Are estimates of 'potential gains in life expectancy' potentially unreliable?

OBJECTIVES: The objective of this study was to investigate whether estimates of 'potential gains in life expectancy' (PGLE) are potentially unreliable. STUDY DESIGN: We compare the sum of the PGLEs from actual 1999-2017 reductions in U.S. mortality from all causes to the actual change in life expectancy of the entire population. METHODS: Multiple-decrement life table techniques are used to calculate the PGLEs from the actual reductions in age-specific rates of mortality from 113 causes. Then, the sum of the estimated PGLEs is compared to the actual change in life expectancy (LE) of the entire population. RESULTS: The sum of the estimated gains in LE at birth is 40% larger than the actual increase in LE at birth: 2.7 years vs 1.9 years. The sum of the estimated gains in LE at age 65 years is 40% smaller than the actual increase in LE at age 65 years: 1.0 years vs 1.7 years. CONCLUSIONS: The fact that the sum of the estimated gains in LE from all diseases differs substantially (in both directions) from the actual increase in LE suggests that estimates of PGLE are potentially unreliable.

Evidence for Jahn-Teller distortions at the antiferromagnetic transition in LaTiO3.

LaTiO3 is known as a Mott insulator which orders antiferromagnetically at T(N)=146 K. We report on results of thermal expansion and temperature dependent x-ray diffraction together with measurements of the heat capacity, electrical transport measurements, and optical spectroscopy in untwinned single crystals. At T(N) significant structural changes appear, which are volume conserving. Concomitant anomalies are also observed in the dc resistivity, in bulk modulus, and optical reflectivity spectra. We interpret these experimental observations as evidence of orbital order.

Extremely small energy gap in the quasi-one-dimensional conducting chain compound SrNbO3.41.

Resistivity, optical, and angle-resolved photoemission experiments reveal unusual one-dimensional electronic properties of highly anisotropic SrNbO3.41. Along the conducting chain direction, we find an extremely small energy gap of only a few meV at the Fermi level. A discussion in terms of typical 1D instabilities (Peierls, Mott-Hubbard) shows that neither seems to provide a satisfactory explanation for the unique properties of SrNbO3.41.

Are the benefits of newer drugs worth their cost? Evidence from the 1996 MEPS.

This study analyzes data on prescribed medicines from the 1996 Medical Expenditure Panel Survey (MEPS) to examine the association between the use of newer medicines and morbidity, mortality, and health spending. We find that people consuming newer drugs were significantly less likely to die by the end of the survey and were significantly less likely to experience work-loss days than were people consuming older drugs. Our most notable finding, however, is that use of newer drugs tends to lower all types of nondrug medical spending, resulting in a substantial net reduction in the total cost of treating a given condition.

Extraction of human Langerhans cells: a method for isolation of epidermis-resident dendritic cells.

Langerhans cells (LCs) are immature dendritic cells in the epidermis that play a central role in T-lymphocyte mediated skin immunity. Upon activation with antigenic stimuli, they differentiate drastically into mature dendritic cells while migrating from the epidermis to regional lymph nodes. Thus, in order to study biological details of immature LCs, it is crucial to isolate epidermis-resident, immature LCs without dermal dendritic cell contamination. Methods for extracting LCs from human skin as well as in vitro derivation of LC-like cells from hematopoietic progenitor cells have been described previously, but the cell preparations can potentially contain a significant number of dendritic cells that are not identical to epidermal LCs. Here, we describe a technique by which purely epidermis-resident LCs are extracted from human skin. Following digestion of human skin with dispase, the epidermis was separated mechanically without any attached dermal component. The trypsinized epidermal cells were then fractionated by centrifugation with a discontinuous density gradient composed of bovine albumin and sodium metrizoate. The LC-enriched preparation thus obtained contained 80% to >90% CD1a+, E-cadherin+ cells that expressed Birbeck granules and the Lag protein. Consistent with their being at an immature stage, the freshly isolated LCs lacked the expression of CD83, a marker for mature dendritic cells. The purified LCs were able to activate allogeneic T cells, indicating that the cells retained T-cell stimulation ability even after extraction. Thus, the present work offers an opportunity for precise in vitro studies of epidermal LCs.

Spin-triplet superconductivity in Sr2RuO4 probed by andreev reflection

The superconducting gap function of Sr2RuO4 was investigated by means of quasiparticle reflection and transmission at the normal conductor-superconductor interface of Sr2RuO4-Pt point contacts. We found two distinctly different types of dV/dI vs V spectra either with a double-minimum structure or with a zero-bias conductance anomaly. Both types of spectra are expected in the limit of high and low transparency, respectively, of the interface barrier between a normal metal and a spin-triplet superconductor. Together with the temperature dependence of the spectra this result strongly supports a spin-triplet superconducting order parameter for Sr2RuO4.

IL-12 gene-deficient C57BL/6 mice are susceptible to Leishmania donovani but have diminished hepatic immunopathology.

To determine the in vivo role of IL-12 in the development of protective immunity in visceral leishmaniasis caused by Leishmania donovani, we examined the course of L. donovani infection in IL-12-deficient C57BL/6 (IL-12-/-) mice. IL-12-/- mice displayed significantly higher parasite burdens in their livers and spleens than wild-type C57BL/6 mice throughout the course of infection. Despite high parasite burdens, the onset of hepatosplenomegaly was significantly delayed in L. donovani-infected IL-12-/-. Moreover, livers and spleens from IL-12-/- mice displayed significantly less inflammation and poorly formed granulomatous lesions than those from IL-12+/+ mice throughout the course of infection. Antigen-stimulated splenocytes from IL-12-/- mice produced significantly less IFN-gamma but more IL-4 than IL-12+/+ mice. These findings indicate that although endogenous IL-12 is critical for the development of protective immunity to L. donovani, it is also responsible for inducing the significant immunopathology associated with visceral leishmaniasis.

Combined microautoradiographic and histopathologic analysis of the fate of challenge Schistosoma mansoni schistosomula in mice immunized with irradiated cercariae.

Combined microautoradiographic and histopathologic methods were used to locate and examine schistosomula of Schistosoma mansoni in the lungs of irradiated cercaria-immunized mice 21 days after percutaneous challenge infection with 75Se-labeled cercariae. Of 75 schistosomula examined in serial sections, 53% were located in the pulmonary microvasculature, 23% in alveolar spaces, 3% with one end in a vessel and the other in an alveolar space, and the locations of 21% were not identified. Inflammatory reactions of variable intensity were observed around schistosomula in both vascular and alveolar sites, although the most intense category of reactions was associated almost entirely with alveolar larvae. All autoradiographic foci contained recognizable schistosomula. Although the concentration of reduced silver grains precluded cyto-structural analysis, observations on schistosomular contour and shape provided no evidence of larval damage. Our findings suggest that immune elimination of schistosomula in mice immunized with irradiated cercariae is partly or largely effected by a process of alveolar extrusion of viable parasites during their lung migration.

Leishmania (Viannia) braziliensis: comparative pathology of golden hamsters infected with isolates from cutaneous and mucosal lesions of patients residing in Tres Bracos, Bahia, Brazil.

The histopathology of primary forepaw and metastatic lymph node, spleen, and liver lesions produced in golden hamsters infected with cutaneous leishmaniasis (CL) strains (LTB 111 and LTB558) and mucocutaneous leishmaniasis (MCL) strains (LTB12 and LTB201) of Leishmania (Viannia) braziliensis isolated from patients residing in Tres Bracos, Bahia, Brazil is described. No pathological features providing clear differentiation of the CL and MCL strains were found. Although amastigotes were plentiful early in the development of primary forepaw lesions, they were either absent or could not be identified with certainty in sections of late stage lesions. Similarly, amastigotes were not found in histologic lesions at metastatic sites; however, leishmanial DNA was detected in both early and late stage forepaw lesions and metastatic lesions using Leishmania kinetoplast DNA and the gene coding for gp63 as hybridization probes. The DNA recovered from metastatic lesions was extracted from formalin-fixed paraffin-embedded tissues that had been stored at room temperature for prolonged periods.

Pathology resulting from the administration of a live attenuated anti-Schistosoma haematobium vaccine in baboons.

Baboons (Papio anubis) were injected in the leg muscle with 18,000 20 Krad irradiated schistosomula of Schistosoma haematobium. Four protocols were followed: single, primary injection; single injection into animals primed by patent S. haematobium infection; secondary vaccine injection following an earlier injection; and single injection following praziquantel treatment of infected animals. Injection of the putative vaccine elicited localized mixed inflammatory infiltration at the site of injection which was both intense and prolonged. Three grades of tissue reaction were seen: the relatively mild primary response; the response in infected animals which had enhanced tissue eosinophilia; and the response in animals primed by prior injection and drug-treated prior infection. The latter 2 showed intensification of eosinophilia, stellate abscesses in the lesion centers, and perischistosomular Hoeppli precipitates. Intramuscular lesions peaked at 14 days for the primary response and at 7 days for all secondary responses. Traces of the milder lesions persisted beyond 4 weeks; more severe reactions healed more rapidly. Some schistosomula survived for 14 days in the milder reactions. A few larvae were deposited in the skin by backflushing of the injectate which produced local inflammation. Compared to mice, live schistosome vaccines injected into baboons elicited greater local inflammation; however, while evidence suggested that sporadic vaccine schistosomula did reach the lymphatic nodes draining the injection sites, no systemic lesions were found and the injection sites healed in approximately 5-6 weeks without permanent damage.

In vivo T cell depletion regulates resistance and morbidity in murine schistosomiasis.

These studies assessed the roles of subpopulations of T lymphocytes in inducing and modulating resistance to schistosomiasis and thereby influencing subsequent morbidity. C57BL/6 mice were depleted in vivo of Lyt-1+, Lyt-2+, and L3T4+ cells by the daily administration of monoclonal antibodies. The development of protective immunity, induced by exposure to irradiated Schistosoma mansoni cercariae as expressed in depleted animals, was compared to that demonstrated in undepleted, normal, and congenitally athymic C57BL/6 mice. The development of morbidity was determined by spleen weight, portal pressure and reticuloendothelial system activity. The results indicated that depletion of specific subpopulations of T lymphocytes minimally affected the primary development of parasites; however, depletion strongly influenced the development of resistance to the parasite and subsequent morbidity due to infection. Depletion of T lymphocytes by anti-Lyt-1+ or anti-L3T4+ antibody decreased the development of resistance, antibody and delayed-type hypersensitivity directed against schistosome antigens. Morbidity due to disease was increased. Depletion of Lyt-2+ cells produced opposite changes with augmented resistance and reduced morbidity. Congenitally athymic mice developed minimal resistance and morbidity. Moreover, resistance was inversely related to the morbidity shown by a given animal. These studies indicate that the development of protective immunity to S. mansoni cercariae is regulated by discrete subpopulations of T lymphocytes. The feasibility of decreasing morbidity by increasing specific immunologically mediated resistance is suggested.

The Wellcome Trust lecture. Inflammatory responses to filarial connective tissue parasites.

The inflammatory responses to lymphatic filariae and to Onchocerca volvulus are reviewed with particular attention to evolutionary biology; inflammatory host spectrum; non-specific components; immunoregulation; immune evasion versus immunomodulation; chronic tissue damage and scarring and disease models. Basic principles of pathogenesis are emphasized, comparisons drawn with schistosome infection, and critical items of missing information are highlighted.

Effects of protective immune serum on the yields of parasites and pulmonary cell reactions in schistosome-infected rats.

Yields of parasites during the period of worm migration from the lungs to the portal circulation were measured in S. mansoni-infected Fischer rats passively immunized with protective serum from twice-infected donor rats. Two effects of protective serum were observed in recipient rats relative to normal serum recipients: yields of schistosomula from lungs were higher and yields of (immature) worms from the portal circulation were lower throughout the period analyzed. Histopathological analysis of lung tissue confirmed the presence of greater numbers of schistosomula in lungs of passively immunized rats. In addition, the percent of lung schistosomula involved in all categories of inflammatory reactions was greater in recipients of protective rat serum. The kinetics of accumulation of worms perfused from the portal circulation of normal and passively immunized rats indicate that in the latter group a smaller fraction of worms successfully migrates to the portal circulation. These findings support the hypothesis that protective activity of the serum prevents a portion of worms from successfully completing migration from the lung to the portal circulation.