Liposome-based depot injection technologies

Liposomes have proven to be versatile carriers for the delivery of drugs. These carriers are biocompatible, since they are generally made from lipids commonly found in biologic systems and are biodegradable by the usual metabolic pathways. A sustained drug delivery system is useful when the efficacy of drugs is limited by the inability to maintain therapeutic concentrations. Furthermore, a depot delivery system can offer important advantages in the clinic, such as significantly reducing dose frequency and providing efficacy without toxicity. Because of their small size (<5μ.m), conventional liposomes (unilamellar and multilamellar) are limited in their ability to provide depot delivery of drugs when administered subcutaneously or intramuscularly. The small size of these liposomes results in relatively fast clearance from the injection site and a short duration of delivery, typically 1–4 days. Multivesicular liposomes (MVLs) are distinct from conventional liposomes in composition, structure, and size and are the only class of commercial liposomes that have demonstrated depot delivery of both small molecule and protein/peptide drugs. These MVLs are characterized by the presence of a continuous bilayer membrane, with numerous internal aqueous compartments that are contiguous and separated by bilayer septums. As a result of their larger size (median diameter typically 10–30μ.m), these MVLs are not rapidly cleared by tissue macrophages and can act as a drug depot providing slow release of drugs delivered through different routes of administration. Moreover, the biocompatibility and biodegradability of the MVL lipid matrix allows for the sustained delivery of drugs to sensitive areas. The unique architecture of MVLs provides high drug loading of water-soluble drugs, reasonable stability during storage, and control over the drug-release rate. Furthermore, the lipid composition of MVLs can be altered to deliver therapeutics over periods ranging from a few days to a month, in order to meet specific therapeutic needs. The capability of altering the rate of drug release from MVLs by varying the lipid composition provides a great deal of versatility for controlled delivery of a wide variety of therapeutics. This article reviews depot delivery with conventional liposomes, demonstrates through several examples the sustained depot delivery of small and macromolecular drugs using MVLs, and summarizes some novel delivery systems that combine liposomes with polymeric matrices and have the potential to expand the platform of liposomal depot delivery.     

Canada's Physical Activity Guide: Examining Print-Based Material for Motivating Physical Activity in the Workplace

The authors conducted a secondary analysis on 202 adults from the Physical Activity Workplace Study. The aim of this analysis was to examine demographic characteristics associated with reading Canada's Physical Activity Guide (CPAG), being motivated by the guide, and whether participants in the Physical Activity Workplace Study who read the CPAG increased their physical activity levels over 1 year. Results revealed that less than 50% of participants read the full version of CPAG, and less than 10% were motivated by it. The CPAG also appears to be more appealing to and effective for women than for men. Although the CPAG had some influence in increasing mild physical activity levels in a workplace sample, there was also a decrease in physical activity levels among some members of the group. Overall, the effectiveness of CPAG was not substantial, and the findings of this analysis could help guide future targeted intervention materials and programs.     

Telehealth transition in a comprehensive care unit for eating disorders: Challenges and long-term benefits

The 2019 novel coronavirus disease (COVID-19) pandemic has forced many eating disorder medical stabilization units to consider adjustments that uphold both the quality of care delivered to patients while also observing social distancing public health directives for patients and staff. To date, inpatient facilities for eating disorders (both medical stabilization units and higher level of care facilities) have not needed to consider how to translate services to electronic platforms, given that most of these programs have in-person staff. We outline our transition to telehealth broadly, emphasizing some unexpected benefits of using telehealth services that we plan on integrating into our work-flow post COVID-19. These may be useful for other higher level of care eating disorder programs, including medical stabilization units, residential, partial hospitalization, and intensive outpatient programs. We also highlight aspects of transition that have been more challenging for this particular patient population, warranting the need for in-person services.     

Oral Exposure to Bisphenol A Increases Dimethylbenzanthracene-Induced Mammary Cancer in Rats

Background

Bisphenol A (BPA) is widely used in the manufacture of polycarbonate plastics, including infant formula bottles.

Objectives

Based on the reported endocrine disruptor activity of this polyphenol, we hypothesized that exposure to BPA early in life would elicit developmental changes in the mammary tissue and cause a predisposition for mammary cancer.

Methods

We exposed neonatal/prepubertal rats to BPA via lactation from nursing dams treated orally with 0, 25, and 250 μg BPA/kg body weight/day. For tumorigenesis studies, female offspring were exposed to 30 mg dimethylbenzanthracene (DMBA)/kg body weight at 50 days of age.

Results

The combination of DMBA treatment with lactational exposure to BPA demonstrated a dose-dependent increase in mammary tumor multiplicity and reduced tumor latency compared with controls. In the absence of DMBA treatment, lactational BPA exposure resulted in increased cell proliferation and decreased apoptosis at 50 but not 21 days postpartum (shortly after last BPA treatment). Using Western blot analysis, we determined that steroid receptor coactivators (SRCs) 1–3, Akt, phosphorylated Akt, progesterone receptor A (PR-A), and erbB3 proteins were significantly up-regulated at 50 days of age.

Conclusions

The data presented here provide the first evidence that maternal exposure to BPA during lactation increases mammary carcinogenesis in a DMBA-induced model of rodent mammary cancer. Changes in PR-A, SRC 1–3, erbB3, and Akt activity are consistent with increased cell proliferation and decreased apoptosis playing a role in mammary cancer susceptibility. These alterations provide an explanation of enhanced mammary carcinogenesis after lactational BPA exposure.     

Modeling conditional dependence between diagnostic tests: A multiple latent variable model

Applications of latent class analysis in diagnostic test studies have assumed that all tests are measuring a common binary latent variable, the true disease status. In this article we describe a new approach that recognizes that tests based on different biological phenomena measure different latent variables, which in turn measure the latent true disease status. This allows for adjustment of conditional dependence between tests within disease categories. The model further allows for the inclusion of measured covariates and unmeasured random effects affecting test performance within latent classes. We describe a Bayesian approach for model estimation and describe a new posterior predictive check for evaluating candidate models. The methods are motivated and illustrated by results from a study of diagnostic tests for Chlamydia trachomatis. Published in 2008 by John Wiley & Sons, Ltd.     

A Qualitative Inquiry About Pruno,an Illicit Alcoholic Beverage Linked to Botulism Outbreaks in United States Prisons

Objectives. Since 2011, 3 outbreaks of botulism in US prisons have been attributed to pruno, which is an alcoholic beverage made by inmates. Following 1 outbreak, we conducted a qualitative inquiry to understand pruno brewing and its social context to inform outbreak prevention measures.Methods. We interviewed staff, inmates, and parolees from 1 prison about pruno production methods, the social aspects of pruno, and strategies for communicating the association between botulism and pruno.Results. Twenty-seven inmates and parolees and 13 staff completed interviews. Pruno is fermented from water, fruit, sugar, and miscellaneous ingredients. Knowledge of pruno making was widespread among inmates; staff were familiar with only the most common ingredients and supplies inmates described. Staff and inmates described inconsistent consequences for pruno possession and suggested using graphic health messages from organizations external to the prison to communicate the risk of botulism from pruno.Conclusions. Pruno making was frequent in this prison. Improved staff recognition of pruno ingredients and supplies might improve detection of brewing activities in this and other prisons. Consistent consequences and clear messages about the association between pruno and botulism might prevent outbreaks.Botulism is a rare but serious illness that can lead to respiratory failure and death. Botulism patients may initially present with blurred or double vision, drooping eyelids, slurred speech, and difficulty swallowing before developing more severe signs and symptoms, such as paralysis and difficulty breathing. In the United States, an average of 145 confirmed botulism cases are reported each year, of which approximately 15% are attributable to foodborne botulism.1 Foodborne botulism is caused by ingestion of botulinum toxin, a bacterial toxin that is produced under the following rarely attained conditions: an anaerobic environment with warm temperatures and low acid, salt, and sugar concentrations.2 Alaska Native foods and home-canned vegetables are the food items most commonly associated with foodborne botulism3,4; however, in the past decade, 5 foodborne botulism outbreaks have been attributed to pruno, an illicit alcoholic beverage made in prisons.5 Pruno was initially recognized as a botulism vehicle after it was implicated in 2 outbreaks in California in 2004 and 2005; these outbreaks resulted in confirmed botulism in 5 inmates, 3 of whom were critically ill and mechanically ventilated.6 No additional outbreaks were reported until 2011, when 8 maximum security inmates in Utah developed botulism after drinking pruno. Three were mechanically ventilated, and most reported persistent symptoms, such as weakness, 11 months after the outbreak.7 The following year, 12 Arizona inmates were sickened in 2 outbreaks of botulism associated with pruno consumption; 8 were mechanically ventilated.5 In all 5 outbreaks, pruno was made with potatoes,5 an uncommon pruno ingredient according to online sources, and a food historically associated with botulism.8,9 Because of these outbreaks, pruno-related botulism accounted for 40% and 48% of foodborne botulism cases in the United States in 2011 and 2012, respectively (Centers for Disease Control and Prevention, unpublished data).Internet sources indicate that pruno is common in US prisons.10–12 Although recent trends suggest future pruno-related botulism outbreaks are likely to occur,5,7 there is a dearth of information about how pruno is made and distributed in prisons, and the social and entrepreneurial aspects of its production and use. To address these gaps and inform botulism outbreak prevention measures, 4 months after the Utah outbreak, we conducted a qualitative inquiry in the affected prison to better understand the brewing process, social context of pruno, and communication strategies for informing inmates about the risk of botulism from pruno.     

Understanding the effects of conditional dependence in research studies involving imperfect diagnostic tests

When two imperfect diagnostic tests are carried out on the same subject, their results may be correlated even after conditioning on the true disease status. While past work has focused on the consequences of ignoring conditional dependence, the degree to which conditional dependence can be induced has not been systematically studied. We examine this issue in detail by introducing a hypothetical missing covariate that affects the sensitivities of two imperfect dichotomous tests. We consider four forms for this covariate, normal, uniform, dichotomous and trichotomous. In the case of a dichotomous covariate, we derive an expression showing that the conditional covariance is a function of the product of the changes in test sensitivities (or specificities) between the subgroups defined by the covariate. The maximum possible covariance is induced by a dichotomous covariate with a very strong effect on both tests. Through simulations, we evaluate the extent to which fitting a latent class model ignoring each type of covariate but including a general covariance term can adjust for the correlation induced by the covariate. We compare the results to when the conditional dependence is ignored. We find that the bias because of ignoring conditional dependence is generally small even for moderate covariate effects, and when bias is present, a model including a covariance term works well. We illustrate our methods by analyzing data from a childhood tuberculosis study. Copyright © 2016 John Wiley & Sons, Ltd.     

Intralenticular changes in eyes with mature senile cataract on modified posterior segment optical coherence tomography

Purpose:To study the morphological changes within mature senile cataracts on modified posterior segment optical coherence tomography (OCT).Methods:A cross-sectional observational study recruiting patients of mature cataracts admitted for elective cataract surgery in tertiary eye care. A modified OCT imaging of the lens was done and lenticular findings were noted by a single observer. Corresponding slit-lamp biomicroscopic findings and intraoperative experiences were also noted by a second observer and respective surgeons.Results:Forty-four eyes of 44 patients were included. The mean age of patients was 65 ± 5.7 years. The intralenticular findings were uniform in groups of eyes, and they were characterized into three stages. First was a stage of early lamellar separation where small intralenticular clefts were noted superficially. Second was the stage of established lamellar separation where crescentic fluid clefts appeared interspersed between the lens fibers, and the depth increased as a function of severity. Both these stages did not show any distinct slit-lamp or intraoperative findings. A third stage of liquefaction identified as extensive lamellar separation with subcapsular fluid pockets. This was also reflected in slit-lamp biomicroscopy, showing the hydrated cortex with intraoperative challenges. Two cases showed peculiar changes, one of a hyperreflective subcapsular sheath and another of superficial nuclear lamellar separation.Conclusion:Mature cataracts may also show graded progression, which could be delineated on lenticular OCT. This could be of immense help in pre-operative planning and optimal management of these high-risk cases.     

Increased binding of LDL and VLDL to apo B,E receptors of hepatic plasma membrane of rats treated with Fibernat

Summary. Background: Research has focussed on the hypocholesterolemic effects of certain types of dietary fiber such as enhancing conversion of hepatic cholesterol to bile acids or increase in catabolism of low density lipoprotein (LDL) via the apo B,E receptor. Aim of the study: The effect of oral administration of a unique fibre cocktail of fenugreek seed powder, guar gum and wheat bran (Fibernat) and its varied effects on some aspects of lipid metabolism and cholesterol homeostasis in rats were examined. Methods: Rats were administered Fibernat along with the atherogenic diet containing 1.5 % cholesterol and 0.1 % cholic acid. Amounts of hepatic lipids, hepatic and fecal bile acids and activity of hepatic triglyceride lipase (HTGL) were determined. Transmission electron microscopic examination of the liver tissue and extent of uptake of ¹²⁵I-LDL and ¹²⁵I-VLDL by the hepatic apo B,E receptor was carried out. Results: Food intake and body weight gain were similar between the 3 different dietary groups. Fibernat intake significantly increased apo B,E receptor expression in rat liver as reflected by an increase in the maximum binding capacity (B_max) of the apo B,E receptor to ¹²⁵I-LDL and ¹²⁵I-VLDL. The activity of HTGL was increased by approximately 1.5-fold in Fibernat-fed rats as compared to those fed the atherogenic diet alone. A marked hypocholesterolemic effect was observed. Cholesterol homeostasis was achieved in Fibernat-fed rats. Conclusion: Two possible mechanisms are postulated to be responsible for the observed hypocholesterolemic effect a) an increase in conversion of cholesterol to bile acids and b) possibly by intra-luminal binding which resulted in increased fecal excretion of bile acids and neutral sterols. The resulting reduction in cholesterol content of liver cells coupled with upregulation of hepatic apo B,E receptors and increased clearance of circulating atherogenic lipoproteins—LDL and very low density lipoprotein (LDL and VLDL)—is the main mechanism involved in the hypocholesterolemic effect of Fibernat. The results suggest that Fibernats effect on plasma LDL concentration is also possibly mediated by increased receptor-mediated catabolism of VLDL. Thus, Fibernat therapy is an effective adjunct to diet therapy and might find potential use in the therapy of hyperlipidemic subjects.