The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of noncardiogenic pulmonary edema, hypoxemia, and the need for mechanical ventilation. ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma, and is present in ~10% of all intensive care unit patients worldwide. Despite some improvements over the past decades, mortality remains high at 30–40% in most studies. Pathologic specimens from patients with ARDS most frequently reveal diffuse alveolar damage, and laboratory studies have demonstrated both alveolar epithelial and lung endothelial injury, resulting in accumulation of protein-rich inflammatory edema fluid in the alveolar space. Diagnosis is based on consensus syndromic criteria, with recent proposed modifications for under-resourced settings and for pediatric patients. Patient management focuses on implementing a lung-protective ventilation strategy; no specific pharmacotherapies have been identified. Long-term outcomes of patients with ARDS are increasingly recognized as important research targets, as many patients survive ARDS only to suffer ongoing functional and/or psychologic sequelae. Future directions include efforts to facilitate earlier recognition of ARDS, prognostic and/or predictive enrichment in clinical studies to identify responsive subsets, and ongoing efforts to understand fundamental mechanisms of lung injury that may respond to specific treatments.

Sepsis, a systemic inflammatory response to infection, commonly progresses to acute lung injury (ALI), an inflammatory lung disease with high morbidity. We postulated that sepsis-associated ALI is initiated by degradation of the pulmonary endothelial glycocalyx, leading to neutrophil adherence and inflammation. Using intravital microscopy, we found that endotoxemia in mice rapidly induced pulmonary microvascular glycocalyx degradation via tumor necrosis factor-α (TNF-α)-dependent mechanisms. Glycocalyx degradation involved the specific loss of heparan sulfate and coincided with activation of endothelial heparanase, a TNF-α–responsive, heparan sulfate–specific glucuronidase. Glycocalyx degradation increased the availability of endothelial surface adhesion molecules to circulating microspheres and contributed to neutrophil adhesion. Heparanase inhibition prevented endotoxemia-associated glycocalyx loss and neutrophil adhesion and, accordingly, attenuated sepsis-induced ALI and mortality in mice. These findings are potentially relevant to human disease, as sepsis-associated respiratory failure in humans was associated with higher plasma heparan sulfate degradation activity; moreover, heparanase content was higher in human lung biopsies showing diffuse alveolar damage than in normal human lung tissue.

The acute respiratory distress syndrome (ARDS) causes 40% mortality in approximately 200,000 critically ill patients annually in the United States. ARDS is caused by protein-rich pulmonary edema that causes severe hypoxemia and impaired carbon dioxide excretion. The clinical disorders associated with the development of ARDS include sepsis, pneumonia, aspiration of gastric contents, and major trauma. The lung injury is caused primarily by neutrophil-dependent and platelet-dependent damage to the endothelial and epithelial barriers of the lung. Resolution is delayed because of injury to the lung epithelial barrier, which prevents removal of alveolar edema fluid and deprives the lung of adequate quantities of surfactant. Lymphocytes may play a role in resolution of lung injury. Mortality has been markedly reduced with a lung-protective ventilatory strategy. However, there is no effective pharmacologic therapy, although cell-based therapy and other therapies currently being tested in clinical trials may provide novel treatments for ARDS.

A polymorphic C -> T transition located on the human Y chromosome was found by the systematic comparative sequencing of Y-specific sequence-tagged sites by denaturing high-performance liquid chromatography We estimate the nucleotide diversity over 4.2 kb of the nonrecombining portion of the Y chromosome to be 0.00014. Compared to autosomes, the majority ofvariation is due to the smaller effective population size of the Y chromosome rather than selective sweeps. There begins to emerge a pattern of pronounced geographical localization of Y-specific nucleotide substitution polymorphisms.The apparently nonrecombining (Y specific) portion of the human Y chromosome provides a unique system for the study of human origins, migration, and admixture (1). However, few such polymorphisms have been identified to date, presumably because of a smaller effective population size relative to autosomes and reduction of variation on the entire chromosome due to selection at a single locus (2-7). Moreover, some of the previously described loci are not amenable to convenient PCR genotyping techniques (e.g., see refs. 8 and 9).Some Y-specific polymorphisms such as the YAlu polymorphic element (10, 11) and an A to G transition (12), which have apparently arisen once in human evolution, have underscored the great potential of such loci in creating readily interpretable Y-chromosomal haplotypes for evolutionary analysis. Such data are of particular value in the study of human migration. A recent report (4) indicated an absence of polymorphism over 729 bp on the human Y chromosome. Here we report on the discovery of a C --T point mutation in association with representative genotype results from globally diverse populations. Our observations of a locus polymorphic only within the Western Hemisphere, which shows the pattern of linkageThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. disequilibrium with a previously described microsatellite locus (13), indicate that the C -> T mutation may have been introduced exclusively during the early stages of human habitation of the Americas. Its potential utility in understanding the pre-Columbian peopling of the New World as well as inferring the degree of admixture within indigenous populations are discussed. The comparative sequencing of >4.2 kb of the nonrecombining portion of the human Y chromosome reveals detectable amounts of base substitution polymorphisms. (14) sequence-tagged sites (STSs) were amplified by using a "touchdown" PCR regime (12, 15). Amplification primers were obtained from Research Genetics (Huntsville, AL). Reaction products were analyzed by agarose gel electrophoresis. We have developed a method of comparative DNA sequencing (16) based on the capability of ion-pair reverse-phase liquid chromatography on alkylated nonporous poly(styrene divinylbenzene) particles (17) to resolve homofrom heteroduplex molecules un...

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