Journal of Investigative Medicine

Peripheral arterial disease is mainly caused by atherosclerosis and is characterized by decreased circulation, lower blood pressure, and insufficient tissue perfusion in the lower extremities. The hemodynamics of standing and altered gravity environments have been well studied relative to arm blood pressures but are less well understood for ankle pressures.

Because regional blood pressure depends, in part, on the gravitational pressure gradient, we hypothesized that artificial gravity exposure on a short-arm centrifuge with the center of rotation above the head would increase blood pressure in the lower extremities. Cardiovascular parameters for 12 healthy subjects were measured during exposure to supine short-arm centrifugation at 20, 25, and 30 revolutions per minute (rpm), corresponding to centripetal accelerations of 0.94, 1.47, and 2.11 Gz at the foot level, respectively.

Systolic ankle blood pressure significantly increased at all levels of centrifugation. Ankle-brachial indices (the ratio of systolic ankle to arm blood pressures) increased significantly from 1.17 ± 0.03 to 1.58 ± 0.03 at 0.94 Gz (P < 0.005), 1.74 ± 0.02 at 1.47 Gz (P < 0.005), and 1.89 ± 0.06 at 2.11 Gz (P < 0.005). Systolic arm blood pressure significantly increased at 2.11 Gz, but heart rate did not change significantly. All parameters returned to normal after cessation of centrifugation.

We demonstrated that short-radius centrifugation leads to an increase in ankle-brachial indices. This could have potential implications for the treatment of peripheral arterial disease.

Endotoxemia is well known to be associated with an excessive host response to bacteria or microbial compounds, resulting in systemic inflammation and organ injury. The aim of the present study was to examine the effects of simvastatin on endotoxemic liver injury.

Male C57BL/6J mice were challenged intraperitoneally with 0.5 mg/kg Escherichia coli-lipopolysaccharide (LPS) and 0.9 g/kg d-galactosamine (Gal). Mice were pretreated with 0.2 mg/kg simvastatin. Lipopolysaccharide/d-Gal-injected mice without simvastatin served as endotoxemic controls, and sham mice served as negative controls. Additional mice were challenged with LPS/d-Gal and co-treated with simvastatin and 10 mg/kg mevalonate to determine the role of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. After 6 hours of endotoxemia serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities as well as caspase-3 and myeloperoxidase activity were determined.

Endotoxemia caused a substantial hepatocellular injury as indicated by significantly elevated serum ALT and AST levels and hepatocellular apoptosis. Leukocyte infiltration in the liver was significantly elevated in endotoxemic mice. Simvastatin significantly reduced endotoxin-induced hepatocellular damage and apoptosis. Moreover, hepatic accumulation of leukocytes was attenuated by simvastatin in endotoxemic animals. Co-administration of mevalonate abolished protective effects of simvastatin on endotoxin-provoked increases in ALT, AST, and hepatocellular apoptosis as well as leukocyte recruitment.

Simvastatin has the capacity to prevent endotoxemic liver injury by inhibiting leukocyte infiltration and hepatocellular apoptosis. These protective effects exerted by simvastatin are dependent on the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase pathway. Thus, simvastatin may represent a potential approach to prevent endotoxemia-associated liver dysfunction.

Neocytolysis, the selective hemolysis of young circulating red blood cells (RBCs), contributes to the physiologic control of red cell mass and to pathophysiologic phenomena such as anemia of renal disease, anemia after spaceflight, and blood doping by athletes. Progress in understanding the process is hampered by the lack of established markers to distinguish young from older RBC.

Twelve potentially informative RBC surface markers were assayed by flow cytometry in normal blood samples, and 4 were preferentially expressed in young RBC. To create a model of neocytolysis, 3 normal volunteers had recombinant human erythropoietin (rhEpo) administered until mild erythrocytosis occurred, then were studied upon rhEpo withdrawal.

Neocytolysis ensued that most evident from a rapid rise in serum ferritin as the iron from young RBC was transferred back to stores. Five additional volunteers had surface markers monitored during and after rhEpo administration. Three subjects with marginal baseline iron stores had blunted response to rhEpo, no significant neocytolysis, and no change in RBC surface marker expression. Two subjects with adequate baseline iron stores developed erythrocytosis followed by neocytolysis. Decreased expression of CD44 (homing-associated cell adhesion molecule) and CD71 (transferrin receptor) seemed to correlate best with neocytolysis; CD35 (complement receptor) less so. Of note, further studies are needed to determine if these changes are causative of red cell destruction.

This study begins to establish a human model of neocytolysis, to establish markers differentiating young and old RBC, and to establish a basis for better definition of the process. Although our study is preliminary, the results support the possibility that flow could be useful to detect blood doping because neocytolysis should predictably occur in athletes who surreptitiously blood dope.

Inhaled asbestos fibers are known to cause progressive lung or pleural fibrosis and malignancies such as lung cancer or diffuse malignant mesothelioma. Transforming growth factor β1 (TGF-β1), a multifunctional cytokine, regulates the proliferation and differentiation of cells. Transforming growth factor β1 is known to promote the pathogenesis of lung fibrosis and acts as a tumor suppressor in normal cells. Two genetic polymorphisms in codons 10 (Leu10Pro) and 25 (Arg25Pro) of the TGF-β1 gene are suggested to be associated with a different TGF-β1 protein production. Therefore, we examined an association between the 2 TGF-β1 gene polymorphisms and asbestos-induced lung fibrosis and lung cancer.

Detection of the 2 polymorphisms was performed by rapid capillary polymerase chain reaction, with melting curve analysis, using fluorescence-labeled hybridization probes. To investigate the association between TGF-β1 gene polymorphisms in codons 10 and 25 and the susceptibility to asbestos-induced diseases, association studies were performed with healthy control subjects (n = 83), patients with pulmonary fibrosis (n = 591), and patients with bronchial carcinoma (n = 147).

Compared with a healthy control group, odds ratio (OR) analysis revealed an inverse relationship for the proline allele at codon 10 or 25 with pulmonary fibrosis (higher risk) and lung cancer (lower risk). The proline allele at codon 10 or 25 is significantly associated with a higher risk for fibrotic lung diseases (OR_crude, 1.46; 95% confidence interval [CI], 1.01-2.11; P = 0.045 and OR_adjusted, 1.76; 95% CI, 1.14-2.72; P = 0.011, respectively, for codon 10; OR, 2.13; 95% CI, 1.33-3.99; P = 0.019 and OR_adjusted, 2.27; 95% CI, 1.14-4.52; P = 0.02, respectively, for codon 25) when compared with patients with lung cancer. A significant association for the proline allele is also revealed when comparing patients with asbestosis (OR_crude, 3.01; 95% CI, 1.44-6.29; P = 0.003 and OR_adjusted, 3.72; 95% CI, 1.56-8.85; P = 0.011) with patients with asbestos-induced lung cancer.

In summary, the results confirm the hypothesis that TGF-β1 polymorphisms are associated with asbestos-induced fibrotic or malignant lung diseases in whites.

Osteogenesis imperfecta (OI) is an inherited bone disease caused by mutations in collagen genes. Because these mutations occur at a wide variety of sites in the genes and differ among populations, we studied the COL1A1 gene in Chinese with OI and compared the results with findings form other populations.

COL1A1 gene mutations were detected by polymerase chain reaction and sequencing from 3 unrelated families and 1 sporadic case in Chinese.

Four COL1A1 mutations that were novel were found. The patients' clinical characteristics were variable, even within the same family. Notably, some of the novel COL1A1 variants were at the same nucleotide positions as previously described but with different nucleotide changes. In addition, we also found 1 patient with OI with 2 mutations in the same haplotypes.

We discuss the differences in phenotype related to the specific mutation sites. Although there have been many reports on mutations of COL1A1 and COL1A2, few cases have been reported in Chinese. Our data showed that the COL1A1 gene mutation might also play an important role in OI among Chinese. The Han Chinese represent a quarter of the world's population, and we believe that our new data contributes to fill in the type I collagen mutation map. We thought that the patient with OI could have 2 mutations in the same haplotypes, without limit to 1 mutation.