Peri-anastomotic microdialysis lactate assessment after esophagectomy

Esophagus - Esophagectomy is the cornerstone in curative treatment for esophageal and gastroesophageal junctional cancer. Esophageal resection is an advanced procedure with many complications,...     

Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease

High individuality causes laboratory reference ranges to be insensitive to changes in test results that are significant for the individual. We undertook a longitudinal study of variation in thyroid function tests in 16 healthy men with monthly sampling for 12 months using standard procedures. We measured serum T(4), T(3), free T(4) index, and TSH. All individuals had different variations of thyroid function tests (P < 0.001 for all variables) around individual mean values (set points) (P < 0.001 for all variables). The width of the individual 95% confidence intervals were approximately half that of the group for all variables. Accordingly, the index of individuality was low: T(4) = 0.58; T(3) = 0.54; free T(4) index = 0.59; TSH = 0.49. One test result described the individual set point with a precision of +/- 25% for T(4), T(3), free T(4) index, and +/- 50% for TSH. The differences required to be 95% confident of significant changes in repeated testing were (average, range): T(4) = 28, 11-62 nmol/liter; T(3) = 0.55, 0.3--0.9 nmol/liter; free T4 index = 33, 15-61 nmol/liter; TSH = 0.75, 0.2-1.6 mU/liter. Our data indicate that each individual had a unique thyroid function. The individual reference ranges for test results were narrow, compared with group reference ranges used to develop laboratory reference ranges. Accordingly, a test result within laboratory reference limits is not necessarily normal for an individual. Because serum TSH responds with logarithmically amplified variation to minor changes in serum T(4) and T(3), abnormal serum TSH may indicate that serum T(4) and T(3) are not normal for an individual. A condition with abnormal serum TSH but with serum T(4) and T(3) within laboratory reference ranges is labeled subclinical thyroid disease. Our data indicate that the distinction between subclinical and overt thyroid disease (abnormal serum TSH and abnormal T(4) and/or T(3)) is somewhat arbitrary. For the same degree of thyroid function abnormality, the diagnosis depends to a considerable extent on the position of the patient's normal set point for T(4) and T(3) within the laboratory reference range.     

Aging as a consequence of selection to reduce the environmental risk of dying

Each animal in the Darwinian theater is exposed to a number of abiotic and biotic risk factors causing mortality. Several of these risk factors are intimately associated with the act of energy acquisition as such and with the amount of reserve the organism has available from this acquisition for overcoming temporary distress. Because a considerable fraction of an individual’s lifetime energy acquisition is spent on somatic maintenance, there is a close link between energy expenditure on somatic maintenance and mortality risk. Here, we show, by simple life-history theory reasoning backed up by empirical cohort survivorship data, how reduction of mortality risk might be achieved by restraining allocation to somatic maintenance, which enhances lifetime fitness but results in aging. Our results predict the ubiquitous presence of senescent individuals in a highly diverse group of natural animal populations, which may display constant, increasing, or decreasing mortality with age. This suggests that allocation to somatic maintenance is primarily tuned to expected life span by stabilizing selection and is not necessarily traded against reproductive effort or other traits. Due to this ubiquitous strategy of modulating the somatic maintenance budget so as to increase fitness under natural conditions, it follows that individuals kept in protected environments with very low environmental mortality risk will have their expected life span primarily defined by somatic damage accumulation mechanisms laid down by natural selection in the wild.

There is substantial empirical support for the notion that animals on average live far longer in a properly designed protected environment than in their natural environment (1–4). This implies that ecological risk factors are major determinants of life expectancy in the wild (5, 6), irrespective of variation in mortality risk with age (7) and of variation in the degree of senescence in wild animals (8–12). Regardless of intraspecies genetic and phenotypic variation and the huge interspecies variability in the repertoires of abiotic and biotic risk factors causing mortality in the wild, all individuals are faced with the destiny that one day, they will draw the fatal ticket in the Darwinian lottery. This raises the question of whether there exists a ubiquitous life-history strategy response to this ominous fact that is favored by natural selection.The hypothesis we will examine is that there exists such a life-history strategy, independent of temporal mortality risk profiles, which is materialized through a universal physiological principle of tuning the allocation to somatic maintenance to expected life span so that lifetime fitness is enhanced. The rationale for this is that an intimate link exists between the energy acquisition needs of an individual and mortality risk. Because somatic maintenance accounts for a substantial part of the lifetime need of acquired energy (13), restraining allocation to somatic maintenance from early on might reduce mortality risk because it allows either reduced energy acquisition activity or alternative use of the freed energy. Restraining the allocation to somatic maintenance incurs costs in terms of increasing somatic damage. However, as long as the accrued somatic damage is controlled in such a way that the costs do not materialize until rather late in life, when an individual would most probably already be dead, the penalty in terms of fitness may be more than compensated for by increased earlier survival (14). A life-history analysis assessing the evolutionary relevance of this hypothesis by elucidating the link between energy acquisition, risk reduction, and somatic maintenance, which is also firmly linked to empirical data, has apparently not yet been articulated.Our assessment of the above hypothesis is based on a simple life-history model illustrated using cohort survivorship data from the same species, obtained both in a natural ecological setting and also in a properly designed protective environment. This allows comparison of different somatic maintenance strategies with regard to female lifetime reproductive success and the intrinsic rate of natural increase, without invoking complex and specific population dynamics models that would narrow the empirical reach of predictions in terms of range of life-history regimes. The life-history model predicts that natural selection will, independent of temporal mortality risk profiles, favor restrained allocation to maintenance, despite causing accumulation of somatic damage in later life.After we present our model and results illustrating its relevance for three real-life case studies, we will examine its implications and relationships with the main current theories of evolution of aging (mutation accumulation, antagonistic pleiotropy, and disposable soma theory) (14). Our hypothesis is conceptually closest to the disposable soma theory. In essence, the disposable soma theory proposes that natural selection should favor allocation to somatic maintenance only as much as is necessary to keep the organism in good functional condition for as long as it has a reasonable chance still to be alive, subject to the prevailing level of risk. Within this viewpoint, it is commonly suggested to be optimal to allocate surplus resources in other activities that enhance fitness, thereby predicting trade-offs between, for example, longevity and reproduction. In our model, however, the emphasis is specifically on how restraining the allocation to maintenance increases fitness in early and middle life by lessening the mortality risk as such, without being traded against any other trait before late in life. If the predicted intimate link between risk reduction and somatic maintenance can be established through further theoretical and experimental work, we anticipate that it will advance our understanding of the evolutionary basis of aging and of the nature of any trade-offs that might arise. We also expect that enhanced understanding of why aging occurs may contribute fresh insights to guide research on physiological causes of and possible interventions to improve the aging process, a matter of high biomedical importance.     

The p20 and Ded1 proteins have antagonistic roles in eIF4E-dependent translation in Saccharomyces cerevisiae

The translation initiation factor eIF4E mediates the binding of the small ribosomal subunit to the cap structure at the 5′ end of the mRNA. In Saccharomyces cerevisiae, the cap-binding protein eIF4E is mainly associated with eIF4G, forming the cap-binding complex eIF4F. Other proteins are detected upon purification of the complex on cap-affinity columns. Among them is p20, a protein of unknown function encoded by the CAF20 gene. Here, we show a negative regulatory role for the p20 protein in translation initiation. Deletion of CAF20 partially suppresses mutations in translation initiation factors. Overexpression of the p20 protein results in a synthetic enhancement of translation mutation phenotypes. Similar effects are observed for mutations in the DED1 gene, which we have isolated as a multicopy suppressor of a temperature-sensitive eIF4E mutation. The DED1 gene encodes a putative RNA helicase of the DEAD-box family. The analyses of its suppressor activity, of polysome profiles of ded1 mutant strains, and of synthetic lethal interactions with different translation mutants indicate that the Ded1 protein has a role in translation initiation in S. cerevisiae.     

Artificial neural network analysis: a novel application for predicting site-specific bone mineral density

Dual X-ray absorptiometry (DXA), which is the most commonly used method for the diagnosis and followup of human bone health, is known to produce accurate estimates of bone mineral density (BMD). However, high costs and problems with availability may prevent its use for mass screening. The objective of the present study was to estimate BMD values for healthy persons and those with conditions known to be associated with BMD, using artificial neural networks (ANN). An ANN was used to quantitatively estimate site-specific BMD values in comparison with reference values obtained by DXA (i. e. BMD(spine), BMD(pelvis), and BMD(total)). Anthropometric measurements (i. e. sex, age, weight, height, body mass index, waist-to-hip ratio, and the sum of four skinfold thicknesses) were fed to the ANN as independent input variables. The estimates based on four input variables were generated as output and were generally identical to the reference values for all studied groups. We believe the ANN is a promising approach for estimating and predicting site-specific BMD values using simple anthropometric measurements.