Fas ligand-induced murine pulmonary inflammation is reduced by a stable decoy receptor 3 analogue

Fas ligand (FasL)-induced lung inflammation has recently been suggested to play an important role in the pathogenesis of acute respiratory disease syndrome (ARDS). In order to further explore this connection, we established a FasL-induced murine model of pulmonary inflammation. Instillation of recombinant FasL (rFasL) into the lung induced neutrophil infiltration and increased pulmonary permeability, as evidenced by increased total protein in the airspace; both occur in patients with ARDS. These effects were accompanied with a rapid induction of proinflammatory mediators: cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) and the chemokines macrophage inflammatory protein-2 (MIP-2) and KC. Pretreatment with a FasL antagonist, a decoy receptor 3 analogue (DcR3 analogue), reduced neutrophil infiltration into the airspace and resulted in a highly significant reduction in the levels of GM-CSF, MIP-2 and KC in bronchoalveolar lavage (BAL) fluid. We postulate that rFasL may be responsible for induction of proinflammatory chemokines and cytokines in the lung, which in turn attract neutrophil infiltration into the airspace. This proinflammatory process and the associated pulmonary permeability may, in part, explain the association of FasL with severe pulmonary inflammation, such as ARDS, and shed new light on FasL and its role in lung injury.     

Ex vivo rapamycin generates Th1/Tc1 or Th2/Tc2 Effector T cells with enhanced in vivo function and differential sensitivity to post-transplant rapamycin therapy.

Rapamycin prevention of murine graft-versus-host disease (GVHD) is associated with a shift toward Th2- and Tc2-type cytokines. Recently, we found that use of rapamycin during ex vivo donor Th2 cell generation enhances the ability of adoptively transferred Th2 cells to prevent murine GVHD. In this study, using a method, without antigen-presenting cells, of T-cell expansion based on CD3,CD28 costimulation, we evaluated whether (1) rapamycin preferentially promotes the generation of Th2/Tc2 cells relative to Th1/Tc1 cells, (2) rapamycin-generated T-cell subsets induce cytokine skewing after allogeneic bone marrow transplantation (BMT), and (3) such in vivo cytokine skewing is sensitive to post-BMT rapamycin therapy. Contrary to our hypothesis, rapamycin did not preferentially promote Th2/Tc2 cell polarity, because rapamycin-generated Th1/Tc1 cells secreted type I cytokines (interleukin [IL]-2 and interferon-gamma) did not secrete type II cytokines (IL-4, IL-5, IL-10, or IL-13) and mediated fasL-based cytolysis. Rapamycin influenced T-cell differentiation, because each of the Th1, Th2, Tc1, and Tc2 subsets generated in rapamycin had increased expression of the central-memory T-cell marker, L-selectin (CD62L). Rapamycin-generated Th1/Tc1 and Th2/Tc2 cells were not anergic but instead had increased expansion after costimulation in vitro, increased expansion in vivo after BMT, and maintained full capacity to skew toward type I or II cytokines after BMT, respectively; further, rapamycin-generated Th1/Tc1 cells mediated increased lethal GVHD relative to control Th1/Tc1 cells. Rapamycin therapy after BMT in recipients of rapamycin-generated Th1/Tc1 cells greatly reduced Th1/Tc1 cell number, greatly reduced type I cytokines, and reduced lethal GVHD; in marked contrast, rapamycin therapy in recipients of rapamycin-generated Th2/Tc2 cells nominally influenced the number of Th2/Tc2 cells in vivo and did not abrogate post-BMT type II cytokine skewing. In conclusion, ex vivo and in vivo usage of rapamycin may be used to modulate the post-BMT balance of Th1/Tc1 and Th2/Tc2 cell subsets.     

Identification of neural pathways involved in genital reflexes in the female: a combined anterograde and retrograde tracing study

The medial preoptic area (MPOA) is important for reproductive behavior in females. However, the descending pathways mediating these responses to the spinal motor output are unknown. The MPOA does not directly innervate the spinal cord. Therefore, pathways mediating MPOA-induced changes in sexual behavior must relay in the brain. The nucleus paragigantocellularis (nPGi) projects heavily to spinal circuits involved in female sexual reflexes and is involved in the tonic inhibition of genital reflexes. However, the periaqueductal gray (PAG) is also important for female sexual behavior. The present study examined the hypothesis that the MPOA output relays through PAG and the nPGi before descending to the spinal cord. We used anterograde and retrograde tracing techniques to examine the descending pathways and relay sites from the MPOA to the spinal cord and the nPGi in the female rat. Injection of biotinylated dextran amine into the MPOA produced dense labeling in specific regions of the PAG and Barrington's nucleus; anterogradely labeled fibers terminated close to neurons retrogradely labeled from the spinal cord in the PAG, Barrington's nucleus, nPGi, lateral hypothalamus and paraventricular nucleus (PVN). Anterogradely labeled fibers and varicosities were also found close to neurons retrogradely labeled from the nPGi in the PAG, lateral hypothalamus and PVN. These results suggest that the major MPOA output relays in the PAG and nPGi before descending to innervate spinal circuits regulating female genital reflexes and that the MPOA plays a multifaceted role in female reproductive behavior through its modulation of PAG output systems.     

The Feasibility of Using Computrition Software for Nutrition Research—A Pilot Study

We evaluated the feasibility of using Computrition to design and implement a low vs. typical sodium meal plan intervention for older adults. Dietitians used Computrition to design a 7-day meal plan with three caloric levels (≤1750, 2000, ≥2250 kcals/day) and two sodium densities (low = 0.9 mg/kcal; n = 11 or typical = 2 mg/kcal; n = 9). Feasibility was determined by post-hoc definitions of effectiveness, sodium compliance, palatability of diet, sustainability, and safety. Given the low number of participants in one of the three calorie groups, the higher calorie groups were combined. Thus, comparisons are between low vs. typical meal plans at two calorie levels (≤1750 or ≥2000 kcals/day). Overall, regardless of the calorie group, the meal plans created with Computrition were effective in reaching the targeted sodium density and were safe for participants. Furthermore, individuals appeared to be equally compliant and reported similar palatability across meal plans. However, one of the three criteria for the sustainability definition was not met. In conclusion, we successfully used Computrition to design low and typical sodium meal plans that were effective, compliable, and safe. Future studies of older adults in similar settings should focus on improving the palatability of the meal plans and scaling this protocol to larger studies in older adults.     

Pretransplant solid organ malignancy and organ transplant candidacy: A consensus expert opinion statement

Patients undergoing evaluation for solid organ transplantation (SOT) often have a history of malignancy. Although the cancer has been treated in these patients, the benefits of transplantation need to be balanced against the risk of tumor recurrence, especially in the setting of immunosuppression. Prior guidelines of when to transplant patients with a prior treated malignancy do not take in to account current staging, disease biology, or advances in cancer treatments. To develop contemporary recommendations, the American Society of Transplantation held a consensus workshop to perform a comprehensive review of current literature regarding cancer therapies, cancer stage-specific prognosis, the kinetics of cancer recurrence, and the limited data on the effects of immunosuppression on cancer-specific outcomes. This document contains prognosis based on contemporary treatment and transplant recommendations for breast, colorectal, anal, urological, gynecological, and nonsmall cell lung cancers. This conference and consensus documents aim to provide recommendations to assist in the evaluation of patients for SOT given a history of a pretransplant malignancy.     

Die Bestimmung des i.m. Morphin-Äquivalents zur Therapie des Krebsschmerzes mit verschiedenen Opioiden oder beim Wechsel des Verabreichungsweges

During the long-term treatment with opioids it is sometimes important to switch the opioid or change the route of administration. The estimation of morphine-equivalents can be helpful in this range because it clarifies the dose in milligramm required for different clinical situations. The basis of this estimation is the equianalgesic potency of opioids. One i.m. morphine-equivalent is the analgesic dose of an opioid (i.m. injected) equal to the analgesic effect of 1 mg morphine (i.m.). The relationships between equianalgesic doses and intramuscular and oral routes of applications are listed in tables. The cross-tolerance between different opioids during long-term treatment is not complete. To avoid an overdose, we suggest a reduction in the calculated opioid dose of 50%. Additional "rescue doses" can be used during the period immediately the change to provied satisfactory pain control. A new opioid dosage should be calculated every 24 hours based on the basaline dose plus the total quantity of "rescue" medication required by the patient. Useful starting point for calculation an effective dose when changing from one opioid or route of administration to another can result in improved pain control that is more responsive to patient need. The limitations are 1. individual differences in the response to opioids, especially during long-term treatment and in the development of analgesic tolerance, 2. individual differences in the response to alternatives routes of administration, and 3. the unknown degree of cross tolerance among opioid drugs. The scientific meaning of the estimation of i.m. morphine-equivalent is discussed.     

Demographic changes and their financial implications

The impressive rise in the number of elderly persons (65 years and over) will continue in the next two to three decades. Urinary incontinence is a common problem in the elderly, adversely affecting medical, social, and "quality of life" aspects. The cost of urinary incontinence is substantial and is expected to escalate enormously (e.g., by 160% from 1980 to 2040). An aggressive approach toward the diagnosis and management of urinary incontinence can result in an impressive reduction in health care costs and improvement in the quality of life.     

Reengineering along departmental product flowlines

This article describes how a medical records department responded to relocating, upgrading a departmental computer system, incorporating severity of illness abstracting, and implementing continuous quality improvement techniques by reengineering along department flowlines over a five-year period. Areas of the department that were restructured were storage and retrieval, record completion, and data collection and reporting functions.