Myocardial infarction leads to loss of tissue and impairment of cardiac performance. The remaining myocytes are unable to reconstitute the necrotic tissue, and the post-infarcted heart deteriorates with time. Injury to a target organ is sensed by distant stem cells, which migrate to the site of damage and undergo alternate stem cell differentiation; these events promote structural and functional repair. This high degree of stem cell plasticity prompted us to test whether dead myocardium could be restored by transplanting bone marrow cells in infarcted mice. We sorted lineage-negative (Lin-) bone marrow cells from transgenic mice expressing enhanced green fluorescent protein by fluorescence-activated cell sorting on the basis of c-kit expression. Shortly after coronary ligation, Lin- c-kitPOS cells were injected in the contracting wall bordering the infarct. Here we report that newly formed myocardium occupied 68% of the infarcted portion of the ventricle 9 days after transplanting the bone marrow cells. The developing tissue comprised proliferating myocytes and vascular structures. Our studies indicate that locally delivered bone marrow cells can generate de novo myocardium, ameliorating the outcome of coronary artery disease.

Gene therapy approaches involving vascular endothelial growth factor (VEGF) to promote therapeutic angiogenesis are under consideration for conditions ranging from ischemic heart disease to nonhealing skin ulcers. Here we make the surprising observation that the transgenic delivery of VEGF to the skin results in a profound inflammatory skin condition with many of the cellular and molecular features of psoriasis, including the characteristic vascular changes, epidermal al-

Recent studies have shown strong temporal correlations between past climate changes and societal crises. However, the specific causal mechanisms underlying this relation have not been addressed. We explored quantitative responses of 14 fine-grained agro-ecological, socioeconomic, and demographic variables to climate fluctuations from A.D. 1500-1800 in Europe. Results show that cooling from A.D. 1560-1660 caused successive agro-ecological, socioeconomic, and demographic catastrophes, leading to the General Crisis of the Seventeenth Century. We identified a set of causal linkages between climate change and human crisis. Using temperature data and climate-driven economic variables, we simulated the alternation of defined "golden" and "dark" ages in Europe and the Northern Hemisphere during the past millennium. Our findings indicate that climate change was the ultimate cause, and climate-driven economic downturn was the direct cause, of large-scale human crises in preindustrial Europe and the Northern Hemisphere.climate-driven economy | Granger Causality Analysis | grain price D ebate about the relation between climate and human crisis has lasted over a century. With recent advances in paleotemperature reconstruction, scholars note that massive social disturbance, societal collapse, and population collapse often coincided with great climate change in America, the Middle East, China, and many other countries in preindustrial times (1-5). Although most of these scientists believe that climate change could cause human catastrophe, their arguments are backed simply by qualitative scrutiny of narrow historic examples. More recent breakthroughs came from research adopting quantitative approaches to all known cases of social crisis. These studies show that, in recent history, climate change was responsible for the outbreak of war, dynastic transition, and population decline in China, Europe, and around the world because of climate-induced

Stimulation of the local renin-angiotensin system and apoptosis characterize the diabetic heart. Because IGF-1 reduces angiotensin (Ang) II and apoptosis, we tested whether streptozotocin-induced diabetic cardiomyopathy was attenuated in IGF-1 transgenic mice (TGM). Diabetes progressively depressed ventricular performance in wild-type mice (WTM) but had no hemodynamic effect on TGM. Myocyte apoptosis measured at 7 and 30 days after the onset of diabetes was twofold higher in WTM than in TGM. Myocyte necrosis was apparent only at 30 days and was more severe in WTM. Diabetic nontransgenic mice lost 24% of their ventricular myocytes and showed a 28% myocyte hypertrophy; both phenomena were prevented by IGF-1. In diabetic WTM, p53 was increased in myocytes, and this activation of p53 was characterized by upregulation of Bax, angiotensinogen, Ang type 1 (AT 1 ) receptors, and Ang II. IGF-1 overexpression decreased these biochemical responses. In vivo accumulation of the reactive O 2 product nitrotyrosine and the in vitro formation of H 2 O 2 -˙OH in myocytes were higher in diabetic WTM than TGM. Apoptosis in vitro was detected in myocytes exhibiting high H 2 O 2 -˙OH fluorescence, and apoptosis in vivo was linked to the presence of nitrotyrosine. H 2 O 2 -˙OH generation and myocyte apoptosis in vitro were inhibited by the AT 1 blocker losartan and the O 2 scavenger Tiron. In conclusion, IGF-1 interferes with the development of diabetic myopathy by attenuating p53 function and Ang II production and thus AT 1 activation. This latter event might be responsible for the decrease in oxidative stress and myocyte death by IGF-1.

SUMMARY:To determine whether myocyte death and angiotensin II (AT II) formation are implicated in the development of diabetic cardiomyopathy, rats were injected with streptozotocin, and apoptosis and necrosis were measured at 3, 10, and 28 days. Expression of the components of the renin-angiotensin system (RAS) and AT II levels were assessed at 3 days. The percentage of AT II-labeled myocytes and the number and distribution of AT II sites in myocytes were measured at 3 and 10 days. The effects of AT 1 blockade on local RAS and cell death were examined at 3 days. Diabetes was characterized by myocyte apoptosis that peaked at 3 days and decreased at 10 and 28 days, in spite of high concentrations of blood glucose. Cell necrosis was absent throughout. Angiotensinogen, renin, and AT 1 receptor increased in myocytes from diabetic rat hearts, while angiotensin-converting enzyme and AT 2 remained constant. AT II quantity increased severalfold, as did the fraction of AT II positive cells and the number of AT II sites per myocyte. However, AT II labeling decreased at 10 days, which paralleled the reduction in myocyte death. AT 1 antagonist inhibited upregulation of this receptor and angiotensinogen, which prevented AT II synthesis and myocyte death at their peaks with diabetes. An aggregate 30% myocyte loss and a 14% increase in the volume of viable cells were found in diabetic rats at 28 days. Thus diabetic cardiomyopathy may be viewed as an AT II-dependent process in which that peptide plays a critical role in myocyte death and hypertrophy. (Lab Invest 2000, 80:513-527).

Recent numerical-modelling and seismological results have raised ne w questions about the dynamics`-' and magnetism of the Earth's core. Knowledge of the elasticity and texture of iron s ' ' at core pressures is crucial for understanding the seismological ; observations, such as the low attenuation of seismic waves, the low shear-wave velocity and the anisotropy of compressional-wave velocity-". The density and bulk modulus of hexagonal-close-packed iron have been previously measured to 1 core pressures by static" and dynamic" , " methods. Here we Acknowledgements. We thank 1. Hu for technical help, L. Stixrude and R. E-Cohen for sharing theoretical data and discussions, T. Duff,-for comments, and NSLS and APS for synchrotron beam rime; the s,mchrn1ron f cili(tes are supported by the DoE. This work was supported by the NSF.

Transgenic mice were generated in which the cDNA for the human insulin-like growth factor 1B (IGF-1B) was placed under the control of a rat a-myosin heavy chain promoter. In mice heterozygous for the transgene, IGF-1B mRNA was not detectable in the fetal heart at the end of gestation, was present in modest levels at 1 day after birth, and increased progressively with postnatal maturation, reaching a peak at 75 days. Myocytes isolated from transgenic mice secreted 1.15 + 0.25 ng of IGF-1 per 106 cells per 24 hr versus 0.27 ± 0.10 ng in myocytes from homozygous wild-type littermates. The plasma level of IGF-1 increased 84% in transgenic mice. Heart weight was comparable in wild-type littermates and transgenic mice up to 45 days of age, but a 42%, 45%, 62%, and 51% increase was found at 75, 135, 210, and 300 days, respectively, after birth. At 45, 75, and 210 days, the number of myocytes in the heart was 21%, 31%, and 55% higher, respectively, in transgenic animals. In contrast, myocyte cell volume was comparable in transgenic and control mice at all ages. In conclusion, overexpression of IGF-1 in myocytes leads to cardiomegaly mediated by an increased number of cells in the heart. Insulin-like growth factor-1 (IGF-1) belongs to the insulin family of peptides and acts as a growth factor in many tissues and tumors (1). Limited information is available on the effects of IGF-1 on the growth of cardiac myocytes. In neonatal ventricular myocytes in culture, lGF-1 activates DNA synthesis (2, 3) and the expression of myosin light chain-2, troponin, and a-skeletal actin (4), which are consistent with a hyperplastic and hypertrophic response of these cells. However, long-term cultures of adult myocytes react to the addition of IGF-1 by increasing only the formation of myofibrils in the cytoplasm (5). An up-regulation of IGF-1 mRNA in the myocardium occurs in pressure overload hypertrophy in vivo (6, 7), and this adaptation has been linked to myocyte hypertrophy. Recent observations have reported that acute ventricular failure is characterized by enhanced expression of IGF-1 and IGF-1 receptor (IGF-1R) in the stressed myocytes, which is followed by DNA replication, nuclear mitotic division, and cell proliferation (8,9). In line with these findings, the decline in DNA synthesis and cellular hyperplasia with postnatal myocardial development (10) is accompanied by attenuation in the expression of IGF-1 and IGF-1 receptor in myocytes in spite of ongoing cellular hypertrophy (11). However, a cause and effect relationship between IGF-1 and myocyte growth in vivo has not been established. For this purpose, a construct was made in which the human IGF-1B cDNA was placed under the control of the rat a-myosin heavy chain (a-MHC) promoter (12), which was then introduced as a transgene in FVB/N mice. This communication presents the effects that this transgene has on cardiac myocytes and on the whole animal, in heterozygous mice, designated as FVB.Igf+/-. Moreover, the consequences of this transgene on the hemodynamic characterist...

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