diabetes, can reduce morbidity, impaired quality of life, monumental healthcare costs, and mortality rates [1, 2, 8, 9]

Challenges Associated With the Design and Deployment of Food Intake Urine Biomarker Technology for Assessment of Habitual Diet in Free-Living Individuals and Populations:A Perspective

Improvement of diet at the population level is a cornerstone of national and international strategies for reducing chronic disease burden. A critical challenge in generating robust data on habitual dietary intake is accurate exposure assessment. Self-reporting instruments (e.g., food frequency questionnaires, dietary recall) are subject to reporting bias and serving size perceptions, while weighed dietary assessments are unfeasible in large-scale studies. However, secondary metabolites derived from individual foods/food groups and present in urine provide an opportunity to develop potential biomarkers of food intake (BFIs). Habitual dietary intake assessment in population surveys using biomarkers presents several challenges, including the need to develop affordable biofluid collection methods, acceptable to participants that allow collection of informative samples. Monitoring diet comprehensively using biomarkers requires analytical methods to quantify the structurally diverse mixture of target biomarkers, at a range of concentrations within urine. The present article provides a perspective on the challenges associated with the development of urine biomarker technology for monitoring diet exposure in free-living individuals with a view to its future deployment in real world situations. An observational study (n = 95), as part of a national survey on eating habits, provided an opportunity to explore biomarker measurement in a free-living population. In a second food intervention study (n = 15), individuals consumed a wide range of foods as a series of menus designed specifically to achieve exposure reflecting a diversity of foods commonly consumed in the UK, emulating normal eating patterns. First Morning Void urines were shown to be suitable samples for biomarker measurement. Triple quadrupole mass spectrometry, coupled with liquid chromatography, was used to assess simultaneously the behavior of a panel of 54 potential BFIs. This panel of chemically diverse biomarkers, reporting intake of a wide range of commonly-consumed foods, can be extended successfully as new biomarker leads are discovered. Towards validation, we demonstrate excellent discrimination of eating patterns and quantitative relationships between biomarker concentrations in urine and the intake of several foods. In conclusion, we believe that the integration of information from BFI technology and dietary self-reporting tools will expedite research on the complex interactions between dietary choices and health. (c) Copyright (c) 2020 Beckmann, Wilson, Lloyd, Torres, Goios, Willis, Lyons, Phillips, Mathers and Draper