Pulmonary gas exchange in Andean natives with excessive polycythemia--effect of hemodilution

Pulmonary gas exchange in Andean natives (n = 8) with excessive high-altitude (3,600-4,200 m) polycythemia (hematocrit 65.1 +/- 6.6%) and hypoxemia (arterial PO2 45.6 +/- 5.6 Torr) in the absence of pulmonary or cardiovascular disease was investigated both before and after isovolemic hemodilution by use of the inert gas elimination technique. The investigations were carried out in La Paz, Bolivia (3,650 m, 500 mmHg barometric pressure). Before hemodilution, a low ventilation-perfusion (VA/Q) mode (VA/Q less than 0.1) without true shunt accounted for 11.6 +/- 5.5% of the total blood flow and was mainly responsible for the hypoxemia. The hypoventilation with a low mixed venous PO2 value may have contributed to the observed hypoxemia in the absence of an impairment in alveolar capillary diffusion. After hemodilution, cardiac output and ventilation increased from 5.5 +/- 1.2 to 6.9 +/- 1.2 l/min and from 8.5 +/- 1.4 to 9.6 +/- 1.3 l/min, respectively, although arterial and venous PO2 remained constant. VA/Q mismatching fell slightly but significantly. The hypoxemia observed in subjects suffering from high-altitude excessive polycythemia was attributed to an increased in blood flow perfusing poorly ventilated areas, but without true intra- or extrapulmonary shunt. Hypoventilation as well as a low mixed venous PO2 value may also have contributed to the observed hypoxemia.     

Immunohistochemical demonstration of catecholaminergic cell bodies in the spinal cord of the rat

Summary In order to elucidate the anatomy of the spinal dopaminergic system, an immunohistochemical study using a tyrosine-hydroxylase (TH) antibody was undertaken in the rat. Intracisternal 6-hydroxydopamine (6-OHDA) injections were administered to destroy most of the noradrenergic fibres that descende to the spinal cord while preserving the dopaminergic fibres. The density of the remaining TH-like immunoreactive fibres was relatively low at all levels of the spinal cord; the highest density was observed in layers III, IV and X. In addition, we report the first evidence for the existence of TH-like immunoreactive cell bodies at definite levels (especially sacral) of the spinal cord.     

Critical review on quantitative autoradiography of D1 and D2 dopaminergic receptors in the striatum of the mammalian brain: differential localization and plastic changes after pharmacological manipulation and dopaminergic input disruption

Major technical progress in the development of computer-based image analysis systems has made possible the entry of autoradiographic and immunohistochemical techniques into a new era where quantification via densitometry and morphometry has become easily accessible. In this context, quantitative biochemical data can be adapted to anatomical and histological resolution. This adaptation is most efficient in the neuroscience fields because of the huge importance of cellular communication via neuronal networks in the nervous system. Therefore, any experimental approach to the brain which considers the brain as a 'black box' appears now as very crude. In fact, subtle heterogeneity in the distribution of biochemical markers can now be demonstrated, as illustrated here by the use of quantitative autoradiography of D1 and D2 dopaminergic receptors in the striatum of the mammalian brain. Also, local adaptive changes resulting from chronic blockade of the dopaminergic input can be detected after repeated treatments with dopaminergic antagonists selective for D1 or D2 receptors or with surgical lesioning of the dopaminergic nigrostriatal pathway. The resulting plastic changes are unevenly distributed throughout the striatal target organ and vary according to the mode of suppressing the dopaminergic flow: direct destruction of the dopaminergic pathway or selective pharmacological manipulation without physical elimination of the dopaminergic cells themselves. All these results are discussed and reviewed in light of the most recent reports in this field.     

Distribution of lung density after strenuous, prolonged exercise.

The postexercise alteration in pulmonary gas exchange in high-aerobically trained subjects depends on both the intensity and the duration of exercise (G. Manier, J. Moinard, and H. Sto?cheff. J. Appl. Physiol. 75: 2580-2585, 1993; G. Manier, J. Moinard, P. Techoueyres, N. Varène, and H. Guénard. Respir. Physiol. 83: 143-154, 1991). In a recent study that used lung computerized tomography (CT), evidence was found for accumulation of water within the lungs after exercise (C. Caillaud, O. Serre-Cousine, F. Anselme, X. Capdevilla, and C. Prefaut. J. Appl. Physiol. 79: 1226-1232, 1995). On representative slices of the lungs, mean lung density increased by 0.040 +/- 0.007 g/cm(3) (19%, P < 0.001) in athletes after a triathlon. To verify and quantify the mechanism, we determined the change in pulmonary density and mass after strenuous and prolonged exercise using another exercise protocol and methodology for CT scanning. Nine trained runners (age 30-46 yr) volunteered to participate in the study. Each subject ran for 2 h on a treadmill at a rate corresponding to 75% of maximum O(2) consumption. CT measurements were made before and immediately after the exercise test with the subject supine and holding his breath at a point close to functional residual capacity. The lungs were scanned from the apex to the diaphragm and reconstructed in 8-mm-thick slices. Attenuation values of X-rays in each part of the lung were expressed in Hounsfield units (HU), which are related to density (D): D = 1 + HU/1,000. No significant alteration in pulmonary density (0.37 +/- 0.04 vs. 0.35 +/- 0.03, not significant) was observed after the 2-h run test. Although lung volume slightly increased (change of 166 +/- 205 ml, P < 0.05), lung mass remained stable because of a change in density distribution. We failed to detect any changes in postexercise lung mass, suggesting that other mechanisms need to be considered to explain the observed alterations in pulmonary gas exchange after prolonged strenuous exercise.     

Large herbivores in sagebrush steppe ecosystems: livestock and wild ungulates influence structure and function

Improving understanding of the connections between vegetation, herbivory, and ecosystem function offers a fundamental challenge in contemporary terrestrial ecology. Using exclosures constructed during the late 1950s, we examined effects of grazing by wild and domestic herbivores on plant community structure, aboveground herbaceous primary production, and nutrient cycling at six sites in semi-arid, sagebrush rangelands during 2001-2002 in Colorado, USA. Enclosures provided three treatments: no grazing, grazing by wild ungulates only, and grazing by wild and domestic ungulates. Excluding all grazing caused an increase in shrub cover (F = 4.97, P = 0.033) and decrease in bare ground (F = 4.74, P = 0.037), but also a decrease in plant species richness (F = 6.19, P = 0.018) and plant diversity (F = 7.93, P = 0.008). Effects of wild ungulate grazing on plant cover and diversity were intermediate to the effects of combined domestic and wild grazing. Aboveground net primary production was higher in both grazed treatments than in the ungrazed one (F(wild + domestic) = 2.98, P = 0.0936 and F(wild only) = 3.55, P = 0.0684). We were unable to detect significant effects of grazing on other ecosystem states and processes including C:N ratios of standing crops, N mineralization potential, or nitrification potential. Best approximating models revealed positive correlation between N availability and herbaceous cover and a negative correlation between herbaceous primary production and the ratio of shrub-herb cover and plant diversity. We conclude that ungulate herbivory, including both wild and domestic ungulates, had significant effects on plant community structure and ecosystem function during this 42-year span. Responses to the wild ungulate treatment were consistently intermediate to responses to the no grazing and wild + domestic grazing treatments. However, we were unable to detect statistical difference between effects of wild ungulates alone and wild ungulates in combination with livestock.     

Population genetic analysis identifies source-sink dynamics for two sympatric garter snake species (Thamnophis elegans and Thamnophis sirtalis)

Population genetic structure can be shaped by multiple ecological and evolutionary factors, but the genetic consequences of these factors for multiple species inhabiting the same environment remain unexplored. We used microsatellite markers to examine the population structures of two coexisting species of garter snake, Thamnophis elegans and Thamnophis sirtalis, to determine if shared landscape and biology imposed similar population genetic structures. These snakes inhabit a series of ponds, lakes and flooded meadows in northern California and tend to converge on prey type wherever they coexist. Both garter snakes had comparable effective population sizes and bidirectional migration rates (estimated using a maximum-likelihood method based on the coalescent) with low but significant levels of genetic differentiation (F(ST) = 0.024 for T. elegans and 0.035 for T. sirtalis). Asymmetrical gene flow revealed large source populations for both species as well as potential sinks, suggesting frequent extinction-recolonization and metapopulation dynamics. In addition, we found a significant correlation between their genetic structures based on both pairwise F(ST)s for shared populations (P = 0.009) and for bidirectional migration rates (P = 0.024). Possible ecological and evolutionary factors influencing similarities and differences in genetic structure for the two species are discussed. Genetic measures of effective population size and migration rates obtained in this study are also compared with estimates obtained from mark-recapture data.     

Global Epigenetic Regulation of MicroRNAs in Multiple Myeloma

Epigenetic changes frequently occur during tumorigenesis and DNA hypermethylation may account for the inactivation of tumor suppressor genes in cancer cells. Studies in Multiple Myeloma (MM) have shown variable DNA methylation patterns with focal hypermethylation changes in clinically aggressive subtypes. We studied global methylation patterns in patients with relapsed/refractory MM and found that the majority of methylation peaks were located in the intronic and intragenic regions in MM samples. Therefore, we investigated the effect of methylation on miRNA regulation in MM. To date, the mechanism by which global miRNA suppression occurs in MM has not been fully described. In this study, we report hypermethylation of miRNAs in MM and perform confirmation in MM cell lines using bisulfite sequencing and methylation-specific PCR (MSP) in the presence or absence of the DNA demethylating agent 5-aza-2′-deoxycytidine. We further characterized the hypermethylation-dependent inhibition of miR-152, -10b-5p and -34c-3p which was shown to exert a putative tumor suppressive role in MM. These findings were corroborated by the demonstration that the same miRNAs were down-regulated in MM patients compared to healthy individuals, alongside enrichment of miR-152-, -10b-5p, and miR-34c-3p-predicted targets, as shown at the mRNA level in primary MM cells. Demethylation or gain of function studies of these specific miRNAs led to induction of apoptosis and inhibition of proliferation as well as down-regulation of putative oncogene targets of these miRNAs such as DNMT1, E2F3, BTRC and MYCBP. These findings provide the rationale for epigenetic therapeutic approaches in subgroups of MM.     

Covariance among premating, post-copulatory and viability fitness components in Drosophila melanogaster and their influence on paternity measurement

In polyandrous mating systems, male fitness depends on success in premating, post-copulatory and offspring viability episodes of selection. We tracked male success across all of these episodes simultaneously, using transgenic Drosophila melanogaster with ubiquitously expressed green fluorescent protein (i.e. GFP) in a series of competitive and noncompetitive matings. This approach permitted us to track paternity-specific viability over all life stages and to distinguish true competitive fertilization success from differential early offspring viability. Relationships between episodes of selection were generally not present when paternity was measured in eggs; however, positive correlations between sperm competitive success and offspring viability became significant when paternity was measured in adult offspring. Additionally, we found a significant male × female interaction on hatching success and a lack of repeatability of offspring viability across a focal male's matings, which may underlay the limited number of correlations found between episodes of selection.