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.     

Total serum bile acids, gamma-glutamyl transferase, prealbumin, and tyrosine: sensitive serum markers of hepatic dysfunction in alcoholic liver cirrhosis

Of 33 components analyzed in overnight fasting serum from 30 patients with alcoholic liver cirrhosis, portal hypertension, and bleeding esophageal varices, total serum bile acids, gamma-glutamyltransferase, prealbumin, and tyrosine were the most frequently abnormal 'liver tests'. Total serum bile acids correlated significantly with bilirubin, immunoglobulin M, threonine, glycine, methionine, and tyrosine. Gamma-glutamyltransferase correlated with aspartate aminotransferase, glutamine, and alanine. Prealbumin correlated with albumin and immunoglobulins G and A. Tyrosine correlated with total bile acids, orosomucoid, and 10 amino acids. The amino acid ratio of valine + isoleucine + leucine to tyrosine + phenylalanine was lowered in all patients. It is concluded that the clinical picture and pattern of serum components in patients with alcoholic liver disease are influenced by many complex pathophysiological mechanisms.     

Trends in leisure time physical activity,smoking, body mass index and alcohol consumption in Danish adults with and without diabetes: A repeat cross-sectional national survey covering the years 2000 to 2010

Aims

In recent decades there has been an increased focus on non-pharmacological treatment of diabetes. The aim of this study was to investigate trends in leisure time physical activity (PA), smoking, body mass index (BMI), and alcohol consumption reported in 2000, 2005 and 2010 by Danish subjects with diabetes.

Methods

Data comprised level of leisure time PA (inactive; moderate active; medium active; high active); smoking; BMI; and alcohol consumption, provided by The Danish Health and Morbidity Surveys. Participants older than 45 years with or without diabetes were included from cross-sectional analyses from 2000, 2005 and 2010.

Results

In participants with diabetes, leisure time PA levels increased from 2000 to 2010: The percentage of those that were physically active increased from 53.5% to 78.2% (p < 0.001; women) and from 67.8% to 79.1% (p = 0.01; men). The prevalence of daily smokers was reduced from 27.2% to 16.4%, p = 0.015, in women with diabetes. In men with diabetes, BMI increased from 27.2 ± 4.0 to 28.6 ± 5.1 kg m⁻², p = 0.003, and men who exceeded the maximum recommendation for alcohol consumption increased from 9.4% to 19.0%, p = 0.007. The leisure time PA level was reduced in participants with diabetes compared to participants without diabetes throughout the study.

Conclusions

The percentage of physically active Danish participants older than 45 years with diabetes increased from 2000 to 2010, and the most beneficial trends in life style were observed among the women. These trends may have serious implications for cardiovascular risk in Danish patients with diabetes.     

Modulation of Intestinal Inflammation by Minimal Enteral Nutrition With Amniotic Fluid in Preterm Pigs

Background: Necrotizing enterocolitis (NEC) is a severe inflammatory disorder, associated with the difficult transition from parenteral to enteral feeding after preterm birth. We hypothesized that minimal enteral nutrition (MEN) with amniotic fluid (AF), prior to enteral formula feeding, would improve resistance to NEC in preterm pigs. Methods: Experiment 1: IEC‐6 cells were incubated with porcine (pAF) and human AF (hAF) to test AF‐stimulated enterocyte proliferation and migration in vitro. Experiment 2: Cesarean‐delivered, preterm pigs were fed parenteral nutrition and MEN with pAF, hAF, or control fluid (MEN‐pAF, MEN‐hAF, or MEN‐CTRL; all n = 9) for 2 days before tissue collection. Experiment 3: Preterm pigs were fed MEN diets as in experiment 2, but followed by 2 days of enteral formula feeding, which predisposes to NEC (NEC‐pAF, NEC‐hAF, or NEC‐CTRL; n = 10–12). Results: Both pAF and hAF stimulated enterocyte proliferation and migration in vitro. In experiment 2, MEN‐pAF and MEN‐hAF pigs showed increased body weight gain and reduced intestinal interleukin (IL)–8 and colonic IL‐6 levels, indicating reduced inflammatory response. In experiment 3, body weight gain was highest in the 2 groups fed AF as MEN, but NEC incidences were similar (NEC‐pAF) or increased (NEC‐hAF) compared with controls. Conclusions: Intake of pAF or hAF improved body growth and modulated intestinal inflammatory cytokines during a period of parenteral nutrition, but did not protect against later formula‐induced NEC in preterm pigs. Further studies are required to show if MEN feeding with species‐specific AF, combined with an optimal enteral diet (eg, human milk), will improve adaptation during the transition from parenteral to enteral feeding in preterm neonates.     

Enhanced levels of urokinase plasminogen activator and its soluble receptor in common variable immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by defective immunoglobulin production and high frequency of bacterial infections, autoimmunity and manifestations of chronic inflammation.The urokinase plasminogen activator (uPA), its cell bound and soluble receptor (uPAR, suPAR) have complex biological functions involving innate immune defense mechanisms and regulation of inflammation. Based on this dual role, we hypothesized that the uPA system could be affected in CVID, and examined expression of components of the uPA system in subgroups of CVID. All CVID-patients had increased plasma levels of suPAR with particularly high levels in those with splenomegaly and thrombocytopenia. Plasma uPA levels were also raised in these patients, and both suPAR and uPA levels correlated with the monocyte activation marker neopterin. Monocytes from CVID patients had increased expression of uPAR. We show an increased activation of the uPA system possibly contributing to the inflammatory phenotype seen in subgroups of CVID patients.