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International audience; Abstract Working animals spend hours each day in close contact with humans and require training to understand commands and fulfil specific tasks. However, factors driving cooperation between humans and animals are still unclear, and novel situations may present challenges that have been little-studied to-date. We investigated factors driving cooperation between humans and animals in a working context through behavioural experiments with 52 working semi-captive Asian elephants. Human-managed Asian elephants constitute approximately a third of the remaining Asian elephants in the world, the majority of which live in their range countries working alongside traditional handlers. We investigated how the familiarity and experience of the handler as well as the elephant’s age and sex affected their responses when asked to perform a basic task and to cross a novel surface. The results highlighted that when novelty is involved in a working context, an elephant’s relationship length with their handler can affect their cooperation: elephants who had worked with their handler for over a year were more willing to cross the novel surface than those who had a shorter relationship with their handler. Older animals also tended to refuse to walk on the novel surface more but the sex did not affect their responses. Our study contributes much needed knowledge on human-working animal relationships which should be considered when adjusting training methods and working habits.

Epigenetic regulation of cell and tissue function requires the coordinated action of transcription factors. However, their combinatorial activities during regeneration remain largely unexplored. Here, we discover an unexpected interaction between the cytoprotective transcription factor NRF2 and p63- a key player in epithelial morphogenesis. Chromatin immunoprecipitation combined with sequencing and reporter assays identifies enhancers and promoters that are simultaneously activated by NRF2 and p63 in human keratinocytes. Modeling of p63 and NRF2 binding to nucleosomal DNA suggests their chromatin-assisted interaction. Pharmacological and genetic activation of NRF2 increases NRF2–p63 binding to enhancers and promotes keratinocyte proliferation, which involves the common NRF2–p63 target cyclin-dependent kinase 12. These results unravel a collaborative function of NRF2 and p63 in the control of epidermal renewal and suggest their combined activation as a strategy to promote repair of human skin and other stratified epithelia.

A fundamental challenge in ecology is to identify the processes which explain how species come to occupy diverse communities. There is uncertainty about whether community composition arises through deterministic processes, whereby trait differences between species make them more or less adapted to certain environmental conditions. We tested the capacity for deterministic processes to explain the long-term dynamics of phytoplankton community structure in Lake Muggelsee—a shallow and eutrophic lake in Berlin, Germany using a trait-based approach. We developed a null model representing random processes alone by generating a time series of random trait distributions derived from the observed long-term data. We determined the extent to which deterministic processes lead to nonrandom patterns in phytoplankton communities by comparing the resulting null-trait distributions with the observed trait distributions in the long-term data. We found that phytoplankton communities fell along a gradient from random to nonrandom trait distributions, suggesting that deterministic processes alone do not fully describe the community structure. Nonrandom patterns were observed in communities with high species richness and during late spring as well as early winter. But neither species richness nor seasonality explained nonrandom patterns consistently for different metrics and traits given the high relevance of random trait distribution patterns. Thus, deterministic and stochastic processes may be needed to fully explain the structure of phytoplankton communities under changing environmental conditions.

Declining wild populations combined with accumulating captive populations of e.g. livestock, pets, draught and zoo animals have resulted in some threatened species with substantial proportions of their populations in captivity. The interactions animals have with humans in captivity depend on handler familiarity and relationship quality and can affect animal health, growth and reproduction with consequences for the success of conservation programmes. However, assessments of how specific human–animal relationships affect a range of physiological and behavioural outcomes are rare. Here, we studied semi-captive Asian elephants with detailed records of elephant–handler (mahout) relationships and veterinary management, allowing assessment of multiple welfare indicators in relation to specific mahout–elephant relationship lengths and mahout experience. These included measures of physiological stress (faecal glucocorticoid metabolite [FGM], heterophil:lymphocyte ratio [H:L]), muscle damage (creatine kinase [CK]), immunological health (total white blood cell count [TWBC]) and behaviour (response to mahout verbal commands). We found no evidence that FGM or H:L related to aspects of the mahout–elephant relationship. Longer overall mahout experience (i.e. years of being a mahout) was linked to increased muscle damage and inflammation, but the lengths of specific mahout–elephant relationships were inversely associated with muscle damage in working-age elephants. Elephants responded more to familiar mahouts in behavioural tasks and faster to mahouts they had known for longer. In summary, our results found little evidence that the mahout–elephant relationship affects physiological stress in this population based on FGM and H:L, but mahout experience and relationships were linked to other physiological responses (CK, TWBC), and elephants require behavioural adjustment periods following mahout changes.

The area of the Inner Asian Mountain Corridor (IAMC) follows the foothills and piedmont zones around the northern limits of Asia’s interior mountains, connecting two important areas for human evolution: the Fergana valley and the Siberian Altai. Prior research has suggested the IAMC may have provided an area of connected refugia from harsh climates during the Pleistocene. To date, this region contains very few secure, dateable Pleistocene sites, but its widely available carbonate deposits present an opportunity for discovering cave sites, which generally preserve longer sequences and organic remains. Here we present two models for predicting karstic cave and rockshelter features in the Kazakh portion of the IAMC. The 2018 model used a combination of lithological data and unsupervised landform classification, while the 2019 model used feature locations from the results of our 2017-2018 field surveys in a supervised classification using a minimum-distance classifier and morphometric features derived from the ASTER digital elevation model (DEM). We present the results of two seasons of survey using two iterations of the karstic cave models (2018 and 2019), and evaluate their performance during survey. In total, we identified 96 cave and rockshelter features from 2017-2019. We conclude that this model-led approach significantly reduces the target area for foot survey.

This study examined the effects of a 3-wk ad libitum, low-carbohydrate (50 g·d) high-fat (~70% of calories) (LCHF) diet on markers of endurance performance in middle-age, recreationally competitive male runners.All subjects (n = 8) after their normal high-carbohydrate (HC) diet had anthropometric measures assessed and completed five 10-min running bouts at multiple individual race paces in the heat while physiological variables, metabolic variables, and perceptual responses were recorded. After 20 min of rest, participants completed a 5-km time trial on a road course. Subjects then consumed an LCHF diet for 3 wk and returned for repeat testing.Body mass and seven-site skinfold thickness sum decreased by approximately 2.5 kg (P0.01) and 13 mm (P0.05) after LCHF diet. Rectal temperature was higher after the first 10 min of exercise (37.7°C ± 0.3°C vs 37.3°C ± 0.2°C) in the HC diet but did not differ at any other time with LCHF diet. Heart rate and perceptual measures did not display any consistent differences between treatments excluding thirst sensation for LCHF diet. RER and carbohydrate oxidation declined significantly, whereas fat oxidation increased after LCHF diet for every pace (P0.01). There was no significant difference (P = 0.25) in a 5-km time trial performance, but LCHF diet (23.45 ± 2.25 min) displayed a trend of improved performance versus HC (23.92 ± 2.57 min).Improved body composition and fat oxidation from LCHF diet potentially negate expected performance decrement from reduced carbohydrate use late in exercise for nonelite runners. An acute decrease in training capacity is expected; however, if performance improvement is not exhibited after 3 wk, diet cessation is suggested for negative responders.

Zusammenfassung Bei ärztlicher Versorgung von Minderjährigen, die sexuelle Gewalt erlebt haben, kommt es für die Rechtfertigung des mit der Behandlung verbundenen körperlichen Eingriffs allein auf die Einwilligung der Minderjährigen selbst an, wenn diese im Hinblick auf die medizinischen Maßnahmen bereits einwilligungsfähig sind. Nur wenn im Einzelfall in Bezug auf die konkrete medizinische Maßnahme keine Einwilligungsfähigkeit vorliegt, ist eine Einwilligung der sorgeberechtigten Eltern erforderlich.

Patella-alta is very common in patients with Cerebral Palsy (CP). While several diagnostic x-ray indices have been developed for patella-alta in general, the specific relationship with walking dysfunction in CP is only partly understood.33 participants with bilateral spastic CP between 4 and 20 years (GMFCS I-II without previous surgery) that underwent 3D gait analysis as well as a radiographic exam within 0.8 (SD 1.2) months were retrospectively included. The Caton-Deschamps, the Insall-Salvati and the Koshino-Index, as well as the moment-arms of the quadriceps, the pattelar-tendon length and patellar tilt angle were analyzed from x-rays. During gait, tempo-spatial parameters, the knee flexion kinematics, the knee moments and the moment impulse were calculated and correlated to x-ray parameters.Smaller quadriceps moment-arms were related to slower walking speed (r=0.48, P=0.005) and less knee extension during stance (r=0.68 P0.001). Smaller quadriceps moment arms and longer patellar-tendons were also significantly related to a larger knee flexion moment impulse in the second half of the stance phase (r=-0.36, P=0.045 and r=0.39, P=0.028) and hence to more abnormal knee loads. Yet, none of the traditional indices was related to any parameter of gait.Traditional radiographic indices for patella-alta possess little to no informative value for walking dysfunction in individuals with CP suspected to have knee pathology. Smaller moment-arms are a key feature of patellofemoral pathology in CP reducing the knee extensor mechanism, an aspect which is not sufficiently picked up by traditional indices.

Habitat-associated crypsis may affect perceived predation vulnerability, selecting for different predator avoidance strategies. Glucocorticoids could mediate the adjustment of escape responses to the extent of crypsis, introducing an overlooked source of variation in glucocorticoid–fitness relationships. However, prolonged exposure to elevated glucocorticoids may be costly, leading to accelerated telomere loss and, consequently, senescence. Here, we examined how nest cover and immunoreactive faecal glucocorticoid metabolite (fGCM) levels are linked to hatching success and telomere length in breeding female Common Eiders (Somateria mollissima (L., 1758)). We hypothesized that the degree of nest crypsis, reflecting differences in perceived predation risk, would moderate the relationship between reproductive success and fGCM levels. We also expected that telomere length would be shorter in birds with higher glucocorticoid concentration. Results showed that individuals with high fGCM levels had higher hatching success in nests with low cover, while low fGCM levels were more successful in well-concealed nests. We found that shorter telomeres were associated with high fGCM in nesting sites offering little cover and with low fGCM in well-concealed ones. This study provides the first evidence of habitat-dependent moderation of the relationships between stress physiology, telomere length and hatching success.

The frequent ACE insertion/deletion polymorphism (I/D) is, albeit inconsistently, associated with impaired glucose tolerance and insulin resistance. We recently observed an enhanced upregulation of ACE by elevated fat intake in GG-carriers of the I/D-surrogate rs4343 variant and therefore investigated its potential nutrigenetic role in glucose metabolism. In this nutritional intervention study 46 healthy and non-obese twin pairs consumed recommended low fat diets for 6 weeks before they received a 6-week high fat (HF) diet under isocaloric conditions. Intravenous glucose tolerance tests were performed before and after 1 and 6 weeks of HF diet. While glucose tolerance did not differ between genotypes at baseline it significantly declined in GG-carriers after 6 weeks HF diet (p = 0.001) with higher 2 h glucose and insulin concentrations compared to AA/AG-carriers (p = 0.003 and p = 0.042). Furthermore, the gene-diet interaction was confirmed in the cross-sectional Metabolic Syndrome Berlin Potsdam study (p = 0.012), with the GG-genotypes being significantly associated with prevalent type 2 diabetes for participants with high dietary fat intake ≥37% (GG vs. AA/AG, OR 2.36 [1.02–5.49], p = 0.045). In conclusion, the association between the rs4343 variant and glucose tolerance is modulated by dietary fat intake. The ACE rs4343 variant is a novel nutrient-sensitive type 2 diabetes risk marker potentially applicable for nutrigenetic dietary counseling.

It is unclear whether bacterial colonization in hidradenitis suppurativa/acne inversa (HS) comprises a primary cause, triggering factor or secondary phenomenon of the disease pathogenesis. Furthermore, the connection between certain bacterial species, the disease severity and its localization is unknown. Bacterial species were isolated from HS lesions to reveal a potential correlation with localization and disease severity. Ninety swab tests were prospectively obtained from 90 HS lesions of 50 consecutive patients. The material was cultured under aerobic and anaerobic conditions. The identified species were statistically correlated with Hurley stage and localization of the lesions. The most prevalent isolates were reported. Hurley stage significantly correlated with disease localization. Particular bacterial species were associated with "extended" disease and Hurley III stage with the detection of both aerobic and anaerobic bacteria and with a higher number of species. The presence of bacterial species is dependent on the local milieu, which correlates with the localization of the disease, its clinical manifestations and its extension.

Calcium and 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) are promoters of epithelial cell functions; however their effects on sebaceous glands are unknown. In this study, morphology, ultrastructure, cell numbers, lipid synthesis and apoptosis of SZ95 sebocytes were assessed in vitro under different concentrations of extracellular calcium with or without 1,25(OH)2D3. Moreover, serum calcium and 1,25(OH)2D3 levels were assessed in acne and non-acne patients (controls). Under conditions of low extracellular calcium, lipogenesis and cell detachment were observed. Increasing extracellular calcium enhanced sebocyte numbers, induced epithelial morphology and reduced lipogenesis. Moreover, a reduction in extracellular calcium reduced E-cadherin and enhanced caspase 3/7 activity (apoptosis), whereas calcium chelation by EGTA (ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid) resulted in enhanced lipogenesis. 1,25(OH)2D3 decreased sebaceous lipogenesis, but also induced signs of autophagy. In the clinical study, patients and controls exhibited normal serum calcium levels. Younger acne patients presented lower 1,25(OH)2D3 levels than did older ones. In conclusion, extracellular calcium and 1,25(OH)2D3 regulate sebocyte morphology, increase cell numbers, decrease sebaceous lipogenesis and induce cell autophagy in vitro. The increased ionized calcium and the reduced 1,25(OH)2D3 levels detected in the serum of younger patients with acne may contribute respectively to increased sebaceous gland volume and enhanced lipogenesis.

OBJECTIVES: To assess knowledge deficits of patients/parents and prevention strategies. METHODS: After receiving ethics approval, we performed a controlled, quasi-randomised, prospective intervention study. We enrolled patients/parents involved in managing oral medicines in three groups: control (routine care only), handbook intervention and pharmaceutical counselling intervention group. At baseline and after the interventions, we assessed patients’/parents’ knowledge deficits (incorrect or missing answers) by questionnaire. RESULTS: We enrolled 64 patients/parents. At baseline, knowledge deficits among the groups were similar: 17% in controls, 22% in the handbook group and 24% in the pharmaceutical counselling group. After the intervention, knowledge deficits decreased to 13% in the handbook group and to 8% in the pharmaceutical counselling group (NS; p=0.003 compared with controls, respectively). For controls, knowledge deficits remained almost unchanged (19%). Results for the pharmaceutical counselling group showed a strong correlation between baseline knowledge deficits and the extent of the deficit decrease after the intervention (τ=−0.74; p

The sebaceous gland displays key functions of the human skin, such as hormone synthesis in situ, antimicrobial activity and participation to inflammatory responses. Consequently, there is an emerging need of advanced in vitro models to study complex interactions between the sebaceous gland and the other skin compartments. Despite the evolution of both full-skin organ culture and reconstructed three-dimensional skin models, no satisfactory solutions have been provided for the integration of sebaceous glands and/or sebaceous gland cells in those models, probably due to their problematic maintenance both in vitro and ex vivo. We have developed a coculture model of explant skin in direct contact with immortalized SZ95 sebocytes, which resulted in overall improved structural integrity of the epidermis, higher percentage of proliferating basal epidermal cells and reduced apoptosis of differentiating keratinocytes after 6 days, as detected by Ki67 and TUNEL staining, respectively. Furthermore SZ95 sebocytes exhibited morphological and biochemical signs of normal differentiation and lipid accumulation, while interleukin-6 expression in the supernatant of the cocultures was decreased in comparison with the control. The data provide evidence of a beneficial interaction between sebocytes and skin explants and provide the rationale for their integration in future three-dimensional skin models.

Low environmental humidity aggravates symptoms of the inflammatory skin disease atopic dermatitis (AD). Using mice that develop AD-like signs, we show that an increase in environmental humidity rescues their cutaneous inflammation and associated epidermal abnormalities. Quantitative proteomics analysis of epidermal lysates of mice kept at low or high humidity identified humidity-regulated proteins, including chloride channel accessory 3A2 (CLCA3A2), a protein with previously unknown function in the skin. The epidermis of patients with AD, organotypic skin cultures under dry conditions, and cultured keratinocytes exposed to hyperosmotic stress showed up-regulation of the nonorthologous human homolog CLCA2. Hyperosmolarity-induced CLCA2 expression occurred via p38/c-Jun N-terminal kinase–activating transcription factor 2 signaling. CLCA2 knockdown promoted keratinocyte apoptosis induced by hyperosmotic stress through impairment of cell-cell adhesion. These findings provide a mechanistic explanation for the beneficial effect of high environmental humidity for AD patients and identify CLCA3A2/CLCA2 up-regulation as a mechanism to protect keratinocytes from damage induced by low humidity.

cope Obesity is associated with hyperlipidemia, hepatic steatosis, and low-grade inflammation. Studies have shown that MUFA as well as PUFA have beneficial effects on blood lipids and the inflammatory state. Methods and results This study investigates the effects of a daily supplementation of either 50 g of rapeseed/canola (RA) or olive (OL) oil over 4 wk on serum lipids, serum liver enzymes, and inflammatory gene expression in subcutaneous (s. c.) adipose tissue in obese men. Consuming RA resulted in increased serum n-3 fatty acids and a reduction in total cholesterol, LDL cholesterol, and serum aspartate aminotransferase compared to OL. In s. c. adipose tissue, gene expression of the pro-inflammatory cytokine IL6 was reduced in RA compared to OL. However, after 4 h after a test meal, containing the appropriate oil, white bread, and 400 mL of liquid diet drink (835 kcal in total), gene expression of IL6, IL1B, and EMR1 (egf-like module containing Mucin-like hormone receptor-like 1) was increased in RA and of monocyte chemoattractant protein-1 (CCL2) in both RA and OL. Conclusion This demonstrates that consuming RA for 4 wk improves serum lipids, liver enzymes, and basal inflammation in s. c. adipose tissue, but it mediates an acute pro-inflammatory response in adipose tissue upon consuming a meal.

Background Angiotensin‐converting enzyme ( ACE ) plays a major role in blood pressure regulation and cardiovascular homeostasis. Contrary to the assumption that ACE levels are stable, circulating ACE has been shown to be altered in obesity and weight loss. We sought to examine effects of a high‐saturated‐fat ( HF ) diet on ACE within the NU triGenomic Analysis in Twins ( NUGAT ) study. Methods and Results Forty‐six healthy and nonobese twin pairs initially consumed a carbohydrate‐rich, low‐fat diet over a period of 6 weeks to standardize for nutritional behavior prior to the study, followed by 6 weeks of HF diet under isocaloric conditions. After 6 weeks of HF diet, circulating ACE concentrations increased by 15% ( P =1.6×10 −30 ), accompanied by an increased ACE gene expression in adipose tissue ( P =3.8×10 −6 ). Stratification by ACE rs4343, a proxy for the ACE insertion/deletion polymorphism (I/D), revealed that homozygous carriers ( GG ) of the variant had higher baseline ACE concentrations ( P =7.5×10 −8 ) and additionally showed a 2‐fold increase in ACE concentrations in response to the HF diet as compared to non‐ or heterozygous carriers ( AA / AG , P =2×10 −6 ). GG carriers also responded with higher systolic blood pressure as compared to AA / AG carriers ( P= 0.008). The strong gene‐diet interaction was confirmed in a second independent, cross‐sectional cohort, the Metabolic Syndrome Berlin Potsdam (MeSyBePo) study. Conclusions The HF ‐diet‐induced increase of ACE serum concentrations reveals ACE to be a potential molecular link between dietary fat intake and hypertension and cardiovascular disease ( CVD ). The GG genotype of the ACE rs4343 polymorphism represents a robust nutrigenetic marker for an unfavorable response to high‐saturated‐fat diets. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01631123.

Effective radiation dose from a single coronary artery calcification CT scan can range from 0.8 to 10.5 mSv, depending on the protocol. Reducing the effective radiation dose to reasonable levels without affecting diagnostic image quality can result in substantial dose reduction in CT.We prospectively compared tube voltages of 120 and 100 kV in a low-dose CT acquisition protocol for measuring coronary artery calcified plaque with prospectively electrocardiogram (ECG)-triggered high-pitch spiral acquisition.In 150 consecutive patients, measurement of coronary artery calcified plaque was performed with prospectively ECG-triggered high-pitch spiral acquisition. Imaging was first done with tube voltage of 120 kV voltage and subsequently repeated with 100 kV and otherwise unchanged parameters. CT was performed with a dual-source CT system with 280 milliseconds of rotation time, 2 × 128 slices, pitch of 3.4, triggered at 60% of the R-R interval. Tube current for both protocols was set at 80 mAs. With the use of a medium sharp reconstruction kernel (Siemens B35f), cross-sectional images were reconstructed with 3.0-mm slice thickness and 1.5-mm increment. Agatston scores were determined per patient for both scan settings by 2 independent readers with the use of a standard threshold of 130 HU for calcium detection. In addition, the Agatston score was calculated with a previously proposed threshold of 147 HU for 100-kV acquisitions.Mean image noise was 20 ± 5 and 27 ± 7 for 120 and 100 kV, respectively (P0.0001). Mean dose length product was 24 ± 6 cm · cGy for the 120-kV protocol and 14 ± 4 cm · cGy for the 100-kV protocol, corresponding to average estimated effective doses of 0.3 and 0.2 mSv (P0.0001). Five patients were excluded from the analysis. In the remaining 145 patients, using the standard tube voltage of 120 kV, any coronary calcium was detected in 76 identical patients by both observers. In 75 of these patients, calcium was also identified by both observers in 100-kV data sets, whereas 1 patient was scored negative by 1 reader and was assigned an Agatston score of 0.7 (threshold, 130 HU) and 0.2 (threshold, 147 HU) by the other. Interobserver disagreement for assigning a patient a zero Agatston score was the same for both scan settings (each 4 patients). The mean Agatston scores for 120-kV and 100-kV (threshold, 147 HU) scans were 105 ± 245 (range, 0-1865) and 116 ± 261 (range, 0-1917), respectively (P0.0001). Bland-Altman analysis indicated a systematic overestimation of the Agatston score with tube voltage of 100 kV and threshold of 147 HU (mean difference, 11; 95% limits of agreement, 62 to -40). Similar results were observed for coronary calcium volume scores.High-pitch spiral acquisition allows coronary calcium scoring with effective doses below 0.5 mSv. The use of 100-kV tube voltage further reduces effective radiation dose compared with the standard of 120 kV; however, it leads to significant overestimation of the Agatston score when the standard threshold of 130 HU is used. Adjusting the threshold to 147 HU leads to a better agreement compared with standard 120 kV protocols yet with a remaining systematic bias toward overestimation of the Agatston score. For high-pitch spiral acquisition mode, effective radiation dose reduction when using a 100-kV setting is minimal compared with the standard 120-kV setting and may be considered nonsignificant in a clinical setting.

Emerging infectious diseases (EIDs) are considered a major threat to global health. Most EIDs appear to result from increased contact between wildlife and humans, especially when humans encroach into formerly pristine habitats. Habitat deterioration may also negatively affect the physiology and health of wildlife species, which may eventually lead to a higher susceptibility to infectious agents and/or increased shedding of the pathogens causing EIDs. Bats are known to host viruses closely related to important EIDs. Here, we tested in a paleotropical forest with ongoing logging and fragmentation, whether habitat disturbance influences the occurrence of astro- and coronaviruses in eight bat species. In contrast to our hypothesis, anthropogenic habitat disturbance was not associated with corona- and astrovirus detection rates in fecal samples. However, we found that bats infected with either astro- or coronaviruses were likely to be coinfected with the respective other virus. Additionally, we identified two more risk factors influencing astrovirus shedding. First, the detection rate of astroviruses was higher at the beginning of the rainy compared to the dry season. Second, there was a trend that individuals with a poor body condition had a higher probability of shedding astroviruses in their feces. The identification of risk factors for increased viral shedding that may potentially result in increased interspecies transmission is important to prevent viral spillovers from bats to other animals, including humans.

Summary Background Interleukin (IL)-33 is a member of the IL-1 family and has been implicated in Th2-driven allergic diseases such as atopic dermatitis (AD) and asthma. The principal Th2 cytokine IL-4, found highly expressed in acute allergic eczema, is known to downregulate human β-defensin 2 (hBD2) expression in human keratinocytes and this is associated with superinfection in patients with AD. Objectives To investigate the effect of IL-33 on the expression of hBD2 in human keratinocytes. Methods hBD2 production by stimulated keratinocytes was measured by enzyme-linked immunosorbent assay. Results Our results showed that serum is a very potent inducer of hBD2 and 2·5% human serum was much more potent in inducing hBD2 than 20 ng mL−1 of tumour necrosis factor-α. Interestingly, serum from patients with AD showed an impaired ability to induce hBD2 in normal keratinocytes. IL-33 significantly downregulated serum-induced hBD2. The downregulatory capacity of IL-33 was found to be 1·5- to 2-fold weaker compared with IL-4. Conclusions Our data suggest that IL-33 can significantly contribute to the decreased expression of hBD2 in acute eczematous reaction clinically characterized by spongiosis and oozing – thus indicative for contact of the epidermis with serum components.

Natriuretic peptides (NP) regulate cardiovascular homeostasis and have multiple metabolic properties. Decreased levels of NP or "natriuretic handicap" are signs of insulin resistance such as central obesity. Increased expression of NP clearance receptor (NPRC) in sc adipose tissue (SAT) was observed in insulin-resistant subjects.We hypothesized that insulin acutely regulates NP receptor expression in adipose tissue.NPRA, NPRB, and NPRC mRNA expression was measured in paired samples of visceral adipose tissue (VAT) and SAT from 157 subjects (108 with type 2 diabetes). The effect of insulin on NPR gene expression in SAT was studied in euglycemic-hyperinsulinemic and hyperglycemic-hyperinsulinemic clamp experiments. Additionally, the effect of insulin and glucose on NPR expression in the culture of primary human monocytes and macrophages was tested.NPRA and NPRC gene expression was higher in VAT compared with SAT (P0.01), but only NPRC gene expression strongly correlated with fasting insulin levels (r = 0.65, P = 0.04 × 10(-3); and r = 0.54, P = 0.002, for VAT and SAT, respectively). NPRB expression was lower in VAT than in SAT in subjects with type 2 diabetes and was lower compared with nondiabetic subjects. NPRC gene expression was up-regulated in SAT during both euglycemic- and hyperglycemic-hyperinsulinemic clamps (P = 0.038 and P = 0.048, respectively), and was increased in high glucose and insulin treatment in monocytes (70.2%; P = 0.01), but not in mature macrophages.Insulin increased expression of NPRC in SAT independently of circulating glucose concentrations. Thus, insulin might suppress circulating NP via up-regulation of NPRC expression in obesity, providing a novel link between hyperinsulinemia and obesity.

Background Treatment of SZ95 sebocytes with the essential fatty acid linoleic acid (LA) and the polyunsaturated fatty acid arachidonic acid (AA) leads to sebaceous lipogenesis. Animal data indicate that stearoyl-coenzyme A desaturase (SCD), a key enzyme in fatty acid biosynthesis, is involved in sebaceous lipogenesis and proinflammatory signalling in the sebaceous gland. On the other hand, fatty acid delta-6 desaturase-2 (FADS2) catalyses the conversion of LA to AA. Objectives To identify the effects of LA and AA on the expression of SCD and FADS2 and to detect its biological relevance. Methods SZ95 sebocytes were treated with LA (10(-5) and 10(-4) mol L(-1) ), AA (10(-6) and 10(-5) mol L(-1) ) and the combination of LA (10(-4) mol L(-1) ) and testosterone (2 × 10(-8) mol L(-1) ), with or without addition of the SCD inhibitor FPCA (10(-8) and 10(-6) mol L(-1) ). Cytotoxicity was determined by the lactate dehydrogenase assay. SCD and FACS2 mRNA levels were assessed by semiquantitative reverse transcription-polymerase chain reaction and protein expression by Western blot analysis. SZ95 sebocyte lipid content and cell number were measured by the Nile red and the fluorescein diacetate microassays, respectively. Determination of interleukin (IL)-6 and IL-8 release was evaluated by enzyme-linked immunosorbent assay. Results LA treatment induced an increase of SCD and FADS2 at mRNA and protein levels in SZ95 sebocytes after 1·5 h. Treatment with AA led to an increase of SCD but to a decrease of FADS2 mRNA levels. LA/testosterone cotreatment stimulated lipogenesis in SZ95 sebocytes. A distinct proinflammatory pattern was registered: whereas LA strongly upregulated IL-6 secretion only, AA induced a mild level of IL-6 and IL-8 release from SZ95 sebocytes. Treatment with the SCD inhibitor FPCA reduced the LA/testosterone-upregulated SCD and FADS2 mRNA levels and resulted in an anti-inflammatory effect, but did not affect sebaceous lipogenesis. Conclusions LA-induced sebaceous lipogenesis is likely to be an SCD-independent effect. Regulation of SCD and FADS2 expression by LA and AA leads to enhancement of proinflammatory activity but does not affect lipogenesis in human sebocytes.

It has been previously reported that the sensitivity and specificity of multislice CT for detecting significant CAD (coronary artery disease) is high. Chest pain is a common presentation in patients with uncontrolled hypertension. We investigated the sensitivity and specificity of Dual-Source CT to detect and rule out significant CAD in patients presenting with uncontrolled hypertension accompanied by chest pain. 260 consecutive patients presenting with acute chest pain in the context of stage 2 hypertension (systolic pressure ≥160 and/or diastolic pressure ≥100) were enrolled in the study. After admission, control of blood pressure and risk stratification, 82 patients were excluded due to renal insufficiency, prior coronary revascularisation or refused participation in the study. 90 further patients with low pre-test probability of CAD were also excluded. 88 remaining patients were subjected to CT coronary angiography using Dual-Source CT (Definition, Siemens Medical Solutions, Forchheim, Germany) within 24 h before invasive coronary angiography. A contrast-enhanced volume dataset was acquired (120 kV, 400 mAs/rot, collimation 2 × 64 × 0.6 mm, retrospective ECG gating). Data sets were evaluated concerning the presence or absence of significant coronary stenoses and validated against invasive coronary angiography. A significant stenosis was assumed if the diameter reduction was ≥50%. 88 patients (mean age 66 ± 11 years, mean heart rate 61 ± 9 bpm) were evaluated regarding the presence or absence of significant CAD (at least one stenosis ≥50% diameter reduction). Mean systolic blood pressure on presentation was 203 ± 20 mmHg and mean diastolic blood pressure was 103 ± 13 mmHg. On a per patient basis, the sensitivity and specificity for Dual-Source CT to detect significant CAD in vessels >1.5 mm diameter was 100% (36/36, 95% CI 90–100) and 90% (47/52, 95% CI 79–97), respectively with a negative predictive value (NPV) of 100% (47/47, 95% CI 92–100) and a positive predictive value (PPV) of 88% (36/41, 95% CI 74–96). On a per artery basis, 352 vessels were evaluated (left main, left anterior descending, left circumflex and right coronary artery in 88 patients, 12 vessels could not be assessed due to either motion artefacts or heavy calcification and were considered positive for stenoses) with a sensitivity of 84% (54/64, 95% CI 72–95) and specificity of 94% (272/288, 95% CI 88–100); NPV was 96% (272/282, 95% CI 90–100) and PPV was 77% (54/70, 95% CI 62–91). Our study demonstrates high sensitivity, specificity and negative predictive value of Dual-Source CT to detect significant CAD in patients presenting with uncontrolled hypertension accompanied by chest pain. Dual-Source CT angiography may be useful to safely rule out coronary artery stenoses and avoid invasive angiograms in these patients.

Objectives We sought to evaluate the diagnostic accuracy of a new prospectively electrocardiogram (ECG)-triggered high-pitch scan mode for coronary computed tomography angiography (CTA), which allows an effective dose of less than 1 mSv. Background Coronary CTA provides increasingly reliable image quality, but the associated radiation exposure can be high. Methods Seventy-five patients with suspected coronary artery disease and in sinus rhythm were screened for participation. After exclusion of 25 patients for body weight >100 kg or failure to lower heart rate to ≤60 beats/min, 50 patients were studied by prospectively ECG-triggered high-pitch spiral computed tomography (CT). Coronary CTA was performed using a dual-source CT system with 2 × 128 × 0.6-mm collimation, 0.28-s rotation time, a pitch of 3.4, 100-kVp tube voltage, and current of 320 mA. Data acquisition was prospectively triggered at 60% of the R-R interval and completed within 1 cardiac cycle. Diagnostic accuracy for detection of coronary artery stenoses ≥50% diameter stenosis was determined by comparison to invasive coronary angiography. Per-patient diagnostic performance was the primary form of analysis. Results In all 50 patients (34 males, 59 ± 12 years of age), imaging was successful. For the detection of 16 patients with at least 1 coronary artery stenosis, CT demonstrated a sensitivity of 100% (95% confidence interval [CI]: 79% to 100%) and specificity of 82% (95% CI: 65% to 93%). The positive predictive value was 72% (95% CI: 49% to 89%) and the negative predictive value was 100% (95% CI: 87% to 100%). Sensitivity was 100% (95% CI: 88% to 100%) and specificity was 94% (95% CI: 89% to 97%) on a per-vessel basis. Per-segment sensitivity was 92% (95% CI: 80% to 97%), and specificity was 98% (95% CI: 96% to 98%). Mean dose-length product for coronary CTA was 54 ± 6 mGy · cm, the effective dose was 0.76 ± 0.08 mSv (0.64 to 0.95 mSv). Conclusions In nonobese patients with a low and stable heart rate, prospectively ECG-triggered high-pitch spiral coronary CTA provides high diagnostic accuracy for the detection of coronary artery stenoses.

We conducted a study on nest mortality of an individually marked population of European rabbits (Oryctolagus cuniculus L., 1758) living in a field enclosure. Over 4 years, we determined maternities and quantified pup mortality during the nest period of 703 pups born in subterranean breeding burrows. Overall, pup mortality occurred in 42.7% of the litters, whereas 32.4% of all born pups were affected. Mortality was highest during the first few postnatal days. In about 50% of the cases, we managed to quantify different causes of mortality such as malnutrition, flooding, cooling of the pups, infanticide, or predation. The pups’ body mass on postnatal day 1, the thermal environment and the number of litter mates were the most important predictors of nest mortality. Litter mortality risk decreased with increasing soil temperature around the subterranean nests. A comparatively higher average pup body mass lowered the nest mortality risk of a litter, whereas this effect was more pronounced when soil temperatures were low. Furthermore, mortality was lowest in medium-sized litters, most probably due to the balance between the thermal benefits of huddling with litter siblings and the costs of having them due to the lower share of milk obtained by the individual pups in larger litters. In addition, nest mortality depended on characteristics of the mother; mortality was increased in litters of low-ranking females and of mothers with lower body mass. In conclusion, our study highlights multiple causes and the effects of different environmental and social factors on nest mortality of this small mammal.

Extraneuronal acetylcholine (ACh) has been demonstrated to influence a plethora of cutaneous cell functions in an autocrine, paracrine and endocrine fashion. Previously, we could demonstrate a differentiation-specific expression of its nicotinic (nAChR) and muscarinic receptors (mAChR) in human epidermis and its adnexal structures including sebaceous glands. Using an immortalized human sebaceous gland cell line (SZ95 sebocytes), we examined the AChR expression pattern in vitro. In proliferating and confluent SZ95 sebocytes, a wide range of AChR subunits could be detected using RT-PCR. In particular, we detected mRNA coding for the α3, α5, α6, α7, α10, β1, β2 and β4 nAChR as well as the M1, and M3−5. The α1 and M2 and M5 subunits could only be detected in confluent SZ95 sebocytes, while in proliferating ones these subunits remained negative. The α2, α4, α9 and β3 nAChR could not be detected. Using functional assays, we assessed the impact of cholinergic agonists and antagonists on sebocyte proliferation and differentiation as evidenced by lipid production. Atropine (inhibition of all mAChR) and himbacine (inhibition of M2 and M4) potently inhibited SZ95 sebocyte proliferation in a dose-dependent manner with a maximum effect at milimolar concentrations, while glycopyrrolate (inhibition of M1 and M3) inhibited proliferation only at high concentrations (100 µM). Interestingly also muscarine inhibited SZ95 sebocyte proliferation, however, with a maximum effect (50%) at nanomolar concentrations. The inhibitory effect of mecamylamine was less pronounced (20%). Nicotine strongly induced SZ95 sebocyte proliferation to more than 200% in a dose-dependent manner. Lipid production was increased by nicotine and muscarine in the micromolar range. Inhibition of nAChR by mecamylamine did not significantly influence lipid production, while even nanomolar concentrations of atropine significantly increased lipid production. In conclusion, we could demonstrate highly potent effects of the cholinergic system on sebocyte proliferation and lipid production in vitro, mediated by wealth of different AChR subunits present at least at the mRNA level. In particular, promotion of sebocyte proliferation seems to be an attractive explanation for the exacerbation of sebaceous gland–related disorders like acne under the influence of chronic nicotine ingestion. In addition, seborrhea observed after treatment with anticholinergic drugs is well in line with an increase in lipid production that we found after treatment of sebocytes with atropine.

Overproduction of sebum, especially during adolescence, is causally related to acne and inflammation. As a way to reduce sebum and its interference with the process of follicular keratinization in the pilosebaceous unit leading to inflammatory acne lesions, antihistamines were investigated for their effect on sebocytes, the major cell of the sebaceous gland responsible for producing sebum. Reverse transcriptase-PCR analysis and immunofluorescence of an immortalized sebocyte cell line (SZ95) revealed the presence of histamine-1 receptor (H-1 receptor), and thus indicated that histamines and, conversely, antihistamines could potentially modulate sebocyte function directly. When sebocytes were incubated with an H-1 receptor antagonist, diphenhydramine (DPH), at non-cytotoxic doses, a significant decrease in squalene levels, a biomarker for sebum, was observed. As determined by high-performance liquid chromatography, untreated sebocytes contained 6.27 (+/-0.73) nmol squalene per 10(6) cells, whereas for DPH-treated cells, the levels were 2.37 (+/-0.24) and 2.03 (+/-0.97) nmol squalene per 10(6) cells at 50 and 100 microM, respectively. These data were further substantiated by the identification of histamine receptors in human sebaceous glands. In conclusion, our data show the presence of histamine receptors on sebocytes, demonstrate how an antagonist to these receptors modulated cellular function, and may indicate a new paradigm for acne therapy involving an H-1 receptor-mediated pathway.

Topical cyproterone acetate (CPA) treatment of skin diseases should reduce side effects currently excluding the use in males and demanding contraceptive measures in females. To improve skin penetration of the poorly absorbed drug, we intended to identify the active moiety and to load it to particulate carrier systems. CPA metabolism in human fibroblasts, keratinocytes and a sebocyte cell line as well as androgen receptor affinity of native CPA and the hydrolysis product cyproterone were determined. CPA 0.05% loaded solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), a nanoemulsion and micropheres were characterized for drug-particle interaction and CPA absorption using human skin ex-vivo. Native CPA proved to be the active agent. Application of CPA attached to SLN increased skin penetration at least four-fold over the uptake from cream and nanoemulsion. Incorporation into the lipid matrix of NLC and microspheres resulted in a 2–3-fold increase in CPA absorption. Drug amounts within the dermis were low with all preparations. No difference was seen in the penetration into intact and stripped skin. With particulate systems topical CPA treatment may be an additional therapeutic option for acne and other diseases of the pilosebaceous unit.

CONTEXT: The circadian clock coordinates numerous metabolic processes with light-dark and feeding regimens. However, in humans it is unknown whether dietary patterns influence circadian rhythms. OBJECTIVE: We examined the effects of switching from a high-carbohydrate, low-fat diet to a low-carbohydrate, high fat (LC/HFD) isocaloric diet on the central and peripheral circadian clocks in humans. DESIGN: Diurnal patterns of salivary cortisol and gene expression were analyzed in blood monocytes of 29 nonobese healthy subjects before and 1 and 6 weeks after the dietary switch. For this, we established a method of rhythm prediction by 3-time point data. RESULTS: The centrally driven cortisol rhythm showed a phase delay 1 and 6 weeks after the dietary switch to a LC/HFD as well as an amplitude increase. The dietary switch altered diurnal oscillations of core clock genes (PER1, PER2, PER3, and TEF) and inflammatory genes (CD14, CD180, NFKBIA, and IL1B). The LC/HFD also affected the expression of nonoscillating genes contributing to energy metabolism (SIRT1) and fat metabolism (ACOX3 and IDH3A). Expression of clock genes but not of salivary cortisol in monocytes tightly correlated with levels of blood lipids and with expression of metabolic and inflammatory genes. CONCLUSIONS: Our results suggest that the modulation of the dietary fat and carbohydrate content alters the function of the central and peripheral circadian clocks in humans.