NZB/NZW F1 mice of both sexes were castrated at 2 wk of age and implanted subcutaneously with silastic tubes containing either 5-alpha-dihydrotestosterone or estradiol-17-beta. Mice receiving androgen showed improved survival, reduced anti-nucleic acid antibodies, or less evidence of glomerulonephritis as determined by light, immunofluorescent, and electron microscopy. By contrast, opposite effects were observed in castrated mice receiving estrogen. Intact male NZB/NZW F1 mice received androgen implants at 8 mo, an age when they develop an accelerated autoimmune disease associated with a decline in serum testosterone concentration. Such treated mice had improved survival and reduced concentrations of antibodies to DNA and to polyadenylic acid (Poly A). Prepubertal castration of male NZB/NZW F1 mice results in an earlier appearance of IgG antibodies to Poly A. This effect of castration was prevented if neonatal thymectomy was also performed.

We analyze a Massachusetts merit aid program that gives high-scoring students tuition waivers at in-state public colleges with lower graduation rates than available alternative colleges. A regression discontinuity design comparing students just above and below the eligibility threshold finds that students are remarkably willing to forgo college quality and that scholarship use actually lowered college completion rates. These results suggest that college quality affects college completion rates. The theoretical prediction that in-kind subsidies of public institutions can reduce consumption of the subsidized good is shown to be empirically important.

Although Mycobacterium tuberculosis is assumed to infect primarily alveolar macrophages after being aspirated into the lung in aerosol form, it is plausible to hypothesize that M. tuberculosis can come in contact with alveolar epithelial cells upon arrival into the alveolar space. Therefore, as a first step toward investigation of the interaction between M. tuberculosis and alveolar epithelial cells, we examined the ability of M. tuberculosis to bind to and invade alveolar epithelial cells in vitro. The H37Rv and H37Ra strains of M. tuberculosis were cultured to mid-log phase and used in both adherence and invasion assays. The A549 human type II alveolar cell line was cultured to confluence in RPMI 1640 supplemented with 5% fetal bovine serum, L-glutamine, and nonessential amino acids. H37Rv was more efficient in entering A549 cells than H37Ra, Mycobacterium avium, and Escherichia coli HB101, a nonpiliated strain (4.7% ؎ 1.0% of the initial inoculum in 2 h compared with 3.1% ؎ 0.8%, 2.1% ؎ 0.9%, and 0.03% ؎ 0.0%, respectively). The invasion was more efficient at 37؇C than at 30؇C (4.7% ؎ 1.0% compared with 2.3% ؎ 0.8%). H37Rv and H37Ra were both capable of multiplying intracellularly at a similar ratio over 4 days. Binding was inhibited up to 55.7% by anti-CD51 antibody (antivitronectin receptor), up to 55% with anti-CD29 antibody (␤ 1 integrin), and 79% with both antibodies used together. Uptake of M. tuberculosis H37Rv was microtubule and microfilament dependent. It was inhibited by 61.4% in the presence of 10 M colchicine and by 72.3% in the presence of 3 M cytochalasin D, suggesting two separate pathways for uptake. Our results show that M. tuberculosis is capable of invading type II alveolar epithelial cells and raise the possibility that invasion of alveolar epithelial cells is associated with the pathogenesis of lung infection.

The mechanism(s) by which Mycobacterium tuberculosis crosses the alveolar wall to establish infection in the lung is not well known. In an attempt to better understand the mechanism of translocation and create a model to study the different stages of bacterial crossing through the alveolar wall, we established a two-layer transwell system. M. tuberculosis H37Rv was evaluated regarding the ability to cross and disrupt the membrane. M. tuberculosis invaded A549 type II alveolar cells with an efficiency of 2 to 3% of the initial inoculum, although it was not efficient in invading endothelial cells. However, bacteria that invaded A549 cells were subsequently able to be taken up by endothelial cells with an efficiency of 5 to 6% of the inoculum. When incubated with a bicellular transwell monolayer (epithelial and endothelial cells), M. tuberculosis translocated into the lower chamber with efficiency (3 to 4%). M. tuberculosis was also able to efficiently translocate across the bicellular layer when inside monocytes. Infected monocytes crossed the barrier with greater efficiency when A549 alveolar cells were infected with M. tuberculosis than when A549 cells were not infected. We identified two potential mechanisms by which M. tuberculosis gains access to deeper tissues, by translocating across epithelial cells and by traveling into the blood vessels within monocytes.Infection caused by M. tuberculosis represents one of the great tragedies in world history. Approximately 3 million people die annually of the disease (7), despite the availability of cheap, efficacious, and curative therapy for tuberculosis.Once more, it seems clear that the improvement of the knowledge about the mechanisms employed by M. tuberculosis to infect the host will certainly offer new opportunities for the development of both effective therapy and vaccine.M. tuberculosis is inhaled into the respiratory tract, eventually reaching the alveolar space. It has been assumed that the bacterium is ingested by alveolar macrophages and subsequently gains access to the bloodstream by being transported by the alveolar macrophages and blood monocytes across the alveolar wall (10). Recently, however, it was demonstrated by several groups that M. tuberculosis invades and survives within human type II alveolar epithelial cells in vitro (3, 14, 17), and a possible role for alveolar epithelial cells in vivo has been postulated. In fact, the chance that M. tuberculosis would encounter an alveolar epithelial cell (the average human male has 1,500 type II and 28,000 type I alveolar epithelial cells [22]) is significantly greater than encountering an alveolar macrophage (50 macrophages per alveolus [8]). Therefore, the participation of type II alveolar epithelial cells, alveolar macrophages, and blood monocytes in the translocation of M. tuberculosis across the alveolar wall is currently poorly understood. Previous work has established the use of an in vitro model with a bilayer with alveolar epithelial cells and human lung endothelial cells (6). Using this model, i...

Despite the fact that the average American student is absent more than two weeks out of every school year, most research on the effect of instructional time has focused not on attendance but on the length of the school day or year. Student and school fixed effects models using Massachusetts data show a strong relationship between student absences and achievement but no impact of lost instructional time due to school closures. I confirm those findings in instrumental variables models exploiting the fact that moderate snowfall induces student absences while extreme snowfall induces school closures. Prior work ignoring this non-linearity may have mis-attributed the effect of absences to such snow days. Each absence induced by bad weather reduces math achievement by 0.05 standard deviations, suggesting that attendance can account for up to one-fourth of the achievement gap by income. That absences matter but closures do not is consistent with a model of instruction in which coordination of students is the central challenge, as in Lazear (2001). Teachers appear to deal well with coordinated disruptions of instructional time like snow days but deal poorly with disruptions like absences that affect different students at different times.