[Modern diagnosis and therapy of benign thyroid diseases]. / Moderne Abklärung und Therapie benigner Schilddrüsenerkrankungen.

Modern diagnosis and therapy of benign thyroid diseases Abstract. Benign thyroid diseases continue to be widespread endocrine disorders. Early recognition of their symptoms and exact diagnosis are the prerequisite of targeted therapy and minimal impairment of the patient's well-being. Drug treatment, radioiodine therapy, thermal ablation procedures and surgery have been shown to be successful treatment options. As guidelines for diagnosis and treatment of patients continue to evolve, an interdisciplinary approach ensures optimal diagnosis and management on every step in the care for these patients. We present three clinical scenarios for benign thyroid disease: the symptomatic goitre, the painful thyroid and the thyroid with hyperthyroidism.

Calibration of life history traits with epiphyseal closure, dental eruption and bone histology in captive and wild red deer.

The study of skeletochronology and bone tissue as a record of information on ontogenetic stages and events is widely used for improving the knowledge about life histories (LHs) of extinct and extant vertebrates. Compared with dinosaurs and extant reptiles, mammalian bone histology has received little attention. Here, we calibrate for the first time bone and dental age with histological bone characteristics and LH stages in ontogenetic series of red deer. We rely on known LHs of different aged individuals of captive Cervus elaphus hippelaphus from Austria to correlate epiphyseal closure, dental eruption pattern, bone growth marks and bone tissue patterns in femora and tibiae, and of wild Cervus elaphus hispanicus from Spain. Our data show that females (of both subspecies) attain skeletal maturity earlier than males. At this moment, epiphyseal closure (in femora and tibiae) and dental eruption are complete and long bones start to deposit an external fundamental system. The results also show that the attainment of reproductive maturity in red deer occurs slightly before skeletal maturity.

Ecophysiology of omega Fatty acids: a lid for every jar.

Omega fatty acids affect various physiological functions, such as locomotion, cardiac function, and thermogenesis. We highlight evidence from animal models that points to pathways by which specific omega fatty acids exert differential effects. We suggest that optimizing the omega fatty acid composition of tissues involves trade-offs between costs and benefits of specific fatty acids.

Metastatic spread in patients with non-small cell lung cancer is associated with a reduced density of tumor-infiltrating T cells.

Tumor-infiltrating lymphocytes play an important role in cell-mediated immune destruction of cancer cells and tumor growth control. We investigated the heterogeneity of immune cell infiltrates between primary non-small cell lung carcinomas (NSCLC) and corresponding metastases. Formalin-fixed, paraffin-embedded primary tumors and corresponding metastases from 34 NSCLC patients were analyzed by immunohistochemistry for CD4, CD8, CD11c, CD68, CD163 and PD-L1. The percentage of positively stained cells within the stroma and tumor cell clusters was recorded and compared between primary tumors and metastases. We found significantly fewer CD4(+) and CD8(+) T cells within tumor cell clusters as compared with the stromal compartment, both in primary tumors and corresponding metastases. CD8(+) T cell counts were significantly lower in metastatic lesions than in the corresponding primary tumors, both in the stroma and the tumor cell islets. Of note, the CD8/CD4 ratio was significantly reduced in metastatic lesions compared with the corresponding primary tumors in tumor cell islets, but not in the stroma. We noted significantly fewer CD11c(+) cells and CD68(+) as well as CD163(+) macrophages in tumor cell islets compared with the tumor stroma, but no difference between primary and metastatic lesions. Furthermore, the CD8/CD68 ratio was higher in primary tumors than in the corresponding metastases. We demonstrate a differential pattern of immune cell infiltration in matched primary and metastatic NSCLC lesions, with a significantly lower density of CD8(+) T cells in metastatic lesions compared with the primary tumors. The lower CD8/CD4 and CD8/CD68 ratios observed in metastases indicate a rather tolerogenic and tumor-promoting microenvironment at the metastatic site.

Contrary seasonal changes of rates of nutrient uptake, organ mass, and voluntary food intake in red deer (Cervus elaphus).

Northern ungulates acclimatize to winter conditions with restricted food supply and unfavorable weather conditions by reducing energy expenditure and voluntary food intake. We investigated in a study on red deer whether rates of peptide and glucose transport in the small intestines are also reduced during winter as part of the thrifty phenotype of winter-acclimatized animals, or whether transport rates are increased during winter in order to exploit poor forage more efficiently. Our results support the latter hypothesis. We found in a feeding experiment that total energy intake was considerably lower during winter despite ad libitum feeding. Together with reduced food intake, mass of visceral organs was significantly lower and body fat reserves were used as metabolic fuel in addition to food. However, efficacy of nutrient absorption seemed to be increased simultaneously. Extraction of crude protein from forage was higher in winter animals, at any level of crude protein intake, as indicated by the lower concentration of crude protein in feces. In line with these in vivo results, Ussing chamber experiments revealed greater electrogenic responses to both peptides and glucose in the small intestines of winter-acclimatized animals, and peptide uptake into jejunal brush-border membrane vesicles was increased. We conclude that reduced appetite of red deer during winter avoids energy expenditure for unproductive search of scarcely available food and further renders the energetically costly maintenance of a large gut and visceral organs unnecessary. Nevertheless, extraction of nutrients from forage is more efficient in the winter to attenuate an inevitably negative energy balance.

Summer fades, deer change: Photoperiodic control of cellular seasonal acclimatization of skeletal muscle.

We found major seasonal changes of polyunsaturated fatty acids (PUFAs) in muscular phospholipids (PL) in a large non-hibernating mammal, the red deer (Cervus elaphus). Dietary supply of essential linoleic acid (LA) and α-linolenic acid (ALA) had no, or only weak influence, respectively. We further found correlations of PL PUFA concentrations with the activity of key metabolic enzymes, independent of higher winter expression. Activity of the sarcoplasmic reticulum (SR) Ca++-ATPase increased with SR PL concentrations of n-6 PUFA, and of cytochrome c oxidase and citrate synthase, indicators of ATP-production, with concentrations of eicosapentaenoic acid in mitochondrial PL. All detected cyclic molecular changes were controlled by photoperiod and are likely of general relevance for mammals living in seasonal environments, including humans. During winter, these changes at the molecular level presumably compensate for Arrhenius effects in the colder peripheral body parts and thus enable a thrifty life at lower body temperature.

The Influence of Photoperiod, Intake of Polyunsaturated Fatty Acids, and Food Availability on Seasonal Acclimatization in Red Deer (Cervus elaphus).

Hypometabolism and hypothermia are common reactions of birds and mammals to cope with harsh winter conditions. In small mammals, the occurrence of hibernation and daily torpor is entrained by photoperiod, and the magnitude of hypometabolism and decrease of body temperature (Tb) is influenced by the dietary supply of essential polyunsaturated fatty acids. We investigated whether similar effects exist in a non-hibernating large mammal, the red deer (Cervus elaphus). We fed adult females with pellets enriched with either linoleic acid (LA) or α-linolenic acid (ALA) during alternating periods of ad libitum and restricted feeding in a cross-over experimental design. Further, we scrutinized the role of photoperiod for physiological and behavioral seasonal changes by manipulating the amount of circulating melatonin. The deer were equipped with data loggers recording heart rate, core and peripheral Tb, and locomotor activity. Further, we regularly weighed the animals and measured their daily intake of food pellets. All physiological and behavioral parameters measured varied seasonally, with amplitudes exacerbated by restricted feeding, but with only few and inconsistent effects of supplementation with LA or ALA. Administering melatonin around the summer solstice caused a change into the winter phenotype weeks ahead of time in all traits measured. We conclude that red deer reduce energy expenditure for thermoregulation upon short daylength, a reaction amplified by food restriction.

Insular giant leporid matured later than predicted by scaling.

The island syndrome describes morphological, behavioral, and life history traits that evolve in parallel in endemic insular organisms. A basic axiom of the island syndrome is that insular endemics slow down their pace of life. Although this is already confirmed for insular dwarfs, a slow life history in giants may not be adaptive, but merely a consequence of increasing body size. We tested this question in the fossil insular giant leporid Nuralagus rex. Using bone histology, we constructed both a continental extant taxon model derived from experimentally fluorochrome-labeled Lepus europaeus to calibrate life history events, and a growth model for the insular taxon. N. rex grew extremely slowly and delayed maturity well beyond predictions from continental phylogenetically corrected scaling models. Our results support the life history axiom of the island syndrome as generality for insular mammals, regardless of whether they have evolved into dwarfs or giants.

Sex-specific selection for MHC variability in Alpine chamois.

BACKGROUND: In mammals, males typically have shorter lives than females. This difference is thought to be due to behavioural traits which enhance competitive abilities, and hence male reproductive success, but impair survival. Furthermore, in many species males usually show higher parasite burden than females. Consequently, the intensity of selection for genetic factors which reduce susceptibility to pathogens may differ between sexes. High variability at the major histocompatibility complex (MHC) genes is believed to be advantageous for detecting and combating the range of infectious agents present in the environment. Increased heterozygosity at these immune genes is expected to be important for individual longevity. However, whether males in natural populations benefit more from MHC heterozygosity than females has rarely been investigated. We investigated this question in a long-term study of free-living Alpine chamois (Rupicapra rupicapra), a polygynous mountain ungulate. RESULTS: Here we show that male chamois survive significantly (P = 0.022) longer if heterozygous at the MHC class II DRB locus, whereas females do not. Improved survival of males was not a result of heterozygote advantage per se, as background heterozygosity (estimated across twelve microsatellite loci) did not change significantly with age. Furthermore, reproductively active males depleted their body fat reserves earlier than females leading to significantly impaired survival rates in this sex (P < 0.008). This sex-difference was even more pronounced in areas affected by scabies, a severe parasitosis, as reproductively active males were less likely to survive than females. However, we did not find evidence for a survival advantage associated with specific MHC alleles in areas affected by scabies. CONCLUSIONS: Increased MHC class II DRB heterozygosity with age in males, suggests that MHC heterozygous males survive longer than homozygotes. Reproductively active males appear to be less likely to survive than females most likely because of the energetic challenge of the winter rut, accompanied by earlier depletion of their body fat stores, and a generally higher parasite burden. This scenario renders the MHC-mediated immune response more important for males than for females, which implies a relatively stronger selection pressure on MHC genes in males than in females.

Local elastic properties of a metallic glass.

The nature of non-crystalline materials causes the local potential energy of a cluster of atoms or molecules to vary significantly in space. Different configurations of an ensemble of atoms in a metallic glass lead therefore to a distribution of elastic constants which also changes in space. This is totally different to their crystalline counterparts, where a long-range order exists in space and therefore a much more unified elastic modulus is expected. Using atomic force acoustic microscopy, we present data which show that the local so-called indentation modulus M indeed exhibits a wide distribution on a scale below 10 nm in amorphous PdCuSi, with ΔM/M≈30%. About 10(4) atoms are probed in an individual measurement. Crystallized PdCuSi shows a variation that is 10-30 times smaller and which is determined by the resolution of the microscope and by the polycrystalline structure of the material.

Physiological implications of pair-bond status in greylag geese.

In group-living vertebrates, reliable social allies play a decisive role in dealing with stressors. For example, support by social allies is known to dampen glucocorticoid responses. It remains unknown, however, how social embedding affects the sympatho-adrenergic axis as indicated by heart rate (HR) in non-human animals. We studied the relationships between HR, pair-bond status and distance from the pair-partner in twenty-five free-ranging greylag geese (Anser anser) in a natural social environment. In three individuals, we investigated HR responses following partner loss. Overall, we found a context- and sex-dependent difference in HR between paired and unpaired individuals, paired males having a lower HR during agonistic encounters, and unpaired females having a lower HR during resting. Also, in paired females HR increased with increasing distance from the partner. Our data suggest that HR is modulated by pair-bond status in greylag geese in a context- and sex-dependent manner, which may be representative for social vertebrates in general. Despite the low sample size, the present study indicates that proper social embedding may optimize an individual's physiological investment in the social domain. This reduces individual energy expenditure and may benefit health and reproductive success.

Effects of severe anthropogenic disturbance on the heart rate and body temperature in free-living greylag geese (Anser anser).

Anthropogenic disturbances are a major concern for the welfare and conservation of wildlife. We recorded heart rate and body temperature of 20 free-living greylag geese in response to a major regularly re-occurring anthropogenic disturbance-New Year's Eve fireworks. Heart rate and body temperature were significantly higher in the first and second hour of the new year, compared with the same hour on the 31st of December, the average during December and the average during January. Heart rate and body temperature was not significantly affected by sex or age. From 0200 to 0300 onwards, 1st of January heart rates did not significantly differ from the other periods; however, body temperatures were significantly increased until 0300-0400. From 0400 to 0500, heart rate was not affected by any of the investigated factors, whereas body temperature was significantly increased on the 1st of January compared with the 31st of December and the December average but not compared with the January average. To conclude, our results show that New Year's Eve fireworks cause a substantial physiological response, indicative of a stress response in greylag geese, which is costly in terms of energy expenditure.

Effect of season and diet on heart rate and blood pressure in female red deer (Cervus elaphus) anaesthetised with medetomidine-tiletamine-zolazepam.

Temperate zone ungulates like red deer (Cervus elaphus) show pronounced seasonal acclimatisation. Hypometabolism during winter is associated with cardiovascular changes, including a reduction in heart rate (fH) and temporal peripheral vasoconstriction. How anaesthesia with vasoactive substances such as medetomidine affect the seasonally acclimatised cardiovascular system is not yet known. We anaesthetised eleven healthy female red deer with medetomidine (0.1 mg/kg) and tiletamine/zolazepam (3 mg/kg) twice in winter (ad libitum and restricted feed) and in summer (ad libitum and restricted feed), with a two-week washout-period in-between, to test for the effect of season, food availability and supplementation with omega-3 or omega-6 polyunsaturated fatty acid (PUFA) on fH and arterial blood pressure (ABP) during anaesthesia. Six animals received pellets enriched with omega-6 fatty acids (FA), and five animals with omega-3 FA. Anaesthesia significantly decreased fH in summer but not in winter and ABP was lower in winter (p < 0.05). The combination of omega-6 FA enriched pellets and food restriction resulted in a lower fH and higher ABP during anaesthesia with more pronounced changes in winter (p < 0.001). Our results demonstrate that season, food availability and type of PUFA supplementation in red deer affect the cardiovascular system during anaesthesia.

Regulation of heart rate and rumen temperature in red deer: effects of season and food intake.

Red deer, Cervus elaphus, like other temperate-zone animals, show a large seasonal fluctuation in energy intake and expenditure. Many seasonal phenotypic adjustments are coordinated by endogenous signals entrained to the photoperiod. The cues determining variation in the resting metabolism of ungulates remain equivocal, however, largely because of the confounding effects of food intake and thus the heat increment of feeding. To distinguish endogenous seasonal and environmental effects on metabolism, we subjected 15 female red deer to two feeding treatments, 80% food restriction and low/high protein content, over two winter seasons in a cross-over design experiment. We used rumen-located transmitters to measure heart rate and rumen temperature, which provided indices of metabolism and core body temperature, respectively. Our mixed model (R²=0.85) indicated a residual seasonal effect on mean daily heart rate that was unexplained by the pellet food treatments, activity, body mass or air temperature. In addition to an apparently endogenous down-regulation of heart rate in winter, the deer further reduced heart rate over about 8 days in response to food restriction. We found a strong correlation between rumen temperature and seasonal or periodic variation in heart rate. An effect of lowered rumen (and hence core body) temperature was enhanced during winter, perhaps owing to peripheral cooling, which is known to accompany bouts of hypometabolism. Our experimental results therefore support the hypothesis that a reduction in body temperature is a physiological mechanism employed even by large mammals, like red deer, to reduce their energy expenditure during periods of negative energy balance.

Recurrence of membranoproliferative glomerulonephritis after renal transplantation in Denys-Drash.

Denys-Drash syndrome (DDS) consists of the triad of nephropathy, male pseudohermaphroditism, and Wilms tumor caused by mutations within exons 8 or 9 of the Wilms tumor suppressor gene 1. Early onset nephrotic syndrome progresses to end-stage renal failure. The characteristic histological lesion is diffuse mesangial sclerosis. Here, we report on a boy with DDS who presented early with diffuse mesangial sclerosis, but subsequently also developed immune complex glomerulonephritis with a membranoproliferative pattern (MPGN-pattern GN) in his native kidneys. Four years after renal transplantation, immune complex glomerulonephritis with an MPGN pattern recurred in the renal graft resulting in proteinuria and progressive renal insufficiency.

Labelling experiments in red deer provide a general model for early bone growth dynamics in ruminants.

Growth rates importantly determine developmental time and are, therefore, a key variable of a species' life history. A widely used method to reconstruct growth rates and to estimate age at death in extant and particularly in fossil vertebrates is the analysis of bone tissue apposition rates. Lines of arrested growth (LAGs) are of special interest here, as they indicate a halt in bone growth. However, although of great importance, the time intervals between, and particularly the reason of growth arrests remains unknown. Therefore, experiments are increasingly called for to calibrate growth rates with tissue types and life history events, and to provide reliable measurements of the time involved in the formation of LAGs. Based on in vivo bone labelling, we calibrated periods of bone tissue apposition, growth arrest, drift and resorption over the period from birth to post-weaning in a large mammal, the red deer. We found that bone growth rates tightly matched the daily weight gain curve, i.e. decreased with age, with two discrete periods of growth rate disruption that coincided with the life history events birth and weaning, that were visually recognisable in bone tissue as either partial LAGs or annuli. Our study identified for the first time in a large mammal a general pattern for juvenile bone growth rates, including periods of growth arrest. The tight correlation between daily weight gain and bone tissue apposition suggests that the red deer bone growth model is valid for ruminants in general where the daily weight gain curve is comparable.

Maternal effects on reproduction in the precocial European hare (Lepus europaeus).

In female mammals, reproduction, and in particular lactation, is the energetically most exigent life-history phase. Reproduction is strongly controlled by body reserves and food availability, so females with better body condition or food supply are believed to have higher reproductive output. Additionally, the growth and mortality of young mammals depends on their postnatal development. Therefore, the degree of precociality affects energetic demands for both mothers and young. To study the reproductive performance of the precocial European hare (Lepus europaeus), we analysed relationships between six predictor variables describing maternal and environmental effects and nine response variables relating to reproduction from 217 captive females. We compared the data with those of precocial and altricial mammal species from an extensive literature search. For hares, we found: (1) Heavier females had heavier litters at birth. (2) In summer and spring, total litter mass was larger than in winter. (3) At the end of lactation, the litters of multiparous females were heavier than those of primiparous females. (4) Both older females and females giving birth for the first time had relatively high leveret mortality during lactation. Comparing our results with the literature for other mammals revealed that the body condition (i.e., body mass) of females before birth is predictive of reproductive parameters in both precocial and altricial species. In the precocial hare, female body condition is no longer predictive of reproductive parameters at the end of lactation, whereas in altricial species, female body condition remains predictive of reproduction (litter mass at the end of lactation, offspring mortality) until the end of lactation. We conclude that these effects are caused by precocial offspring feeding on solid food soon after birth and, thus, being less dependent on the mother's body condition during lactation than altricial offspring. In line with this, precociality might have evolved as a way of buffering offspring against maternal effects.

Determinants of heart rate in Svalbard reindeer reveal mechanisms of seasonal energy management.

Seasonal energetic challenges may constrain an animal's ability to respond to changing individual and environmental conditions. Here, we investigated variation in heart rate, a well-established proxy for metabolic rate, in Svalbard reindeer (Rangifer tarandus platyrhynchus), a species with strong seasonal changes in foraging and metabolic activity. In 19 adult females, we recorded heart rate, subcutaneous temperature and activity using biologgers. Mean heart rate more than doubled from winter to summer. Typical drivers of energy expenditure, such as reproduction and activity, explained a relatively limited amount of variation (2-6% in winter and 16-24% in summer) compared to seasonality, which explained 75% of annual variation in heart rate. The relationship between heart rate and subcutaneous temperature depended on individual state via body mass, age and reproductive status, and the results suggested that peripheral heterothermy is an important pathway of energy management in both winter and summer. While the seasonal plasticity in energetics makes Svalbard reindeer well-adapted to their highly seasonal environment, intraseasonal constraints on modulation of their heart rate may limit their ability to respond to severe environmental change. This study emphasizes the importance of encompassing individual state and seasonal context when studying energetics in free-living animals. This article is part of the theme issue 'Measuring physiology in free-living animals (Part II)'.

Complete genome sequence and lifestyle of black-pigmented Corynebacterium aurimucosum ATCC 700975 (formerly C. nigricans CN-1) isolated from a vaginal swab of a woman with spontaneous abortion.

BACKGROUND: Corynebacterium aurimucosum is a slightly yellowish, non-lipophilic, facultative anaerobic member of the genus Corynebacterium and predominantly isolated from human clinical specimens. Unusual black-pigmented variants of C. aurimucosum (originally named as C. nigricans) continue to be recovered from the female urogenital tract and they are associated with complications during pregnancy. C. aurimucosum ATCC 700975 (C. nigricans CN-1) was originally isolated from a vaginal swab of a 34-year-old woman who experienced a spontaneous abortion during month six of pregnancy. For a better understanding of the physiology and lifestyle of this potential urogenital pathogen, the complete genome sequence of C. aurimucosum ATCC 700975 was determined. RESULTS: Sequencing and assembly of the C. aurimucosum ATCC 700975 genome yielded a circular chromosome of 2,790,189 bp in size and the 29,037-bp plasmid pET44827. Specific gene sets associated with the central metabolism of C. aurimucosum apparently provide enhanced metabolic flexibility and adaptability in aerobic, anaerobic and low-pH environments, including gene clusters for the uptake and degradation of aromatic amines, L-histidine and L-tartrate as well as a gene region for the formation of selenocysteine and its incorporation into formate dehydrogenase. Plasmid pET44827 codes for a non-ribosomal peptide synthetase that plays the pivotal role in the synthesis of the characteristic black pigment of C. aurimucosum ATCC 700975. CONCLUSIONS: The data obtained by the genome project suggest that C. aurimucosum could be both a resident of the human gut and possibly a pathogen in the female genital tract causing complications during pregnancy. Since hitherto all black-pigmented C. aurimucosum strains have been recovered from female genital source, biosynthesis of the pigment is apparently required for colonization by protecting the bacterial cells against the high hydrogen peroxide concentration in the vaginal environment. The location of the corresponding genes on plasmid pET44827 explains why black-pigmented (formerly C. nigricans) and non-pigmented C. aurimucosum strains were isolated from clinical specimens.

Marmots.

Walter Arnold introduces the biology of marmots.