Individual Organ Systems Research Articles

Molecular and cellular themes in inflammation and immunology

This issue of the Journal of Pathology contains a series of cutting-edge review articles that deal with the broad issue of inflammatory and immunological disease mechanisms. Of necessity, these reviews deal with selected topics but the mixture of articles on specific signalling pathways and mediators with articles addressing individual organ systems provides a broad overview of the field. These contributions provide insight into current areas of debate in inflammation and immunology. In particular, they highlight current interest in the interface between innate and adaptive immunity and present intriguing prospects for future therapeutic developments in a variety of disease areas.

Cardiopulmonary exercise testing and its application

Cardiopulmonary exercise testing CPET has become an important clinical tool to evaluate exercise capacity and predict outcome in patients with heart failure and other cardiac conditions. It provides assessment of...

Anesthesia and Orthopaedic Surgery.

Anesthesia and Orthopaedic Surgery.

Genetic linkage analysis of sarcoidosis phenotypes: the sarcoidosis genetic analysis (SAGA) study

The sarcoidosis genetic analysis (SAGA) study previously identified eight chromosomal regions with suggestive evidence for linkage to sarcoidosis susceptibility in African-American sib pairs. Since the clinical course of sarcoidosis is variable and likely under genetic control, we used the affected relative pair portion of the SAGA sample (n=344 pairs) to perform multipoint linkage analyses with covariates based on pulmonary and organ involvement phenotypes. Chest radiographic resolution was the pulmonary phenotype with the highest LOD (logarithm of the backward odds, or likelihood ratio) score of 5.11 at D1S3720 on chromosome 1p36 (P=4 x 10(-5)). In general, higher LOD scores were attained for covariates that modeled clustered organ system involvement rather than individual organ systems, with the cardiac/renal group having the highest LOD score of 6.65 at chromosome 18q22 (P=2 x 10(-5)). The highest LOD scores for the other three organ involvement groups of liver/spleen/bone marrow, neuro/lymph and ocular/skin/joint were 3.72 at 10p11 (P=0.0004), 5.16 at 7p22 (P=4 x 10(-5)) and 2.93 at 10q26 (P=0.001), respectively. Most of the phenotype linkages did not overlap with the regions previously found linked to susceptibility. Our results suggest that genes influencing clinical presentation of sarcoidosis in African Americans are likely to be different from those that underlie disease susceptibility.

Emphasizing the need to more fully understand development: a stem cells and regenerative medicine meeting report

A shared enthusiasm towards the highly promising utility of stem cell research brought together clinicians and scientists from academic institutions, government, and industry at the Second Annual International Stem Cells and Regenerative Medicine meeting presented by GeneExpression Systems, Inc. earlier this year. A common theme was echoed by presenters that a deeper understanding of natural development of the whole organism and individual organ systems is needed. Armed with this greater knowledge, a more efficient and conscientious translation of stem cell research may be achieved. Guest lectures included presentations by Dr. Elizabeth H. Blackburn, Dr. Irving L. Weissman, and Dr. Erin Lavik. Attendees were updated and encouraged by these and several other speakers on such topics as stem cell biology, epigenetics, biotechnology, regenerative medicine, tissue engineering, and bioethics. Biomedical engineers and scientists are making steady strides in designing specific three dimensional scaffolds, tracking and controlling stem cells. The future of stem cell research continues to be promising with applications for treating cardiac and neurodegenerative diseases, hearing loss, diabetes, and so on.

Statement on cardiopulmonary exercise testing in chronic heart failure due to left ventricular dysfunction: recommendations for performance and interpretation Part I: Definition of cardiopulmonary exercise testing parameters for appropriate use in chronic heart failure

Cardiopulmonary exercise testing (CPET) provides a global assessment of the integrated response to exercise involving the pulmonary, cardiovascular, haematopoietic, neuropsychological, and skeletal muscle systems. This information cannot be obtained through investigation of the individual organ systems in isolation. The non-invasive, dynamic physiological overview permits the evaluation of both submaximal and peak exercise responses, providing the physician with relevant information for clinical decision making. The use of CPET in management of the chronic heart failure patient is increasing with the understanding that resting pulmonary and cardiac function testing cannot reliably predict exercise performance and functional capacity and that, furthermore, overall health status and prognosis are predicted better by indices of exercise tolerance than by resting measurements. Our aim is to produce a statement which provides recommendations on the interpretation and clinical application of CPET in heart failure, based on contemporary scientific knowledge and technical advances: the focus is on clinical indications, issues of standardization, and interpretative strategies for CPET.

Identification of Zebrafish Insertional Mutants With Defects in Visual System Development and Function

Genetic analysis in zebrafish has been instrumental in identifying genes necessary for visual system development and function. Recently, a large-scale retroviral insertional mutagenesis screen, in which 315 different genes were mutated, that resulted in obvious phenotypic defects by 5 days postfertilization was completed. That the disrupted gene has been identified in each of these mutants provides unique resource through which the formation, function, or physiology of individual organ systems can be studied. To that end, a screen for visual system mutants was performed on 250 of the mutants in this collection, examining each of them histologically for morphological defects in the eye and behaviorally for overall visual system function. Forty loci whose disruption resulted in defects in eye development and/or visual function were identified. The mutants have been divided into the following phenotypic classes that show defects in: (1) morphogenesis, (2) growth and central retinal development, (3) the peripheral marginal zone, (4) retinal lamination, (5) the photoreceptor cell layer, (6) the retinal pigment epithelium, (7) the lens, (8) retinal containment, and (9) behavior. The affected genes in these mutants highlight a diverse set of proteins necessary for the development, maintenance, and function of the vertebrate visual system.

Archive Additions

Archive AdditionsArchive AdditionsPublished Online:01 Dec 2004https://doi.org/10.1152/advan.00044.2004MoreSectionsPDF (59 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat The APS Archive of Teaching Resources is a repository of case histories, simulations, figures, lectures and course syllabi, animations, and links to physiology teaching resources for use by APS members and other educators. The Archive is a searchable database that can be used by teachers at all levels (K–12, undergraduate, graduate, and medical school) to enhance and supplement their current teaching resources and is part of the National Science Digital Library Project and the BiosciEd Net collaborative ( http://www.biosciednet.org). The APS Archive of Teaching Resources was established as an initiative of the APS Education Committee and APS Council with additional support from the National Science Foundation (DUE 0226185). Authors submitting materials to the Archive for review and inclusion have the option of developing an abstract for publication in Advances. The following abstracts are from items that have been accepted into the Archive following peer review.Milk Secretion—A Transport Question (Learning Object #125). Dee U. Silverthorn PhD, Dept. of Integrative Biology, University of Texas at Austin, Austin, TX 78712.One method for testing student understanding is to ask them to apply what they have learned to a new situation. For example, students who have memorized mechanisms by which molecules cross cell membranes can be asked to create a transporting epithelial cell that will absorb or secrete one or more substrates. This learning object in the Archive asks students to apply their understanding of basic transport processes to mammary gland epithelial cells. The activity consists of a text paragraph describing the process of milk secretion question, followed by questions that ask the student to draw and label a figure of the cell in question and to illustrate the processes described in the paragraph (synthesis and secretion of milk proteins, and secretion of immunoglobulins and calcium ions). The activity also tests student recall of cell biology, histology, and the steps of protein synthesis. The Archive learning object includes a brief discussion of the most common student mistakes.Understanding Feedback Loops (Learning Object #381). Barbara E. Goodman PhD, Physiology/Pharmacology-Division of Basic Biomedical Science, University of South Dakota School of Medicine, Vermillion, SD 57069.The learning object includes a flow chart that describes how feedback loops may contribute to homeostasis and two different think, pair, share activities that can be used sequentially to help students understand the differences between the results of negative and positive feedback loops on a more personal level. The activities appear to help undergraduates to remember the differences.Temperature Regulation (Learning Objects #438–440). Thomas A. Pressley PhD, Dept. of Physiology, Texas Tech University Health Sciences Center, 3601 4th St., STOP 6551, Lubbock, TX 79430.In the context of teaching physiology, a discussion of thermoregulation provides an opportunity to integrate many concepts introduced from earlier coverage of individual organ systems. Three learning objects have been developed to support a relatively self-contained presentation on the subject. To maintain the interest and enthusiasm of students, the lecture materials include references, posters, and stills from the cinema that illustrate key points. Topics covered include processes of heat transfer, mechanisms and hypothalamic control of thermoregulation, and various pathologies. The first learning object is a set of figures in Microsoft PowerPoint format. These are accompanied by a second object, a detailed outline for use by the instructor. Finally, there is an abbreviated handout for distribution to the students that includes copies of critical figures. These latter two objects are provided in Adobe Acrobat format, and minor changes can be made to them with appropriate software. Over the past 10 years, this material has been the basis of two 50-minute lectures for first-year medical students as part of their course in medical physiology. With the addition of representative research papers, the presentation could also be adapted for use with graduate students.This article has no references to display. Download PDF Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 28Issue 4December 2004Pages 129-129 Copyright & Permissions© 2004 American Physiological Societyhttps://doi.org/10.1152/advan.00044.2004History Published online 1 December 2004 Published in print 1 December 2004 Metrics

The Lung in Sepsis: Fueling the Fire

Advances in our understanding of the molecular mechanisms underlying the pathophysiology of sepsis have generated considerable efforts in manipulating the host response during this frequently lethal condition. While existing trials of immune modulation have been largely unsuccessful, an appreciation for the roles of individual organ systems in sepsis is important to enable clinicians to discern how each functions as both a target for injury and a contributor to the derangement in homeostasis seen in sepsis. Such awareness will encourage treatment decisions aimed at optimizing conventional therapy while minimizing the adverse effects of supportive care, and it may also guide the incorporation of newer immunomodulatory therapeutics into our existing modalities. This article discusses the lung's response to sepsis, from the standpoint of organ dysfunction related to sepsis as well as its participation in the generation and maintenance of the systemic inflammatory state.

14. Drotrecogin Alfa (Activated) Improves Respiratory and Cardiovascular Function in Patients With Severe Sepsis

The timely assessment and treatment of patients with severe sepsis is a critical determinant in the efficacy of therapy, in which emergency nurses play an important role. Cardiovascular and respiratory dysfunction are common components of severe sepsis that are known to strongly influence patient outcomes. Although the administration of drotrecogin alfa (activated) [DrotAA] has been shown to reduce mortality in adult severe sepsis patients at high risk of death, its effects on individual organ system function remain incompletely defined.

Subversion of B lymphocyte signaling by infectious agents.

Infectious agents and their hosts interact in a complex manner, involving not only superficially apparent mechanisms, but also the signaling machinery that governs host cells responses. Thus, signaling events, surface molecule expression, and transcriptional control may be affected in various cell types, with profound consequences for the function of individual cells and organ systems. Studies of the biochemistry of cell signaling and cell invasion by infectious agents have begun to detail the interplay between elements of infectious organisms and the host at the molecular level. Consequently, the resulting interferences with lymphocyte signaling may disturb the function of the immune system. In B cells, alterations of immune receptor signaling has implications for human diseases. By affecting the mechanisms of the host's immune defense, this may not only lead to inadequate elimination of an infectious agent, but also to autoimmunity or neoplasia.

Complex systems analysis: a tool for shock research.

For the past century, students of shock have focused research efforts to illuminate specific mechanisms that cause, or fail as a consequence of, circulatory collapse. Although clinical strategies aimed at supporting or restoring individual organ systems have proven effective, many patients succumb to more generalized multiple organ system failure. We suggest that general biological systems failure cannot be interpreted through reliance on reductionist science. We propose that complex systems analysis is an essential tool for shock research and we evaluate its application to genomic technologies.

Dissecting the energy needs of the body.

The majority of the resting energy expenditure can be explained by the energy needs of a few highly metabolic organs, making up a small percentage of the body by weight. The relationship of the specific size, individual metabolism, and proportional contribution to the actual body weight and total energy expenditure for each of these organs is a dynamic process throughout growth and development, the onset of disease, and changes in nutritional status. Defining the energy needs of the individual tissues and organ systems immeasurably enhances our understanding of the body's response to these clinical processes, which otherwise could not easily be evaluated by focusing solely on total energy expenditure, fat-free mass, nitrogen imbalance, or actual body weight. Recently reported studies have served mainly to reinforce concepts described previously, and clarify some areas of controversy.

The Impact of Liver Dysfunction on Outcome in Patients with Multiple Injuries

Multiple organ dysfunction syndrome (MODS) is the leading cause of late deaths after traumatic injury. The relative importance of dysfunction of individual organ systems in determining outcome from MODS has not been clearly defined. Some studies have suggested that hepatic dysfunction associated with MODS increases mortality, whereas others have suggested that it contributes little to outcome in trauma patients. To clarify the role of the hepatic dysfunction after traumatic injury we retrospectively reviewed all trauma patients with an Injury Severity Score > or = 14 admitted from January 1, 1994 through June 30, 1997 for the presence of hepatic dysfunction defined as a serum bilirubin > or = 2.0 mg/dL. Of the 1962 patients who met the entry criteria 154 developed hepatic dysfunction during their hospital stay. Patients with hepatic dysfunction were older (46 +/- 2 versus 41 +/- 1 years), were more severely injured (Injury Severity Score 31.5 +/- 0.9 versus 23.3 + 0.2), and had a lower prehospital blood pressure (102 +/- 3 versus 117 +/- 1 mm Hg) compared with patients who did not develop hepatic dysfunction. Patients with hepatic dysfunction were more likely to present with shock as reflected in a lower initial emergency room blood pressure (109 +/- 3 versus 128 +/- 1 mm Hg) and base deficit (-6.9 +/- 0.6 versus -3.5 +/- 0.1 mEq/L). Patients who developed hyperbilirubinemia had longer lengths of stay in the intensive care unit (15.8 +/- 1.2 versus 3.4 +/- 0.2 days) and the hospital (27.4 +/- 1.7 versus 11.1 +/- 0.2 days) and a higher in-hospital mortality (16.2% versus 2.5%). These data demonstrate that the development of hepatic dysfunction reflects the severity of injury and is associated with a significantly worse outcome after traumatic injury.

A decrease in complement is associated with increased renal and hematologic activity in patients with systemic lupus erythematosus.

To determine the degree to which changes in C3 and C4 precede or coincide with changes in systemic lupus erythematosus (SLE) activity, as measured by 5 global activity indices, the physician's global assessment (PGA), modified SLE Disease Activity Index (M-SLEDAI), modified Lupus Activity Index (M-LAI), Systemic Lupus Activity Measure (SLAM), and the modified British Isles Lupus Assessment Group (M-BILAG), and to evaluate the association between changes in C3 and C4 levels and SLE activity in individual organ systems. Fifty-three lupus patients were observed monthly for 1 year in a longitudinal study. Lupus disease activity and complement levels were measured at each visit. Lupus flare was defined as a 1.0 (or greater) increase in the PGA, a 3-point increase in the M-SLEDAI, a 0.1 increase in the M-LAI, a 3-point increase in the SLAM, or a 4-point increase in the M-BILAG within a 1-month period. Flare rates were calculated for subgroups defined by previous (1 month before) or concurrent changes in complement levels. Logistic regression models were used to determine the significance of the association between recent changes in complement levels and flare, controlling for prednisone dosage. Similar models were used to assess the association between changes in C3 or C4 levels and increased SLE activity in specific organ systems. Lupus flares occurred at 12% of visits based on the PGA, 19% based on the M-SLEDAI, 25% based on the M-LAI, 13% based on the SLAM, and 12% based on the M-BILAG. Recent changes in C3 and C4 levels were not associated with flares based on 3 of the 5 activity indices. Flares defined by the M-LAI were more frequent when there was a concurrent decrease in C3 (odds ratio [OR] 1.9, 95% confidence interval [95% CI] 1.1-3.1) or C4 (OR 2.1, 95% CI 1.3-3.6). Higher flare rates, as defined by the SLAM, were associated with previous increases in C3 (OR 1.6, 95% CI 1.0-2.6) and C4 (OR 2.2, 95% CI 1.2-3.9). When individual organ systems were analyzed, decreases in C3 and C4 were associated with a concurrent increase in renal disease activity (OR 2.2, 95% CI 1.4-3.5 and OR 1.9, 95% CI 1.1-3.4, respectively). Decreases in C3 were also associated with concurrent decreases in the hematocrit (OR 4.6, 95% CI 1.7-12.3), platelet (OR 2.5, 95% CI 1.5-4.1), and white blood cell (OR 2.2, 95% CI 1.3-3.6) counts. Previous increases in C3 levels were associated with a decrease in platelets (OR 1.7, 95% CI 1.1-2.7). A decrease in C4 was associated with a concurrent decrease in the hematocrit level (OR 3.2, 95% CI 1.3-7.5) and platelet count (OR 1.6, 95% CI 1.0-2.5). Decreases in complement levels were not consistently associated with SLE flares, as defined by global measures of disease activity. However, decreasing complement was associated with a concurrent increase in renal and hematologic SLE activity.

Linkage analysis of human systemic lupus erythematosus-related traits: a principal component approach.

To identify chromosomal regions containing genes involved in the susceptibility to human systemic lupus erythematosus (SLE)-related traits. In the context of a genome scan, we analyzed 101 SLE-affected sibpairs with respect to dermatologic, renal, immunologic, hematologic, neurologic, cardiopulmonary, and arthritic characteristics. Phenotypes were redefined in terms of principal components, which are synthetic variables composed of linear combinations of the original traits. Using 9 principal components obtained from these 7 traits plus age at SLE onset and race, we analyzed genome scan data with the multivariate version of the new Haseman-Elston regression model. The largest linkage for an individual trait was on chromosome 2 at 228 cM (immunologic; P = 0.00048). The most significant linkage to an individual principal component was on chromosome 4 at 208 cM (P = 0.00007). The largest multivariate linkage was on chromosome 7 at 69 cM (P = 0.0001). Of the individual organ systems, dermatologic involvement had the largest effect (P = 0.0083) at this peak at 7p13 on chromosome 7. Further analyses revealed that malar rash, a subtype of dermatologic involvement, was linked significantly (P = 0.00458) to this location. These results provide evidence of the presence and locations of genes that are involved in the genetic susceptibility to SLE-related traits in humans.

The Potential of Lpsd/Ran cDNA in Gene Therapy for Septic Shock

EACH YEAR, there are about 500,000 patients who develop sepsis, which has a mortality rate of about 50% (1). More than half of the sepsis cases are derived from infection of Gram-negative bacteria. A variety of pharmacophysiological responses are derived from the host’s inflammatory response to endotoxin of these Gram-negative bacteria. The hyperinflammatory responses of the host are thought to be the cause of organ injury and death in patients with sepsis. These responses include the release of a large amount of pro-inflammatory cytokines, including but are not limiting to tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1), IL-6, IL-8, platelet activating factor (PAF), eicosanoids, complement components, kinins, and other mediators. Production of these mediators cause systemic inflammatory response syndrome (SIRS), which could progress to hypotension, hypoperfusion, dysfunction of individual or multiple organ systems (2,3). The important role of proinflammatory cytokines in sepsis development has been demonstrated in many studies. One to 2 h after endotoxin administration, the production of TNF-a was highest in sera of mice, rats, chimpanzees, and humans (4–14). Depending on the species, the level reverts back to normal by 2–10 h. With a little delay of few hours, similar response curves are observed for IL-1, IL-6, and IL-8 after endotoxin administration in many of these studies. The consequence observed in the host is the active hyperdynamic response, which includes an increased cardiac output, tachycardia, decreased vascular resistance, lymphopenia, neutrophilia, organ injury, anorexia, inflammation, fever, chills, myalgia, headache, and other symptoms (15–22). Elevation of these proinflammatory cytokines is correlated with mortality in patients with sepsis in the intensive care unit in several of the above studies. On the basis of these observations, a number of clinical trials were done in blocking the activity of these cytokines. The administration was done either in the form of antibodies to a particular cytokine, such as TNF-a and IL-1, in the form of soluble receptors capable of binding and inactivating the cytokine of interest (23–31). None of these studies has been shown to be beneficial in clinical terms. Some of the major reasons include the fact that endotoxin instead of bacterial infection was used in many animal studies. Furthermore, blocking the activity or production of the active cytokines involved in the very inflammatory response to eliminate the invading pathogen effectively may be a mistake in designing a therapy for treating patients with sepsis. Therefore, new treatment approaches will be undoubtedly attractive for this clinical problem.

Changing pattern of organ dysfunction in early human sepsis is related to mortality.

We examined the pattern of organ system dysfunction, the evolution of this pattern over time, and the relationship of these features to mortality in patients who had sepsis syndrome. Prospective, multicenter, observational study. Intensive care units in tertiary referral teaching hospitals. A total of 287 patients who had sepsis syndrome were prospectively identified in intensive care units. MATERIALS AND MEASUREMENTS: Cardiovascular, pulmonary, neurologic, coagulation, renal, and hepatic dysfunction were assessed at onset and on day 3 of sepsis syndrome. Organ dysfunction was classified as normal, mild, moderate, severe, and extreme dysfunction. We calculated the occurrence rate and associated 30-day mortality rate of organ dysfunction at the onset of sepsis syndrome. We then measured the change in organ dysfunction from onset to day 3 of sepsis syndrome and determined, for individual organ systems, the associated 30-day mortality rate. At the onset of sepsis syndrome, clinically significant pulmonary dysfunction was the most common organ failure, but was not related to 30-day mortality. Clinically significant cardiovascular, neurologic, coagulation, renal, and hepatic dysfunction were less common at the onset of sepsis syndrome but were significantly associated with the 30-day mortality rate. Worsening neurologic, coagulation, and renal dysfunction from onset to day 3 of sepsis syndrome were associated with significantly higher 30-day mortality than with improvement or no change in organ dysfunction. Increased mortality rate in sepsis syndrome is associated with a pattern characterized by failure of nonpulmonary organ systems and, in particular, worsening neurologic, coagulation, and renal dysfunction over the first 3 days. Although initial pulmonary dysfunction is common in patients with sepsis syndrome, it is not associated with an increased mortality rate.

Ventricular Cerebrospinal Fluid and Serum Concentrations of sTNFR-I, IL-1ra, and IL-6 After Aneurysmal Subarachnoid Hemorrhage

Postsubarachnoid hemorrhage, systemic inflammatory response syndrome and associated organ system failure are more frequently found in patients in poor neurologic condition. Since subarachnoid hemorrhage causes a profound intrathecal inflammatory response with production of proinflammatory cytokines TNFalpha, IL-1beta, and IL-6, a possible explanation for this association is that brain-derived cytokines may enter the systemic circulation in the presence of postsubarachnoid hemorrhage blood brain barrier disruption to systemically activate inflammatory cascades and thereby contribute to the development of postsubarachnoid hemorrhage systemic inflammatory response syndrome and extracerebral organ system failures. In 44 patients with aneurysmal subarachnoid hemorrhage admitted within 3 days of the initial bleed, extracerebral organ system functions were assessed individually and in aggregate using the modified Multiple Organ Dysfunction Score. Serum and cerebrospinal fluid concentrations of soluble tumor necrosis factor-alpha receptor-I, interleukin-1beta receptor antagonist, and IL-6 were determined during the first 2 weeks after subarachnoid hemorrhage and tested for correlation with (1) admission Hunt-Hess grade, (2) development of systemic inflammatory response syndrome and extracerebral organ system failures, and (3) neurologic outcome. The development of postsubarachnoid hemorrhage systemic inflammatory response syndrome and extracerebral organ system failures was paralleled by a significant increase in serum but not in cerebrospinal fluid levels of soluble tumor necrosis factor-alpha receptor-I and IL-1ra, that is, patients with and without extracerebral organ system failures did not differ in pattern and time course of cerebrospinal fluid cytokine concentrations. In contrast, increasing soluble tumor necrosis factor-alpha receptor-I and interleukin-1beta receptor antagonist serum levels correlated with a higher Multiple Organ Dysfunction score and with individual organ system dysfunctions. Postsubarachnoid hemorrhage, systemic inflammatory response syndrome and extracerebral organ system failures could therefore not be linked to changes in cerebrospinal fluid cytokine concentration profiles.

University of New Mexico School of Medicine.

University of New Mexico School of Medicine.