Search

•Bark-stripping by ungulates can result in significant damages to standing timber•The area with internal wood damage was smaller than the external damage area•Length of the damaged stem section was always greater inside than outside•Wound status should be considered for a better prediction of internal damages

We investigate the chances that neutron stars act as the lens in a gravitational microlensing event towards the galactic bulge or a spiral arm. The observation of neutron stars by means of gravitational microlensing would allow the estimation of neutron star masses independently of the property of being a pulsar in a binary system. We estimate the contribution of neutron stars to the optical depth and the lensing rate based on two different models of pulsar distribution in the galaxy. Since only a small fraction of all neutron stars are pulsars, it is unlikely to find a pulsar that acts as a microlens by chance. A position comparison of known radio pulsars with observed microlensing candidates towards the galactic bulge and spiral arms shows no candidate pairs, which is consistent with the theoretical expectation. To improve the probability of microlensing a pulsar, we suggest a search for gravitational microlensing events of known nearby high proper motion pulsars. The pulsar PSR J1932+1059is a good candidate for an astrometric detection of gravitational lensing.

Die Spirometrie ist eine einfache und in der Arbeitsmedizin häufig angewandte Methode zur Diagnostik von Erkrankungen der Atemwege und der Lungen. Für die Beurteilung sind dabei die verwendeten Referenzwerte von großer Bedeutung. Neue Referenzwerte wurden 2012 durch die GLI (Global Lungs Initiative) publiziert. Mit der Anwendung der neuen Referenzwerte stellt sich die Frage, ob mehr oder weniger auffällige Befunde zu erwarten sind. Um eine praxisbezogene Abschätzung der Auswirkung der neuen Referenzwerte auf die betriebsärztliche Bewertung als auffälligbzw. nicht auffälligzu erhalten, wurden die im Rahmen der arbeitsmedizinischen Vorsorge bei 1323 Probanden erhobenen Lungenfunktionswerte vergleichend nach EGKS 1993 sowie GLI ausgewertet. Es zeigt sich, dass bei Anwendung der GLI-Referenzwerte der Anteil der auffälligen Werte bei der FVC etwa doppelt so hoch und bei der FEV1 etwa 70 % höher sind im Vergleich zu den EGKS-Sollwerten. Beim Tiffeneau-Index wurde in unserem Kollektiv kein wesentlicher Anstieg auffälliger Befunde detektiert. Inwieweit sich dies auf Sensitivität und Spezifität des Nachweises obstruktiver oder restriktiver Ventilationsstörungen auswirkt, muss durch zukünftige Studien beurteilt werden. Für die betriebsärztliche Praxis ist zu folgern, dass sich der Beratungsaufwand und ggf. auch der Aufwand an weitergehenden Untersuchungen zunächst deutlich steigern werden, da es mehr auffällige Befunde in der Spirometrie geben wird, ohne dass sich im Einzelfall der Gesundheitszustand der Versicherten geändert hat. Sofern vorhanden, sollte immer ein Vergleich mit den individuellen Vorbefunden erfolgen. Spirometry is a commonly used method for diagnosing diseases of the lungs and the pulmonary system which is often used in occupational health. For spirometry, reference values are of great importance and in 2012 new reference values were published by the global lungs initiative (GLI). Working with the new reference values the question arises whether more or less results varying from the normal are to be expected. The results of 1323 lung function tests registered during routine occupational health medical examinations for prevention purposes were compared using either the European Coal and Steel Community (ECSC) or GLI values. The aim was to evaluate the new reference values on the practice-related medical assessment as being “normal” or “not normal”. Using the GLI reference values “not normal” results for forced vital capacity (FVC) were twice as high and for the forced expiratory volume in 1 s (FEV1) approximately 70 % higher than using ECSC reference values. Regarding the Tiffeneau index in this collective no essential increase in conspicuous results was detected. Future studies will have to be carried out to show to what extent these results influence the sensitivity and specificity of the diagnosis of obstructive or restrictive lung diseases. Consequently, as far as the occupational health practice is concerned, initially the number of consultations and perhaps also the need for further tests will noticeably rise because there will be more “not normal” spirometry results without health changes of the individual test subject. Therefore, results should always be compared to previous results when possible.

We study stability and spectral purity of a microresonator-based Kerr frequency comb oscillator experimentally and observe a correlation between the frequency of the continuous wave laser pumping the nonlinear resonator and the repetition frequency of the comb. This correlation is used in a proof-of-principle demonstration of a Kerr frequency comb stabilized with an optical transition of Rb87.

Objective:To compare the clinical efficacy of a collagen dressing covered with a foam dressing with the same foam used as a primary dressing in stagnating granulating pressure ulcer patients.Method:Patients were randomised to receive either a foam dressing (Suprasorb P; Lohmann & Rauscher) as a primary dressing (group A), or a combination of a collagen dressing (Suprasorb C; Lohmann & Rauscher) covered with the same foam dressing (group B). Wound fluid was collected and evaluated prior to treatment (day 0), and on days 3, 7, 14 and 21. The level and expression of matrix metalloproteinases (MMPs) MMP-2 and MMP-9, and tissue inhibitors of metalloproteinases (TIMPs) TIMP-1 and TIMP-2, as well as elastase content in wound fluid and angiogenesis, were evaluated, comparing results on day 0 and day 21. Time to ulcer healing, reduction in ulcer area, safety of treatment, patient-reported ulcer pain and comfort of the dressing regimen were evaluated as secondary outcomes. Patients received standard preventive measures, in line with the pressure ulcer prevention guidelines.Results:Ten patients were included in the pilot; five were treated with the foam dressing (group A) and five patients received the collagen dressing, using the foam as a secondary dressing (group B). Wound fluid from group B displayed a significant positive effect on angiogenesis (p < 0.05) compared with group A. In the collagen and foam group TIMP-1 and -2 increased faster and levels were higher than in group A. Furthermore, MMP-2, MMP-9 (p < 0.04) and elastase in group B showed faster and greater decrease in levels, compared with group A, indicating a faster and superior reduction of inflammation. In both groups the ulcers started to heal, with a faster onset of healing for group B.Conclusion:The results of this pilot support published data on the use of collagen dressings compared with foam for stagnating wounds, shown in clinical studies.Declaration of interest:This study was supported with an educational grant by Lohmann & Rauscher GmbH. Apart from Dr Abel, the sponsors had no role in the design or conduct of the study, in the collection, analysis and interpretation of the data, or in the preparation, review or approval of the manuscript. Dr Abel gave input to the study design from a scientific perspective. None of the authors received administrative, technical or material support for the conduct of this study. The authors have no other relevant financial interests to declare.

We investigate opto-mechanical oscillation (OMO) and subsequent generation of acoustic wave frequency combs in monolithic crystalline whispering gallery mode (WGM) resonators. The OMO is observed in resonators made of electro-optic (lithium tantalate), non-electro-optic birefringent (magnesium fluoride), and non-birefringent (calcium fluoride) materials. The phenomenon manifests itself as generation of optical harmonics separated by the eigenfrequency of a surface acoustic wave (SAW) mechanical mode of the same WGM resonator. We show that the light escaping the resonator and demodulated on a fast photodiode produces a spectrally pure radio frequency (RF) signal. For instance, we demonstrate generation of 200 MHz signals with instantaneous linewidth of 0.2 Hz.

The Meier-Moir economic model for Pulsed Power Driven Inertial Fusion Energy shows at least two approaches for fusion energy at 7 to 8 cents/kw-hr: One with large yield at 0.1 Hz and presented by M. E. Cuneo at ICENES 2011 and one with smaller yield at 3 Hz presented in this paper. Both use very efficient and low cost Linear Transformer Drivers (LTDs) for the pulsed power. We report the system configuration and end-to-end simulation for the latter option, which is called the Plasma Power Station (PPS), and report the first results on the two, least mature, enabling technologies: a magnetically driven Quasi Spherical Direct Drive (QSDD) capsule for the fusion yield and an Inverse Diode for coupling the driver to the target. In addition, we describe the issues and propose to address the issues with a prototype of the PPS on the Saturn accelerator and with experiments on a short pulse modification of the Z accelerator test the validity of simulations showing megajoule thermonuclear yield with DT on a modified Z.

According to the ITRS roadmap, semiconductor industry drives the 193nm lithography to its limits, using techniques like double exposure, double patterning, mask-source optimization and inverse lithography. For photomask metrology this translates to full in-die measurement capability for registration and critical dimension together with challenging specifications for repeatability and accuracy. Especially, overlay becomes more and more critical and must be ensured on every die. For this, Carl Zeiss SMS has developed the next generation photomask registration and overlay metrology tool PROVE® which serves the 32nm node and below and which is already well established in the market. PROVE® features highly stable hardware components for the stage and environmental control. To ensure in-die measurement capability, sophisticated image analysis methods based on 2D correlations have been developed. In this paper we demonstrate the in-die capability of PROVE® and present corresponding measurement results for shortterm and long-term measurements as well as the attainable accuracy for feature sizes down to 85nm using different illumination modes and mask types. Standard measurement methods based on threshold criteria are compared with the new 2D correlation methods to demonstrate the performance gain of the latter. In addition, mask-to-mask overlay results of typical box-in-frame structures down to 200nm feature size are presented. It is shown, that from overlay measurements a reproducibility budget can be derived that takes into account stage, image analysis and global effects like mask loading and environmental control. The parts of the budget are quantified from measurement results to identify critical error contributions and to focus on the corresponding improvement strategies.

We report on the realization of a compact-package (44x27x14mm) narrow linewidth laser based on self-injection locking of a distributed feedback semiconductor diode laser to a high-Q whispering gallery mode resonator fabricated with electro-optic material. The packaged device operates at 1,550 nm and offers instantaneous spectral linewidth performance smaller than 1.8 kHz for 3 mW of output power. We are able to tune the laser frequency by applying voltage to the resonator. This suggest that the technology enables fabrication of ultra narrow linewidth semiconductor lasers in a broad wavelength range of 390 nm to 2,900 nm. The laser source in a compact footprint enables a multitude of sensing, monitoring, and metrology applications where high resolution and precision and absolute accuracy are required.

We investigate several possibilities of designing spectrum of a whispering gallery mode resonators to create groups of optical modes with desired free spectral range as well as group velocity dispersion. This will enable efficient resonant nonlinear frequency conversion processes such as hyper-parametric and parametric oscillations, frequency doubling, and electro-optical frequency shifting and modulation. We show that the spectral design can be achieved via a proper modification of the shape of the resonator and via the change of the distribution of the refractive index of the resonator host material.

The new photomask registration and overlay metrology system PROVETMat Carl Zeiss has been developed and already delivered to customers to meet the increased industry requirements for pattern registration tools in terms of resolution and in-die measurement capability. Main drivers of the tool performance specifications are double exposure and double patterning approaches which will help to extend the 193nm lithography platforms while keeping the semiconductor industry conform to ITRS roadmap requirements. To guarantee the demanding tool performance, PROVETMfeatures highly stable hardware components for the stage and environmental control. Moreover, sophisticated image analysis algorithms as for instance correlation methods have been developed to overcome limitations of standard approaches. In this paper we focus on mask-to-mask overlay metrology as one of the critical components of modern lithography. To achieve the challenging requirements with the PROVETMtool, an overlay reproducibility budget is prepared that takes into account stage, image analysis and global effects like mask loading and environmental control. The corresponding parts of the budget are quantified by means of PROVETMoverlay measurements, performed on typical box-in-frame structures. This allows the identification of critical error contributions and the corresponding improvement strategies. In particular, it will be shown, that the new developed correlation methods of PROVETMwill significantly reduce image analysis and camera noise contributions.

Eine Vielzahl von experimentellen und klinischen Studien zeigt, daβ Zytokine eine zentrale Rolle bei der Entstehung der Sepsis spielen. Im Rahmen von Entzündungsreaktionen werden Zytokine freigesetzt, die als Signaltransmitter die verschie-denen Komponenten des Immunsystems zu einer zielgerichte-ten Immunantwort koordinieren. Obwohl an der komplexen Entstehung der Sepsis viele Zytokine beteiligt sind, können im Serum septischer Patienten nur wenige Zytokine wie Interleukin-1 (IL-1), Interleukin-6 (IL-6) und Tumor-Nekrose-Faktor-alpha (TNF) sowie neuerdings auch Interleukin-8 (ΓL-8) und Interleukin-10 (IL-10) verläβlich bestimmt werden. Dariiber hinaus wurden für einige Zytokinantagonisten – wie lösliche TNF-Rezeptoren und der IL-1-Rezeptor-Antagonist (IL-1RA) – ebenfalls meβbare Serumspiegel gefunden. Die höchste prognostische Aussagekraft in der Beurteilung der Sepsis ergibt sich für IL-6-Serumspiegel, die dariiber hinaus mit dem Schweregrad der Organdysfunktion korrelieren. Die klinische Wertigkeit von TNF-Messungen im Serum septischer Patienten ist eingeschränkt, da die TNF-Serumspiegel relativ groβe Variationen aufweisen. Neuere Befunde zeigen aber, daβ lösliche TNF-Rezeptoren auf Grund ihrer längeren biologischen Halbwertzeit besser zur Prognose-Beurteilung (Letalitäts-Risi-ko) geeignet sind. Sowohl für die TNF-Rezeptoren als auch für einige andere Zytokine stehen heute automatisierte Testsyste-me zur Verfügung, die eine Messung innerhalb weniger Stun-den ermöglichen und somit klinisch anwendbar sind.

Wir untersuchten prospektiv den prognostischen Wert erhöhter Serumkon-zentrationen der löslichen Tumor-Nekrose-Faktor-Rezeptoren (sTNFR) bei imminenter Sepsis. Die Studienpopulation bestand aus jenen 27 von insgesamt 870 konsekutiven postkardiochirurgischen Patienten, welche ein zuvor validiertes Hochrisikokriterium für eine imminente Sepsis aufwiesen [APACHE-II-Score (APII) > 24 am 1. postoperativen Tag (Tag 1)]. In dieser Population lag ein systemisches Inflammations-Reaktions-Syndrom (SIRS) bei 96% der Patienten vor, die Krankenhausletalität betrug 30%. Zusätzlich wurden 10 postkardiochirurgische Patienten mit unkompliziertem Verlauf (Letalität: 0%) zum Vergleich untersucht. Verglichen mit den 10 Patienten mit unkompliziertem Verlauf (Gruppe A), wiesen die Hochri-sikopatienten signifikant höhere Ausgangswerte (Tag 1) für sTNFR-p55 (9,2 vs. 4,2ng/ml) und sTNFR-p75 (9,2 vs. 5,5 ng/ml) auf. Für den vorgefundenen Kreatinin-Wertebereich (Maximalwert: 2,48 mg/dl) fanden wir keine Korrelation zwischen Kreatinin und sTNFR-p55 (r=0,10) bzw. sTNFR-p75 (r=0,19). Die Hochrisikopatienten konnten in 2 Subgruppen differenziert werden: in die Subgruppe B mit einem prompten Abfall des APII und einer guten Prognose (Letalität: 0%) und Subgruppe C mit persistierend hohem Risiko und hoher Letalität (40%, p < 0,05). Trotz vergleichbarer APII-Ausgangswerte in beiden Hochrisikosubgruppen wa-ren die sTNFR-p55-Spiegel in der Subgruppe C im Vergleich zu B bereits am Tag 1 signifikant erhöht (10,7 vs. 4,7 ng/ml). Die ROC-Kurve für die Subgruppenklassifikation mittels sTNFR-p55 zeigte bereits am Tag 1 eine gute Trennschärfe mit einer Fläche von 0,773+0,096, was den Parameter als Prognoseprädikator bestätigte. Die sTNFR-p75-Ausgangskonzentratio-nen wiesen eine geringere prädiktive Wertigkeit auf. Zusammengefaβt weist unsere Studie darauf hin, daβ erhöhte sTNFR-p55-Serumspiegel bei postkardiochirurgischen Patienten frühzeitiger den Schweregrad von Krankheitsverlauf und Prognose anzeigen als APII-Scores allein. Dies spricht dafür, daβ durch die Kombination von physiolo-gischen Scores und Zytokinrezeptormessungen die prädiktive Wertigkeit einer frühzeitigen postoperativen Risikostratifizierung erhöht werden kann.

For studies of pharmacokinetics and drug metabolism of the new soluble guanylate cyclase activator cinaciguat BAY 582667 the 14Clabelled compound was synthesized. The tritiated compound was required to elucidate the mode of action and the stable labelled compound was required for bioanalytical studies by quantitative mass spectrometry as well. Two radiosyntheses are described with different formation of the labelled intermediate 1chloro14Cmethyl42phenylethylbenzene. The first one started with 14Ccarboxylation of 1bromo42phenylethylbenzene yielding the desired product in 5 steps. In the second synthesis intermediate 1chloro14Cmethyl42phenylethylbenzene was formed by chloromethylation of bibenzyl with 14Cparaformaldehydehydrochloric acid subsequently resulting in the final product in three steps. Tritium labelling was performed by tritium exchange of the diester intermediate using an organoiridium catalyst and subsequent saponification. The stable labelled compound was synthesized via a convergent synthesis starting with 13C,15Ncyanation of 1chloromethyl242phenylethylbenzyloxybenzene and 13Ccyanation of methyl 4bromobenzoate, respectively. The labelled product was obtained after 7 chemical steps. Copyright © 2010 John Wiley & Sons, Ltd.

Acarbose is a potent α‐glucosidase inhibitor which is used successfully as a drug for the treatment of type II diabetes. The compound prevents enzymes of the α‐glucosidase group from cleaving carbohydrates. For the investigation of pharmacokinetics and drug metabolism a first carbon‐14 labelling synthesis was performed in 1981. According to the pharmaceutical production process, the radiosynthesis was performed by fermentation. Due to limited radiolytic stability, repeated radiosyntheses were necessary. Finally, carbon‐14 labelling was optimized to prepare [14C]acarbose on a gram scale with a significant increase of the radiochemical yield. The aspects of the fermentation over a period of about 20 years are described focussing the attention on the optimized radiosynthesis. Copyright © 2007 John Wiley & Sons, Ltd.

We study the scattering of two-level atoms at narrow laser fields, modelled by a ?-shape intensity profile. The unique properties of these potentials allow us to give simple analytic solutions for one or two field zones. Several applications are studied: a single ?-laser may serve as a model for atom detection and arrival-time measurements, either by means of fluorescence or variations in occupation probabilities. We show that, in principle, this ideal detector can measure the particle density, the quantum mechanical flux, arrival-time distributions or local kinetic energy densities. Moreover, two spatially separated ?-lasers are used to investigate quantized-motion effects in Ramsey interferometry.

BAY 59‐7939 is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic diseases. Radiolabeled BAY 59‐7939 was required for drug absorption, distribution, metabolism and excretion (ADME studies). The BAY 59‐7939 was labeled with carbon‐14 in the carboxamide group in one step in an overall radiochemical yield of 85% starting from 4‐{4‐[(5S)‐5‐(aminomethyl)‐2‐oxo‐1,3‐oxazolidin‐3‐yl]phenyl}mor‐pholin‐3‐one and 5‐chlorothiophene‐2‐[14C]carboxylic acid. The radiolabeled metabolite M‐4 was prepared in 77% yield starting from [1‐14C]glycine and 5‐chlorothiophene‐5‐carboxylic acid. Copyright © 2006 John Wiley & Sons, Ltd.

Nexavar™, Sorafenib tosylate (BAY 43‐9006 tosylate) is a potent small molecule Raf kinase inhibitor for the treatment of hyperproliferative disorders such as cancer. Both radiolabeled and stable isotope labeled compounds were required for drug absorption, distribution, metabolism and excretion (ADME) and quantitative mass spectrometry bio‐analytical studies. Nexavar™ labeled with carbon‐14 in the carboxamide group was prepared in two steps in an overall radiochemical yield of 42% starting from 4‐chloro‐N‐methyl‐2‐pyridine‐[14C]carboxamide. The [2H3,15N] version of Nexavar™ was prepared in 75% yield based on 4‐chloro‐N‐[2H3]methyl‐2‐pyridine‐[15N]carboxamide. The pyridine N‐oxide metabolite labeled with carbon‐14 as well as with deuterium and nitrogen‐15 and was synthesized by oxidation in yields of 59% and 87%, respectively. Starting from [2H2, 13C]formaldehyde the N‐hydroxymethyl metabolite was labeled with carbon‐13 and deuterium in one step in a 45% overall yield. Copyright © 2006 John Wiley & Sons, Ltd.

α,α-Linked oligopyrroles are attractive precursors for both expanded porphyrin and conducting polymer chemistry. We demonstrate facile methods for synthesizing quater-, penta-, and sexipyrroles from more readily available bi- and terpyrrole intermediates. These products demonstrate stability in their brightly colored oxidized forms, while reduction using borohydride reagents gives the corresponding all-pyrrole oligomers, which oxidize readily in air. The oxidized quater- and sexipyrroles were characterized by single-crystal X-ray diffraction analysis.

Use of Microwaves in Organic Synthesis: Application in the Synthesis of Isotopically Labelled Compounds Preparation of Tritium-Labelled BIIL 260 with High Specific Radioactivity Synthesis of [³H]-, [¹⁴C]- and [¹³C,²H]-labelled Org 12962 Derivatives Labeling of BAY 58-2667, an Activator of sGC Preparation and Use of [¹⁴C]N,N'-Carbonylditriazole in the Labelling of Urea Derivatives Efficient Carbon-14 Labeling of 2-(3-Hydroxypropyl)-1H-benzimidazole Synthesis of Some ¹⁴C-Labelled Fungicides C-14 Labelling of NVP-ABE651 and NVP-ABE697 Synthesis of Carbon-13,14 Isotopomers of a Novel 4-Substituted-2-Carboxy Tetrahydroquinoline [¹⁴C]CH2N2: A Suitable Precursor for the Preparation of ¹⁴C-Labelled Anthracyclines Preparative HPLC: a Useful Approach to Speed-up the Purification of Labelled Compounds. Use of Stable Isotopes for the Biosynthesis and Biodegradation of Fosfomycin Metalloradiopharmaceuticals for Nuclear Medicine Strategic outlook: Future Methods in DMPK and subsequent requirements for isotopically labelled compounds Isotopic Imaging of Glass-based cDNA Microarray Hybridization New Developments in Radiation Measuring Technique

For studies of pharmacokinetics and drug metabolism of the new 5-HT1A agonist repinotan, the ¹⁴C-labelled version was synthesized. Starting from [U-¹⁴C]phenol, a 10-step synthesis led to 457 mg (1.58 GBq) of [U-¹⁴C]repinotan hydrochloride, labelled uniformly in the aromatic ring of the chromane moiety. For a study in man, a mono-carbon-14 labelled substance was required. Therefore a 7-step synthesis was performed starting from [carbonyl-¹⁴C]2-hydroxy-acetophenone. The yield was 106 mg (0.396 GBq) of [4-chromane-¹⁴C]repinotan hydrochloride. The carbon-14 labelled major metabolite, hydroxylated in the 6-position of the chromane moiety, was synthesised as reference compound. Copyright © 2002 John Wiley & Sons, Ltd.

Hypercoagulability is a key contributor to acute cardiovascular syndromes and to various microcirculatory disorders. The use of heparin-mediated extracorporeal low-density lipoprotein/fibrinogen precipitation (HELP) apheresis makes a controlled, immediately effective reduction of clotting factors possible, and induces subsequent positive effects on plasma viscosity, erythrocyte aggregation, and microcirculation. Oxygen supply to an ischemic artery can thus be increased without hemodilution, qualifying the HELP system as a possible therapeutic tool in the treatment of acute cardiovascular syndromes and microcirculatory disorders.

In the Celebes Sea Basin the Middle Miocene turbidites were correlated from ODP site 767 throughout the studied area. Differences in their regional thickness variations and distribution indicate two source areas. The Middle Miocene turbidite–fan complexes of the central and southern Celebes Sea Basin are controlled by the paleo-Tarakan delta system, the tectonic events and the basin floor morphology, respectively. The main source area for the time correlative turbidites along the southern Sulu Arc is assumed to be Mindanao.

The reaction of benzaldehyde with excess pyrrole at room temperature in the absence of solvent affords a mixture of meso-substituted polypyrranes species. After separation by column chromatography, these may be used to prepare a range of calix[4]phyrin macrocycles by condensation with acetone under conditions of acid catalysis.

For studies of pharmacokinetics and metabolism of the new antiinfective moxifloxacin, the corresponding carbon-14 labelled substance was required. Starting from the appropriately substituted benzoic acid chloride and diethyl [2-¹⁴C]malonate, a 7-step synthesis and the final crystallisation of the hydrochloride led to [¹⁴C]moxifloxacin hydrochloride, labelled in position 3 of the quinolone ring system. Two radiosyntheses were performed leading to 0·108 g (0·340 GBq) of the labelled product in the first and 0·729 g (2·143 GBq) of the labelled product in the second synthesis. Copyright © 2000 John Wiley & Sons, Ltd.

Apolipoprotein B (apoB) metabolism was investigated in 20 men with plasma triglyceride 0.66-2.40 mmol/l and plasma cholesterol 3.95-6. 95 mmol/l. Kinetics of VLDL(1) (S(f) 60-400), VLDL(2) (S(f) 20-60), IDL (S(f) 12-20), and LDL (S(f) 0;-12) apoB were analyzed using a trideuterated leucine tracer and a multicompartmental model which allowed input into each fraction. VLDL(1) apoB production varied widely (from 5.4 to 26.6 mg/kg/d) as did VLDL(2) apoB production (from 0.18 to 8.4 mg/kg/d) but the two were not correlated. IDL plus LDL apoB direct production accounted for up to half of total apoB production and was inversely related to plasma triglyceride (r = -0.54, P = 0.009). Percent of direct apoB production into the IDL/LDL density range (r = 0.50, P < 0.02) was positively related to the LDL apoB fractional catabolic rate (FCR). Plasma triglyceride in these subjects was determined principally by VLDL(1) and VLDL(2) apoB fractional transfer rates (FTR), i.e., lipolysis. IDL apoB concentration was regulated mainly by the IDL to LDL FTR (r = -0.71, P < 0.0001). LDL apoB concentration correlated with VLDL(2) apoB production (r = 0.48, P = 0.018) and the LDL FCR (r = -0.77, P < 0. 001) but not with VLDL(1), IDL, or LDL apoB production. Subjects with predominantly small, dense LDL (pattern B) had lower VLDL(1) and VLDL(2) apoB FTRs, higher VLDL(2) apoB production, and a lower LDL apoB FCR than those with large LDL (pattern A). Thus, the metabolic conditions that favored appearance of small, dense LDL were diminished lipolysis of VLDL, resulting in a raised plasma triglyceride above the putative threshold of 1.5 mmol/l, and a prolonged residence time for LDL. This latter condition presumably permitted sufficient time for the processes of lipid exchange and lipolysis to generate small LDL particles.

Cholesteryl ester storage disease and Wolman disease are rare autosomal recessive lipoprotein-processing disorders caused by mutations in the gene encoding human lysosomal acid lipase. Thus far we have elucidated the genetic defects in 15 unrelated CESD patients. Seven were homozygotes for the prevalent hLAL exon 8 splice junction mutation which results in incomplete exon skipping, while eight probands were compound heterozygotes for E8SJM and a rare mutation on the second chromosome. In this report, we describe the molecular basis of CESD in three compound heterozygous subjects of Czech and Irish origin. RFLP and DNA sequence analysis revealed that they were heteroallelic for the common G(934)-->A substitution in exon 8 of the hLAL gene and a mutation which, if inherited on both alleles, would be expected to result in complete loss of enzyme activity and to cause Wolman disease. In patients A. M. and J. J., two nucleotide deletions in exons 7 and 10 were detected, involving a T at position 722, 723, or 724 and a G in a stretch of five guanosines at positions 1064;-1068 of the hLAL cDNA. Both mutations result in premature termination of protein translation at residues 219 and 336, respectively, and in the production of truncated, inactive enzymes. Subject D. H., in contrast, is a compound heterozygote for the Arg(44)-->Stop mutation previously described in a French CESD proband. Combined with data in the literature, our results demonstrate that compound heterozygosity for a mutation causing Wolman disease is common among cholesteryl ester storage disease patients.