The Effects of Prodrug Size and a Carbonyl Linker on l-Type Amino Acid Transporter 1-Targeted Cellular and Brain Uptake.

The l-type amino acid transporter 1 (LAT1, SLC7A5) imports dietary amino acids and amino acid drugs (e. g., l-DOPA) into the brain, and plays a role in cancer metabolism. Though there have been numerous reports of LAT1-targeted amino acid-drug conjugates (prodrugs), identifying the structural determinants to enhance substrate activity has been challenging. In this work, we investigated the position and orientation of a carbonyl group in linking hydrophobic moieties including the anti-inflammatory drug ketoprofen to l-tyrosine and l-phenylalanine. We found that esters of meta-carboxyl l-phenylalanine had better LAT1 transport rates than the corresponding acylated l-tyrosine analogues. However, as the size of the hydrophobic moiety increased, we observed a decrease in LAT1 transport rate with a concomitant increase in potency of inhibition. Our results have important implications for designing amino acid prodrugs that target LAT1 at the blood-brain barrier or on cancer cells.

Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1).

The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.

Gendered role of appraisals of safety in psychological outcome in relation to trauma.

OBJECTIVE: This study investigated gender differences in the role of appraisals of safety in the relationship between exposure to violence and trauma-related symptoms among South African adolescents living in low socioeconomic settings. Limited research exists in developing contexts on the role of cognitive appraisals in mitigating outcome following exposure to violence. Given the prevalence of violence in South Africa and the vulnerability of youth, this type of research is valuable in identifying adolescents at risk of negative psychological outcome following exposure, and in informing intervention efforts. METHOD: Adolescents (N = 498) completed an adapted version of the Harvard Trauma Questionnaire (Mollica et al., 1992) and the Safety Index (Ward, Flisher, Zissis, Muller, & Lombard, 2001). RESULTS: The results indicate a significant positive relationship between all violence subscales and trauma-related symptoms, whereas a significant negative relationship was found between sense of safety and trauma-related symptoms. Important gender differences were identified in the role of appraisals of safety, with more effects noted for women than men. For men, the obtained results only demonstrated a health-sustaining role. For women, the results indicated a health-sustaining role, an indirect effect, and a stress-reducing role. CONCLUSION: These findings stress the necessity of gender-specific interventions. Assessment of psychological trauma, particularly among female adolescents, needs to include measures of cognitive appraisals related to safety. Therapeutic techniques that may be particularly beneficial to adolescent girls are those focusing on promoting sense of safety and targeting dysfunctional threat appraisals. (PsycINFO Database Record

The role of fortitude in relation to exposure to violence among adolescents living in lower socio-economic areas in South Africa.

OBJECTIVE: There is compelling evidence that a significant proportion of adolescents exposed to violence do not develop trauma-related symptoms, but adapt successfully. This differential vulnerability has propelled research into identifying factors that promote coping. This study focused on the role of fortitude in the relationship between violence and trauma-related symptoms among South African adolescents living in two low-income communities. Fortitude is derived from positive cognitive appraisals of the self, the family and external sources of support. METHOD: Adolescents (n = 498) completed an adapted version of the Harvard Trauma Scale (HTS) and the Fortitude Questionnaire (FORQ). RESULTS: Moderated regression analysis demonstrated that fortitude had a health-sustaining and stress-buffering role. Adolescents who displayed high levels of fortitude had lower levels of trauma symptoms in relation to exposure to violence (stress-buffering) and were able to maintain their levels of wellbeing irrespective of the nature and extent of such exposure (health-sustaining). CONCLUSION: The study provides evidence for fortitude as a protective factor by highlighting the role of specific cognitive appraisals related to fortitude in facilitating adaptation in relation to trauma. The study also underscores the relevance of using clinical interventions that target problematic cognitive appraisals and strengthen perceptions of coping.

Viral gastroenteritis: the USS THEODORE ROOSEVELT experience.

Although the spread of disease on board Navy ships is not a novel concept, the medical department of the USS THEODORE ROOSEVELT recently experienced a significant outbreak of viral gastroenteritis while at sea. The impact on the crew and medical department is reviewed in this case report. The use of the Navy Disease Non-Battle Injury tracking system was validated. Furthermore, we proposed the placement of waterless, isopropyl alcohol-based, hand-cleaning systems in strategic locations throughout the ship, to help prevent and minimize the spread of future disease. Finally, more stringent recommendations regarding sick in quarters status and careful utilization of consumable resources are necessary components of an effective outbreak management strategy.