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• W2917251210 abstract "The ability to transfuse platelets has had a major impact on the ability to deliver myelosuppressive chemotherapy with acceptable risk; it's hard to imagine leukemia induction or bone marrow transplantation without it. However, there are still immunologic and technical barriers to effective platelet replacement. Foremost among these is the tendency of some recipients to develop alloantibodies that limit the response to platelet transfusion. Also important is the simple fact that platelets do not live very long and are quite labile in storage. Avoiding overcooling and maintaining favorable gas exchange (through the use of gas-permeable bags and gentle agitation) allow several days to pass between donation and successful transfusion, but longer storage has been an elusive goal. One barrier to prolonged storage is that platelets tend to become activated when they are cooled much below room temperature; thus, using cold to quiet the cells metabolically has not been a rewarding strategy. This activation is also of concern in cardiac surgery (when hypothermia may be used to protect the heart from ischemia) and may even play a role in cold injury to extremities. Understanding the mechanism whereby platelets become activated in the cold is clearly important if one is ever to overcome this limitation to storage, and it could bear fruit in better management of deliberate or accidental hypothermia. An article in this month's Journal is directed at exactly that problem (see page 339 ). Fern Tablin and her colleagues from the University of California at Davis compared human platelets with those from other mammals as part of an attempt to develop models for the cold storage problems in human transfusion medicine. The same workers had earlier demonstrated that human platelets become activated coincident with (and perhaps because of) a membrane lipid phase transition that occurs at about 12°C to 20°C. Using Fourier transform infrared spectra obtained at small temperature intervals, they mapped the phase transition in platelets from several species. Interestingly, there was quite a substantial inter-species difference in the location and abruptness of the transition. Rodents, lagomorphs, and cattle had broader transition ranges; platelets from pigs had a phase transition profile that closely mimicked that of human platelets. Platelets from primates did not ape those from humans, showing broad phase transitions more like those of cattle. Because of these findings, the authors suggest that the pig might be an especially appropriate model for the study of platelet activation by cooling. About 20 years ago it was observed that irreversibly sickled red blood cells were calcium-laden and that manipulations of the calcium content of sickle erythrocytes could create rigid cells much like those that had been through multiple sickling/unsickling cycles. Moreover, such cells had lost some of their phospholipid asymmetry, such that pro-coagulant anionic phospholipids were overexpressed on the outside surface of the cells. Might this process be important in red cell function—and indeed thrombotic risk—in circumstances less dramatic than sickle cell anemia? Dr Michael Mark and his associates from the Kantonsspital Chur (Switzerland) and the AO/ASIF Research Institute (Davos, Switzerland) asked that question by exposing red cells to a variety of physiologic modifiers of calcium traffic and also by loading them with calcium directly with an ionophore. As described beginning on page 347 , exposure of red cells to the calcium ionophore A23187 led to echinocyte formation and to an increased whole-blood viscosity at high shear rates. At low shear rates (where the tendency of red cells to clump is of greater importance and the deformability of individual cells is less important), the viscosity was somewhat diminished. Responding to observations that clinical states characterized by high parathyroid hormone (PTH) levels are sometimes associated with anemia and diminished red blood cell survival, the authors tested whether similar results could be obtained simply by incubating red blood cells in a medium containing high calcium concentrations or by exposing them to altered concentrations of PTH, calcitonin, or vitamin D. They could not. Exposing red cells to physiologic or supraphysiologic concentrations of PTH, calcitonin, or 1,25 dihydroxy cholecalciferol had no effect on red cell morphology or on measured whole blood viscosity. From these results it appears unlikely that red cell changes caused by PTH excess explain the anemia or shortened erythrocyte survival seen in some patients with hyperparathyroidism, kidney failure, or congestive heart failure. A particularly nice example of an ionophore-treated red blood cell is displayed on this month's cover together with a normal red blood cell for comparison. Our understanding of growth and repair is rapidly advancing, especially since the identification of a number of growth factors that direct the processes. Of particular interest is the concept that careful orchestration of the production of these factors is necessary for inflammation to be contained and repairs to be effected without “overdoing it” by producing hyperplasia, hypertrophy, or scarring. The lung is an organ of particular interest in this regard, for several reasons. Florid inflammation may be followed by orderly repair and little residual damage in some circumstances (such as pneumococcal infection), while fibrotic damage or even frank tissue destruction may occur in others. Patients at high risk can be identified, and the production of some growth factors may be measured in fluid or cells obtained by bronchoalveolar lavage (BAL). Vascular endothelial growth factor (VEGF) is known to be produced in the lung, is presumably important to pulmonary repair, and has been proposed as a mediator in some lung injury scenarios. Drs Meyer, Cardoni, and Xiang, of the University of Wisconsin, therefore assayed VEGF levels in BAL fluid from normal volunteers and from patients with cystic fibrosis, interstitial pulmonary fibrosis, or sarcoidosis. Among normal subjects, they found that the VEGF levels in BAL fluid declined with age; in all groups, the concentration of VEGF was considerably higher in BAL fluid than it was in serum. Patients with cystic fibrosis had serum VEGF levels that were approximately two and a half times those of normal subjects of comparable age; in contrast, the VEGF concentrations in their BAL fluids were a bit less than two thirds the concentrations in the control samples. The serum values were not different between normal subjects and patients with interstitial lung disease, but once again the levels of VEGF in BAL fluid were lower than control values. This was true for many of the patients with sarcoidosis, and it was uniformly true for the patients with interstitial fibrosis. Does this make sense? One might have predicted that the levels of VEGF would have been higher in BAL fluid taken from the subjects with the most active inflammation, the cystic fibrosis patients with bronchiectasis. Although these patients had high serum VEGF levels, their BAL fluid had low levels. This seeming paradox may be explained by the fact that neutrophil elastase cleaves VEGF, which the authors showed to impair its detection in an ELISA. Alternatively, the most inflamed areas of the bronchial tree may be partly inaccessible to BAL because of mucous plugging, or inflamed lung may not secrete VEGF as freely as does normal lung. Most interesting of all, however, is the possibility that this observation is exactly what it seems—that underproduction of VEGF in pulmonary epithelium leads to disordered healing and is part of the disease mechanism. This article may be found beginning on page 332. Several articles in the Journal in the past 3 years have addressed the roles of various growth factors in kidney disease. This month an original article and an accompanying editorial specifically address what is known about endothelin-1 (ET-1) and add a potentially new insight. This potent cytokine is known to cause cell proliferation and extracellular matrix accumulation in a variety of situations, and inhibition of its function can delay the progression of kidney disease in some experimental models, such as subtotal nephrectomy. More recent evidence has strongly supported a role for ET-1 in diabetic nephropathy. Of particular interest, ET-1 production is increased in diabetic nephropathy, and this may be causally associated with increased production of reactive oxygen species. Dr Hung-Chun Chen and several collaborators from Kaogsiung University (Taiwan) exposed the glomeruli of diabetic rats to a variety of oxidants or oxidant-generating systems, then measured ET-1 production. As described beginning on page 309 , they found that the production of both oxidants and ET-1 was increased in glomeruli from diabetic animals even without provocation. Adding oxidants or oxidant-generating systems led to an increase in ET-1 production, while the presence of oxidant scavengers led to a decrease in ET-1 production. Thus, two-pronged therapy aimed at the reduction of oxidant generation and the inhibition of ET-1 expression or function may help slow the progression of diabetic nephropathy. This story is put in context for readers in an editorial on page 300 by Dr Donald Kohan of the University of Utah. Cardiac remodeling after ischemic injury—especially infarction—is increasingly being recognized as an important determinant of the ultimate functional import of the damage that has been sustained. On page 316 , Dr Yao Sun et alii from the University of Tennessee at Memphis present the results of their studies of cytokine expression and collagen production in rat hearts after infarction. They establish the time course of inflammatory cell and myofibroblast inmigration, as well as collagen turnover, TGFβ expression, and levels of matrix metalloproteinase and its major inhibitor. A possibly related process is the hypertrophy that occurs in hearts exposed to increased systolic pressures, for which angiotensin-II (AT-II) appears to be an important mediator. A team of 10 researchers from Yamanashi University, Hokkaido University (Sapporo), and Jikei University (Tokyo) studied whether the protective effect of angiotensin-converting enzyme inhibitors was directly related to their effect on AT-II or whether it might be related to the effects on blood pressure or on bradykinin kinetics. Using spontaneously hypertensive, stroke-prone rats, they found differences in cardiac hypertrophy and function among animals treated with different antihypertensive strategies, suggesting that the inhibition of AT-II's effect was a specific protectant rather than just another way to lower blood pressure (see page 353 ). Animal models for studies on cold-induced platelet activation in human beingsThe Journal of Laboratory and Clinical MedicineVol. 135Issue 4PreviewWhen human platelets are chilled below about 20°C, they spontaneously activate, a phenomenon that limits their storage lifetime. We have previously shown that this activation in chilled human platelets is associated with passage through a lipid phase transition. Because animal models are necessary for investigating methods for cold storage of platelets, it is essential to determine whether such phase transitions and chilling-induced activation are found in these models. In this study we examined platelets from some commonly used animal models—pigs, rhesus monkeys, mice, dogs, and rabbits. Full-Text PDF Influence of parathyroid hormone, calcitonin, 1,25(OH)2 cholecalciferol, calcium, and the calcium ionophore A23187 on erythrocyte morphology and blood viscosityThe Journal of Laboratory and Clinical MedicineVol. 135Issue 4PreviewParathyroid hormone and calcitonin, both endocrine modulators of calcium homeo- stasis, may influence blood rheology. Parathyroid hormone is known to reduce erythrocyte survival, leading to anemia. Calcitonin has been found to have some vascular effects. We have analyzed the influence of parathyroid hormone (10–7 to 10–10 mol/L), calcitonin (10–6 to 10–12 mol/L), 1,25(OH)2 cholecalciferol (10–7 to 10–10 mol/L), additional calcium in plasma (+1 and 2 mmol/L), and the calcium ionophore A23187 (50 μmol/L) on erythrocyte morphology and blood viscosity at high shear rate (94 s–1) and low shear rate (0.1 s–1) in vitro. Full-Text PDF Vascular endothelial growth factor in bronchoalveolar lavage from normal subjects and patients with diffuse parenchymal lung diseaseThe Journal of Laboratory and Clinical MedicineVol. 135Issue 4PreviewVascular endothelial growth factor (VEGF) is a potent angiogenic agent that is expressed by epithelial cells in the mature lung of various animal species. We hypothesized that VEGF levels in lower respiratory tract secretions may vary with age or with lung inflammation in human beings. We measured VEGF165 in bronchoalveolar lavage fluid (BALF) from normal volunteers (NVs) of varying age and from patients with cystic fibrosis (CF), sarcoidosis, or idiopathic pulmonary fibrosis (IPF). A considerable gradient in VEGF levels was found with relatively high VEGF concentrations in BALF as compared with serum VEGF. Full-Text PDF Reactive oxygen species enhances endothelin-1 production of diabetic rat glomeruli in vitro and in vivoThe Journal of Laboratory and Clinical MedicineVol. 135Issue 4PreviewBoth reactive oxygen species (ROS) and endothelin-1 (ET-1) have been implicated in the pathophysiology of diabetic nephropathy. The interrelationship between them, however, has not been documented in this disease. To determine whether ROS regulates ET-1 production in diabetic kidneys, we examined the in vitro and in vivo effects of ROS donors and scavengers on ET-1 production of diabetic rat glomeruli. For in vitro study, the glomeruli were isolated with a sieving method from streptozotocin-induced diabetic rats and killed at 1 week, 1 month, and 3 months, respectively. Full-Text PDF Reactive oxygen species and endothelins in diabetic nephropathyThe Journal of Laboratory and Clinical MedicineVol. 135Issue 4PreviewEndothelin-1 is an extremely potent 21-amino-acid peptide with multiple biologic actions, including stimulation of smooth muscle contraction, cell proliferation, and extracellular matrix accumulation.1 Because of these vasoconstrictive and profibrotic effects, the role of ET-1 in the pathogenesis of chronic kidney failure has been the subject of intense investigation. These studies have generally found that ET-1 is involved in kidney deterioration: in models of progressive kidney disease due to reduced kidney mass, intrarenal ET-1 levels are elevated while sustained endothelin receptor blockade ameliorates kidney dysfunction and histologic damage. Full-Text PDF Cardiac remodeling by fibrous tissue after infarction in ratsThe Journal of Laboratory and Clinical MedicineVol. 135Issue 4PreviewAfter transmural myocardial infarction (MI), extensive myocardial remodeling by fibrous tissue appears in both infarcted and noninfarcted myocardium, which contributes to ventricular diastolic dysfunction. In the present study we sought to assess the time course of collagen remodeling in the infarcted rat hearts by detecting spatial and time-dependent cellular events related to collagen synthesis and degradation 2 to 28 days after left coronary artery ligation. In infarcted hearts, and compared with findings in sham-operated and unoperated rat hearts, we found the following: (1) macrophages infiltrated into sites of MI and visceral pericardium on day 2 and gradually disappeared after day 14; (2) myofibroblasts (MyoFb) first appeared at these sites of repair on day 3 and remained abundant thereafter at all time points examined; (3) transforming growth factor-β1 (TGF-β1) mRNA was enhanced in infarcted and noninfarcted myocardium on day 2 and remained throughout 28 days; (4) type I and III collagen mRNAs began to increase at and remote to MI on day 3 and remained elevated thereafter; (5) matrix metalloproteinase-1 mRNA was significantly increased at and remote to MI on day 3, declined to the control level on day 7, and remained low thereafter; (6) tissue inhibitor of matrix metalloproteinase (TIMP)–I, -II, and -III mRNAs were markedly elevated at sites of repair on day 3 and sustained throughout 28 days; (7) fibrillar collagen accumulation that was evident at and remote to MI on day 7 continued to accumulate thereafter at each site over 4 weeks. Full-Text PDF Angiotensin II–induced cardiomyocyte hypertrophy and cardiac fibrosis in stroke-prone spontaneously hypertensive ratsThe Journal of Laboratory and Clinical MedicineVol. 135Issue 4PreviewAngiotensin-converting enzyme inhibitors (ACEIs) cause regression of hypertensive left ventricular hypertrophy (LVH) by reducing angiotensin II, increasing bradykinin, or both. The mechanisms of these cardioprotective effects remain controversial. The aims of this study were to determine whether the cardioprotective effects of ACEIs are mediated by reducing angiotensin II and whether ACEIs ameliorate the morphologic, physiologic, and biochemical changes in the hearts of stroke-prone spontaneously hypertensive rats (SHRSPs). Full-Text PDF" @default.
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