An animal model of hypoxia-induced perinatal seizures

Clinically, neonatal hypoxic encephalopathy is commonly associated with seizure activity. Here we describe a rodent model of cerebral hypoxia in which there is are age dependent effects of hypoxia, with hypoxia inducing seizure activity in the immature rat, but not in the adult. Global hypoxia (3-4% O2) induced acute seizure activity during a window of development between postnatal day (P5-17), peaking at P10-12. Animals which had been rendered hypoxic between P10-12 had long term decreases in seizure threshold, while animals exposed at younger (P5) or older (P60) ages did not. Antagonists of excitatory amino acid (EAA) transmission appear to be superior to benzodiazepines in suppressing the acute and long term effects of perinatal hypoxia, suggesting involvement of the EAA system in these phenomena. No significant histologic damage occurs in this model, suggesting that functional alterations take place in neurons when exposed to an hypoxic insult at a critical developmental stage. Future work is directed at evaluating molecular and cellular events underlying the permanent increase in seizure susceptibility produced by this model.     

Effect of genetically modified, low-phytic acid maize on absorption of iron from tortillas

BACKGROUND: Genetically modified, low-phytic acid strains of maize were developed to enhance mineral absorption, but have not been tested previously in humans. OBJECTIVES: We evaluated the mineral and phytic acid contents of a low-phytic acid "flint" maize (LPM, the lpa-1-1 mutant) and its parent, wild-type strain (WTM) and measured iron absorption from tortillas prepared with each type of maize and from a reference dose of ferrous ascorbate. DESIGN: Proximate composition and mineral and phytic acid contents were measured by standard techniques. Iron absorption from tortillas was evaluated by using the extrinsic tag method and was measured as the incorporation of radiolabeled iron into the red blood cells of 14 nonanemic men 2 wk after intake. RESULTS: The phytic acid content of LPM was 3.48 mg/g, approximately 35% of the phytic acid content of WTM; concentrations of macronutrients and most minerals were not significantly different between strains. Iron absorption results were adjusted to 40% absorption of ferrous ascorbate. Iron absorption was 49% greater from LPM (8.2% of intake) than from WTM (5.5% of intake) tortillas (P < 0.001, repeated-measures analysis of variance). CONCLUSION: Consumption of genetically modified, low-phytic acid strains of maize may improve iron absorption in human populations that consume maize-based diets.     

NMR determination of the major solution conformation of a peptoid pentamer with chiral side chains

Polymers of N-substituted glycines ("peptoids") containing chiral centers at the alpha position of their side chains can form stable structures in solution. We studied a prototypical peptoid, consisting of five para-substituted (S)-N-(1-phenylethyl)glycine residues, by NMR spectroscopy. Multiple configurational isomers were observed, but because of extensive signal overlap, only the major isomer containing all cis-amide bonds was examined in detail. The NMR data for this molecule, in conjunction with previous CD spectroscopic results, indicate that the major species in methanol is a right-handed helix with cis-amide bonds. The periodicity of the helix is three residues per turn, with a pitch of approximately 6 A. This conformation is similar to that anticipated by computational studies of a chiral peptoid octamer. The helical repeat orients the amide bond chromophores in a manner consistent with the intensity of the CD signal exhibited by this molecule. Many other chiral polypeptoids have similar CD spectra, suggesting that a whole family of peptoids containing chiral side chains is capable of adopting this secondary structure motif. Taken together, our experimental and theoretical studies of the structural properties of chiral peptoids lay the groundwork for the rational design of more complex polypeptoid molecules, with a variety of applications, ranging from nanostructures to nonviral gene delivery systems.     

Capillary electrophoresis of insulin-like growth factors: enhanced ultraviolet detection using dynamically coated capillaries and on-line solid-phase extraction

We consider a model of an integrate-and-fire neuron with synaptic current dynamics, in which the synaptic time constant tau' is much smaller than the membrane time constant tau. We calculate analytically the firing frequency of such a neuron for inputs described by a random Gaussian process. We find that the first order correction to the frequency due to tau' is proportional to the square root of the ratio between these time constants radicaltau'/tau. This implies that the correction is important even when the synaptic time constant is small compared with that of the potential. The frequency of a neuron with tau'>0 can be reduced to that of the basic IF neuron (corresponding to tau'=1) using an "effective" threshold which has a linear dependence on radical tau'/tau. Numerical simulations show a very good agreement with the analytical result, and permit an extrapolation of the "effective" threshold to higher orders in radical tau'/tau. The obtained frequency agrees with simulation data for a wide range of parameters.     

Structural and kinetic evidence for strain in biological catalysis

A classic hypothesis for enzyme catalysis is the induction of strain in the substrate. This notion was first expressed by Haldane with the lock and key analogy-"the key does not fit the lock perfectly but exercises a certain strain on it" (1). This mechanism has often been invoked to explain the catalytic efficiency of enzymes but has been difficult to establish conclusively (2-7). Here we describe X-ray crystallographic and mutational studies of an antibody metal chelatase which strongly support the notion that this antibody catalyzes metal ion insertion into the porphyrin ring by inducing strain. Analysis of the germline precursor suggests that this strain mechanism arose during the process of affinity maturation in response to a conformationally distorted N-alkylmesoporphyrin.     

Sensorimotor state of the contralateral leg affects ipsilateral muscle coordination of pedaling

The objective of this study was to determine if independent central pattern generating elements controlling the legs in bipedal and unipedal locomotion is a viable theory for locomotor propulsion in humans. Coordinative coupling of the limbs could then be accomplished through mechanical interactions and ipsilateral feedback control rather than through central interlimb neural pathways. Pedaling was chosen as the locomotor task to study because interlimb mechanics can be significantly altered, as pedaling can be executed with the use of either one leg or two legs (cf. walking) and because the load on the limb can be well-controlled. Subjects pedaled a modified bicycle ergometer in a two-legged (bilateral) and a one-legged (unilateral) pedaling condition. The loading on the leg during unilateral pedaling was designed to be identical to the loading experienced by the leg during bilateral pedaling. This loading was achieved by having a trained human "motor" pedal along with the subject and exert on the opposite crank the torque that the subject's contralateral leg generated in bilateral pedaling. The human "motor" was successful at reproducing each subject's one-leg crank torque. The shape of the motor's torque trajectory was similar to that of subjects, and the amount of work done during extension and flexion was not significantly different. Thus the same muscle coordination pattern would allow subjects to pedal successfully in both the bilateral and unilateral conditions, and the afferent signals from the pedaling leg could be the same for both conditions. Although the overall work done by each leg did not change, an 86% decrease in retarding (negative) crank torque during limb flexion was measured in all 11 subjects during the unilateral condition. This corresponded to an increase in integrated electromyography of tibialis anterior (70%), rectus femoris (43%), and biceps femoris (59%) during flexion. Even given visual torque feedback in the unilateral condition, subjects still showed a 33% decrease in negative torque during flexion. These results are consistent with the existence of an inhibitory pathway from elements controlling extension onto contralateral flexion elements, with the pathway operating during two-legged pedaling but not during one-legged pedaling, in which case flexor activity increases. However, this centrally mediated coupling can be overcome with practice, as the human "motor" was able to effectively match the bilateral crank torque after a longer practice regimen. We conclude that the sensorimotor control of a unipedal task is affected by interlimb neural pathways. Thus a task performed unilaterally is not performed with the same muscle coordination utilized in a bipedal condition, even if such coordination would be equally effective in the execution of the unilateral task.     

A reappraisal of early hominid phylogeny

We report here on the results of a new cladistic analysis of early hominid relationships. Ingroup taxa included Australopithecus afarensis, Australopithecus africanus, Australopithecus aethiopicus, Australopithecus robustus, Australopithecus boisei, Homo habilis, Homo rudolfensis, Homo ergaster and Homo sapiens. Outgroup taxa included Pan troglodytes and Gorilla gorilla. Sixty craniodental characters were selected for analysis. These were drawn from the trait lists of other studies and our own observations. Eight parsimony analyses were performed that differed with respect to the number of characters examined and the manner in which the characters were treated. Seven employed ordered characters, and included analyses in which (1) taxa that were variable with respect to a character were coded as having an intermediate state, (2) characters with variable states in any taxon were excluded; (3) a variable taxon was coded as having the state exhibited by the majority of its hypodigm, (4) variable taxa were coded as missing data for that character, (5) some characters were considered irreversible, (6) masticatory characters were excluded, and (7) characters whose states were unknown in some taxa were excluded. In the final analysis, (8) all characters were unordered. All analyses were performed using PAUP 3.0s. Despite the fact that the eight analyses differed with respect to methodology, they produced several consistent results. All agreed that the "robust" australopithecines form a clade, A. afarensis is the sister taxon of all other hominids, and the genus Australopithecus, as conventionally defined, is paraphyletic. All eight also supported trees in which A. africanus is the sister taxon of a joint Homo+ "robust" clade, although in one analysis an equally parsimonious topology found A. africanus to be the sister of the "robust" species. In most analyses, the relationships of A. africanus and H. habilis were unstable, in the sense that their positions vary in trees that are marginally less parsimonious than the favored one. Trees in which "robust" australopithecines are paraphyletic were found to be extremely unparsimonious.     

Quantum device-simulation with the density-gradient model onunstructured grids

We describe an implementation of the density-gradient device equations which is simple and works in any dimension without imposing additional requirements on the mesh compared to classical simulations. It is therefore applicable to real-world device simulation with complex geometries. We use our implementation to determine the quantum mechanical effects for a MOS-diode, a MOSFET and a double-gated SOI MOSFET. The results are compared to those obtained by a 1D-Schrodinger-Poisson solver. We also investigate a simplified variant of the density-gradient term and show that, while it can reproduce terminal characteristics, it does not give the correct density distribution inside the device     

Fusarium and mycotoxin spectra in Swiss barley are affected by various cropping techniques

Fusarium head blight is one of the most important cereal diseases worldwide. Cereals differ in terms of the main occurring Fusarium species and the infection is influenced by various factors, such as weather and cropping measures. Little is known about Fusarium species in barley in Switzerland, hence harvest samples from growers were collected in 2013 and 2014, along with information on respective cropping factors. The incidence of different Fusarium species was obtained by using a seed health test and mycotoxins were quantified by LC-MS/MS. With these techniques, the most dominant species, F. graminearum, and the most prominent mycotoxin, deoxynivalenol (DON), were identified. Between the three main Swiss cropping systems, Organic, Extenso and Proof of ecological performance, we observed differences with the lowest incidence and toxin accumulation in organically cultivated barley. Hence, we hypothesise that this finding was based on an array of growing techniques within a given cropping system. We observed that barley samples from fields with maize as previous crop had a substantially higher F. graminearum incidence and elevated DON accumulation compared with other previous crops. Furthermore, the use of reduced tillage led to a higher disease incidence and toxin content compared with samples from ploughed fields. Further factors increasing Fusarium infection were high nitrogen fertilisation as well as the application of fungicides and growth regulators. Results from the current study can be used to develop optimised cropping systems that reduce the risks of mycotoxin contamination.     

Daily prognostic estimates for critically ill adults in intensive care units: results from a prospective, multicenter, inception cohort analysis

OBJECTIVE: To develop daily prognostic estimates for individual patients treated in adult intensive care units (ICU). DESIGN: Prospective, multicenter, inception cohort analysis. SETTING: Forty-two ICUs at 40 U.S. hospitals with > 200 beds including 20 ICUs in tertiary care centers with major teaching activities. PATIENTS: A consecutive sample of 17,440 ICU admissions. MEASUREMENTS AND MAIN RESULTS: A series of multivariate equations were developed using the patient's primary reason for ICU admission, age, chronic health status, treatment before ICU admission, admission Acute Physiology Score, current day Acute Physiology Score, and change between the current and previous day's Acute Physiology Score. The equations were used to create daily risk predictions and cross-validated within the 17,440-patient sample. The single most important factor determining daily risk of hospital death during each of the initial 7 days of ICU care was the current day's Acute Physiology Score of the Acute Physiology and Chronic Health Evaluation (APACHE) III score. The admission Acute Physiology Score and change from previous to current day's Acute Physiology Score were also important, as were ICU admission diagnosis, age, chronic health status, and treatment before ICU admission. Equations incorporating these risk factors had receiver operating characteristics areas ranging from 0.9 on the first ICU day to 0.84 for patients remaining in the ICU for 7 days. The percent of cases with cross-validated predicted risks over 90% increased from 2.3% (n = 406) of cases on day 1 to 9% of all patients remaining in the ICU on ICU day 7 (n = 218). The 1,033 patients who had a daily risk estimate of > 90% during any of their initial 7 ICU days had a 90% mortality rate and represented 47% of all ICU deaths and 31% of the total number of hospital deaths. CONCLUSIONS: Equations using initial and repeated physiologic measurements provide a high degree of explanatory power for subsequent hospital mortality rate. These daily prognostic estimates deserve evaluation for their potential role in improving the process and outcome from clinical decision-making.