Lightweight composite fighting cover prototype development program

The U.S. Army Field Assistance Science and Technology Program requested Oak Ridge National Laboratory (ORNL) to demonstrate the use of lightweight composite materials in construction of overhead covers for reinforced infantry fighting positions. In recent years, ORNL researchers have designed and tested several concepts for lightweight ballistic protection structures, and they have developed numerous prototype composite structures for military and civilian applications. In the current program, composite panel designs and materials are tested and optimized to meet anticipated static and dynamic load conditions for the overhead cover structure. Ten prototype composite covers were built at ORNL for use in Army field tests. Each composite cover has a nominal surface area of 12 ft[sup 2] and a nominal weight of 8 lb. Four of the prototypes are made with folding sections to improve their handling characteristics. The composite covers exhibit equivalent performance in Army field tests to covers made with conventional materials that weigh four times as much

Reactivity-Dependent PCR: Direct, Solution-Phase in Vitro Selection for Bond Formation

In vitro selection is a key component of efforts to discover functional nucleic acids and small molecules from libraries of DNA, RNA, and DNA-encoded small molecules. Such selections have been widely used to evolve RNA and DNA catalysts and, more recently, to discover new reactions from DNA-encoded libraries of potential substrates. While effective, current strategies for selections of bond-forming and bond-cleaving reactivity are generally indirect, require the synthesis of biotin-linked substrates, and involve multiple solution-phase and solid-phase manipulations. In this work we report the successful development and validation of reactivity-dependent PCR (RDPCR), a new method that more directly links bond formation or bond cleavage with the amplification of desired sequences and that obviates the need for solid-phase capture, washing, and elution steps. We show that RDPCR can be used to select for bond formation in the context of reaction discovery and for bond cleavage in the context of protease activity profiling.Chemistry and Chemical Biolog

In Vitro Selection of a DNA-Templated Small-Molecule Library Reveals a Class of Macrocyclic Kinase Inhibitors

DNA-templated organic synthesis enables the translation of DNA sequences into synthetic small-molecule libraries suitable for in vitro selection. Previously, we described the DNA-templated multistep synthesis of a 13 824-membered small-molecule macrocycle library. Here, we report the discovery of small molecules that modulate the activity of kinase enzymes through the in vitro selection of this DNA-templated small-molecule macrocycle library against 36 biomedically relevant protein targets. DNA encoding selection survivors was amplified by PCR and identified by ultra-high-throughput DNA sequencing. Macrocycles corresponding to DNA sequences enriched upon selection against several protein kinases were synthesized on a multimilligram scale. In vitro assays revealed that these macrocycles inhibit (or activate) the kinases against which they were selected with IC50 values as low as 680 nM. We characterized in depth a family of macrocycles enriched upon selection against Src kinase, and showed that inhibition was highly dependent on the identity of macrocycle building blocks as well as on backbone conformation. Two macrocycles in this family exhibited unusually strong Src inhibition selectivity even among kinases closely related to Src. One macrocycle was found to activate, rather than inhibit, its target kinase, VEGFR2. Taken together, these results establish the use of DNA-templated synthesis and in vitro selection to discover small molecules that modulate enzyme activities, and also reveal a new scaffold for selective ATP-competitive kinase inhibition.Chemistry and Chemical Biolog

Contribution of limbic norepinephrine to cannabinoid-induced aversion

RATIONALE: The cannabinoid system has risen to the forefront in the development of novel treatments for a number of pathophysiological processes. However, significant side effects have been observed in clinical trials raising concerns regarding the potential clinical utility of cannabinoid-based agents. Understanding the neural circuits and neurochemical substrates impacted by cannabinoids will provide a better means of gaging their actions within the central nervous system that may contribute to the expression of unwanted side effects. OBJECTIVES: In the present study, we investigated whether norepinephrine (NE) in the limbic forebrain is a critical determinant of cannabinoid receptor agonist-induced aversion and anxiety in rats. METHODS: An immunotoxin lesion approach was combined with behavioral analysis using a place conditioning paradigm and the elevated zero maze. RESULTS: Our results show that the non-selective CB1/CB2 receptor agonist, WIN 55,212-2, produced a significant place aversion in rats. Further, NE in the nucleus accumbens was critical for WIN 55,212-2-induced aversion but did not affect anxiety-like behaviors. Depletion of NE from the bed nucleus of the stria terminalis was ineffective in altering WIN 55,212-2-induced aversion and anxiety. CONCLUSIONS: These results indicate that limbic, specifically accumbal, NE is required for cannabinoid-induced aversion but is not essential to cannabinoid-induced anxiety.This works was supported by PHS grant DA 020129. Ana Franky Carvalho was supported by the Portuguese Foundation for Science and Technology (SFRH/BD/33236/2007)

Discordant identification of pediatric severe sepsis by research and clinical definitions in the SPROUT international point prevalence study

Introduction: Consensus criteria for pediatric severe sepsis have standardized enrollment for research studies. However, the extent to which critically ill children identified by consensus criteria reflect physician diagnosis of severe sepsis, which underlies external validity for pediatric sepsis research, is not known. We sought to determine the agreement between physician diagnosis and consensus criteria to identify pediatric patients with severe sepsis across a network of international pediatric intensive care units (PICUs). Methods: We conducted a point prevalence study involving 128 PICUs in 26 countries across 6 continents. Over the course of 5 study days, 6925 PICU patients <18 years of age were screened, and 706 with severe sepsis defined either by physician diagnosis or on the basis of 2005 International Pediatric Sepsis Consensus Conference consensus criteria were enrolled. The primary endpoint was agreement of pediatric severe sepsis between physician diagnosis and consensus criteria as measured using Cohen's ?. Secondary endpoints included characteristics and clinical outcomes for patients identified using physician diagnosis versus consensus criteria. Results: Of the 706 patients, 301 (42.6 %) met both definitions. The inter-rater agreement (? ± SE) between physician diagnosis and consensus criteria was 0.57 ± 0.02. Of the 438 patients with a physician's diagnosis of severe sepsis, only 69 % (301 of 438) would have been eligible to participate in a clinical trial of pediatric severe sepsis that enrolled patients based on consensus criteria. Patients with physician-diagnosed severe sepsis who did not meet consensus criteria were younger and had lower severity of illness and lower PICU mortality than those meeting consensus criteria or both definitions. After controlling for age, severity of illness, number of comorbid conditions, and treatment in developed versus resource-limited regions, patients identified with severe sepsis by physician diagnosis alone or by consensus criteria alone did not have PICU mortality significantly different from that of patients identified by both physician diagnosis and consensus criteria. Conclusions: Physician diagnosis of pediatric severe sepsis achieved only moderate agreement with consensus criteria, with physicians diagnosing severe sepsis more broadly. Consequently, the results of a research study based on consensus criteria may have limited generalizability to nearly one-third of PICU patients diagnosed with severe sepsis

Clinically Unapparent Infantile Thiamin Deficiency in Vientiane, Laos

Infantile beriberi, or clinical thiamin (vitamin B1) deficiency in infants, is a forgotten disease in Asia, where 100 years ago it was a major public health problem. Infants with this deficiency, commonly aged ∼ 2–3 months, present in cardiac failure but usually rapidly improve if given thiamin injections. It remains relatively common in Vientiane, Lao PDR (Laos), probably because of prolonged intra- and post-partum food avoidance behaviours. Clinical disease may be the tip of an iceberg with subclinical thiamin deficiency contributing to sickness in infants without overt clinical beriberi. We therefore recruited 778 sick infants admitted during one year at Mahosot Hospital, Vientiane, without clinical evidence of beriberi, and performed erythrocyte transketolase (ETK) assays. 13.4 % of infants had basal ETK<0.59 micromoles/min/gHb suggesting biochemical thiamin deficiency. Mortality was 5.5% but, among infants ≥2 months old, mortality was higher in those with basal ETK<0.59 micromoles/min/gHb (3/47, 6.4%) than in those with basal ETK≥0.59 micromoles/min/gHb (1/146, 0.7%) (P = 0.045, relative risk = 9.32 (95%CI 0.99 to 87.5)). We conclude that clinically unapparent thiamin deficiency is common among sick infants (≥2 months old) admitted to hospital in Vientiane. This may contribute to mortality and a low clinical threshold for providing thiamin to sick infants may be needed

Adverse effects of extra-articular corticosteroid injections: a systematic review

<p>Abstract</p> <p>Background</p> <p>To estimate the occurrence and type of adverse effects after application of an extra-articular (soft tissue) corticosteroid injection.</p> <p>Methods</p> <p>A systematic review of the literature was made based on a PubMed and Embase search covering the period 1956 to January 2010. Case reports were included, as were prospective and retrospective studies that reported adverse events of corticosteroid injection. All clinical trials which used extra-articular corticosteroid injections were examined. We divided the reported adverse events into major (defined as those needing intervention or not disappearing) and minor ones (transient, not requiring intervention).</p> <p>Results</p> <p>The search yielded 87 relevant studies:44 case reports, 37 prospective studies and 6 retrospective studies. The major adverse events included osteomyelitis and protothecosis; one fatal necrotizing fasciitis; cellulitis and ecchymosis; tendon ruptures; atrophy of the plantar fat was described after injecting a neuroma; and local skin effects appeared as atrophy, hypopigmentation or as skin defect. The minor adverse events effects ranged from skin rash to flushing and disturbed menstrual pattern. Increased pain or steroid flare after injection was reported in 19 studies. After extra-articular injection, the incidence of major adverse events ranged from 0-5.8% and that of minor adverse events from 0-81%. It was not feasible to pool the risk for adverse effects due to heterogeneity of study populations and difference in interventions and variance in reporting.</p> <p>Conclusion</p> <p>In this literature review it was difficult to accurately quantify the incidence of adverse effects after extra-articular corticosteroid injection. The reported adverse events were relatively mild, although one fatal reaction was reported.</p