We have recently found that an extracellular protein, ␣ 1 proteinase inhibitor (␣ 1 PI; ␣ 1 antitrypsin), is required for in vitro human immunodeficiency virus (HIV) infectivity outcome. We show here in a study of HIVseropositive patients that decreased viral load is significantly correlated with decreased circulating ␣ 1 PI. In the asymptomatic category of HIV disease, 100% of patients manifest deficient levels of active ␣ 1 PI, a condition known to lead to degenerative lung diseases and a dramatically reduced life span. Further, HIV-associated ␣ 1 PI deficiency is correlated with circulating anti-␣ 1 PI immunoglobulin G. These results suggest that preventing HIVassociated ␣ 1 PI deficiency may provide a strategic target for preventing HIV-associated pathophysiology.In general, proteinase inhibitors are inhibitory for a single class of proteinases, often resulting in mutual inactivation. On the other hand, proteinases may inactivate many classes of inhibitors without being inactivated themselves and, in the process, may produce bioactive fragments, e.g., complement fragments. The proteinase inhibitor in serum exhibiting the greatest concentration is ␣ 1 PI, and the proteinase inhibitor encompassing the broadest spectrum is ␣ 2 macroglobulin (␣ 2 M). Multiple molecular conformations of active and inactive ␣ 1 PI are known to exist and to be receptor recognized. For example, active ␣ 1 PI has been found to react with surface-associated human leukocyte elastase (HLE), and inactive ␣ 1 PI has been found to react with the well-characterized scavenger receptor, ␣ 2 M receptor-low-density-lipoprotein receptor-related protein (␣ 2 MR-LRP) (2, 21). The highly conserved ␣ 2 M uniquely inhibits all four classes of proteinases and exhibits a receptorrecognized conformation involved in signaling as well as an ␣ 2 MR-LRP-recognized conformation (17). A significant body of evidence suggests that receptor recognition of the multiple forms of circulating proteinase inhibitors results in activation of discrete cellular subsets of the mononuclear phagocyte system (27).Whereas ␣ 1 PI covalently inhibits the catalytic site of HLE, it has been shown that in certain situations the association of HLE with ␣ 2 M in plasma is favored (6). When proteinases are complexed with ␣ 2 M, proteolysis of low-molecular-weight peptides and cytokines can persist. The balance between available HLE activity, the inhibitor ␣ 1 PI, and the substrate-restricting ␣ 2 M represents a tightly regulated mechanism for discrete targeting of proteolytic activity in tissues. It has been shown that inter-␣-trypsin inhibitor (I␣I) uniquely acts as a shuttle by transferring HLE to ␣ 1 PI or ␣ 2 M (25). It is the active site of I␣I which is identical with the principle HIV-neutralizing determinant in the V3 loop, and it is this region of the V3 loop which has been shown to reversibly inhibit proteinases (1). This suggests the possibility that HIV envelope proteins themselves may disrupt the homeostasis between proteinases and proteinase inhibitors.The importance of ...
Sarcoidosis is a systemic disease characterized by noncaseating granulomas in the involved organs. Neurologic manifestations involving the central and/or peripheral nervous system occur in about 5% of patients. Neurosarcoidosis is often refractory to conventional treatment and therefore more effective treatment options are needed. While the etiology of the disease is still unknown, there is now a better understanding of its pathogenesis on a molecular level. It is clear that tumor necrosis factor-α (TNFα) plays a pivotal role in the development of the granulomas and it is believed to be a key cytokine involved in the pathogenesis of the disease. Taking advantage of this better understanding of disease pathogenesis, anti-TNFα agents are being increasingly used to treat refractory sarcoidosis. We report a patient with refractory neurosarcoidosis who showed dramatic improvement in the clinical and radiological manifestations following treatment with infliximab; he suffered a relapse upon discontinuation of the medication.
Aircraft noise is a form of environmental noise pollution that is a cause for resident complaints, especially near larger airports. Noise monitoring is usually performed by placing single microphones at various locations in neighborhoods that are near airports. Single omnidirectional microphones, however, record every sound wave that is incident on the sensor. The sound amplitudes estimated by these single microphones include the contributions from environmental sources other than the aircraft, such as traffic noise, sirens, powered landscaping equipment, and barking dogs. Use of a phased array of microphones in combination with advanced beam-forming algorithms makes possible the selective monitoring of aircrafts’ localized sound amplitudes and thereby more accurately identifies aircraft-specific sound levels while minimizing the contributions from other sound sources. This paper demonstrates the noise source localization abilities of the phased-array system for the application of aircraft environmental noise monitoring.
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