L-2-Hydroxyglutaric aciduria: neuropathological correlations and first report of severe neurodegenerative disease and neonatal death

Chromolaena odorata (formerly Eupatorium odoratum) is used as a traditional medicine in Vietnam (Nghiem, 1992), where its Vietnamese common name is "co hoi." While it has been widely considered a weed by agriculturalists (Holm et al., 1991), the aqueous extract and the decoction from the leaves of this plant have been used throughout Vietnam for the treatment of soft tissue wounds, burn wounds, and skin infections. A number of clinical studies done by Vietnamese as well as foreign medical workers has demonstrated the efficacy of this extract on the wound-healing process. In this article, the effect of the Eupolin extract on hydrated collagen lattice contraction by human dermal fibroblasts, an in vitro model of wound contraction, is described. The significant inhibition of collagen gel contraction by Eupolin extract at 50 to 200 micrograms/ml is demonstrated in various concentrations of collagen. When the extract at 50 to 150 micrograms/ml was washed out of the lattices and replaced by fresh medium without Eupolin, the contraction of collagen by cells was resumed. The visualization of cells in the lattices by incubation in a tetrazolium salt for 2 h showed live cells at 50 to 150 micrograms/ml of extract. In contrast, all cells were killed in the higher extract doses of 300 or 400 micrograms/ml. These preliminary results showing the inhibitory effect of Eupolin extract on collagen contraction suggest that a clinical evaluation of its effect on wound contraction and scar quality should be made. This work illustrates that traditional remedies that are used by folk practitioners to improve healing can be examined in a scientific manner using in vitro wound-healing models. It could be that the synergistic properties of components of the natural extract contribute to the positive effects demonstrated on various wound-healing mechanisms.     

The effect of mammalian anxiety factors on insects. The action of the corticoliberin 2-4 fragment on the behavior of the mealworm beetle Tenebrio molitor

The effect of the corticoliberin 2-4 fragment--tripeptide Pro-Pro-Ile (PPI) inducing increase in epileptiform activity of mammal on T. molitor males behaviour has been studied. The "open field" method modified for insects has been used. PPI in doses of 30, 60, 100, 1000 micrograms/kg was injected in hemolymph of the beetles. The horizontal activity (HA), number of turns (TN) and other parameters were registered during 6 min. The tripeptide in dose 30 micrograms/kg was non-effective. PPI in doses 100 and, especially, 1000 micrograms/kg evoked stable decrease in HA that was observed as early as 0.5 h after injection. This effect lasted throughout 4-24 hrs and, apparently, induced by nonspecific action of high doses of the peptide. PPI in dose 60 micrograms/kg produced the significant intensification of stressogenic influence of experimental situation: in 2-4 hrs after injection the level of HA and TN increased. It is suggested that PPI can be regarded as an anxiogenic factor of insects.     

A comparative study of the nonhistone chromosomal proteins (pp23) from rat and bull kidneys

BACKGROUND: Gastrointestinal myoelectric activity during postoperative ileus has been well characterized. However, the common clinical scenario of ileus occurring during and after episodes of sepsis is not well understood. The aim of our study was to determine the effects of a single, sublethal dose of endotoxin on canine gastrointestinal myoelectric activity. METHODS: Eight dogs underwent placement of serosal electrodes on the stomach and small intestine and insertion of a jejunal cannula. After the animals recovered, electrical activity and jejunal mucosal blood flow were determined during fasting and with feeding. Following completion of these baseline studies dogs were given a single, sublethal dose of Escherichia coli lipopolysaccharide (200 g/kg) intravenously, and the studies were repeated daily for 3 consecutive days. RESULTS: Endotoxin resulted in an absence of the interdigestive migrating myoelectric complex for 2 days, a decrease in duodenal and jejunal action potentials during fasting and with feeding, but no decreases in jejunal mucosal blood flow. The gastrointestinal myoelectrical patterns returned to those found in health on postendotoxin day 3. CONCLUSIONS: A single, sublethal dose of endotoxin results in a temporary disruption of gastrointestinal myoelectric activity similar to that seen during postoperative ileus. The etiology of this "adynamic" ileus is unknown but does not appear to be secondary to intestinal ischemia.     

Biorthogonally accessed three-dimensional two-photon memory for relational database operations

Memory bandwidth is a bottleneck for very large database machines. Parallel-access three-dimensional two-photon memories have the potential of achieving enormous throughput (>100 Gbit/s) and capacity (1 Tbit/cm(3)) [Appl. Opt. 29, 2058 (1990)] and, consequently, are well suited for this application. Our analysis shows that some operations can be completed more than 2 orders of magnitude faster with this type of memory than with a system based on serial-access storage. These particular memories have a further feature of being accessible in orthogonal directions. We show that this property, used in conjunction with a three-dimensional data-organization scheme designed for this approach, leads to improved performance by permitting the user a choice of accessing strategies for a given operation.     

Study of regulation of mitochondrial respiration in vivo. An analysis of influence of ADP diffusion and possible role of cytoskeleton

The purpose of this work was to investigate the mechanism of regulation of mitochondrial respiration in vivo in different muscles of normal rat and mice, and in transgenic mice deficient in desmin. Skinned fiber technique was used to study the mitochondrial respiration in the cells in vivo in the heart, soleus and white gastrocnemius skeletal muscles of these animals. Also, cardiomyocytes were isolated from the normal rat heart, permeabilized by saponin and the "ghost" (phantom) cardiomyocytes were produced by extraction of myosin with 800 mM KCl. Use of confocal immunofluorescent microscopy and anti-desmin antibodies showed good preservation of mitochondria and cytoskeletal system in these phantom cells. Kinetics of respiration regulation by ADP was also studied in these cells in detail before and after binding of anti-desmine antibodies with intermediate filaments. In skinned cardiac or soleus skeletal muscle fibers but not in fibers from fast twitch skeletal muscle the kinetics of mitochondrial respiration regulation by ADP was characterized by very high apparent Km (low affinity) equal to 300-400 microM, exceeding that for isolated mitochondria by factor of 25. In skinned fibers from m. soleus, partial inhibition of respiration by NaN3 did not decrease the apparent Km for ADP significantly, this excluding the possible explanation of low apparent affinity of mitochondria to ADP in these cells by its rapid consumption due to high oxidative activity and by intracellular diffusion problems. However, short treatment of fibers with trypsin decreased this constant value to 40-70 microM, confirming the earlier proposition that mitochondrial sensitivity to ADP in vivo is controlled by some cytoplasmic protein. Phantom cardiomyocytes which contain mostly mitochondria and cytoskeleton and retain the normal shape, showed also high apparent Km values for ADP. Therefore, they are probably the most suitable system for studies of cellular factors which control mitochondrial function in the cells in vivo. In these phantom cells anti-desmin antibodies did not change the kinetics of respiration regulation by ADP. However, in skinned fibers from the heart and m. soleus of transgenic desmin-deficient mice some changes in kinetics of respiration regulation by ADP were observed: in these fibers two populations of mitochondria were observed, one with usually high apparent Km for ADP and the second one with very low apparent Km for ADP. Morphological observations by electron microscopy confirmed the existence of two distinct cellular populations in the muscle cells of desmin-deficient mice. The results conform to the conclusion that the reason for observed high apparent Km for ADP in regulation of oxidative phosphorylation in heart and slow twitch skeletal muscle cells in vivo is low permeability of mitochondrial outer membrane porins but not diffusion problems of ADP into and inside the cells. Most probably, in these cells there is a protein associated with cytoskeleton, which controls the permeability of the outer mitochondrial porin pores (VDAC) for ADP. Desmin itself does not display this type of control of mitochondrial porin pores, but its absence results in appearance of cells with disorganised structure and of altered mitochondrial population probably lacking this unknown VDAC controlling protein. Thus, there may be functional connection between mitochondria, cellular structural organisation and cytoskeleton in the cells in vivo due to the existence of still unidentified protein factor(s).     

The ontological basis of strong artificial life

In 1973, the United States Congress enacted legislation requiring physicians to initiate Peer Review Organizations to monitor utilization and quality of hospital and physician services in the federally funded Medicare program. A hardly noticed provision of the statute intimated the desirability of formulating guidelines for medical treatment. What was originally intended to simplify and universalize general standards by which quality of care could be objectively measured has more recently escalated into formalized projects, subsidized by government, to create "practice parameters". The impetus to define clinical conditions and methods of treatment for specific medical conditions (practice parameters) and standards of practice to avoid or defend malpractice claims (risk management protocols) are part of the movement in the United States for tort reform. If the vague "reasonable man" standard of care in negligence law can be supplanted by a scientifically developed, particularized medical practice standard, it is anticipated that spurious claims and defensive medical practice will be discouraged, quality improved, iatrogenic injury and malpractice litigation diminished. Many U.S. states undertook tort reform in the last decade. A few have embarked on medical-legal reform. One state is conducting a five-year medical liability project that calls for the development of practice parameters and risk management protocols in four medical specialties. The parameters will have the effect of law and may be introduced as evidence in medical malpractice trials. How the parameters are established, their effect on the strategies of litigation, the resultant trial problems in the introduction of evidence and in the burden of proof and their potential for acceptance by a significant number of jurisdictions-are the issues to be explored in this paper.     

Cuttlefish: Color Mapping for Dynamic Multi‐Scale Visualizations

Visualizations of hierarchical data can often be explored interactively. For example, in geographic visualization, there are continents, which can be subdivided into countries, states, counties and cities. Similarly, in models of viruses or bacteria at the highest level are the compartments, and below that are macromolecules, secondary structures (such as α‐helices), amino‐acids, and on the finest level atoms. Distinguishing between items can be assisted through the use of color at all levels. However, currently, there are no hierarchical and adaptive color mapping techniques for very large multi‐scale visualizations that can be explored interactively. We present a novel, multi‐scale, color‐mapping technique for adaptively adjusting the color scheme to the current view and scale. Color is treated as a resource and is smoothly redistributed. The distribution adjusts to the scale of the currently observed detail and maximizes the color range utilization given current viewing requirements. Thus, we ensure that the user is able to distinguish items on any level, even if the color is not constant for a particular feature. The coloring technique is demonstrated for a political map and a mesoscale structural model of HIV. The technique has been tested by users with expertise in structural biology and was overall well received.     

Emergency Flight Planning for an Energy-Constrained Multicopter

Small Unmanned Aircraft Systems (UAS) have diverse commercial applications. Risk mitigation techniques must be developed to minimize the probability of harm to persons and property in the vicinity of the aircraft. This paper presents an emergency flight planner combining sensor-based and map-based elements to collectively plan a landing path for a UAS that experiences an unexpected low energy condition while flying over a populated area. Focus is placed in this work on the use of public databases of population distribution, structure locations, and terrain to create an efficient-to-access cost map of the data. Safe landing plans are generated with an A* search algorithm shown to be feasible for real-time use with the cost map. Simulation-based case studies are presented of a quadrotor UAS operating within New York City to illustrate how different cost terms impact optimal path characteristics.     

A Comparison of the Anti-Inflammatory Effects of <Emphasis Type="Italic">Cis</Emphasis>-9, <Emphasis Type="Italic">Trans</Emphasis>-11 Conjugated Linoleic Acid to Celecoxib in the Collagen-Induced Arthritis Model

Cyclooxygenase (COX)‐2 inhibitors, such as celecoxib, for chronic inflammatory disease are associated with adverse health events, while cis‐9, trans‐11 (c9t11) conjugated linoleic acid (CLA) is anti‐inflammatory without adverse events attributed to pure intake. Mechanistically, celecoxib and c9t11 disrupt the arachidonic acid cascade; however, the equivalency of anti‐inflammatory effects between these compounds is unknown. Therefore, to test the hypothesis that 0.5% dietary c9t11 reduces inflammation equivalently to a celecoxib dose intended to treat rheumatoid arthritis (RA; 5 mg/kg bw), arthritic mice received diets containing one of the following supplements: 1% corn oil (CO, w/w), 0.5% c9t11 (>91% purity) +0.5% CO, or 1% CO + 0.5, 5, or 50 mg/kg bw celecoxib, and were assessed for changes in arthritic severity over 6 weeks. Overall, arthritic severity in mice fed c9t11 was reduced (34%, P < 0.01) while celecoxib doses (0.5, 5, 50 mg/kg) reduced arthritic severity (16, 56, 48%, respectively) compared to CO‐fed arthritic mice. Linear regression of the celecoxib dose‐response showed 0.5% c9t11 (570 mg/kg bw) reduced arthritic severity equivalently to 1.5 mg/kg celecoxib. Interleukin‐6 (IL‐6) was increased in paws of arthritic mice fed CO compared to shams, but was decreased in arthritic groups fed 0.5% c9t11 and 5 mg/kg celecoxib, compared to arthritic mice fed CO (Ps ≤ 0.05). Additionally, paw and plasma IL‐10 levels in arthritic mice were decreased by 5 mg/kg celecoxib, but were unaffected by c9t11 compared to CO. Results suggest dietary c9t11 may be an effective adjunct to COX‐2 inhibition for treating chronic inflammation.     

The organization of an integrated basic medical science curriculum at a new medical school, Nottingham

The detailed organization of an integrated medical sciences curriculum from its initial planning to the final stage of "automatic" administration are described. Although some reduction in departmental autonomy results, this is outweighed by the advantages of a timetable and curriculum prepared, planned and carried out in a cooperative manner. Flexibility and scope for controlled change and experiment are retained.