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OBJECTIVE: To assess reliability, responsiveness, importance to patients, and convergent validity for the Wisconsin Upper Respiratory Symptom Survey (WURSS-44) and to develop a short-form WURSS. STUDY DESIGN AND SETTING: Community-based recruitment of participants with colds. Prospective monitoring from within 48 hours of first symptom until 2 days after end of cold. The WURSS-44 includes 1 global illness severity item, 32 symptom-based items, 10 functional quality-of-life items, and 1 item assessing global change. The SF-36, SF-8, and the Jackson cold scale were used as external comparators. RESULTS: Participants included 104 women and 45 men, aged 18 to 80 years, self-reporting on 1,681 person-days of illness. Factor analysis suggested 10 dimensions, with reliability coefficients from 0.62 to 0.93. Comparing daily WURSS-44 to Jackson and SF-8 yielded Pearson correlation coefficients from 0.73 to 0.93, and from -0.60 to -0.84, respectively. Importance to patients and responsiveness assessment yielded a short version, the WURSS-21. Guyatt's responsiveness index was 0.54 for the SF-8, 0.61 for the Jackson, 0.71 for the WURSS-44, and 0.80 for the WURSS-21, suggesting that a two-armed trial would require 74 participants for the WURSS-21, 92 for the WURSS-44, 124 for the Jackson scale, and 156 for the SF-8. CONCLUSIONS: The construct validity of WURSS-44 is supported by measures of reliability, responsiveness, importance to patients, and convergence. A shorter version, the WURSS-21, may be even more responsive.

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Type II alveolar epithelial cells (AEC) can produce various antimicrobial and proinflammatory effector molecules. This, together with their abundance and strategic location, suggests a role in host defense against pulmonary pathogens. We report that murine type II AEC, like their human counterparts, express class II major histocompatibility complex (MHC). Using a murine model of pulmonary tuberculosis, we find that type II AEC become activated and have increased cell surface expression of class II MHC, CD54, and CD95 following infection. Type II AEC use the class II MHC pathway to process and present mycobacterial antigens to immune CD4+ T cells isolated from mice infected with Mycobacterium tuberculosis. Therefore, not only can type II AEC contribute to the pulmonary immunity by secreting chemokines that recruit inflammatory cells to the lung, but they can also serve as antigen-presenting cells. Although type II AEC are unlikely to prime naïve T cells, their ability to present antigens to T cells demonstrates that they can participate in the effector phase of the immune response. This represents a novel role for type II AEC in the immunological response to pulmonary pathogens.

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CONTEXT: The term "sufficiently important difference" (SID) refers to the overall amount of benefit that people consider sufficient to justify the costs and risks of treatment. Little is known about patient preferences regarding benefits and harms of common cold treatments. OBJECTIVES: To develop methods to assess SID and to estimate SID for common cold. DESIGN: The authors conducted in-person and telephone interviews with people with colds, using benefit harm tradeoff methods. The hypothetical benefit of reduction in length of illness was traded off against best estimates of costs and risks. First, the authors briefly described costs, risks, and possible symptomatic benefits of 4 treatment scenarios, based on evidence regarding vitamin C, echinacea, zinc, and pleconaril, an antiviral. Hypothetical benefit (reduction of illness duration) was then varied until the cold sufferer indicated that the treatment was minimally desirable. PARTICIPANTS: Interviews were conducted in person with 149 community-recruited adult participants, once at the beginning of their colds, and then again within a few days after symptoms had resolved. Additionally, 162 adult callers with self-identified colds completed interviews via telephone. RESULTS: A total of 460 benefit harm tradeoff interviews (1840 treatment scenarios) estimated overall mean SID as 52.6 h (95% CI, 50.6 to 54.6). For the scenario based on vitamin C, mean SID was estimated as 26.1 h (95% CI, 23.2 to 29.3), with 142 of 460 (31%) saying they would take it regardless of duration benefit, and 22 of 460 (5%) saying they would not take it, regardless of duration benefit. For the echinacea-based scenario, mean SID was estimated at 36.8 h (33.4 to 40.2), with 105 (23%) favoring and 41 (9%) rejecting treatment, regardless of duration benefit. For the zinc lozenge-based scenario, mean SID was estimated as 64.8 h (61.0 to 67.9), with 42 (9%) favoring and 109 (24%) rejecting treatment. For the prescription antiviral-based scenario, mean SID was estimated as 82.6 h (78.7 to 86.7), with 29 (6%) favoring and 223 (48%) rejecting. Severity of illness at the time of interview did not appear to significantly influence responses. Possible side effects, treatment type (tablet v. lozenge v. liquid), monetary costs, and opportunity costs (e.g., getting to the doctor or pharmacy, dosing frequency) did appear to be important in influencing these preference patterns. CONCLUSIONS: Our study suggests that, on average, people want the duration of their colds to be reduced by between 26 and 65 h to justify potential harms of popular cold treatments. A prescription antiviral would require a greater benefit (83 h) to justify larger perceived risks.

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Both innate and adaptive immunity play an important role in host resistance to Mycobacterium tuberculosis infection. Although several studies have suggested that the major histocompatibility complex (MHC) haplotype affects susceptibility to infection, it remains unclear whether the modulation of T-cell immunity by the MHC locus determines the host's susceptibility to tuberculosis. To determine whether allelic differences in the MHC locus affect the T-cell immune response after M. tuberculosis infection, we infected inbred and H-2 congenic mouse strains by the respiratory route. The H-2 locus has a profound effect on the antigen-specific CD4+-T-cell response after M. tuberculosis infection. CD4+ T cells from infected mice of the H-2(b) haplotype produced more gamma interferon (IFN-gamma) after in vitro stimulation with mycobacterial antigens than mice of the H-2(k) haplotype. A higher level of IFN-gamma was also detected in bronchoalveolar lavage fluid from infected mice of the H-2(b) haplotype. Furthermore, C3.SW-H2(b)/SnJ mice generate and recruit activated T cells to the lung after infection. Despite a robust immune response, C3.SW-H2(b)/SnJ mice succumbed to infection early and were similarly susceptible to infection as other C3H (H-2(k)) substrains. These results suggest that although the MHC haplotype has a profound impact on the T-cell recognition of M. tuberculosis antigens, the susceptibility of C3H mice to infection is MHC independent.

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Mycobacterium tuberculosis produces a variety of molecules capable of activating Toll-like receptors, a family of pattern recognition receptors expressed by macrophages and a variety of other cells. To determine whether Toll-like receptor 4 (TLR4) was critical in resistance to M. tuberculosis infection, we compared the morbidity and mortality of TLR4-defective C3H/HeJ mice to those of TLR4-sufficient C3H mouse substrains. TLR4-defective C3H/HeJ mice and TLR4-sufficient C3H/HeSnJ, C3HeB/FeJ, and C3H/HeOuJ mice were infected by the aerosol route with M. tuberculosis. TLR4-defective C3H/HeJ mice had levels of cytokines in their bronchoalveolar lavage fluids and in vitro mycobacterial antigen-specific recall responses similar to those of other C3H mouse substrains. In addition, bacterial replication and long-term survival of mice following infection appeared to be independent of TLR4. Interestingly, C3HeB/FeJ mice were significantly more susceptible to M. tuberculosis infection, indicating that genetic heterogeneity among inbred C3H mouse substrains modifies resistance to infection. Therefore, cautious interpretation is required when the C3H/HeJ strain is used as a model of a TLR4-defective mouse strain, as there are significant allelic differences between C3H/HeJ and other C3H mouse substrains in response to M. tuberculosis infection. With this caveat, our data indicate that TLR4 may not be required for optimal immunity of mice to M. tuberculosis.

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We report that dissemination of Mycobacterium tuberculosis in the mouse is under host control and precedes the initiation of T-cell immunity. Nine to eleven days after aerosol inoculation, M. tuberculosis disseminates to the pulmonary lymph nodes (LN), where M. tuberculosis-specific T cells are detected 2 to 3 days thereafter. This indicates that the initial spread of bacteria occurs via lymphatic drainage and that the acquired T-cell immune response is generated in the draining LN. Dissemination to peripheral sites, such as the spleen and the liver, occurs 11 to 14 days postinfection and is followed by the appearance of M. tuberculosis-specific T cells in the lung and the spleen. In all cases studied, dissemination to the LN or the spleen preceded activation of M. tuberculosis-specific T cells in that organ. Interestingly, bacteria disseminate earlier from the lungs of resistant C57BL/6 mice than from the lungs of susceptible C3H mice, and consequently, C57BL/6 mice generate an immune response to M. tuberculosis sooner than C3H mice generate an immune response. Thus, instead of spreading infection, early dissemination of M. tuberculosis may aid in the initiation of an appropriate and timely immune response. We hypothesize that this early initiation of immunity following inoculation with M. tuberculosis may contribute to the superior resistance of C57BL/6 mice.

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