Shear stress-stimulated endothelial cells induce smooth muscle cell chemotaxis via platelet-derived growth factor-BB and interleukin-1α

ObjectiveVascular smooth muscle cell (SMC) migration is critical to the development of atherosclerosis and neointimal hyperplasia. Hemodynamic forces such as shear stress and cyclic strain stimulate endothelial cell signal-transduction pathways, resulting in the secretion of several factors, including SMC chemoattractants such as platelet-derived growth factor (PDGF). We hypothesized that mechanical forces stimulate endothelial cells to secrete SMC chemoattractants to induce migration via the mitogen-activated protein kinase (MAPK) pathway.MethodsBovine aortic endothelial cells were exposed to shear stress, cyclic strain, or static conditions for 16 hours. The resulting conditioned medium was used as a SMC chemoattractant in a Boyden chamber. Activation of SMC extracellular signal-regulated protein kinase 1/2 (ERK1/2) was assessed by Western blot analysis. Pathways were inhibited with anti-PDGF-BB or anti-interleukin-1α (IL-1α) antibodies, or the ERK1/2 upstream pathway inhibitor PD98059.ResultsConditioned medium from endothelial cells exposed to shear stress corresponding to arterial levels of shear stress stimulated SMC migration but lower levels of shear stress or cyclic strain did not. Both PDGF-BB and IL-1α were secreted into the conditioned medium by endothelial cells stimulated with shear stress. Both PDGF-BB and IL-1α stimulated SMC chemotaxis but were not synergistic, and both stimulated SMC ERK1/2 phosphorylation. Inhibition of PDGF-BB or IL-1α inhibited SMC chemotaxis and ERK1/2 phosphorylation.ConclusionShear stress stimulates endothelial cells to secrete several SMC chemoattractants, including PDGF-BB and IL-1α; both PDGF-BB and IL-1α stimulate SMC chemotaxis via the ERK1/2 signal-transduction pathway. These results suggest that the response to vascular injury may have a common pathway amenable to pharmacologic manipulation.Clinical relevanceOne difficulty in the pharmacologic treatment of atherosclerosis or neointimal hyperplasia leading to restenosis is the multiplicity of activated pathways and thus potential treatment targets. This study demonstrates that shear stress, a hemodynamic force that may be a biologically relevant stimulus to induce vascular pathology, stimulates endothelial cells to secrete PDGF-BB and IL-1α. Both of these mediators stimulate the SMC ERK1/2 pathway to induce migration, a critical event in the pathogenesis of atherosclerosis and neointimal hyperplasia. Therefore, this study suggests a relevant common target pathway in SMC that is amenable to manipulation for clinical treatment

Detection of Escherichia coli, rotavirus, and Cryptosporidium spp. from drinking water, kitchenware, and flies in a periurban community of Lusaka, Zambia

Fecal contamination with a poor water, sanitation and hygiene environment in urban informal settlements poses diarrhea risks. Little information is available on the contamination of environmental media with enteric pathogens in such settlements. We investigated the contamination of Escherichia coli, rotavirus, and Cryptosporidium spp. in water, on kitchenware, and on flies in urban informal settlements of Chawama and Kanyama, Lusaka, Zambia. These environmental media were examined by XM-G agar cultivation for E. coli and specific real-time RT-PCR assays to detect rotavirus and Cryptosporidium spp. E. coli; rotavirus, and Cryptosporidium spp. were detected in samples of household stored drinking water (6 of 10 samples, 3 of 10 samples, and 2 of 10 samples, respectively), cups (10 of 20 samples, 2 of 13 samples, 1 of 13 samples, respectively), and flies (35 of 55 samples, 5 of 17 samples, 1 of 17 samples, respectively). The ranges of rotavirus concentrations in household stored drinking water, on cups, and flies were 2.9 × 10²–2.2 × 10⁵ copies/L, 1.2 × 10²–4.3 × 10² copies/cup, and 5.0 × 10¹–2.0 × 10² copies/fly, respectively. These results indicate the contribution of drinking water and kitchenware to enteric pathogen exposure and potential role of flies in microbial transmission

Neuroelectric Mechanisms of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage

Delayed cerebral ischemia (DCI) remains a challenging but very important condition, because DCI is preventable and treatable for improving functional outcomes after aneurysmal subarachnoid hemorrhage (SAH). The pathologies underlying DCI are multifactorial. Classical approaches to DCI focus exclusively on preventing and treating the reduction of blood flow supply. However, recently, glutamate-mediated neuroelectric disruptions, such as excitotoxicity, cortical spreading depolarization and seizures, and epileptiform discharges, have been reported to occur in high frequencies in association with DCI development after SAH. Each of the neuroelectric disruptions can trigger the other, which augments metabolic demand. If increased metabolic demand exceeds the impaired blood supply, the mismatch leads to relative ischemia, resulting in DCI. The neuroelectric disruption also induces inverted vasoconstrictive neurovascular coupling in compromised brain tissues after SAH, causing DCI. Although glutamates and the receptors may play central roles in the development of excitotoxicity, cortical spreading ischemia and epileptic activity-related events, more studies are needed to clarify the pathophysiology and to develop novel therapeutic strategies for preventing or treating neuroelectric disruption-related DCI after SAH. This article reviews the recent advancement in research on neuroelectric disruption after SAH

Sustained orbital shear stress stimulates smooth muscle cell proliferation via the extracellular signal-regulated protein kinase 1/2 pathway

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Combined Distal Venous Arterialization and Free Flap for Patients with Extensive Tissue Loss

http://dx.doi.org/10.1016/j.avsg.2009.07.001Background : We evaluated the mid-term outcome of distal venous arterialization (DVA) and the role of a combined free flap as a bridgehead for blood supply. Methods : In the past 5 years, nine patients with extensive tissue loss and lacking graftable distal arteries underwent DVA. These consisted of four primary DVAs, three combined DVA and free flap procedures, and two adjuvant DVAs for hemodynamically failed distal bypasses. After nine primary DVAs, three redo DVAs were performed for early failure. Etiologies were four Buerger disease and five arteriosclerosis obliterans, including three dialysis patients. Results : Among the nine DVA cases, there were five primary failures: two underwent amputation, two had successful redo DVA, and the remaining one did not require redo DVA. Primary patency, secondary patency, and limb salvage rates were 44.4%, 55.6%, and 77.8%, respectively. The postoperative period was 1–36 months (median 12). Angiography demonstrated DVA was effective in the early period, and development of collaterals or a capillary network from the free flap replaced the DVA function in the intermediate period. Conclusion : DVA can be effective as a procedure for limb salvage in patients without graftable distal arteries, and a combined free flap is effective and functions as a bridgehead for blood supply to the ischemic zone

Tuning Pre-Solution of an Amphiphilic Polymeric Dispersant with Low Acid-Value toward Colored-Ink Preparation

Recently, a variety of amphiphilic block copolymers for water-based color inks as pigment dispersants have been developed. Although such dispersants require both high adsorption of pigments and dispersion-stability in water, the most crucial issue is the difficulty in controlling the affinity balance of the polymeric dispersants between the pigments and aqueous media. Therefore, it is important to increase the solubility of the hydrophobic polymers with low acid-value for ink design. Amphiphilic block copolymers containing styrene-based blocks as hydrophobic segments and methacrylic acid blocks as hydrophilic segments were prepared. The polymers with low acid-value could not dissolve in the alkaline solution directly. They could dissolve in methyl-ethyl-ketone (MEK) at room temperature and diethylene glycol (DEG), with heating. Polymer aqueous solutions were successfully prepared using polymer solutions in DEG as the pre-solutions. Because they were also unable to dissolve directly even in an alkaline solution containing DEG, the existence of DEG is not important, but the process employing the pre-solution is important. The influence of pre-solution viscosity on solubility in water was evaluated. The result suggests that the high viscosity of the DEG solution would work to slowly disperse the polymers in the alkaline solution, efficiently converting polymers into an aqueous soluble state, owing to there being enough time for the neutralization of the carboxylic acids of the polymers. Note that in the pre-solution of a lower concentration, the aqueous solution did not become clear, and the larger particle sizes were detected. These results showed that the viscosity of the pre-solution is an essential factor in solubilization in water. Using this method, the polymeric dispersants with low hydrophilicity were well dissolved in water, up to a high concentration

Corticosterone facilitates fluoxetine-induced neuronal plasticity in the hippocampus.

The hippocampal dentate gyrus has been implicated in a neuronal basis of antidepressant action. We have recently shown a distinct form of neuronal plasticity induced by the serotonergic antidepressant fluoxetine, that is, a reversal of maturation of the dentate granule cells in adult mice. This "dematuration" is induced in a large population of dentate neurons and maintained for at least one month after withdrawal of fluoxetine, suggesting long-lasting strong influence of dematuration on brain functioning. However, reliable induction of dematuration required doses of fluoxetine higher than suggested optimal doses for mice (10 to 18 mg/kg/day), which casts doubt on the clinical relevance of this effect. Since our previous studies were performed in naive mice, in the present study, we reexamined effects of fluoxetine using mice treated with chronic corticosterone that model neuroendocrine pathophysiology associated with depression. In corticosterone-treated mice, fluoxetine at 10 mg/kg/day downregulated expression of mature granule cell markers and attenuated strong frequency facilitation at the synapse formed by the granule cell axon mossy fiber, suggesting the induction of granule cell dematuration. In addition, fluoxetine caused marked enhancement of dopaminergic modulation at the mossy fiber synapse. In vehicle-treated mice, however, fluoxetine at this dose had no significant effects. The plasma level of fluoxetine was comparable to that in patients taking chronic fluoxetine, and corticosterone did not affect it. These results indicate that corticosterone facilitates fluoxetine-induced plastic changes in the dentate granule cells. Our finding may provide insight into neuronal mechanisms underlying enhanced responsiveness to antidepressant medication in certain pathological conditions

Cerebrovascular pathophysiology of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage (SAH) remains a serious cerebrovascular disease. Even if SAH patients survive the initial insults, delayed cerebral ischemia (DCI) may occur at 4 days or later post-SAH. DCI is characteristics of SAH, and is considered to develop by blood breakdown products and inflammatory reactions, or secondary to early brain injury, acute pathophysiological events that occur in the brain within the first 72 hours of aneurysmal SAH. The pathology underlying DCI may involve large artery vasospasm and/or microcirculatory disturbances by microvasospasm, microthrombosis, dysfunction of venous outflow and compression of microvasculature by vasogenic or cytotoxic tissue edema. Recent clinical evidence has shown that large artery vasospasm is not the only cause of DCI, and that both large artery vasospasm-dependent and -independent cerebral infarction causes poor outcome. Animal studies suggest that mechanisms of vasospasm may differ between large artery and arterioles or capillaries, and that many kinds of cells in the vascular wall and brain parenchyma may be involved in the pathogenesis of microcirculatory disturbances. The impairment of the paravascular and glymphatic systems also may play important roles in the development of DCI. As pathological mediators for DCI, glutamate and several matricellular proteins have been investigated in addition to inflammatory molecules. Glutamate is involved in excitotoxicity contributing to cortical spreading ischemia and epileptic activity-related events. Microvascular dysfunction is an attractive mechanism to explain the cause of poor outcomes independently of large cerebral artery vasospasm, but needs more studies to clarify the pathophysiologies or mechanisms and to develop a novel therapeutic strategy

Tuning Pre-Solution of an Amphiphilic Polymeric Dispersant with Low Acid-Value toward Colored-Ink Preparation

Recently, a variety of amphiphilic block copolymers for water-based color inks as pigment dispersants have been developed. Although such dispersants require both high adsorption of pigments and dispersion-stability in water, the most crucial issue is the difficulty in controlling the affinity balance of the polymeric dispersants between the pigments and aqueous media. Therefore, it is important to increase the solubility of the hydrophobic polymers with low acid-value for ink design. Amphiphilic block copolymers containing styrene-based blocks as hydrophobic segments and methacrylic acid blocks as hydrophilic segments were prepared. The polymers with low acid-value could not dissolve in the alkaline solution directly. They could dissolve in methyl-ethyl-ketone (MEK) at room temperature and diethylene glycol (DEG), with heating. Polymer aqueous solutions were successfully prepared using polymer solutions in DEG as the pre-solutions. Because they were also unable to dissolve directly even in an alkaline solution containing DEG, the existence of DEG is not important, but the process employing the pre-solution is important. The influence of pre-solution viscosity on solubility in water was evaluated. The result suggests that the high viscosity of the DEG solution would work to slowly disperse the polymers in the alkaline solution, efficiently converting polymers into an aqueous soluble state, owing to there being enough time for the neutralization of the carboxylic acids of the polymers. Note that in the pre-solution of a lower concentration, the aqueous solution did not become clear, and the larger particle sizes were detected. These results showed that the viscosity of the pre-solution is an essential factor in solubilization in water. Using this method, the polymeric dispersants with low hydrophilicity were well dissolved in water, up to a high concentration