Adolescents Growing Up in Stressful Environments, Dual Diagnosis, and Sources of Success

This article considers the social and psychological challenges to youth in contemporary society. The authors examine the variety of social impediments that face youths in most of our social institutions, from schools and the juvenile justice system to the family. They underscore the need for prevention, health promotion, and comprehensive assessment. Further, they assert that ‘‘dual diagnosis’’ needs to be considered not as a ‘‘special population’’ but as the typical or common experience of at-risk youths once they are diagnosed at mental health centers or juvenile justice reception and diagnostic centers. They conclude that evidence-based assessment, intervention, prevention, and health promotion will start to unravel the matter of misdirected diagnosis and treatment. The articles in this special issue amply illustrate what can be done

AMPA-receptor mediated plasticity within the rat spinal cord

Previous research from our laboratory has demonstrated that the spinal cord is capable of a simple form of instrumental learning. In this instrumental learning paradigm, rats typically receive a complete spinal transection at the second thoracic vertebra, and are tested 24 hours after surgery. Subjects that receive shock to a hind leg quickly learn to maintain the leg in a flexed position, reducing net shock exposure whenever that leg is extended (controllable shock). Subjects that receive shock that is independent of leg position do not exhibit an increase in flexion duration (uncontrollable shock). This behavioral deficit can be induced with shock to the leg or tail and as little as 6 minutes of uncontrollable shock impairs learning for up to 48 hours. The present thesis explores how the related α-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid-receptor (AMPAR) ionotropic glutamate receptor affects spinal instrumental learning. Experiment 1 showed that inactivation of the AMPAR by administration of an antagonist blocks the acquisition of instrumental learning in a dose dependant fashion. Experiment 2 demonstrated that blocking the AMPAR after the acquisition of the instrumental response subsequently blocked the maintenance of that response. Experiment 3 revealed that antagonizing the AMPAR during uncontrollable shock blocked the acquisition of the learning deficit. Experiments 4-6 demonstrated that the activation of the AMPAR at high levels could acutely block the acquisition spinal instrumental learning. Understanding how the AMPAR influences learning in the spinal cord will lead us to develop therapeutic strategies for recovery of function after spinal cord injury

Deductions and Reductions Decoding Syllogistic Mnemonics

The syllogistic mnemonic known by its first two words Barbara Celarent introduced a constellation of terminology still used today. This concatenation of nineteen words in four lines of verse made its stunning and almost unprecedented appearance around the beginning of the thirteenth century, before or during the lifetimes of the logicians William of Sherwood and Peter of Spain, both of whom owe it their lasting places of honor in the history of syllogistic. The mnemonic, including the theory or theories it encoded, was prominent if not dominant in syllogistics for the next 700 years until a new paradigm was established in the 1950s by the great polymath Jan Łukasiewicz, a scholar equally at home in philosophy, classics, mathematics, and logic. Perhaps surprisingly, the then-prominent syllogistic mnemonic played no role in the Łukasiewicz work. His 1950 masterpiece does not even mention the mnemonic or its two earliest champions William and Peter. The syllogistic mnemonic is equally irrelevant to the post-Łukasiewicz paradigm established in the 1970s and 1980s by John Corcoran, Timothy Smiley, Robin Smith, and others. Robin Smith’s comprehensive 1989 treatment of syllogistic does not even quote the mnemonic’s four verses. Smith’s work devotes only 2 of its 262 pages to the mnemonic. The most recent translation of Prior Analytics by Gisela Striker in 2009 continues the post-Łukasiewicz paradigm and accordingly does not quote the mnemonic or even refer to the code—although it does use the terminology. Full mastery of modern understandings of syllogistic does not require and is not facilitated by ability to decode the mnemonic. Nevertheless, an understanding of the history of logic requires detailed mastery of the syllogistic mnemonic, of the logical theories it spawned, and of the conflicting interpretations of it that have been offered over the years by respected logicians such as De Morgan, Jevons, Keynes, and Peirce. More importantly, an understanding of the issues involved in decoding the mnemonic might lead to an enrichment of the current paradigm—an enrichment so profound as to constitute a new paradigm. After presenting useful expository, bibliographic, hermeneutic, historical, and logical background, this paper gives a critical exposition of Smith’s interpretation

Novel pyrrolobenzodiazepine benzofused hybrid molecules inhibit NF-κB activity and synergise with bortezomib and ibrutinib in hematological cancers

Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are incurable hematological malignancies that are pathologically linked with aberrant NF-κB activation. In this study, we identified a group of novel C8-linked benzofused Pyrrolo[2,1-c][1,4]benzodiazepines (PBD) monomeric hybrids capable of sequence-selective inhibition of NF-κB with low nanomolar LD50 values in CLL (n=46) and MM cell lines (n=5). The lead compound, DC-1-192, significantly inhibited NF-κB DNA binding after just 4h exposure and demonstrating inhibitory effects on both canonical and non-canonical NF-κB subunits. In primary CLL cells, sensitivity to DC-1-192 was inversely correlated with RelA subunit expression (r2=0.2) and samples with BIRC3 or NOTCH1 mutations showed increased sensitivity (P=0.001). RNA-sequencing and gene set enrichment analysis confirmed the over-representation of NF-κB regulated genes in the down-regulated gene list. Furthermore, In vivo efficacy studies in NOD/SCID mice, using a systemic RPMI 8226 human multiple myeloma xenograft model, showed that DC-1-192 significantly prolonged survival (P=0.017). In addition, DC1-192 showed synergy with bortezomib and ibrutinib; synergy with ibrutinib was enhanced when CLL cells were co-cultured on CD40L-expressing fibroblasts in order to mimic the cytoprotective lymph node microenvironment (P = 0.01). Given that NF-κB plays a role in both bortezomib and ibrutinib resistance mechanisms, these data provide a strong rationale for the use of DC-1-192 in the treatment of NF-κB-driven cancers, particularly in the context of relapsed/refractory disease

Wireless aquatic navigator for detection and analysis (WANDA)

The cost of monitoring and detecting pollutants in natural waters is of major concern. Current and forthcoming bodies of legislation will continue to drive demand for spatial and selective monitoring of our environment, as the focus increasingly moves towards effective enforcement of legislation through detection of events, and unambiguous identification of perpetrators. However, these monitoring demands are not being met due to the infrastructure and maintenance costs of conventional sensing models. Advanced autonomous platforms capable of performing complex analytical measurements at remote locations still require individual power, wireless communication, processor and electronic transducer units, along with regular maintenance visits. Hence the cost base for these systems is prohibitively high, and the spatial density and frequency of measurements are insufficient to meet requirements. In this paper we present a more cost effective approach for water quality monitoring using a low cost mobile sensing/communications platform together with very low cost stand-alone ‘satellite’ indicator stations that have an integrated colorimetric sensing material. The mobile platform is equipped with a wireless video camera that is used to interrogate each station to harvest information about the water quality. In simulation experiments, the first cycle of measurements is carried out to identify a ‘normal’ condition followed by a second cycle during which the platform successfully detected and communicated the presence of a chemical contaminant that had been localised at one of the satellite stations

Transferring momentum: Novel drop protection concept for mobile devices

Dropping a tablet (or mobile phone) can be extremely costly, as loss of functionality, visible body damage, screen delamination and failure are all too familiar outcomes. This paper discusses the analysis led design of a novel passive protection concept, capable of isolating a device from the primary impact, and is also insensitive to impact angle and device dependent features. A high fidelity finite element model of an iPad Air was used to develop the BLOKTM protection concept, which utilises different grades of elastomer, optimised internal castellation geometry and a high stiffness backplate. Sensitivity studies include the influence of glass properties, screen bonding and impact angle on the robustness of th

WANDA: A Radically New Approach for Low-Cost Environmental Monitoring

The cost of monitoring pollutants within natural waters is of major concern. Existing and forthcoming bodies of legislation continually drive the demand for spatial and selective monitoring of key pollutants within our environment. Although research and commercial entities continue to drive down the cost of the infrastructure involved in environmental sensing systems (with an aim to increase scalability), the realisation of deploying a number of such systems even now remains out of reach. High cost and maintenance continue to persist as the major limiting factors. The aim of this work is to combine recent advances in robotics with chemical sensing techniques to remove all but the chemo-responsive material from each sensing node, and package the sensing element within a low cost, mobile, biomimetic robotic fish for effective water quality monitoring. Consequently, this approach is believed to radically reduce the systemic cost and maintenance per node and in doing so it will increase the scalability for spatial and selective monitoring of key pollutants within our environment

Risk and protective genetic variants in suicidal behaviour: association with SLC1A2, SLC1A3, 5-HTR1B &NTRK2 polymorphisms

<p>Abstract</p> <p>Background</p> <p>Suicidal behaviour is known to aggregate in families. Patients with psychiatric disorders are at higher risk for suicide attempts (SA), however protective and risk genetic variants for suicide appear to be independent of underlying psychiatric disorders. Here we investigate genetic variants in genes important for neurobiological pathways linked to suicidal behaviour and/or associated endophenotypes, for association with SA among patients with co-existing psychiatric illness. Selected gene-gene and gene-environment interactions were also tested.</p> <p>Methods</p> <p>DNA was obtained from bloods of 159 patients (76 suicide attempters and 83 non-attempters), who were profiled for DSM-IV Axis I psychiatric diagnosis. Twenty-eight single nucleotide polymorphisms (SNPs) from 18 candidate genes (<it>COMT, 5-HT2A, 5-HT1A, 5-HTR1B, TPH1, MAO-A, TPH2, DBH, CNR1, BDNF, ABCG1, GABRA5, GABRG2, GABRB2, SLC1A2, SLC1A3, NTRK2, CRHR1</it>) were genotyped. Genotyping was performed by KBioscience. Tests of association between genetic variants and SA were conducted using Chi squared and Armitage Trend tests. Binary logistical regression analyses were performed to evaluate the contribution of individual genetic variants to the prediction of SA, and to examine SNPs for potential gene-gene and gene-environment interactions.</p> <p>Results</p> <p>Our analysis identified 4 SNPs (rs4755404, rs2269272, rs6296 and rs1659400), which showed evidence of association with SA compared to a non-attempter control group. We provide evidence of a 3-locus gene-gene interaction, and a putative gene-environment interaction, whereby genetic variation at the <it>NTRK2 </it>locus may moderate the risk associated with history of childhood abuse.</p> <p>Conclusion</p> <p>Preliminary findings suggest that allelic variability in <it>SLC1A2/3, 5-HTR1B </it>and <it>NTRK2 </it>may be relevant to the underlying diathesis for suicidal acts.</p