Vascular Growth in Health and Disease

Vascular growth forms the first functional organ system during development, and continues into adult life, wherein it is often associated with disease states. Genetically determined vasculogenesis produces a primary vascular plexus during ontogenesis. Angiogenesis, occurring, e.g., in response to metabolic stress within hypoxic tissues, enhances tissue capillarization. Arteriogenesis denotes the adaptive outgrowth of pre-existent collateral arteries to bypass arterial stenoses in response to hemodynamic changes. It has been debated whether vasculogenesis occurs in the adult, and whether or not circulating progenitor cells structurally contribute to vessel regeneration. Secondly, the major determinants of vascular growth – genetic predisposition, metabolic factors (hypoxia), and hemodynamics – cannot be assigned in a mutually exclusive fashion to vasculogenesis, angiogenesis, and arteriogenesis, respectively; rather, mechanisms overlap. Lastly, all three mechanisms of vessel growth seem to contribute to physiological embryogenesis as well as adult adaptive vascularization as occurs in tumors or to circumvent arterial stenosis. Thus, much conceptual and terminological confusion has been created, while therapies targeting neovascularization have yielded promising results in the lab, but failed randomized studies when taken to the bedside. Therefore, this review article aims at providing an exact definition of the mechanisms of vascular growth and their contribution to embryonic development as well as adult adaptive revascularization. We have been looking for potential reasons for why clinical trials have failed, how vitally the application of appropriate methods of measuring and assessment influences study outcomes, and how relevant, e.g., results gained in models of vascular occlusive disease may be for antineoplastic strategies, advocating a reverse bedside-to-bench approach, which may hopefully yield successful approaches to therapeutically targeting vascular growth

VALUE POSITIONS IN E-GOVERNMENT STRATEGIES: SOMETHING IS (NOT) CHANGING IN THE STATE OF DENMARK

Clarifying what value new information systems (IS) may help to create for government organizations and society is a central concern in the public sector. National e-government strategies present such efforts to clarify the value entailed by IS, however, what is considered valuable is influenced by value positions deeply enshrined in the traditions of public administration. We present a theory directed content analysis of value positions in the national e-government strategy for Denmark published for the first time in 1994 and latest in 2016. Our comparison of the value positions in the two e-government strategies show consistency over time when looking at the ideals of professionalism, ser-vice, and efficiency. While the least dominant ideal of engagement, has declined. The 22-year timespan separating the development of these two strategies had major technological advances, but little transformational impact on Danish e-government strategies in their general value positions. We discuss how our findings contribute to previous research on values in e-government and have practical implications for working with e-government strategies

Vildagliptin Reduces Glucagon during Hyperglycemia and Sustains Glucagon Counterregulation during Hypoglycemia in Type 1 Diabetes.

Context: The dipeptidyl peptidase-4 inhibitor, vildagliptin, inhibits glucagon secretion at hyperglycemia but appears to enhance glucagon counterregulation during hypoglycemia in type 2 diabetes.Objective:The objective of the investigation was to study whether vildagliptin also improves α-cell function in type 1 diabetes (T1D). Patients and Methods: The study was a single-center, double-blind, randomized, placebo-controlled crossover study involving 28 patients with C-peptide negative and antibody positive T1D [21 males, seven females, glycosylated hemoglobin 57.9 mmol/mol (7.5%)]. Patients received vildagliptin (50 mg twice a day) or placebo as an add-on to their insulin therapy for 4 wk each. On d 28 of the respective treatment period, patients were served a standard meal (500 kcal) to raise the circulating incretin hormone levels followed by a hyperinsulinemic hypoglycemic clamp at 2.5 mmol/liter. Main Outcome Measure: The increase in plasma glucagon levels during the 30-min hypoglycemic clamp (min 165-195 of the test) was measured.Results:During the meal, glucagon levels were lower with vildagliptin than with placebo (120 min area under the curve(glucagon) 2.4 ± 0.2 vs. 2.6 ± 0.2 nmol/liter × minutes, P = 0.022 for between group difference). In contrast, during hypoglycemia, the glucagon counterregulation was not reduced by vildagliptin (increase in glucagon 1.5 ± 1.0 pmol/liter with vildagliptin vs. 1.7 ± 0.8 pmol/liter with placebo, P = NS). In addition, the counterregulatory responses in epinephrine, norepinephrine, cortisol, and pancreatic polypeptide were not different between the treatments. During the 4-wk treatment period, vildagliptin reduced the mean glycosylated hemoglobin, whereas there was no change with placebo [between group difference was -3.4 ± 1.0 mmol/mol (-0.32 ± 0.09%; P = 0.002)] from baseline of 57.9 mmol/mol (7.5%). Conclusions: Vildagliptin, although inhibiting glucagon secretion during hyperglycemia, does not compromise the glucagon counterregulatory response during hypoglycemia in T1D

First encounters in the north : cultural diversity and gene flow in Early Mesolithic Scandinavia

Population genetic studies often overlook the evidence for variability and change in past material culture. Here, the authors use a Mesolithic example to demonstrate the importance of integrating archaeological evidence into the interpretation of the Scandinavian hunter-gatherer genetic group. Genetic studies conclude that this group resulted from two singleevent dispersals into Scandinavia before 7500 BC. Archaeological evidence, however, shows at least six immigration events pre-dating the earliest DNA, and that the first incoming groups arrived in Scandinavia before 9000 BC. The findings underline the importance of conducting careful archaeological analysis of prehistoric human dispersal in tandem with the study of ancient population genomics.Population genetic studies often overlook the evidence for variability and change in past material culture. Here, the authors use a Mesolithic example to demonstrate the importance of integrating archaeological evidence into the interpretation of the Scandinavian hunter-gatherer genetic group. Genetic studies conclude that this group resulted from two single-event dispersals into Scandinavia before 7500 BC. Archaeological evidence, however, shows at least six immigration events pre-dating the earliest DNA, and that the first incoming groups arrived in Scandinavia before 9000 BC. The findings underline the importance of conducting careful archaeological analysis of prehistoric human dispersal in tandem with the study of ancient population genomics.Peer reviewe

C57Bl/6N mice have an attenuated lung inflammatory response to dsRNA compared to C57Bl/6J and BALB/c mice

Background Lower respiratory infections caused by ssRNA viruses are a major health burden globally. Translational mouse models are a valuable tool for medical research, including research on respiratory viral infections. In in vivo mouse models, synthetic dsRNA can be used as a surrogate for ssRNA virus replication. However, studies investigating how genetic background of mice impacts the murine lung inflammatory response to dsRNA is lacking. Hence, we have compared lung immunological responses of BALB/c, C57Bl/6N and C57Bl/6J mice to synthetic dsRNA. Methods dsRNA was administered intranasally to BALB/c, C57Bl/6N and C57Bl/6J mice once/day for three consecutive days. Lactate dehydrogenase (LDH) activity, inflammatory cells, and total protein concentration were analyzed in bronchoalveolar lavage fluid (BALF). Pattern recognition receptors levels (TLR3, MDA5 and RIG-I) were measured in lung homogenates using RT-qPCR and western blot. Gene expression of IFN-β, TNF-α, IL-1β and CXCL1 was assessed in lung homogenates by RT-qPCR. ELISA was used to analyze protein concentrations of CXCL1 and IL-1β in BALF and lung homogenates. Results BALB/c and C57Bl/6J mice showed infiltration of neutrophils to the lung, and an increase in total protein concentration and LDH activity in response to dsRNA administration. Only modest increases in these parameters were observed for C57Bl/6N mice. Similarly, dsRNA administration evoked an upregulation of MDA5 and RIG-I gene and protein expression in BALB/c and C57Bl/6J, but not C57Bl/6N, mice. Further, dsRNA provoked an increase in gene expression of TNF-α in BALB/c and C57Bl/6J mice, IL-1β only in C57Bl/6N mice and CXCL1 exclusively in BALB/c mice. BALF levels of CXCL1 and IL-1β were increased in BALB/c and C57Bl/6J mice in response to dsRNA, whereas the response of C57Bl/6N was blunt. Overall, inter-strain comparisons of the lung reactivity to dsRNA revealed that BALB/c, followed by C57Bl/6J, had the most pronounced respiratory inflammatory responses, while the responses of C57Bl/6N mice were attenuated. Conclusions We report clear differences of the lung innate inflammatory response to dsRNA between BALB/c, C57Bl/6J and C57Bl/6N mice. Of particular note, the highlighted differences in the inflammatory response of C57Bl/6J and C57Bl/6N substrains underscore the value of strain selection in mouse models of respiratory viral infections

A global view of protein expression in human cells, tissues, and organs

Defining the protein profiles of tissues and organs is critical to understanding the unique characteristics of the various cell types in the human body. In this study, we report on an anatomically comprehensive analysis of 4842 protein profiles in 48 human tissues and 45 human cell lines. A detailed analysis of over 2 million manually annotated, high-resolution, immunohistochemistry-based images showed a high fraction (>65%) of expressed proteins in most cells and tissues, with very few proteins (<2%) detected in any single cell type. Similarly, confocal microscopy in three human cell lines detected expression of more than 70% of the analyzed proteins. Despite this ubiquitous expression, hierarchical clustering analysis, based on global protein expression patterns, shows that the analyzed cells can be still subdivided into groups according to the current concepts of histology and cellular differentiation. This study suggests that tissue specificity is achieved by precise regulation of protein levels in space and time, and that different tissues in the body acquire their unique characteristics by controlling not which proteins are expressed but how much of each is produced

Carbohydrate Intake in the Etiology of Crohn's Disease and Ulcerative Colitis

Background: Diet may have a role in the etiology of inflammatory bowel disease. In previous studies, the associations between increased intakes of carbohydrates, sugar, starch, and inflammatory bowel disease are inconsistent. However, few prospective studies have investigated the associations between these macronutrients and incident Crohn's disease (CD) or ulcerative colitis (UC). Methods: A total of 401,326 men and women were recruited between 1991 and 1998. At recruitment, dietary intakes of carbohydrate, sugar, and starch were measured using validated food frequency questionnaires. The cohort was monitored identifying participants who developed incident CD or UC. Cases were matched with 4 controls, and odds ratios were calculated for quintiles of total carbohydrate, sugar, and starch intakes adjusted for total energy intake, body mass index, and smoking. Results: One hundred ten participants developed CD, and 244 participants developed UC during follow-up. The adjusted odds ratio for the highest versus the lowest quintiles of total carbohydrate intake for CD was 0.87, 95% CI = 0.24 to 3.12 and for UC 1.46, 95% CI = 0.62 to 3.46, with no significant trends across quintiles for either (CD, Ptrend = 0.70; UC, Ptrend = 0.41). Similarly, no associations were observed with intakes of total sugar (CD, Ptrend = 0.50; UC, Ptrend = 0.71) or starch (CD, Ptrend = 0.69; UC, Ptrend = 0.17). Conclusions: The lack of associations with these nutrients is in agreement with many case–control studies that have not identified associations with CD or UC. As there is biological plausibility for how specific carbohydrates could have an etiological role in inflammatory bowel disease, future epidemiological work should assess individual carbohydrates, although there does not seem to be a macronutrient effect

Timing and synchrony of birth in Eurasian lynx across Europe

The ecology and evolution of reproductive timing and synchrony have been a topic of great interest in evolutionary ecology for decades. Originally motivated by questions related to behavioral and reproductive adaptation to environmental conditions, the topic has acquired new relevance in the face of climate change. However, there has been relatively little research on reproductive phenology in mammalian carnivores. The Eurasian lynx (Lynx lynx) occurs across the Eurasian continent, covering three of the four main climate regions of the world. Thus, their distribution includes a large variation in climatic conditions, making it an ideal species to explore reproductive phenology. Here, we used data on multiple reproductive events from 169 lynx females across Europe. Mean birth date was May 28 (April 23 to July 1), but was similar to 10 days later in northern Europe than in central and southern Europe. Birth dates were relatively synchronized across Europe, but more so in the north than in the south. Timing of birth was delayed by colder May temperatures. Severe and cold weather may affect neonatal survival via hypothermia and avoiding inclement weather early in the season may select against early births, especially at northern latitudes. Overall, only about half of the kittens born survived until onset of winter but whether kittens were born relatively late or early did not affect kitten survival. Lynx are strict seasonal breeders but still show a degree of flexibility to adapt the timing of birth to surrounding environmental conditions. We argue that lynx give birth later when exposed to colder spring temperatures and have more synchronized births when the window of favorable conditions for raising kittens is shorter. This suggests that lynx are well adapted to different environmental conditions, from dry and warm climates to alpine, boreal, and arctic climates. This variation in reproductive timing will be favorable in times of climate change, as organisms with high plasticity are more likely to adjust to new environmental conditions

Prerequisites for coexistence: human pressure and refuge habitat availability shape continental‑scale habitat use patterns of a large carnivore

Context Adjustments in habitat use by large carnivores can be a key factor facilitating their coexistence with people in shared landscapes. Landscape composition might be a key factor determining how large carnivores can adapt to occurring alongside humans, yet broad-scale analyses investigating adjustments of habitat use across large gradients of human pressure and landscape composition are lacking. Objectives Here, we investigate adjustments in habitat use by Eurasian lynx (Lynx lynx) in response to varying availability of refuge habitats (i.e., forests and rugged terrain) and human landscape modifcation. Methods Using a large tracking dataset including 434 individuals from seven populations, we assess functional responses in lynx habitat use across two spatial scales, testing for variation by sex, daytime, and season. Results We found that lynx use refuge habitats more intensively with increasing landscape modifcation across spatial scales, selecting forests most strongly in otherwise open landscapes and rugged terrain in mountainous regions. Moreover, higher forest availability enabled lynx to place their home ranges in more human-modifed landscapes. Human pressure and refuge habitat availability also shaped temporal patterns of lynx habitat use, with lynx increasing refuge habitat use and reducing their use of human-modifed areas during periods of high exposure (daytime) or high vulnerability (postnatal period) to human pressure. Conclusions Our fndings suggest a remarkable adaptive capacity of lynx towards human pressure and underline the importance of refuge habitats across scales for enabling coexistence between large carnivores and people. More broadly, we highlight that the composition of landscapes determines how large carnivores can adapt to human pressure and thus play an important role shaping large carnivore habitat use and distributions.publishedVersio

Lipoprotein(a) as a risk factor for atherosclerotic cardiovascular disease in patients in non-metropolitan areas of Brandenburg, Germany

Background and aimsIn the non-metropolitan region of Brandenburg (Germany), which is characterized by high rates of cardiovascular diseases and underserved medical care, there is a lack of awareness regarding lipoprotein(a) [Lp(a)] as a risk factor. In addition, data from patients with atherosclerotic cardiovascular disease (ASCVD) in diverse regional backgrounds, including the understudied Brandenburg cohort, and various healthcare statuses remain insufficient.MethodsIn this WalkByLab study, Lp(a) levels were monitored in a non-metropolitan cohort (n = 850) in Brandenburg, Germany, comprising 533 patients at high cardiovascular risk and 317 healthy controls. Patients underwent a comprehensive angiological screening, which included blood serum analysis, assessment of medical and family history, cardiovascular risk, and disease status, and evaluation of lifestyle and quality of life. All parameters were evaluated with regard to two groups based on Lp(a) levels: low (&lt;50 mg/dl) and high (≥50 mg/dl).ResultsBrandenburg patients with cardiovascular diseases showed higher Lp(a) levels than healthy controls (24.2% vs. 14.8%, p = 0.001). Logistic regression analysis with different characteristics revealed that Lp(a) was an independent risk factor significantly associated with ASCVD (OR 2.26, 95% CI 1.32–3.95, p = 0.003). The high-Lp(a) group showed a higher proportion of patients with coronary artery disease, peripheral artery disease, or cerebrovascular disease compared to the low-Lp(a) group (50% vs. 36.8%; 57.7% vs. 45.8%; 17.6% vs. 9.2%; p = 0.004); also, a higher percentage of patients in the high-Lp(a) group had heart failure (72.8% vs. 53.2%, p = 0.014) and myocardial infarction (24.7% vs. 13.9%, p = 0.001). The high-Lp(a) group exhibited higher rates of statins (63.1% vs. 50.4%, p = 0.003), ezetimibe (14.8% vs. 5.5.%, p = 0.001), and beta-blockers (55.7% vs. 40.7%, p = 0.001) use. Lp(a) levels were found to be independent of physical activity or smoking behavior and did not change over time (12 months).ConclusionsOur study highlights the significance of elevated Lp(a) levels in Brandenburg cardiovascular patients and identifies them as an independent risk factor for ASCVD, which has implications for addressing cardiovascular health of non-metropolitan populations