Association of the (CA)n repeat polymorphism of insulin-like growth factor-I and -202 A/C IGF-binding protein-3 promoter polymorphism with adult height in patients with severe growth hormone deficiency

A number of mathematical models for predicting growth and final height outcome have been proposed to enable the clinician to 'individualize' growth-promoting treatment. However, despite optimizing these models, many patients with isolated growth hormone deficiency (IGHD) do not reach their target height. The aim of this study was to analyse the impact of polymorphic genotypes [CA repeat promoter polymorphism of insulin-like growth factor-I (IGF-I) and the -202 A/C promoter polymorphism of IGF-Binding Protein-3 (IGFBP-3)] on variable growth factors as well as final height in severe IGHD following GH treatment. DESIGN, PATIENTS AND CONTROLS: One hundred seventy eight (IGF-I) and 167 (IGFBP-3) subjects with severe growth retardation because of IGHD were studied. In addition, the various genotypes were also studied in a healthy control group of 211 subjects.

Impact of Holocene climate changes on alpine and treeline vegetation at Sanetsch Pass, Bernese Alps, Switzerland

In order to infer reactions of treeline and alpine vegetation to climatic change, past vegetation changes are reconstructed on the basis of pollen, macrofossil and charcoal analysis. The sampled sediment cores originate from the small pond Emines, located at the Sanetsch Pass (connecting the Valais and Bern, Switzerland) at an altitude of 2288 m a.s.l. Today's treeline is at ca. 2200 m a.s.l. in the area, though due to special pass (saddle) conditions it is locally depressed to ca. 2060 m a.s.l. Our results reveal that the area around Emines was covered by treeless alpine vegetation during most of the past 12,000 years. Single individuals of Betula, Larix decidua and possibly Pinus cembra occurred during the Holocene. Major centennial to millennial-scale responses of treeline vegetation to climatic changes are evident. However, alpine vegetation composition remained rather stable between 11,500 and 6000 cal. BP, showing that Holocene climatic changes of +/− 1 °C hardly influenced the local vegetation at Emines. The rapid warming of 3–4 °C at the Late Glacial/Holocene transition (11,600 cal. BP) caused significant altitudinal displacements of alpine species that were additionally affected by the rapid upward movement of trees and shrubs. Since the beginning of the Neolithic, vegetation changes at Sanetsch Pass resulted from a combination of climate change and human impact. Anthropogenic fire increase and land-use change combined with a natural change from subcontinental to more oceanic climate during the second half of the Holocene led to the disappearance of P. cembra in the study area, but favoured the occurrence of Picea abies and Alnus viridis. The mid- to late-Holocene decline of Abies alba was primarily a consequence of human impact, since this mesic species should have benefitted from a shift to more oceanic conditions. Future alpine vegetation changes will be a function of the amplitude and rapidity of global warming as well as human land use. Our results imply that alpine vegetation at our treeline pass site was never replaced by forests since the last ice-age. This may change in the future if anticipated climate change will induce upslope migration of trees. The results of this study emphasise the necessity of climate change mitigation in order to prevent biodiversity losses as a consequence of unprecedented community and species displacement in response to climatic change.

Agonist specific L-type Ca(2+)-current stimulation in ventricular myocytes by a novel steroid-like compound

In cardiac muscle the amplitude of Ca(2+) transients can be increased by enhancing Ca(2+) influx. Among the processes leading to increased Ca(2+) influx, agonists of the L-type Ca(2+)-channel can play an important role. Known pharmacological Ca(2+)-channel agonists act on different binding sites on the channel protein, which may lead not only to enhanced peak currents, but also to distinct changes in other biophysical characteristics of the current. In this study, membrane currents were recorded with the patch-clamp technique in the whole-cell configuration in guinea pig isolated ventricular myocytes in combination with confocal fluorescence Ca(2+) imaging techniques and a variety of pharmacological tools. Testing a new positive inotropic steroid-like compound, we found that it increased the L-type Ca(2+)-current by 2.5-fold by shifting the voltage-dependence of activation by 20.2 mV towards negative potentials. The dose-response relationship revealed two vastly different affinities (EC(50(high-affinity))=4.5+/-1.7 nM, EC(50(low-affinity))=8.0+/-1.1 microM) exhibiting differential pharmacological interactions with three classes of Ca(2+)-current antagonists, suggesting more than one binding site on the channel protein. Therefore, we identified and characterized a novel positive inotropic compound (F90927) as a member of a new class of Ca(2+)-channel agonists exhibiting unique features, which set it apart from other presently known L-type Ca(2+)-channel agonists.

Ca(2+) release from the sarcoplasmic reticulum activated by the low affinity Ca(2+) chelator TPEN in ventricular myocytes

The Ca(2+) content of the sarcoplasmic reticulum (SR) of cardiac myocytes is thought to play a role in the regulation and termination of SR Ca(2+) release through the ryanodine receptors (RyRs). Experimentally altering the amount of Ca(2+) within the SR with the membrane-permeant low affinity Ca(2+) chelator TPEN could improve our understanding of the mechanism(s) by which SR Ca(2+) content and SR Ca(2+) depletion can influence Ca(2+) release sensitivity and termination. We applied laser-scanning confocal microscopy to examine SR Ca(2+) release in freshly isolated ventricular myocytes loaded with fluo-3, while simultaneously recording membrane currents using the whole-cell patch-clamp technique. Following application of TPEN, local spontaneous Ca(2+) releases increased in frequency and developed into cell-wide Ca(2+) waves. SR Ca(2+) load after TPEN application was found to be reduced to about 60% of control. Isolated cardiac RyRs reconstituted into lipid bilayers exhibited a two-fold increase of their open probability. At the low concentration used (20-40muM), TPEN did not significantly inhibit the SR-Ca(2+)-ATPase in SR vesicles. These results indicate that TPEN, traditionally used as a low affinity Ca(2+) chelator in intracellular Ca(2+) stores, may also act directly on the RyRs inducing an increase in their open probability. This in turn results in an increased Ca(2+) leak from the SR leading to its Ca(2+) depletion. Lowering of SR Ca(2+) content may be a mechanism underlying the recently reported cardioprotective and antiarrhythmic features of TPEN.