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Amino acid compositions of the eggs of five lepidopteran hosts for Trichogramma minutum were compared with each other and with a non-host species, Rhodnius prolixus, in which T. minutum oviposits but does not develop. Host eggs are quite homogeneous, particularly when compared according to groupings of potentially interconvertible amino acids. Combined mole percent values for glycine, serine and alanine were higher in hosts (27.5–29.2 mole%) than in R. prolixus eggs (21.5 mole%), in bovine serum albumin (14.9%), which has been used as a protein source in artificial diets for T. minutum, or in many of the mixtures used in published diets for this species. Since these three amino acids make up 26.3 mole% of the adult amino acid content of T. minutum, their deficiency in diets could require metabolic compensation detrimental to development. Adult T. minutum arising from eggs of Manduca sexta, Choristoneura fumiferana, and Sitotroga cerealella are similar in amino acid composition to each other and, in general, to their hosts. Variability appears greater in hosts than in adult wasp composition, suggesting some interconversion of host amino acids to accommodate inflexible nutritional requirements of T. minutum. In the three host species tested, free amino acids constituted 15.8–19.3% by weight of the amino acid in egg contents. In M. sexta eggs, glycine, serine and alanine together make up 28.4% by weight of the total free amino acid, a much higher proportion than in many published diets. The four free amino acids (isoleucine, leucine, phenylalanine and histidine) reported to be oviposition stimulants in experiments on encapsulated diets are present in sufficient concentrations to induce oviposition in the host species tested and in R. prolixus. S. cerealella egg contents having approximately 1.8 μg amino acid, yield one or rarely two adult T. minutum (1 μg amino acid/insect). In contrast, M. sexta eggs with 94 μg amino acid each yield an average of 10–12 adults (8.2 μg amino acid/insect). This suggests that small hosts are allocated few eggs which can only develop into small adults because of nutrient supply (parasitoid size in metabolically restricted), whereas much larger hosts are allocated proportionately fewer eggs than the former resulting in larger, and presumably more viable and fecund, adults (parasitoid size is established behaviourally).

We investigate the theory of resonant tunneling of the phase difference {phi} in current-biased, small-capacitance Josephson junctions. Tunneling of {phi} occurs between states localized in adjacent wells of the tilted cosine ( washboard'') potential when the states are nearly degenerate, and leads to unique junction behavior. Most notable are the presence of voltage spikes along the supercurrent branch of the current-voltage characteristic, the reduction of the bias current at which the junction switches to the free-running state to a value well below the thermodynamic value, and peaks in the distribution of rates at which this switching occurs as a function of bias current. For a range of junction parameters, we estimate the magnitude and width of the first (lowest bias current) voltage spike and the rate of switching to the free-running state in the zero temperature, low damping limit. Experimentally, the most readily observable signature of resonant tunneling should be the characteristic peaks in the switching distribution.

[1] We present 2 1/2 D numerical MagnetoHydroDynamic (MHD) simulations of coronal mass ejections (CMEs) in conjunction with plasma simulations of radio emission from the CME-driven shocks. The CME-driven shock extends to an almost spherical shape during the temporal evolution of the CME. Our plasma simulations can reproduce the dynamic spectra of coronal type II radio bursts, with the frequency drift rates corresponding to the shock speeds. We find further, that the CME-driven shock is an effective radio emitter at metric wavelengths, when the CME has reached a heliocentric distance of about two solar radii (). We apply our simulation results to explain the radio images of type II bursts obtained by radio heliographs, in particular to the banana-shaped images of radio sources associated with fast CMEs.

Conventional paradigms for the management of elevated intracranial pressure (ICP) are in many ways imperfect. Clinicians respond to increases in ICP, or to worsening of the clinical neurological examination, after critical thresholds of brain ischemia have been crossed, at a point when irreversible injury may have already occurred and the window of opportunity for therapeutic intervention has closed. Even with the benefit of direct ICP monitoring, the true biochemical environment of the brain is unknown, so that measurable changes in blood pressure, cerebral perfusion pressure (CPP), circulating blood volume and rheology, blood oxygen and glucose levels, and other clinical parameters result in uncertain global or regional effects in areas of the brain at risk. The goal of multimodality monitoring is to titrate clinical therapy at the bedside to foster a biochemical environment that favors preservation of function and healing within the brain — a proactive, in place of a reactive, approach. This chapter suggests different ways in which ICP, brain tissue and jugular bulb oxygen content, microdialysis, continuous electroencephalography (EEG), and transcranial Doppler ultrasound data can be integrated into a practical management algorithm for patients with elevated ICP.

Type II solar radio bursts have resisted detailed explanation for over 60 years despite being the archetype for collective radio emission associated with shocks. Type II bursts are important because they involve fundamental physics and because most large space weather events at Earth are associated with large, fast, coronal mass ejections (CMEs) and so with type II bursts. Here we present strong evidence for the accurate and quantitative simulation of a type II burst from the deep corona (near 3 solar radii) to near 0.5 AU. The event was observed by the widely separated STEREO A and B spacecraft between 29 November and 1 December 2013. To do so we combine data-driven three-dimensional magnetohydrodynamic simulations (the BATS-R-US code) for the CME and plasma background with an analytic quantitative kinetic model for electron reflection at the shock, transfer of electron energy into Langmuir waves and radio emission, and propagation of radiation to an arbitrary observer. The intensities and frequencies of the radio emissions vary by factors ≈ 104 and ≈ 102, respectively. The theory predicts the intensities, frequencies, and timings of the multiple islands of type II emission very well, with the theory typically in error by less than a factor of 10, 20%, and less than an hour, respectively, for both STEREO A and B. This agreement is strong evidence for the type II theory itself and for accurate prediction by BATS-R-US, when carefully initialised with available data, of the background plasma and magnetic field configurations and of the CME's properties and motion.

Background and purpose The purpose of this study was to analyze whether early treatment of ruptured aneurysms improves clinical outcomes independent of aneurysm rebleeding. Methods A prospectively maintained database of ruptured intracranial aneurysms treated at our center from 1996 to 2014 was analyzed. Patients Results We identified 1176 consecutive patients with ruptured aneurysms who underwent treatment. Seven hundred and seven patients had their aneurysms secured within 48 h of subarachnoid hemorrhage. Treatment was delayed in 469 patients due to delayed presentation or transfer from other centers. No significant difference was seen between the two groups with respect to Age, Sex, Smoking status and pre-rupture modified Rankin scale. Patients in the early treatment group were more likely to have poor World Federation of Neurological Surgeons clinical grade (mean WFNS 2 vs. 1 p Conclusions Securing ruptured aneurysms early improves mid and long-term clinical outcomes independent of aneurysm rebleeding. Further investigation is required to define the mechanism of the benefit. Disclosures N. Manning: None. E. Meyers: None. J. Schmidt: None. J. Claassen: None. E. Connolly: None. S. Lavine: None. P. Meyers: None.

Resource recovery, including that of urine water extraction, is one of the most crucial aspects of long-term life support in interplanetary space travel. This effort consequently examined an innovative approach to processing raw, undiluted urine based on low-temperature freezing. A strategy uniquely different from NASA’s current emphasis on either ‘integrated’ (co-treatment of mixed urine, grey, and condensate waters) or ‘high-temperature’ distillation processing strategies, whereby this liquid freeze-thaw (LiFT) procedure avoids both chemical and microbial crosscontamination concerns while at the same time securing highly desirable reductions in likely energy requirement levels. In essence, this research effort investigated an innovative, first-generation eutectic freeze concentration strategy for extraction of potable water from urine. The existing project’s experimental unit, which couples the sequential steps normally associated with conventional eutectic freeze crystallization (e.g., seed crystal growth followed by ice ripening, concentration, washing, extraction, and final ice-water recovery), has proven capable of generating highquality product water, (i.e., greater than 99% reduction of contaminant concentrations; inorganics, organics, biological and antibiotics), along with a theoretical percent water recovery of 85-95%.

The authors performed serial transcranial Doppler (TCD) and carbon dioxide reactivity (CO2R) testing in 20 aneurysmal subarachnoid hemorrhage patients to determine whether impaired cerebrovascular reactivity was associated with symptomatic vasospasm. Symptomatic vasospasm occurred in 9 of 14 patients with abnormal CO2R and in none of 6 patients with preserved reactivity (p = 0.011). Abnormal CO2R preceded the onset of vasospasm in 7 of 9 patients. Abnormal standard TCD testing was not associated with vasospasm.

This chapter provides an overview of current efforts in the theory and modeling of CMEs. Five key areas are discussed: (1) CME initiation; (2) CME evolution and propagation; (3) the structure of interplanetary CMEs derived from flux rope modeling; (4) CME shock formation in the inner corona; and (5) particle acceleration and transport at CME driven shocks. In the section on CME initiation three contemporary models are highlighted. Two of these focus on how energy stored in the coronal magnetic field can be released violently to drive CMEs. The third model assumes that CMEs can be directly driven by currents from below the photosphere. CMEs evolve considerably as they expand from the magnetically dominated lower corona into the advectively dominated solar wind. The section on evolution and propagation presents two approaches to the problem. One is primarily analytical and focuses on the key physical processes involved. The other is primarily numerical and illustrates the complexity of possible interactions between the CME and the ambient medium. The section on flux rope fitting reviews the accuracy and reliability of various methods. The section on shock formation considers the effect of the rapid decrease in the magnetic field and plasma density with height. Finally, in the section on particle acceleration and transport, some recent developments in the theory of diffusive particle acceleration at CME shocks are discussed. These include efforts to combine self-consistently the process of particle acceleration in the vicinity of the shock with the subsequent escape and transport of particles to distant regions.

This report assesses the current status of research relating the origin at the Sun, the evolution through the inner heliosphere and the effects on the inner heliosphere of the interplanetary counterparts of coronal mass ejections (ICMEs). The signatures of ICMEs measured by in-situ spacecraft are determined both by the physical processes associated with their origin in the low corona, as observed by space-borne coronagraphs, and by the physical processes occurring as the ICMEs propagate out through the inner heliosphere, interacting with the ambient solar wind. The solar and in-situ observations are discussed as are efforts to model the evolution of ICMEs from the Sun out to 1 AU.

[1] This paper presents a numerical study of magnetic reconnection processes between magnetically organized structures in the solar wind (e.g., magnetic clouds or plasma bubbles) and the solar wind magnetic field. Magnetic reconnection occurs at points along the surface bounding the two flux systems where antiparallel field lines are forced together. For a magnetic cloud moving outward in an unidirectional radial magnetic field, the reconnection occurs asymmetrically, the location depending on the sense of rotation of the cloud's magnetic field. When a cloud moves in a current sheet, reconnection occurs either symmetrically along both sides of the interface or not at all, depending on the relative orientation of the cloud and solar wind fields. The effectiveness of the reconnection process increases with increasing relative speed between the cloud and the solar wind. When the cloud moves faster (slower) than the solar wind, reconnection takes places at the leading (trailing) edge of the cloud. While important, reconnection does not appear to be able to destroy the overall magnetic cloud structure over distances of 1 AU.

A method is described for the rapid and automatic analysis of flexible molecular alignments using multidimensional scaling and a normalized scoring scheme. A projection scheme was devised to separate orientational and conformational effects. It is shown that the approach can be utilized for the identification of common binding orientations or to the study of differences in partioning behavior. It is suggested that the method can be employed as a novel approach exploring molecular similarity as a dynamic property, so that it includes aspects of motion (by way of mutual orientations), conformations and molecular properties.

The original synthesis of combretastatin A-2 (1a) was modified to provide an efficient scale-up procedure for obtaining this antineoplastic stilbene. Subsequent conversion to a useful prodrug was accomplished by phosphorylation employing in situ formation of dibenzylchlorophosphite followed by cleavage of the benzyl ester protective groups with bromotrimethylsilane to afford the phosphoric acid intermediate 11. The latter was immediately treated with sodium methoxide to complete a practical route to the disodium phosphate prodrug (2a). The phosphoric acid precursor (11) of phosphate 2a was employed in a parallel series of reactions to produce a selection of metal and ammonium cation prodrug candidates. Each of the phosphate salts (2a-q) was evaluated with respect to relative solubility behavior, cancer cell growth inhibition and antimicrobial activity.

ABT-770 [(S)-N-[1-[[4'-trifluoromethoxy-[1,1'-biphenyl]-4-yl]oxy]methyl-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-N-hydroxyformamide], a matrix metalloproteinase inhibitor (MMPI), produced generalized phospholipidosis in rats. Phospholipid accumulation was accompanied by retention of drug-related material and was associated with increased mortality. Generation of a successful drug candidate depended upon understanding the cause of the phospholipidosis and redesigning the chemical structure accordingly. ABT-770 and other MMPIs, plus several metabolites of each, were assayed for their ability to induce phospholipidosis in primary cultured rat and human hepatocytes. Phospholipid accumulation was detected by following the incorporation of a fluorescent phospholipid analogue into intracytoplasmic inclusion bodies characteristic of phospholipid storage disorders. At 24 and 48 hr, none of the parent compounds induced phospholipidosis in vitro in rat or human hepatocytes. Phospholipidosis was associated primarily with an amine metabolite of ABT-770. The amine metabolite of another MMPI, ABT-518 ([S-(R*,R*)]-N-[1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]ethyl]-N-hydroxyformamide), produced little phospholipidosis in rat and human hepatocytes even at concentrations up to 100 microM. The presence or absence of phospholipidosis in the in vitro assay correlated well with ultrastructural findings and drug accumulation in rat tissues. ABT-770, which produced phospholipidosis associated with its amine metabolite in vitro and in vivo, also generated a higher tissue to plasma distribution of metabolites particularly in tissues where phospholipidosis was observed. ABT-518 and its amine metabolite, however, produced low tissue to plasma ratios and induced little to no phospholipidosis in vitro or in vivo. These results demonstrate that the phospholipidosis observed for ABT-770 could be attributed to a cationic metabolite, and that altering the properties of such a metabolite, by modification of the parent compound, alleviated the disorder.

The application of metric and multidimensional scaling to conformer ensembles was demonstrated in this work. An automated process was devised to cluster and assign group memberships and cluster representatives. The method allows rapid clustering, leading to intuitive results that can be visually inspected. Multidimensional scaling was found to be superior to metric scaling for clustering conformers. The performance of different hierarchical clustering algorithms was compared using multidimensional plots, and the group average method was found to perform best.

Constant-time 3D heteronuclear relayed E.COSY [Schmidt et al. (1996) J. Biomol. NMR, 7, 142-152], as based on generic 2D small-flip-angle HMQC-COSY [Schmidt et al. (1995) J. Biomol. NMR, 6, 95-105], has been modified to allow for quantitative determination of heteronuclear three-bond 3J(H(alpha),C(gamma)) couplings. The method is applicable to amino acid spin topologies with carbons in the gamma position which lack attached protons, i.e. to asparagine, aspartate, and aromatic residues in uniformly 13C-enriched proteins. The pulse sequence critically exploits heteronuclear triple-quantum coherence (HTQC) of CH2 moieties involving geminal H(beta) proton pairs, taking advantage of improved multiple-quantum relaxation properties, at the same time avoiding scalar couplings between those spins involved in multiple-quantum coherence, thus yielding E.COSY-type multiplets with a splitting structure that is simpler than with the original scheme. Numerical least-squares 2D line-shape simulation is used to extract 3J(H(alpha),C(gamma)) coupling constants which are of relevance to side-chain chi1 dihedral-angle conformations in polypeptides. Methods are demonstrated with recombinant 15N,13C-enriched ribonuclease T1 and Desulfovibrio vulgaris flavodoxin with bound oxidized FMN.

The balance of virus production and clearance for untreated patients with chronic hepatitis C virus (HCV) results in a decline of viraemia when initiating active antiviral treatment. During the first phase of interferon-alpha therapy, after a delay of about 8-9 h, the kinetics of the viral load is characterized by a rapid dose-dependent decline. This early response can be observed for almost all patients treated with interferon-alpha. After about 24-48 h, the viral decline enters a second phase of relatively slow exponential decay during the following weeks of therapy. Non-responding patients, however, show constant viraemia or even a rebound during this second phase. The rate of the exponential decline of the viral load in responding patients in this second phase is less sensitive to the dose of interferon-alpha and varies considerably among patients. Furthermore, combination therapy with interferon-alpha plus ribavirin does not significantly improve the initial viral decay, although it may prevent more patients from rebounding. Mathematical modelling of viral dynamics reveals high turnover rates of pre-treatment viral production and clearance, and permits the estimation of in vivo half-lives of a few hours for free HCV virions and of 1-70 days for productively infected cells. Infected cell death rate, which determines the second phase decline slope, is predictive of response to treatment. Current models indicate that the early biphasic viral decline is explained if interferon-alpha partially blocks virion production from infected cells, yet they do not rule out additional antiviral or immunological effects. Therapeutic implications are the advisability of use of frequent (daily) and comparatively high initial doses. In conclusion, kinetic analysis of the viral decay during the first weeks of treatment permits the prediction of response at the end-of-therapy and might help to evaluate new drugs and to optimize therapy.

One of the primary advantages for the use of SQUID magnetometers fabricated from high temperature superconductors (HTS) in biomagnetic applications lies in the potential for greatly simplified and cheaper cryogenics. However, the costly and inconvenient magnetic shielding presently required also presents an obstacle to the widespread use of HTS magnetometers. One of the common problems associated with unshielded operation of HTS sensors is the adverse effect of the Earth’s magnetic field, nominally 50 μT, on the sensitivity of these devices [1]. Although the noise at high frequencies, usually white in character, is not usually affected by fields of this magnitude, an increase in the low frequency noise is typically observed. This is generally believed to result from a hopping motion of magnetic flux vortices trapped in the film of the device. As the ambient field is increased, the density of trapped vortices also tends to increase, resulting in greater sensor noise.

A Montana soil actinomycete, Streptomyces anulatus, produced (1 x 10(-2)% yield) a new cancer cell growth inhibitory cyclooctadepsipeptide named montanastatin (1) accompanied by the potent anticancer antibiotic valinomycin (2) in very high (5.1%) yields. Valinomycin but not montanastatin inhibited growth of a number of pathogenic bacteria and fungi. Interpretation of high-field (500 MHz) NMR and high-resolution FAB mass spectral data allowed assignment of the structure cyclo-(D-Val-L-Lac-L-Val-D-Hiv) to montanastatin. Valinomycin (2) was also isolated from actinomycetes cultured from a tree branch and animal feces collected in Malaysia. Streptomyces exfoliatus, isolated from the tree branch, was found to contain valinomycin in 1.6% yield, while the fecal isolate, S. anulatus, gave valinomycin in 0.9% yield.

Context In order to optimize student learning during clinical rotations, the learning situation could be better structured. A student log was developed in order to improve the structure of clinical education. In this log, students systematically register essential learning activities. Students record daily the patient problems with which they had been confronted and in which fashion (passive, active, without or with feedback). Objectives/research questions Two questions were addressed. Firstly, did the log provide insight into the content and nature of students' learning experiences and did these learning experiences differ between hospitals? Secondly, was the log used by students, supervisors and the faculty to improve the structure of student learning during clinical education? Method Three student logs, used in an ear, nose and throat, an ophthalmology and a paediatrics clerkship at the Medical School of the University of Maastricht, were developed and implemented. In order to answer the first question, a number of completed student logs were analysed. In order to answer the second question, students were asked to rate the log on five evaluative statements. In addition, the clerkship coordinators were interviewed. Results The results showed that the logs provided the clerkship coordinators with a useful overview of the content and nature of students' learning experiences in the hospitals. The differences between hospitals were small. However, the logs were not used by students, supervisors and faculty to improve the structure of student learning. Conclusions In order to be effective, i.e. to better structure clinical education, a student log should be integrated into the supervision activities.

We present an overview of the properties of magnetohydrodynamic turbulence within corotating interaction regions (CIRs) and its effects on energetic particles. We stress the importance of both the population of fluctuations in the inner heliosphere and the changing local environment in determining their properties at larger heliospheric distances. We present observations from two typical CIRs, one at 0.3 AU before compression regions have formed and the other well developed at 5.1 AU, and discuss the properties of fluctuations within them and show that it is possible to distinguish different regions of the CIR on the basis of the turbulence itself. The strength of the turbulence varies strongly within and close to the CIRs, explaining changes in the mean free path of energetic particles of several orders of magnitude with implications for the modulation of cosmic rays and for diffusive acceleration of particles. The mechanisms by which turbulent fluctuations within interaction regions scatter energetic particles are briefly discussed on a theoretical basis.

Corotating interaction regions (CIRs) in the middle heliosphere have distinct morphological features and associated patterns of turbulence and energetic particles. This report summarizes current understanding of those features and patterns, discusses how they can vary from case to case and with distance from the Sun and possible causes of those variations, presents an analytical model of the morphological features found in earlier qualitative models and numerical simulations, and identifies aspects of the features and patterns that have yet to be resolved.

Continuous awareness of systemic mycosis in immunocompromised patients is important. Early diagnosis is based on (direct) histologal examination and CT scan. Since treatment should start as early as possible, there is usually no time to await results of tissue cultures. Systemic treatment with amphotericin B and aggressive surgical débridement should be performed as soon as possible, while the place of hyperbaric oxygen and G-CSF remains to be established. In addition to routine preventive measures, prophylactic intranasal application of amphotericin B seems to be of value.

The remarkable anticancer drug dolastatin 10 (1a) from the Indian Ocean sea hare Dolabella auricularia is currently undergoing phase I clinical trials. Thirty-eight new structural modifications of this unusual peptide have been synthesized and evaluated against a variety of human and murine cancer cell lines, and for their ability to inhibit tubulin polymerization and vinblastine and GTP binding to tubulin. Dolastatin 10 and one structural modification was found to have antifungal activity, while one other structural modification of the parent compound exhibited antibacterial activity. Some of the new peptides approximated the antineoplastic potency of dolastatin 10, especially those based on replacement of the Doe unit with Met, Phe or an appropriately substituted phenylethylamide.

Dolastatin 15 (1), a potent antineoplastic constituent of the Indian Ocean shell-less mollusk Dolabella auricularia, was utilized as the lead substance for a series of structure-activity studies. The synthetic methods, in vitro evaluations against a variety of murine and human cancer cell lines, as well as a selection of bacteria and fungi, and inhibition of tubulin polymerization are described. Remarkably, all of the compounds studied, in which the C-terminal (S)-dolapyrrolidinone unit (Dpy) was replaced with a series of structurally diverse and more readily available amides, showed cancer cell growth inhibition activities generally quite comparable to those of the parent molecule (1). All analogues, however, were less potent than 1 as inhibitors of tubulin polymerization. The structurally modified peptides, like the parent compound, caused mitotic arrest in cultured cells, consistent with tubulin being the primary cellular target. The ability of dolastatin 15 and eight modifications or precursors thereof to inhibit the growth of a Gram-negative bacterium suggests that these compounds have an additional target distinct from tubulin.

An investigation of the sea hare Dolabella auricularia from Papua New Guinea has led to discovery of the new cyclodepsipeptide dolastatin 16 (3) containing two new amino acid units designated dolamethylleuine (Dml) and dolaphenvaline (Dpv). The structural elucidation was achieved by means of high-field (500 MHz) NMR and tandem MS/MS mass spectral interpretations and allowed the assignment of cyclo-(Pro-Dpv-Pro-Dml-O-Lac-Pro-O-Hiv-MeVal). The new depsipeptide exhibited strong inhibition of growth against a variety of human cancer cell lines.

Type II solar radio bursts are the primary radio emissions generated by shocks and they are linked with impending space weather events at Earth. We simulate type II bursts by combining elaborate three-dimensional MHD simulations of realistic coronal mass ejections (CMEs) at the Sun with an analytic kinetic radiation theory developed recently. The modeling includes initialization with solar magnetic and active region fields reconstructed from magnetograms of the Sun, a flux rope of the initial CME dimensioned with STEREO spacecraft observations, and a solar wind driven with averaged empirical data. We demonstrate impressive accuracy in time, frequency, and intensity for the CME and type II burst observed on 2011 February 15. This implies real understanding of the physical processes involved regarding the radio emission excitation by shocks and supports the near-term development of a capability to predict and track these events for space weather prediction.

Holdfast exopolymers of the dimorphic oligotrophic bacterium Seliberia stellata were examined using fluorescent lectins under light microscopy and colloidal gold lectins using transmission electron microscopy. Examination using fluorescent-labeled lectins revealed that lectins specific for polysaccharides and monosaccharides such as glucose and/or mannose, galactose, N-acetylgalactosamine, and N-acetylglucosamine (and its dimer) adhered to holdfast structure. Colloidal gold-labeled lectin assays also suggested the presence of these sugars. Both the holdfast that mediates swarmer cell adhesion and the holdfast that facilitates rosette formation gave similar results, suggesting the structures may be the same. Another exopolymer produced later in the growth cycle was observed using transmission electron microscopy. It appeared as an amorphous glycocalyx-like material very different from holdfast exo-polymers. Retention of the gold lectin (Wheat Germ Agglutinin (WGA), suggested the presence of N-acetylglucosamine, but fluorescent analyses were unsuccessful. The data suggest that S. stellata produces at least two different exopolymers: (a) the exopolymer of the swarmer cell and rosette holdfast whose function is adhesion and whose composition is (but may not be limited to) polysaccharides and (b) a slime-like exopolymer whose composition and function remain unknown.

Currently, the description of chemical and biochemical phenomena is heavily based on the conception of a molecular “structure”, i. e. of a rigid arrangement of atoms in space, defining the conformation of a molecule. This view matches our limited means of representation and visualization with pen and pencil. Chemical reactions are conceived as instantaneous conversions of an initial into a final structure, occurring with a certain probability per unit time. Molecules are imagined to hop from one minimum to another on the potential-energy hypersurface.

New structural modifications of the marine shell-less mollusk peptide constituent dolastatin 10 (1) have been synthesized, and evaluated against a variety of cancer cell lines and for their ability to inhibit tubulin polymerization. A number of useful structure-activity relationships were uncovered. The most important observation was that the dolaphenine unit of dolastatin 10 could be satisfactorily replaced with a phenethylamine. Peptide 11C, designated auristatin PE, was found to exhibit inhibition of cancer cell growth and tubulin assembly comparable to that of dolastatin 10.

The antineoplastic constituents of Combretum caffrum (Eckl. and Zeyh) Kuntze (Combretaceae family), a species indigenous to South Africa, have been investigated. Subsequently we isolated a series of closely related bibenzyls, stilbenes, and phenanthrenes from C. caffrum. Some of the stilbenes proved to be potent antimitotic agents which inhibited both tubulin polymerization and the binding of colchicine to tubulin. Combretastatin A-4 has been shown to be the most potent cancer cell growth inhibitor of the series. Presently this cis-stilbene is the most effective inhibitor of colchicine binding to tubulin and the simplest natural product yet described with such potent antitubulin effects. Combretastatin A-4, A-5, and A-6 were also found to inhibit growth of Neisseria gonorrhoeae. Details of the isolation and syntheses of combretastatins A-4 (2a), A-5 (2c), and A-6 (3a) have been described.

We have prepared [3H]dolastatin 10 and examined its interactions with tubulin. Binding kinetics appeared to be biphasic, with a rapid initial reaction that could not be accurately measured, followed by a slower second reaction. Bound drug was stable in centrifugal gel filtration, column gel filtration, and high performance liquid chromatography gel filtration, but the bound drug could be displaced by an active isomer of dolastatin 10. Scatchard analysis of binding data was consistent with two classes of binding sites. However, dolastatin 10 induced an aggregation reaction upon binding to tubulin, complicating analysis of the data, and incorporation of [3H]dolastatin 10 into large aggregates was readily demonstrated. The chromatographic properties of the smallest radiolabeled species that could be documented were most consistent with a complex consisting of two molecules of alpha/beta-tubulin dimer and two molecules of [3H]dolastatin 10. The coexistence of an aggregation reaction with a binding reaction at a single site probably underlies the biphasic binding kinetics and the biphasic Scatchard plot. Of peptides that strongly inhibit tubulin polymerization (dolastatin 10, dolastatin 10 isomers, segments, and analogs, dolastatin 15, and phomopsin A), only those previously shown to be strong inhibitors of vinblastine binding and nucleotide exchange also strongly inhibited [3H]dolastatin 10 binding and induced tubulin aggregation (dolastatin 10 itself, two chiral isomers of dolastatin 10, and phomopsin A). The morphology of dolastatin 10-induced aggregates was compared with that of vinblastine-induced aggregates under a variety of reaction conditions. With both drugs the aggregates had a more organized appearance when microtubule-associated proteins were included in the reaction.

This investigation examined the effects of 6-methylene progesterone (6MP), an irreversible inhibitor of 5-alpha-reductase, on prostatic cancer (PC) cell lines. Dose titration microculture tetrazolium assays were used to evaluate cytotoxicity in cultures treated for 72 hr with 6MP (0-20 micrograms/ml). An androgen-sensitive cell line, LNCaP, was drug-sensitive with a mean 50% lethal dose value (LD50) of 2.632 +/- 0.103. Hormone-resistant PC cell lines 1-LN, DU 145, and PC3 also demonstrated sensitivity with LD50 values between 0.8579-1.110 micrograms/ml with a group average of 1.023 +/- 0.082 micrograms/ml. Increasing dosages of dihydrotestosterone in the growth media did not alter 6MP cytotoxicity in androgen-insensitive prostatic cancer cell lines. No correlation between androgen-responsiveness and 6MP-induced cytotoxicity was observed. In nonprostatic malignancies, 6MP inhibited adenocarcinoma cell lines with a mean group LD50 value of 0.7772 micrograms/ml +/- 0.110. J82, a transitional cell carcinoma cell line of bladder origin, exhibited an average LD50 value of 1.041 +/- 0.260. In an epidermoid cervical cancer cell line, ME180, an LD50 value of 0.5356 micrograms/ml +/- 0.010 was noted. In a melanoma cell line, Du Mel 6, a mean LD50 of 0.7428 +/- 0.023 micrograms/ml was achieved with 6MP. We conclude that 6MP, a novel 5-alpha-reductase inhibitor, has potential as a cytotoxic agent in prostatic carcinoma and additional human malignancies. Further study is justified.

We tend not to think of music as noise but as a pleasant sound. Yet, played loud enough, music can become a threat to the human ear. The question arises whether professional musicians suffer from hearing losses caused by their playing of music. The hearing of students at the Rotterdam conservatory was studied; medical students served as a reference group. High percentages of audiometric noise dips (16%) and high-frequency losses (20%) were found in students of the conservatory, as well as a high percentage (72%) of extended high-frequency losses relative to the reference curves of Dreschler et al. Surprisingly, an equally large (and in the high-frequency region an even higher) percentage of hearing losses was found in the control group of medical students with the same median age. In sum, the exposure of conservatory students to the practice of music has as yet had no effect on their hearing.

After an enormous spread in the United States of America during the 19th century homeopathy had almost completely vanished from the scene by the beginning of the 20th century. For the past two decades, however, it seems once again to experience a kind of renaissance. Major aspects of this development-in terms of medical and cultural history, sociology, politics, and economics-are illustrated on the basis of a general history of homeopathy in the United States. Using original sources, a first attempt is made to reconstruct the history of homeopathy in San Francisco which has some institutional peculiarities that make it unique within the whole country.

We simulated an expanding loop or slow coronal mass ejection (CME) in the solar corona dimensioned with size parameters taken from real coronal expanding loops observed with the STEREO spacecraft. We find that the loop expands to Sun's size within about one hour, consistent with slow CME observations. At the top of the loop, plasma is being blown off the loop, enabled with the reconnection between the loop's flux rope magnetic field and the radial magnetic field of the Sun, thus yielding feeding material for the formation of the slow solar wind. This mechanism is in accordance with the observed blob formation of the slow solar wind. We find wave packets traveling with local sound speed downward toward the footpoints of the loop, already seen in coronal seismology observations and simulations of stationary coronal loops. Here, we generalize these results for an expanding medium. We also find a reflection of the wave packets, identified as slow magnetoacoustic waves, at the footpoints of the loop. This confirms the formation of standing waves within the coronal loop. In particular, the reflected waves can partly escape the loop top and contribute to the heating of the solar wind. The present study improves our understanding on how loop material can emerge to form blobs, major ingredients of slow CMEs, and how the release of the wave energy stored in slow magnetoacoustic waves, and transported away from the Sun within expanding loops, contributes to the acceleration and formation of the slow solar wind.

In this study the incidence of hypochondriasis among new ENT out-patients was investigated. A validated questionnaire, which was administered twice with an interval of 3 months, was used to make the diagnosis. Medical information also played a part in the assessment. The diagnosis hypochondriasis applied to 13% of the patients who completed the entire diagnostic procedure. This group made very frequent use of a range of medical services and took a large amount of medicine. Compared with the non-hypochondriacal ENT group, the hypochondriacal group had a more negative opinion about their own health, although those in the latter group were less ill, measured by objective criteria. In order to be able to diagnose hypochondriasis in ENT practice, psychological or psychiatrical consultation is necessary.

Continuation of a structure/activity relationship study of the bryostatins was focused on bryostatin 2. Stepwise catalytic hydrogenation of bryostatin 2 gave the following results. Reduction of the side-chain diene system to saturated ester 2a (P388 cell line ED50 8.5 x 10(-3) micrograms/ml) did not significantly affect the murine P388 cell line inhibition by bryostatin 2. Further hydrogenation to hexahydro derivative 2b gave a reduced P388 ED50 of 5.1 x 10(-2) micrograms/ml. Conversion to the octahydrobryostatin 2c caused a further reduction of P388 cell line activity to ED50 2.9 x 10(-1) micrograms/ml. Other structural modifications of bryostatin 2 in respect to esterification at the C-7 position significantly affected the P388 lymphocytic leukemia cell line response. Each of the bryostatin 2 derivatives was also evaluated with respect to protein kinase C binding.

We evaluated the time interval required for wound healing using a standard wound management protocol with and without aloe vera gel. Twenty-one women were studied who had wound complications requiring healing by second intention after cesarean delivery or laparotomy for gynecologic surgery. Wounds treated with standard management healed in a mean (+/- SD) time interval of 53 +/- 24 days, whereas those treated with aloe vera gel required 83 +/- 28 days (P = .003). The use of aloe vera dermal wound gel was associated with a significant delay in wound healing compared with treatment with an otherwise identical regimen that did not include aloe vera.

The current-voltage characteristics of submicron normal-metal tunnel junctions at millikelvin temperatures are observed to exhibit a sharp Coulomb blockade with high-resistance thin-film leads, but to be heavily smeared for low-resistance leads. As the temperature is lowered, the zero-bias differential resistance tends asymptotically to a limit that is greater for junctions with high-resistance leads. Both observations are explained in terms of a model in which quantum fluctuations in the external circuit enhance the low-temperature tunneling rate. The predictions are in reasonable agreement with the data.