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Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗

Field physiology: physiological insights from animals in nature.

Whereas comparative physiology documents the range of physiological variation across a range of organisms, field physiology provides insight into the actual mechanisms an organism employs to maintain homeostasis in its everyday life. This requires an understanding of an organism's natural history and is prerequisite to developing hypotheses about physiological mechanisms. This review focuses on a few areas of field physiology that exemplify how the underlying physiology could not have been understood without appropriate field measurements. The examples we have chosen highlight the methods and inference afforded by an application of this physiological analysis to organismal function in nature, often in extreme environments. The specific areas examined are diving physiology, the thermal physiology of large endothermic fishes, reproductive physiology of air breathing vertebrates, and endocrine physiology of reproductive homeostasis. These areas form a bridge from physiological ecology to evolutionary ecology. All our examples revolve around the central issue of physiological limits as they apply to organismal homeostasis. We view this theme as the cornerstone of physiological analysis and supply a number of paradigms on homeostasis that have been tested in the context of field physiology.

Animals↗

Clinical physiology: an accepted branch of physiology.

Clinical physiology is a branch of physiology particularly dealing with functional disturbances in disease (pathophysiology) and the integrated function of the human body in disease against the background of normal function in healthy subjects, suitable physiological methods for the study of patients--particularly for diagnostic purposes--as well as for research, and the education of medical students and laboratory assistants in these fields. Departments of clinical physiology in university hospitals form a bridge between basic physiology and many clinical specialties. Independent departments of clinical physiology developed early in Sweden due to the work of Professor Torgny Sjöstrand at the Karolinska Hospital in Stockholm, and have been models of research, teaching and hospital organization which have been followed in several other countries. The International Union of Physiological Sciences (IUPS) has recognized clinical physiology as a separate branch of physiology by approving a Commission of Clinical Physiology which has contributed to the programme of this and, we hope, future congresses, as well as promote the development of clinical physiology internationally.

Humans↗

Basic anatomical and physiological data for use in radiological protection: reference values. A report of age- and gender-related differences in the anatomical and physiological characteristics of reference individuals. ICRP Publication 89.

This report presents detailed information on age- and gender-related differences in the anatomical and physiological characteristics of reference individuals. These reference values provide needed input to prospective dosimetry calculations for radiation protection purposes for both workers and members of the general public. The purpose of this report is to consolidate and unify in one publication, important new information on reference anatomical and physiological values that has become available since Publication 23 was published by the ICRP in 1975. There are two aspects of this work. The first is to revise and extend the information in Publication 23 as appropriate. The second is to provide additional information on individual variation among grossly normal individuals resulting from differences in age, gender, race, or other factors. This publication collects, unifies, and expands the updated ICRP reference values for the purpose of providing a comprehensive and consistent set of age- and gender-specific reference values for anatomical and physiological features of the human body pertinent to radiation dosimetry. The reference values given in this report are based on: (a) anatomical and physiological information not published before by the ICRP; (b) recent ICRP publications containing reference value information; and (c) information in Publication 23 that is still considered valid and appropriate for radiation protection purposes. Moving from the past emphasis on 'Reference Man', the new report presents a series of reference values for both male and female subjects of six different ages: newborn, 1 year, 5 years, 10 years, 15 years, and adult. In selecting reference values, the Commission has used data on Western Europeans and North Americans because these populations have been well studied with respect to antomy, body composition, and physiology. When appropriate, comparisons are made between the chosen reference values and data from several Asian populations. The first section of the report provides summary tables of all the anatomical and physiological parameters given as reference values in this publication. These results give a comprehensive view of reference values for an individual as influenced by age and gender. The second section describes characteristics of dosimetric importance for the embryo and fetus. Information is provided on the development of the total body and the timing of appearance and development of the various organ systems. Reference values are provided on the mass of the total body and selected organs and tissues, as well as a number of physiological parameters. The third section deals with reference values of important anatomical and physiological characteristics of reference individuals from birth to adulthood. This section begins with details on the growth and composition of the total body in males and females. It then describes and quantifies anatomical and physiological characteristics of various organ systems and changes in these characteristics during growth, maturity, and pregnancy. Reference values are specified for characteristics of dosimetric importance. The final section gives a brief summary of the elemental composition of individuals. Focusing on the elements of dosimetric importance, information is presented on the body content of 13 elements: calcium, carbon, chloride, hydrogen, iodine, iron, magnesium, nitrogen, oxygen, potassium, sodium, sulphur, and phosphorus.

Adolescent↗

The Pediatric Risk of Mortality III--Acute Physiology Score (PRISM III-APS): a method of assessing physiologic instability for pediatric intensive care unit patients.

OBJECTIVE: To develop a physiology-based measure of physiologic instability for use in pediatric patients that has an expanded scale compared with the Pediatric Risk of Mortality (PRISM) III score. STUDY DESIGN: Data were collected from consecutive admissions to 32 pediatric ICUs (11,165 admission, 543 deaths). Patient-level data included physiologic data, outcomes, descriptive information, and diagnoses. Physiologic data included the most abnormal values in the first 24 hours of pediatric ICU stay from 27 variables. Initially, ranges of each physiologic variable were evaluated for their association with mortality. A multi-variate logistic regression analysis was used to determine the final variables and their ranges. Integer scores reflecting the relative contribution to mortality risk were assigned to the variable ranges. RESULTS: A total of 59 ranges of 21 physiologic variables were selected. This score is called the Pediatric Risk of Mortality III--Acute Physiology Score (PRISM III-APS). Mortality increased as the PRISM III-APS score increased. Most patients have PRISM III-APS scores less than 10, and these patients have a mortality risk of less than 1%. At the other extreme, the mortality rate of the 137 patients with a PRISM III-APS score of greater than 80 was greater than 97%. CONCLUSION: The PRISM III-APS score is an expanded measure of physiologic instability that has been validated against mortality. Compared with PRISM III, PRISM III-APS should be more sensitive to small changes in physiologic status.

Acute Disease↗

Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian Trial of Physiologic Pacing Investigators.

BACKGROUND: Evidence suggests that physiologic pacing (dual-chamber or atrial) may be superior to single-chamber (ventricular) pacing because it is associated with lower risks of atrial fibrillation, stroke, and death. These benefits have not been evaluated in a large, randomized, controlled trial. METHODS: At 32 Canadian centers, patients without chronic atrial fibrillation who were scheduled for a first implantation of a pacemaker to treat symptomatic bradycardia were eligible for enrollment. We randomly assigned patients to receive either a ventricular pacemaker or a physiologic pacemaker and followed them for an average of three years. The primary outcome was stroke or death due to cardiovascular causes. Secondary outcomes were death from any cause, atrial fibrillation, and hospitalization for heart failure. RESULTS: A total of 1474 patients were randomly assigned to receive a ventricular pacemaker and 1094 to receive a physiologic pacemaker. The annual rate of stroke or death due to cardiovascular causes was 5.5 percent with ventricular pacing, as compared with 4.9 percent with physiologic pacing (reduction in relative risk, 9.4 percent; 95 percent confidence interval, -10.5 to 25.7 percent [the negative value indicates an increase in risk]; P=0.33). The annual rate of atrial fibrillation was significantly lower among the patients in the physiologic-pacing group (5.3 percent) than among those in the ventricular-pacing group (6.6 percent), for a reduction in relative risk of 18.0 percent (95 percent confidence interval, 0.3 to 32.6 percent; P=0.05). The effect on the rate of atrial fibrillation was not apparent until two years after implantation. The observed annual rates of death from all causes and of hospitalization for heart failure were lower among the patients with a physiologic pacemaker than among those with a ventricular pacemaker, but not significantly so (annual rates of death, 6.6 percent with ventricular pacing and 6.3 percent with physiologic pacing; annual rates of hospitalization for heart failure, 3.5 percent and 3.1 percent, respectively). There were significantly more perioperative complications with physiologic pacing than with ventricular pacing (9.0 percent vs. 3.8 percent, P<0.001). CONCLUSIONS: Physiologic pacing provides little benefit over ventricular pacing for the prevention of stroke or death due to cardiovascular causes.

Aged↗

Herpetological diversity along Andean elevational gradients: links with physiological ecology and evolutionary physiology.

A well-defined macroecological pattern is the decline in biodiversity with altitude. However, this decline is taxa-specific. For example, amphibians are more diverse than squamates at extreme elevations in the tropical Andes, but this pattern is reversed at extreme elevations in the southern latitudes. Several ecophysiological and evolutionary factors may be related to this difference. At high-elevations in southern latitudes temperature differs dramatically among seasons and dry soils dominate, characteristics that appear to favor lizard physiological ecology. Tropical high altitudes, in contrast, are humid and offer abundant and diverse water resources. These characteristics allow for a richer anuran community but might complicate lizard egg development through temperature and oxygen constrains. Differences in strategies of thermal adaptation might also modulate diversity patterns. The thermal physiology of anurans is extremely labile so that behavioral and physiological performance is maintained despite an altitudinal decrease in field body temperature. Lizards, in contrast, exhibit a conservative thermal physiology and rely on behavioral thermoregulation to face cold and variable temperatures. Both, lizard behavioral strategies and anuran physiological adjustments seem equally efficient in allowing ecological success and diversification for both groups in the tropics up to approximately 3000 m. At higher elevations physiological thermal adaptation is required, and lizards are ecologically constrained, perhaps at various ontogenetic stages. Patterns of biodiversity along environmental clines can be better understood through a physiological approach, and can help to refine and propose hypotheses in evolutionary physiology.

Adaptation, Physiological↗

Cost-effectiveness of physiologic pacing: results of the Canadian Health Economic Assessment of Physiologic Pacing.

OBJECTIVES: The purpose of this study was to determine the cost-effectiveness of physiologic pacemakers. BACKGROUND: The Canadian Trial of Physiologic Pacing (CTOPP) was a large randomized trial that evaluated the efficacy of physiologic pacing compared with ventricular pacing. CTOPP also included a prospective cost-effectiveness substudy. METHODS: Resource usage and costs were collected from a subset of 472 patients (of 1,094) who received a physiologic pacemaker and 586 (of 1,474) who received a ventricular pacemaker. Costs included initial pacemaker implantation and all health care follow-up costs over a follow-up of 5.2 years. Costs are reported in 2004 Canadian dollars (1 Canadian dollar = 0.76 US dollars), with adjustments for censoring. Incremental cost-effectiveness was estimated as the ratio of the difference (treatment-control) in mean cost to the difference in life expectancy (mean survival), with costs and effects discounted at 3% per year. RESULTS: Over a mean follow-up of 3.1 years, physiologic pacing was associated with a gain of 0.01 life-years. This benefit increases to 0.25 life-years in the subgroup of patients with an intrinsic (unpaced) heart rate < or =60 bpm. Physiologic pacing was more expensive than ventricular (16,833 Canadian dollars vs 13,857 US dollars), largely because of the increased cost of dual-chamber devices. Among all substudy patients, the incremental cost-effectiveness of physiologic pacing is 297,600 Canadian dollars per life-year gained; however, this value falls to 16,343 Canadian dollars in patients with an intrinsic heart rate >60. CONCLUSIONS: In the short term, a strategy of routine implantation of physiologic pacemakers is not cost-effective by currently accepted standards. The selective use of these devices in patients likely to be pacemaker dependent appears to be cost-effective. Further studies with longer follow-up and which consider the benefit of reducing nonfatal cardiac events would be valuable.

Arrhythmias, Cardiac↗

Canadian Trial of Physiological Pacing: Effects of physiological pacing during long-term follow-up.

BACKGROUND: The Canadian Trial of Physiological Pacing (CTOPP) reported that the risk of stroke or cardiovascular death was similar between patients receiving ventricular versus physiological pacemakers at the end of the original follow-up period of 3 years. However, the occurrence of atrial fibrillation was significantly less frequent with physiological pacemakers. To assess a potential delayed benefit of physiological pacing, follow-up of patients in this study was extended to 6 years. METHODS AND RESULTS: A total of 1474 patients requiring a pacemaker for symptomatic bradycardia were randomized to receive ventricular and 1094 to physiological pacemakers. The primary outcome was stroke or cardiovascular death. The study was completed in July 1998, and follow-up was extended to July 2001. At a mean follow-up of 6.4 years, there was no difference between treatment groups in the primary outcome of cardiovascular death or stroke. There was no significant difference in total mortality or stroke between groups. There was a significantly lower rate of development of atrial fibrillation in the physiological group, with a relative risk reduction of 20.1% (CI, 5.4 to 32.5; P=0.009). CONCLUSIONS: The CTOPP extended study does not show a difference in cardiovascular death or stroke, or in total mortality, or in stroke between patients implanted with ventricular or physiological pacemakers over a mean follow-up of >6 years. However, there is a persistent significant reduction in the development of atrial fibrillation with physiological pacing.

Atrial Fibrillation↗

Taking physiology to the field: using physiological approaches to answer questions about animals in their environments.

Both technological and conceptual advances continue to enhance our ability to evaluate physiological mechanisms in free-living animals. Although complex and uncontrolled natural environments may challenge our ability to define causal mechanistic relationships, they provide opportunities not available in more conventional laboratory settings. Among these opportunities are the ability to observe the interplay between physiology and behavior, the potential inspiration to physiological studies from novel observations in the field, and the ability to evaluate the extent to which particular physiological systems are challenged under natural conditions. As we accumulate information about physiological function in the field, we are often forced to reconsider established paradigms: hibernating bears may contract their muscles to maintain strength and tone, testosterone levels in male stonechats maintaining territories in winter are exceptionally low, wintering emperor penguins may risk overheating, and large desert mammals may eschew brain-cooling mechanisms. Measuring and quantifying the organismal response to a changing environment provides a link between mechanistic physiology and behavior, ecology, and evolution and gives us new tools to understand population, community, and ecosystem-level processes.

Adaptation, Physiological↗

The physiological challenges of the 1952 Copenhagen poliomyelitis epidemic and a renaissance in clinical respiratory physiology.

The 1952 Copenhagen poliomyelitis epidemic provided extraordinary challenges in applied physiology. Over 300 patients developed respiratory paralysis within a few weeks, and the ventilator facilities at the infectious disease hospital were completely overwhelmed. The heroic solution was to call upon 200 medical students to provide round-the-clock manual ventilation using a rubber bag attached to a tracheostomy tube. Some patients were ventilated in this way for several weeks. A second challenge was to understand the gas exchange and acid-base status of these patients. At the onset of the epidemic, the only measurement routinely available in the hospital was the carbon dioxide concentration in the blood, and the high values were initially misinterpreted as a mysterious "alkalosis." However, pH measurements were quickly instituted, the Pco(2) was shown to be high, and modern clinical respiratory acid-base physiology was born. Taking a broader view, the problems highlighted by the epidemic underscored the gap between recent advances made by physiologists and their application to the clinical environment. However, the 1950s ushered in a renaissance in clinical respiratory physiology. In 1950 the coverage of respiratory physiology in textbooks was often woefully inadequate, but the decade saw major advances in topics such as mechanics and gas exchange. An important development was the translation of the new knowledge from departments of physiology to the clinical setting. In many respects, this period was therefore the beginning of modern clinical respiratory physiology.

Comorbidity↗