Future research directions in pneumonia

Pneumonia is a complex pulmonary disease in need of new clinical approaches. Although triggered by a pathogen, pneumonia often results from dysregulations of host defense that likely precede infection. The coordinated activities of immune resistance and tissue resilience then dictate whether and how pneumonia progresses or resolves. Inadequate or inappropriate host responses lead to more severe outcomes such as acute respiratory distress syndrome and to organ dysfunction beyond the lungs and over extended time frames after pathogen clearance, some of which increase the risk for subsequent pneumonia. Improved understanding of such host responses will guide the development of novel approaches for preventing and curing pneumonia and for mitigating the subsequent pulmonary and extrapulmonary complications of pneumonia. The NHLBI assembled a working group of extramural investigators to prioritize avenues of host-directed pneumonia research that should yield novel approaches for interrupting the cycle of unhealthy decline caused by pneumonia. This report summarizes the working group’s specific recommendations in the areas of pneumonia susceptibility, host response, and consequences. Overarching goals include the development of more host-focused clinical approaches for preventing and treating pneumonia, the generation of predictive tools (for pneumonia occurrence, severity, and outcome), and the elucidation of mechanisms mediating immune resistance and tissue resilience in the lung. Specific areas of research are highlighted as especially promising for making advances against pneumonia

History of clinical transplantation

How transplantation came to be a clinical discipline can be pieced together by perusing two volumes of reminiscences collected by Paul I. Terasaki in 1991-1992 from many of the persons who were directly involved. One volume was devoted to the discovery of the major histocompatibility complex (MHC), with particular reference to the human leukocyte antigens (HLAs) that are widely used today for tissue matching.1 The other focused on milestones in the development of clinical transplantation.2 All the contributions described in both volumes can be traced back in one way or other to the demonstration in the mid-1940s by Peter Brian Medawar that the rejection of allografts is an immunological phenomenon.3,4 © 2008 Springer New York

New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Plant and microbial controls on nitrogen retention and loss in a Humid Tropical Forest

Humid tropical forests are generally characterized by the lack of nitrogen (N) limitation to net primary productivity, yet paradoxically have high potential for N loss. We conducted an intensive field experiment with {sup 15}NH{sub 4} and {sup 15}NO{sub 3} additions to highly weathered tropical forest soils to determine the relative importance of N retention and loss mechanisms. Over half of all the NH{sub 4}{sup +} produced from gross mineralization was rapidly converted to NO{sub 3}{sup -} during the process of gross nitrification. During the first 24 h plant roots took up 28 % of the N mineralized, dominantly as NH{sub 4}{sup +}, and were a greater sink for N than soil microbial biomass. Soil microbes were not a significant sink for added {sup 15}NH{sub 4}{sup +} or {sup 15}NO{sub 3}{sup -} during the first 24 hr, and only for {sup 15}NH{sub 4}{sup +} after 7 d. Patterns of microbial community composition, as determined by Terminal Restriction Fragment Length Polymorphism analysis, were weakly, but significantly correlated with nitrification and denitrification to N{sub 2}O. Rates of dissimilatory NO{sub 3}{sup -} reduction to NH{sub 4}{sup +} (DNRA) were high in this forest, accounting for up to 25 % of gross mineralization and 35 % of gross nitrification. DNRA was a major sink for NO{sub 3}{sup -} which may have contributed to the lower rates of N{sub 2}O and leaching losses. Despite considerable N conservation via DNRA and plant NH{sub 4}{sup +} uptake, the fate of approximately 45% of the NO{sub 3}{sup -} produced and 22% of the NH{sub 4}{sup +} produced were not measured in our fluxes, suggesting that other important pathways for N retention and loss (e.g., denitrification to N{sub 2}) are important in this system. The high proportion of mineralized N that was rapidly nitrified and the fates of that NO{sub 3}{sup -} highlight the key role of gross nitrification as a proximate control on N retention and loss in humid tropical forest soils. Furthermore, our results demonstrate the importance of the coupling between DNRA and plant uptake of NH{sub 4}{sup +} as a potential N conserving mechanism within tropical forests

Scenarios for ITER (International Thermonuclear Experimental Reactor) steady-state and technology testing operation

Operational scenarios for the International Thermonuclear Experimental Reactor (ITER) steady-state and technology testing phases are identified by trade-offs among wall load, burn time, and divertor heat loads. Steady-state operation with Q {ge} 5 is limited to wall loads {ge}0.5 MW/m{sup 2} and injection powers {ge} 100 MW. Even at steady-state wall loads of 0.5 MW/m{sup 2}, the divertor heat loads are higher than predicted for the physics phase. For technology testing, hybrid operation (with simultaneous inductive and noninductive current drive) results in a wall load of 0.8 MW/m{sup 2}, with injection power of about 100 MW, and a burn time of about 1200 s, with a divertor heat load similar to that of the physics phase. Significant uncertainty exists in our present understanding of the divertor conditions. Should conditions prove to be more favorable than assumed here, the operational windows would open considerably. For factor of {approx}3 reductions in predicted divertor loads, we show potential steady-state cases at wall loads of 0.8 MW/m{sup 2}, injection powers of about 130 MW, and Q near 7. With factors of {approx}1.5--2.5 reduction in the predicted divertor loads, hybrid technology testing could be accomplished with wall loads of 0.8 MW/m{sup 2} burn times of 1--3 h, and injection powers of 100--150 MW. 5 refs., 3 figs., 2 tabs

Ray tracing and absorption of electron cyclotron waves in the L-2 stellarator

The absorption of electron cyclotron waves in L-2 stellarator plasmas has been investigated by adapting the RAYS geometrical optics code developed at Oak Ridge National Laboratory to the parameters of L-2. Two heating schemes were considered: Low-field launching of the ordinary wave at the fundamental resonance and low-field launching of the extraordinary wave at the second harmonic. Significant power absorption (up to 100%) of the extraordinary mode at the second harmonic resonance was obtained. A multipass absorption model was used to estimate the contribution to plasma heating of the power that remains after the first pass which is subsequently reflected from the vessel walls. Finally, results obtained with the RAYS code and with a code developed at the Institute of Automation and Electrometry were compared and found to be in good agreement. 6 refs., 4 figs