M01 as a novel drug enhancer for specifically targeting the blood-brain barrier

Drug delivery to the brain is limited for most pharmaceuticals by the blood-brain barrier (BBB) where claudin-5 dominates the paraendothelial tightening. For circumventing the BBB, we identified the compound M01 as a claudin-5 interaction inhibitor. M01 causes transient permeabilisation of the BBB depending on the concentration of small molecules in different cell culture models within 3 to 48 h. In mice, brain uptake of fluorescein peaked within the first 3 h after M01 injection and normalised within 48 h. Compared to the cytostatic paclitaxel alone, M01 improved delivery of paclitaxel to mouse brain and reduced orthotopic glioblastoma growth. Results on interactions of M01 with claudin-5 were incorporated into a binding model which suggests association of its aromatic parts with highly conserved residues of the extracellular domain of claudin-5 and adjacent transmembrane segments. Our results indicate the following mode of action: M01 preferentially binds to the extracellular claudin-5 domain, which weakens trans-interactions between adhering cells. Further decrease in membranous claudin-5 levels due to internalization and transcriptional downregulation enables the paracellular passage of small molecules. In summary, the first small molecule is introduced here as a drug enhancer, which specifically permeabilises the BBB for a sufficient interval for allowing neuropharmaceuticals to enter the brain

Economic Globalization, Nutrition and Health: a review of quantitative evidence

BACKGROUND: Unhealthy dietary patterns have in recent decades contributed to an endemic-level burden from non-communicable disease (NCDs) in high-income countries. In low- and middle-income countries rapid changes in diets are also increasingly linked to malnutrition in all its forms as persistent undernutrition and micronutrient deficiencies continue to coexist with a rising prevalence of obesity and associated NCDs. Economic globalization and trade liberalization have been identified as potentially important factors driving these trends, but the mechanisms, pathways and actual impact are subject to continued debate. METHODS: We use a ‘rigorous review’ to synthesize evidence from empirical quantitative studies analysing the links between economic globalization processes and nutritional outcomes, with a focus on impact as well as improving the understanding of the main underlying mechanisms and their interactions. FINDINGS: While the literature remains mixed regarding the impacts of overall globalization, trade liberalization or economic globalization on nutritional outcomes, it is possible to identify different patterns of association and impact across specific sub-components of globalization processes. Although results depend on the context and methods of analysis, foreign direct investment (FDI) appears to be more clearly associated with increases in overnutrition and NCD prevalence than to changes in undernutrition. Existing evidence does not clearly show associations between trade liberalization and NCD prevalence, but there is some evidence of a broad association with improved dietary quality and reductions in undernutrition. Socio-cultural aspects of globalization appear to play an important yet under-studied role, with potential associations with increased prevalence of overweight and obesity. The limited evidence available also suggests that the association between trade liberalization or globalization and nutritional outcomes might differ substantially across population sub-groups. Overall, our findings suggest that policymakers do not necessarily face a trade-off when considering the implications of trade or economic liberalization for malnutrition in all its forms. On the contrary, a combination of nutrition-sensitive trade policy and adequate regulation of FDI could help reduce all forms of malnutrition. In the context of trade negotiations and agreements it is fundamental, therefore, to protect the policy space for governments to adopt nutrition-sensitive interventions

Psychosocial impact of serological diagnosis of herpes simplex virus type 2: a qualitative assessment

Objectives: To assess the emotional and psychosocial responses to a serological diagnosis of HSV-2 infection in individuals without previous history of genital herpes. Methods: 24 individuals who had a positive HSV-2 serology by western blot and no clinical history of disease were recruited from four clinics (sexually transmitted disease, maternal and infant care, family medicine, and virology research) over a 10 month period. In-depth qualitative interviews were conducted to elicit an individual's responses to the HSV-2 diagnosis. Results: Three categories of themes were identified from the interviews. Short term emotional responses included surprise, denial, confusion, distress, sadness, disappointment, and relief to know. Short term psychosocial responses included fear of telling sex partners, anger at the source partner, guilt about acquiring or transmitting, and concern about transmitting to a child. Perceived ongoing responses included fear of telling future partners, concern about transmitting to a sex partner, feeling sexually undesirable, feeling socially stigmatised, feeling like "damaged goods," sex avoidance due to social responsibility, fear of transmitting to a newborn, and relationship concerns relating to the diagnosis. Conclusions: Individuals exhibit strong emotional and psychosocial responses to a serological diagnosis of HSV-2 infection. Many of the negative responses may be time limited and influenced by factors that are potentially amenable to counselling

Tight junction proteins at the blood-brain barrier: far more than claudin-5

At the blood-brain barrier (BBB), claudin (Cldn)-5 is thought to be the dominant tight junction (TJ) protein, with minor contributions from Cldn3 and -12, and occludin. However, the BBB appears ultrastructurally normal in Cldn5 knock-out mice, suggesting that further Cldns and/or TJ-associated marvel proteins (TAMPs) are involved. Microdissected human and murine brain capillaries, quickly frozen to recapitulate the in vivo situation, showed high transcript expression of Cldn5, -11, -12, and -25, and occludin, but also abundant levels of Cldn1 and -27 in man. Protein levels were quantified by a novel epitope dilution assay and confirmed the respective mRNA data. In contrast to the in vivo situation, Cldn5 dominates BBB expression in vitro, since all other TJ proteins are at comparably low levels or are not expressed. Cldn11 was highly abundant in vivo and contributed to paracellular tightness by homophilic oligomerization, but almost disappeared in vitro. Cldn25, also found at high levels, neither tightened the paracellular barrier nor interconnected opposing cells, but contributed to proper TJ strand morphology. Pathological conditions (in vivo ischemia and in vitro hypoxia) down-regulated Cldn1, -3, and -12, and occludin in cerebral capillaries, which was paralleled by up-regulation of Cldn5 after middle cerebral artery occlusion in rats. Cldn1 expression increased after Cldn5 knock-down. In conclusion, this complete Cldn/TAMP profile demonstrates the presence of up to a dozen TJ proteins in brain capillaries. Mouse and human share a similar and complex TJ profile in vivo, but this complexity is widely lost under in vitro conditions

Challenges for Designing Adaptive Gamification in Telerehabilitation Systems for Heart Failure Patients’ Self-management

The conventional patient education model for heart failure patients assumes that increasing knowledge leads to self-management behaviour changes, but patients need motivation for changing their behaviour. Telerehabilitation technologies can provide a digital toolbox for engaging in self-management, and adding gamification on top may increase motivation to improve the telerehabilitation experience. This paper analyses how adaptive gamification can promote long-term motivation in a telerehabilitation program and discusses design opportunities and challenges within an adaptive approach within patient education of heart failure patients.</p