VASOPRESSOR AGENTS—Influence of Acidosis on Cardiac and Vascular Responsiveness

Clinical observations have indicated that patients who are in shock and who have coexisting acidosis respond relatively poorly to sympathomimetic amines. In experiments with dogs, it was found that, in the presence of acidosis, the pressor action of epinephrine, norepinephrine and metaraminol was considerably reduced. The effect on cardiac rhythm was also considerably lessened after the pH value of the blood had been lowered.In view of these observations in animals, six human patients with profound shock and acidosis were studied. All had a considerably lessened pressor response to vasopressor agents; then, after elevation of the blood pH by intravenous infusion of a 1-molar solution of sodium lactate, responsiveness was restored.These observations emphasize the desirability of close observation of the acid-base status, and early treatment of acidosis, as an important aspect in the management of patients with shock.     

Population structure and growth-stress relationship of Pinus taeda in rock outcrop habitats

Abstract. On the granite outcrops of the southeastern United States, soil accumulates in shallow depressions on the rock surface. A specific sequence of vascular plants characterizes the temporal development of these systems. The edaphic end point of the succession is apparently attained with a herb-shrub-tree stage with Pinus taeda as the dominant tree. We studied the characteristics of this stage and the population structure of P. taeda on outcrop islands in order to specify the successional status of the species in this habitat. We compared the radial growth pattern of outcrop and Piedmont populations of P. taeda, and of two outcrop sub-populations. We checked whether trees on outcrops experience more limiting conditions than trees on the Piedmont, and studied the recent change in the relationship between growth and stress (e.g. drought and atmospheric deposition) reported for loblolly pine in the southeastern United States. We also attempted to identify the climatic variables most critical for tree growth on outcrops. On outcrop soil islands, P. taeda maintains populations that are of irregular age distribution, possibly in response to irregular recruitment and survival. There are no signs of loblolly pine replacement by hardwood species on any of the islands studied, although an understory of shrubby oak appears to characterize larger and deeper-soil islands. Although trees on the Piedmont were growing at a higher rate than those on the outcrop in the first part of the 1950–1988 period, their growth declined at a higher rate than that of trees on the outcrop. As a result, at the end of the period considered (1950–1988), the differences in radial growth between outcrop and Piedmont populations were relatively small. On the outcrop, trees < 22 yr old in 1989 were growing at a rate somewhat lower than that of trees of similar age, 40 yr ago. Differences were apparent in the initial growth patterns between the two outcrop subpopulations (1989 and 1949 stems), and these could have resulted from differences in competition regime, stress or climatic conditions, or a combination thereof. However, a repeated-measures ANOVA failed to reveal a significant recent decrease in the radial growth of loblolly pine in the system studied. The identification of numerous signature years (years with ≥ 80 % of the trees with similar increasing or decreasing trend in their radial growth) suggests that similar environmental variables control the growth of loblolly pine in both outcrop and Piedmont habitats. High temperature and low precipitation in the first part of the summer (June-July) seem to limit radial growth. Those pines growing on outcrop soil islands, however, appear more sensitive to climatic fluctuations.     

Impact of passive permeability and gut efflux transport on the oral bioavailability of novel series of piperidine-based renin inhibitors in rodents

An oral bioavailability issue encountered during the course of lead optimization in the renin program is described herein. The low F(po) of pyridone analogs was shown to be caused by a combination of poor passive permeability and gut efflux transport. Substitution of pyridone ring for a more lipophilic moiety (logD>1.7) had minimal effect on rMdr1a transport but led to increased passive permeability (P(app)>10 × 10(-6) cm/s), which contributed to overwhelm gut transporters and increase rat F(po). LogD and in vitro passive permeability determination were found to be key in guiding SAR and improve oral exposure of renin inhibitors.     

Age-specific properties of spontaneous mutations affecting mortality in Drosophila melanogaster.

An analysis of the effects of spontaneous mutations affecting age-specific mortality was conducted using 29 lines of Drosophila melanogaster that had accumulated spontaneous mutations for 19 generations. Divergence among the lines was used to estimate the mutational variance for weekly mortality rates and the covariance between weekly mortality rates at different ages. Significant mutational variance was observed in both males and females early in life (up to approximately 30 days of age). Mutational variance was not significantly different from zero for mortality rates at older ages. Mutational correlations between ages separated by 1 or 2 wk were generally positive, but they declined monotonically with increasing separation such that mutational effects on early-age mortality were uncorrelated with effects at later ages. Analyses of individual lines revealed several instances of mutation-induced changes in mortality over a limited range of ages. Significant age-specific effects of mutations were identified in early and middle ages, but surprisingly, mortality rates at older ages were essentially unaffected by the accumulation procedure. Our results provide strong evidence for the existence of a class of polygenic mutations that affect mortality rates on an age-specific basis. The patterns of mutational effects measured here relate directly to recently published estimates of standing genetic variance for mortality in Drosophila, and they support mutation accumulation as a viable mechanism for the evolution of senescence.     

Untersuchungen zur Tiergesundheit,Leistung und zum Rückstandsverhalten beim Schwein bei gleichzeitiger Aufnahme der Mykotoxine Ochratoxin A,Deoxynivalenol, Zearalenon über das Futter im 90-Tage-Test

The effect of the administration of the mycotoxins OTA, ZEA and DON alone resp. in combination on animal health and the residue behavior of pigs from 50 – 60 kg living weight over 90 days was investigated in 4 separate studies. Due to its fast metabolisation the administration of 1000 µg DON resp. 250 µg ZEA per kg feed alone or in combination with other mycotoxins does not lead to detectable residues of these mycotoxins in organs and tissues. Therefore these mycotoxins should not be relevant to the consumer.There is an effect of the simultaneous administration of ZEA resp. DON on the metabolisation resp. secretion of OTA. OTA is of relevance from the point of view of residue toxicology.     

Analysis of forward and backward Second Harmonic Generation images to probe the nanoscale structure of collagen within bone and cartilage

Collagen ultrastructure plays a central role in the function of a wide range of connective tissues. Studying collagen structure at the microscopic scale is therefore of considerable interest to understand the mechanisms of tissue pathologies. Here, we use second harmonic generation microscopy to characterize collagen structure within bone and articular cartilage in human knees. We analyze the intensity dependence on polarization and discuss the differences between Forward and Backward images in both tissues. Focusing on articular cartilage, we observe an increase in Forward/Backward ratio from the cartilage surface to the bone. Coupling these results to numerical simulations reveals the evolution of collagen fibril diameter and spatial organization as a function of depth within cartilage.

     

Different endoplasmic reticulum trafficking and processing pathways for calsequestrin (CSQ) and epitope-tagged CSQ

Cardiac calsequestrin (CSQ) is a protein that traffics to and concentrates inside sarcoplasmic reticulum (SR) terminal cisternae, a protein secretory compartment of uncertain origin. To investigate trafficking of CSQ within standard ER compartments, we expressed CSQ in nonmuscle cell lines and examined its localization by immunofluorescence and its molecular structure from the mass spectrum of total cellular CSQ. In all cells examined, CSQ was a highly phosphorylated protein with a glycan structure predictive of ER-retained proteins: Man9,8GlcNAc2 lacking terminal GlcNAc. Immunostaining was restricted to polymeric ER cisternae. Secretory pathway disruption by brefeldin A and thapsigargin led to altered CSQ glycosylation and phosphorylation consistent with post-ER trafficking. When epitope-tagged forms of CSQ were expressed in the same cells, mannose trimming of CSQ glycans was far more extensive, and C-terminal phosphorylation sites were nearly devoid of phosphate, in complete contrast to the highly phosphorylated wild-type protein that concentrates in all cells tested. Epitope-tagged CSQ also showed a reduced ER staining compared to wild-type protein, with significant staining in juxta-Golgi compartments. Loss of ER retention due to epitope tags or thapsigargin and resultant changes in protein structure or levels of bound Ca(2+) point to CSQ polymerization as an ER/SR retention mechanism.     

Short-term responses of the understory to the removal of plant functional groups in the cold-temperate deciduous forest

It is widely believed that functional diversity contributes to the stability of ecosystems. Indeed, greater redundancy among species within functional groups and greater complementarity among functional groups within communities should increase the resistance and resilience of ecosystems. In the present study, we tested for functional group complementarity by examining how the loss of specific functional groups may alter the role that other groups play in ecosystem functions. We removed different functional groups, one at a time, from the understory of three maple-dominated forests in southern Québec (Canada) and followed the understory response over a 2-year period. The experimental design included a control and five removal treatments. Five functional groups were defined: spring-flowering ephemeral species; spring-flowering persistent species; summer-flowering species; fern species; and seedlings and juveniles of woody species. Richness, cover, soil pH and organic matter content were determined after two years of removal. The results of our experiment revealed that richness was significantly lower than what we expected when spring-flowering persistent species or seedlings and juveniles of woody species were removed, suggesting not only direct but also indirect positive effects of both of these groups on understory richness (mostly through effects on summer-flowering species and fern species). Removal of the seedlings and juveniles of woody species and, to a lesser extent, of spring-flowering persistent species and of fern species lead to a decrease in the cover of summer-flowering species, implying a positive effect of the former groups on the latter. The cover–richness relationship in the control and in each one of the five removal treatments was positive and well fitted by a linear regression. Yet, the slope of the relationship differed among treatments, but not between the control and any one of the removal treatments (pair-wise comparisons). Our results suggest that the different functional groups are complementary and that positive interactions predominate over negative ones. Contrary to common belief, understory plants can respond quite rapidly to changes in community functional composition. Although we have not investigated the specific mechanisms responsible for the short-term responses reported here, we suggest that complex intergroup interactions may favour functional diversity and enhance ecosystem functions.     

Addressing time-dependent CYP 3A4 inhibition observed in a novel series of substituted amino propanamide renin inhibitors,a case study

Time-dependent inhibitors of CYPs have the potential to perpetrate drug–drug interactions in the clinical setting. After finding that several leading compounds in a novel series of substituted amino propanamide renin inhibitors inactivated CYP3A4 in an NADPH-dependent and time-dependent manner, a search to identify the cause of this liability was initiated. Extensive SAR revealed that the amide bridge present in compound 1 as a possible culprit. Through the installation of a metabolic soft spot distal to this moiety, potent renin inhibitors with improved CYP profile were identified.