Adaptation of human left ventricular volumes to the onset of supine exercise

The purpose of this study was to measure the changes and rates of adaptation of left ventricular volumes at the onset of exercise. Eight asymptomatic subjects, in whom intramyocardial markers had been implanted 3-6 years previously during aortocoronary bypass surgery, exercised in the supine position at a constant workload of 73.6 W for 5 min. Six also exercised first at 16.4 W, and then against a workload which progressively increased by 8.2 W every 15 s. Cardiac volumes were measured by computer assisted analysis of the motion of the implanted markers. In the constant workload test, cardiac output increased rapidly from 5.7 +/- 1 min-1 to 10.3 +/- 1.9 1 min-1 by 2 min and then increased more slowly to 10.8 +/- 2.0 1 min-1 by 5 min. The cardiac output increase was mainly due to an increase in heart rate from 68 +/- 12 beats min-1 to 120 +/- 16 beats min-1 with minimal changes in stroke volume. The time constant for the early increase in cardiac output was 45s and for heart rate, 35s. With progressively increasing workloads, there was an almost linear increase of heart rate and cardiac output, but these increased at a slower rate than during the early phase of the constant load exercise test. In conclusion: rapid changes in cardiac output during supine exercise were produced by changes in heart rate; changes in stroke volume provided minor adjustments to cardiac output; the end-diastolic volume was almost constant.     

Methyl bromide inhibits ripening and ethylene production in tomato (lycopersicon esculentum mill.) fruit

Tomato fruit ripening and ethylene production were inhibited following treatment with methyl bromide (MB). Methyl bromide significantly delayed ripening initiation in mature-green (MG) fruit and retarded the rate of ripening of turning (T) fruit as measured by color development and flesh softening. Treatment with MB caused an initial transient burst of ethylene production, but the subsequent ripening-associated increase in ethylene was delayed. Ethylene treatment partially overcame MB inhibition in MG fruit but had no affect on T fruit. The inhibition of ethylene production by MB appears to be due to lack of formation of 1-aminocycloprone-1-carboxylic acid (ACC) in MG fruit, whereas in T fruit lack of conversion of ACC to ethylene is indicated. A key feature of MB inhibition of ripening in tomato appears to be reduced sensitivity to ethylene.     

Chylomicron-chylomicron remnant clearance by liver and bone marrow in rabbits. Factors that modify tissue-specific uptake

The metabolism of [14C]cholesterol- and [3H]retinol-labeled chylomicrons obtained from canine thoracic duct or rabbit mesenteric lymph was investigated in normal fasted rabbits. Typically, 70-80% of the chylomicrons injected into the rabbits were cleared from the plasma in 20 min, and their uptake was accounted for principally by the liver and the bone marrow. Surprisingly, the bone marrow was a major site of uptake; the uptake ranged from about half that of the liver to a nearly equal amount. The importance and specificity of chylomicron-chylomicron remnant uptake by the bone marrow were established by demonstrating that (a) bone marrow throughout the body accumulated these lipoproteins, (b) the level of uptake was consistent regardless of how the values were calculated or how the chylomicrons were prepared, (c) the uptake represented specific binding, and (d) radiolabeled intestinal lipoproteins induced in vivo delivered cholesterol and retinol to the marrow. Electron microscopic examination of the rabbit bone marrow established that perisinusoidal macrophages uniquely accounted for the uptake of the chylomicrons. Whereas liver cleared a variety of both triglyceride-rich lipoproteins (chylomicrons, chylomicron remnants, and very low density lipoproteins) and cholesterol-rich lipoproteins (beta-very low density lipoproteins and high density lipoproteins containing apolipoprotein E), bone marrow uptake appeared to be restricted to the triglyceride-rich lipoproteins. More chylomicron remnants (generated in a hepatectomized rabbit) were cleared by the liver than by the bone marrow, and the addition of excess apolipoprotein E to chylomicrons resulted in their preferential uptake by the liver. The role of chylomicron-chylomicron remnant delivery of lipids or lipid-soluble vitamins to rabbit bone marrow is open to speculation, and whether triglyceride-rich lipoprotein uptake occurs to a significant extent in the bone marrow of humans remains to be determined.     

beta'-COP, a novel subunit of coatomer.

Several lines of evidence favour the hypothesis that intracellular biosynthetic protein transport in eukaryotes is mediated by non-clathrin-coated vesicles (for a review see Rothman and Orci, 1992). The vesicles have been isolated and a set of their surface proteins has been characterized as coat proteins (COPs). These COPs exist in the cytosol as a preformed complex, the coatomer, which was prior to this study known to contain six subunits: four (alpha-, beta-, gamma- and delta-COP) with molecular weights between 160 and 58 kDa, and two additional proteins of approximately 36 and 20 kDa, epsilon- and xi-COP. Here we describe a novel subunit of the coatomer complex, beta'-COP. This subunit occurs in amounts stoichiometric to the established COPs both in the coatomer and in nonclathrin-coated vesicles and shows homology to the beta-subunits of trimeric G proteins.     

The effect of diffusion, electric transport and convection on heterogeneous enzyme catalysis]

The consideration of electric and volume transport additionally to diffusion leads to the dependence of concentration profiles in heterogeneous enzyme catalysis on additional parameters (e. g. electrical field strength, convection velocity) which are valuable for influencing and optimizing these systems. For autocatalysis the local periodic concentration profiles are influenced essentially by these phenomena (change of onset and wavelength). When diffusion is negligible equations are given to determine the kinetic parameters vmax and KM from transport measurements.     

Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates

The structure–activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio.     

Pediatric Invasive Pneumococcal Disease Caused by Vaccine Serotypes following the Introduction of Conjugate Vaccination in Denmark

A seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the Danish childhood immunization program (2+1 schedule) in October 2007, followed by PCV13 starting from April 2010. The nationwide incidence of IPD among children younger than 5 years nearly halved after the introduction of PCV7 in the program, mainly due to a decline in IPD caused by PCV7-serotypes. We report the results from a nationwide population-based cohort study of laboratory confirmed IPD cases in children younger than 5 years during October 1, 2007 to December 31, 2010 and describe the characteristics of children suspected to present with a vaccine failure. The period between April 19 and December 31, 2010 was considered a PCV7/PCV13 transitional period, where both vaccines were offered. We identified 45 episodes of IPD caused by a PCV7 serotype (23% of the total number) and 105 (55%) caused by one of the 6 additional serotypes in PCV13. Ten children had received at least one PCV7 dose before the onset of IPD caused by a PCV7 serotype. Seven children were considered to be incompletely vaccinated before IPD, but only three cases fulfilled the criteria of vaccine failure (caused by serotypes 14, 19F and 23F). One case of vaccine failure was observed in a severely immunosuppressed child following three PCV7 doses, and two cases were observed in immunocompetent children following two infant doses before they were eligible for their booster. None of the IPD cases caused by the additional PCV13 serotypes had been vaccinated by PCV13 and there were therefore no PCV13-vaccine failures in the first 8-months after PCV13 introduction in Denmark.