Recent progress towards development of effective systemic chemotherapy for the treatment of malignant brain tumors

Systemic chemotherapy has been relatively ineffective in the treatment of malignant brain tumors even though systemic chemotherapy drugs are small molecules that can readily extravasate across the porous blood-brain tumor barrier of malignant brain tumor microvasculature. Small molecule systemic chemotherapy drugs maintain peak blood concentrations for only minutes, and therefore, do not accumulate to therapeutic concentrations within individual brain tumor cells. The physiologic upper limit of pore size in the blood-brain tumor barrier of malignant brain tumor microvasculature is approximately 12 nanometers. Spherical nanoparticles ranging between 7 nm and 10 nm in diameter maintain peak blood concentrations for several hours and are sufficiently smaller than the 12 nm physiologic upper limit of pore size in the blood-brain tumor barrier to accumulate to therapeutic concentrations within individual brain tumor cells. Therefore, nanoparticles bearing chemotherapy that are within the 7 to 10 nm size range can be used to deliver therapeutic concentrations of small molecule chemotherapy drugs across the blood-brain tumor barrier into individual brain tumor cells. The initial therapeutic efficacy of the Gd-G5-doxorubicin dendrimer, an imageable nanoparticle bearing chemotherapy within the 7 to 10 nm size range, has been demonstrated in the orthotopic RG-2 rodent malignant glioma model. Herein I discuss this novel strategy to improve the effectiveness of systemic chemotherapy for the treatment of malignant brain tumors and the therapeutic implications thereof

Deliberate self-harm and attachment: mediating and moderating roles of depression, anxiety, social support and interpersonal problems among Pakistani school going adolescents

Introduction: In Pakistan there is dearth of research on deliberate self-harm (DSH) and its predictors among adolescents. While the lack of research in Pakistan can be partly attributed to the sacrilegious status, criminalization and stigmatization attached to DSH, it is also an attribute of paucity of Urdu versions of the standardized psychological instruments. Previous research in developed countries has indicated that attachment theory can be used as a useful framework to understand the development of austere psychopathologies like DSH, as well as for studying pathways of interaction of interpersonal and intrapersonal factors of psychopathologies. In this study, standardized psychological instruments are translated into Urdu language as a first step. These instruments are then used to study pathways of interaction of interpersonal and intrapersonal factors of DSH, conceptualized within attachment framework. Method: The study was conducted in two steps. In step 1, Youth Health Risk Behavior Survey (YHRB), Inventory of Interpersonal Problems-32 (IIP-32) and Significant Others Scale (SOS), were translated into Urdu language. Along with these scales, Urdu translated versions of Hospital Anxiety and Depression Scale (HADS), Adolescent Relationship Scales Questionnaire (ARSQ), Life Events scale (LES) from CASE questionnaire and Family Affluence Scale-II (FAS-II) were reviewed for accuracy of translation through expert judgement and psychometric evaluation. Secondly, a cross sectional survey was conducted with 1290 adolescents (10 - 19 years age) using the translated Urdu versions of the instruments and demographic pro forma. Structural equation modelling was used to study the pathways of associations between predictors of DSH. Results: The extensive process of translation resulted in establishment of semantic, content, technical and construct equivalence of the translated instruments with the original English versions. Multiple imputation was performed to account for missing values in SPSS 20. Important structural adaptations were made in the scales based on factor analyses conducted in M plus. After modifications, all scales showed satisfactory CFI (≥ 0.90) and RMSEA (≤ 0.06). Results of the survey indicated that the prevalence of DSH (with, without and ambivalent suicidal intentions) was 7%. Two SEM models were constructed involving both mediation and moderation pathways. Results of Model 1 showed association of attachment with DSH was double mediated by social support, depression and anxiety. Model 2 also confirmed association of attachment with DSH with double mediation through relationship style problems, depression and anxiety. In order to understand the contextual picture of the concepts studied in this research both SEM models were also constructed by controlling for demographic factors. This resulted in confirming age, gender and family affluence as significant contributors but with very small effects. Discussion and conclusion: In the present study translation of the instruments helped in building a reservoir for future research. The results of translation and validation of instruments indicated that cultural differences, language needs and age must be accounted for while using standardized psychological instruments. Taking into consideration specific cultural and demographic background of Pakistan, this study also confirms the key role of attachment in influencing interaction of predictors of DSH. It is suggested that intrapersonal and interpersonal factors are influential points of intervention for designing clinical, school and community based awareness and prevention programs for DSH. The thesis also discusses the implications for policy guidelines along with recommendations for future research and other applications of the study

Large Wood Inhibits Debris Flow Runout in Forested Southeast Alaska

Due to their potentially long runout, debris flows are a major hazard and an important geomorphic process in mountainous environments. Understanding runout is therefore essential to minimize risk in the near‐term and interpret the pace and pattern of debris flow erosion and deposition over geomorphic timescales. Many debris flows occur in forested landscapes where they mobilize large volumes of large woody debris (LWD) in addition to sediment, but few studies have quantitatively documented the effects of LWD on runout. Here, we analyze recent and historic debris flows in southeast Alaska, a mountainous, forested system with minimal human alteration. Sixteen debris flows near Sitka triggered on August 18, 2015 or more recently had volumes of 80 to 25 000 m3 and limited mobility compared to a global compilation of similarly‐sized debris flows. Their deposits inundated 31% of the planimetric area, and their runout lengths were 48% of that predicted by the global dataset. Depositional slopes were 6°–26°, and mobility index, defined as the ratio of horizontal runout to vertical elevation change, ranged from 1.2 to 3, further indicating low mobility. In the broader southeast Alaskan region consisting of Chichagof and Baranof Islands, remote sensing‐based analysis of 1061 historic debris flows showed that mobility index decreased from 2.3–2.5 to 1.4–1.8 as average forest age increased from 0 to 416 years. We therefore interpret that the presence of LWD within a debris flow and standing trees, stumps, and logs in the deposition zone inhibit runout, primarily through granular phenomena such as jamming due to force chains. Calibration of debris flow runout models should therefore incorporate the ecologic as well as geologic setting, and feedbacks between debris flows and vegetation likely control the transport of sediment and organic material through steep, forested catchments over geomorphic time. © 2020 John Wiley & Sons, Ltd