A transgenic model for conditional induction and rescue of portal hypertension reveals a role of VEGF-mediated regulation of sinusoidal fenestrations

Portal hypertension (PH) is a common complication and a leading cause of death in patients with chronic liver diseases. PH is underlined by structural and functional derangement of liver sinusoid vessels and its fenestrated endothelium. Because in most clinical settings PH is accompanied by parenchymal injury, it has been difficult to determine the precise role of microvascular perturbations in causing PH. Reasoning that Vascular Endothelial Growth Factor (VEGF) is required to maintain functional integrity of the hepatic microcirculation, we developed a transgenic mouse system for a liver-specific-, reversible VEGF inhibition. The system is based on conditional induction and de-induction of a VEGF decoy receptor that sequesters VEGF and preclude signaling. VEGF blockade results in sinusoidal endothelial cells (SECs) fenestrations closure and in accumulation and transformation of the normally quiescent hepatic stellate cells, i.e. provoking the two processes underlying sinusoidal capillarization. Importantly, sinusoidal capillarization was sufficient to cause PH and its typical sequela, ascites, splenomegaly and venous collateralization without inflicting parenchymal damage or fibrosis. Remarkably, these dramatic phenotypes were fully reversed within few days from lifting-off VEGF blockade and resultant re-opening of SECs' fenestrations. This study not only uncovered an indispensible role for VEGF in maintaining structure and function of mature SECs, but also highlights the vasculo-centric nature of PH pathogenesis. Unprecedented ability to rescue PH and its secondary manifestations via manipulating a single vascular factor may also be harnessed for examining the potential utility of de-capillarization treatment modalities.

Transgenic system for conditional induction and rescue of chronic myocardial hibernation provides insights into genomic programs of hibernation

A key energy-saving adaptation to chronic hypoxia that enables cardiomyocytes to withstand severe ischemic insults is hibernation, i.e., a reversible arrest of contractile function. Whereas hibernating cardiomyocytes represent the critical reserve of dysfunctional cells that can be potentially rescued, a lack of a suitable animal model has hampered insights on this medically important condition. We developed a transgenic mouse system for conditional induction of long-term hibernation and a system to rescue hibernating cardiomyocytes at will. Via myocardium-specific induction (and, in turn, deinduction) of a VEGF-sequestering soluble receptor, we show that VEGF is indispensable for adjusting the coronary vasculature to match increased oxygen consumption and exploit this finding to generate a hypoperfused heart. Importantly, ensuing ischemia is tunable to a level at which large cohorts of cardiomyocytes are driven to enter a hibernation mode, without cardiac cell death. Relieving the VEGF blockade even months later resulted in rapid revascularization and full recovery of contractile function. Furthermore, we show that left ventricular remodeling associated with hibernation is also fully reversible. The unique opportunity to uncouple hibernation from other ischemic heart phenotypes (e.g., infarction) was used to determine the genetic program of hibernation; uncovering hypoxia-inducible factor target genes associated with metabolic adjustments and induced expression of several cardioprotective genes. Autophagy, specifically self-digestion of mitochondria, was identified as a key prosurvival mechanism in hibernating cardiomyocytes. This system may lend itself for examining the potential utility of treatments to rescue dysfunctional cardiomyocytes and reverse maladaptive remodeling.

Holocene climate, fire and vegetation dynamics at the treeline in the Northwestern Swiss Alps

Treelines are expected to rise to higher elevations with climate warming; the rate and extent however are still largely unknown. Here we present the first multi-proxy palaeoecological study from the treeline in the Northwestern Swiss Alps that covers the entire Holocene. We reconstructed climate, fire and vegetation dynamics at Iffigsee, an alpine lake at 2,065 m a.s.l., by using seismic sedimentary surveys, loss on ignition, visible spectrum reflectance spectroscopy, pollen, spore, macrofossil and charcoal analyses. Afforestation with Larix decidua and tree Betula (probably B. pendula) started at ~9,800 cal. b.p., more than 1,000 years later than at similar elevations in the Central and Southern Alps, indicating cooler temperatures and/or a high seasonality. Highest biomass production and forest position of ~2,100–2,300 m a.s.l. are inferred during the Holocene Thermal Maximum from 7,000 to 5,000 cal. b.p. With the onset of pastoralism and transhumance at 6,800–6,500 cal. b.p., human impact became an important factor in the vegetation dynamics at Iffigsee. This early evidence of pastoralism is documented by the presence of grazing indicators (pollen, spores), as well as a wealth of archaeological finds at the nearby mountain pass of Schnidejoch. Human and fire impact during the Neolithic and Bronze Ages led to the establishment of pastures and facilitated the expansion of Picea abies and Alnus viridis. We expect that in mountain areas with land abandonment, the treeline will react quickly to future climate warming by shifting to higher elevations, causing drastic changes in species distribution and composition as well as severe biodiversity losses.

The role of human-induced fire and sweet chestnut (Castanea sativa Mill.) cultivation on the long-term landscape dynamics of the southern Swiss Alps

Changes in fire occurrence during the last decades in the southern Swiss Alps make knowledge on fire history essential to understand future evolution of the ecosystem composition and functioning. In this context, palaeoecology provides useful insights into processes operating at decadal-to-millennial time scales, such as the response of plant communities to intensified fire disturbances during periods of cultural change. We provide a high-resolution macroscopic charcoal and pollen series from Guèr, a well-dated peat sequence at mid-elevation (832 m.a.s.l.) in southern Switzerland, where the presence of local settlements is documented since the late Bronze Age and the Iron Age. Quantitative fire reconstruction shows that fire activity sharply increased from the Neolithic period (1–3 episodes/1000 year) to the late Bronze and Iron Age (7–9 episodes/1000 year), leading to extensive clearance of the former mixed deciduous forest (Alnus glutinosa, Betula, deciduous Quercus). The increase in anthropogenic pollen indicators (e.g. Cerealia-type, Plantago lanceolata) together with macroscopic charcoal suggests anthropogenic rather than climatic forcing as the main cause of the observed vegetation shift. Fire and controlled burning were extensively used during the late Roman Times and early Middle Ages to promote the introduction and establishment of chestnut (Castanea sativa) stands, which provided an important wood and food supply. Fire occurrence declined markedly (from 9 to 5–6 episodes/1000 year) during late Middle Ages because of fire suppression, biomass removal by human population, and landscape fragmentation. Land-abandonment during the last decades allowed forest to partly re-expand (mainly Alnus glutinosa, Betula) and fire frequency to increase.

Effects of climate, fire, and humans on forest dynamics: forest simulations compared to the palaeological record

In order to find out which factors influenced the forest dynamics in northern Italy during the Holocene, a palaeoecological approach involving pollen analysis was combined with ecosystem modelling. The dynamic and distribution based forest model DisCForm was run with different input scenarios for climate, species immigration, fire, and human impact and the similarity of the simulations with the original pollen record was assessed. From the comparisons of the model output and the pollen core, it appears that immigration was most important in the first part of the Holocene, and that fire and human activity had a major influence in the second half. Species not well represented in the simulation outputs are species with a higher abundance in the past than today (Corylus), with their habitat in riparian forests (Alnus) or with a strong response to human impact (Castanea).

Fire ecology north and south of the Alps since the last ice age

Wildfires are very rare in central Europe, which is probably why fire effects on vegetation have been neglected by most central European ecologists and palaeoecologists. Presently, reconstructions of fire history and fire ecology are almost absent. We analysed sediment cores from lakes on the Swiss Plateau (Lobsigensee and Soppensee) for pollen and charcoal to investigate the relationship between vegetation and fire. Microscopic charcoal evidence suggests increasing regional fire frequencies during the Neolithic (7350-4150 cal. BP, 5400-2200 BC) and the subsequent prehistoric epochs at Lobsigensee, whereas at Soppensee burnings remained rather rare until modern times. Neolithic peaks of charcoal at 6200 and 5500 cal. BP (4250 and 3550 BC) coincided with declines of pollen of fire-sensitive taxa at both sites (e.g., Ulmus, Tilia, Hedera, Fagus), suggesting synchronous vegetational responses to fire at regional scales. However, correlation analysis between charcoal and pollen for the period 6600-4400 cal. BP (4650-2650 BC) revealed no significant link between fire and vegetation at Soppensee, whereas at Lobsigensee increases of Corylus and decreases of Fagus were related to fire events. Fire impact on vegetation increased during the subsequent epochs at both sites. Correlation analyses of charcoal and pollen data for the period 4250-1150 cal. BP (2300 BC -AD 800) suggest that fires were intentionally set to disrupt forests and to provide open areas for arable and pastoral farming (e.g., significant positive correlations between charcoal and Cerealia, Plantago lanceolata, Asteroideae). These results are compared with southern European records (Lago di Origlio, Lago di Muzzano), which are situated in particularly fire-prone environments. After the Mesolithic period (I1 200-7350 cal. BP, 9250-5400 BC), charcoal influx was higher by an order of magnitude in the south, suggesting more frequent fires. Neolithic fires caused similar though more pronounced responses of vegetation in the south (e.g., expansions of Corylus). Post-Neolithic land-use practices involving (controlled) burning culminated in both regions at about 2550 cal. BP (c. 600 BC). However, fire-caused disappearances of entire forest communities were confined to the southern sites. Such differences in fire effects among the sites are explained by the dissimilar importance of fire as a result of different climatic conditions and cultural activities. Our results imply that the remaining (fire-sensitive) fragments of central European vegetation north of the Alps are especially endangered by increasing fire frequencies resulting from predicted climatic change.

A case of homicidal intraoral gunshot and review of the literature

Determination of the manner of death in case of intraoral firearm wounds can be a challenge, especially if the circumstances of the incident are unclear and crime scene investigation is inadequate. It is a well-known fact that the mouth is one of the selected sites for suicide with firearms. Homicidal shooting through the mouth is said to be rare, but does occur, and can be mistaken for a suicide. For discrimination between suicide and homicide in cases of intraoral firearm wounds, some useful points are the site of entry wound, the direction of the internal bullet path, the range of fire and the circumstances of death. We demonstrate these points in a case of a homicidal gunshot to the mouth assessed by both classical autopsy and post-mortem CT (PMCT).

Do we need new personalized emergency telehealth solutions? A survey of 100 emergency department patients and a first report of the swiss limmex emergency wristwatch: an original study

Development of new personal mobile and wireless devices for healthcare has become essential due to our aging population characterized by constant rise in chronic diseases that consequently require a complex treatment and close monitoring. Personal telehealth devices allow patients to adequately receive their appropriate treatment, followup with their doctors, and report any emergency without the need of the presence of any caregivers with them thus increasing their quality of life in a cost-effective fashion. This paper includes a brief overview of personal telehealth systems, a survey of 100 consecutive ED patients aged >65 years, and introduces "Limmex" a new GSM based technology packaged in a wristwatch. Limmex can by a push of a button initiate multiple emergency call and establish mobile communication between the patient and a preselected person, institution, or a search and rescue service. To the best of our knowledge, Limmex is the first of its kind worldwide.

Impacts of changing climate and land use on vegetation dynamics in a Mediterranean ecosystem: insights from paleoecology and dynamic modeling

Forests near the Mediterranean coast have been shaped by millennia of human disturbance. Consequently, ecological studies relying on modern observations or historical records may have difficulty assessing natural vegetation dynamics under current and future climate. We combined a sedimentary pollen record from Lago di Massacciucoli, Tuscany, Italy with simulations from the LandClim dynamic vegetation model to determine what vegetation preceded intense human disturbance, how past changes in vegetation relate to fire and browsing, and the potential of an extinct vegetation type under present climate. We simulated vegetation dynamics near Lago di Massaciucoli for the last 7,000 years using a local chironomid-inferred temperature reconstruction with combinations of three fire regimes (small infrequent, large infrequent, small frequent) and three browsing intensities (no browsing, light browsing, and moderate browsing), and compared model output to pollen data. Simulations with low disturbance support pollen-inferred evidence for a mixed forest dominated by Quercus ilex (a Mediterranean species) and Abies alba (a montane species). Whereas pollen data record the collapse of A. alba after 6000 cal yr bp, simulated populations expanded with declining summer temperatures during the late Holocene. Simulations with increased fire and browsing are consistent with evidence for expansion by deciduous species after A. alba collapsed. According to our combined paleo-environmental and modeling evidence, mixed Q. ilex and A. alba forests remain possible with current climate and limited disturbance, and provide a viable management objective for ecosystems near the Mediterranean coast and in regions that are expected to experience a mediterranean-type climate in the future.

Changes in biodiversity and vegetation composition in the central Swiss Alps during the transition from pristine forest to first farming

Aim: We investigate the response of vegetation composition and plant diversity to increasing land clearance, burning and agriculture at the Mesolithic–Neolithic transition (c. 6400–5000 bc) when first farming was introduced. Location: The Valais, a dry alpine valley in Switzerland. Methods: We combine high-resolution pollen, microscopic charcoal and sedimentological data to reconstruct past vegetation, fire and land use. Pollen evenness, rarefaction-based and accumulation-based palynological richness analyses were used to reconstruct past trends in plant diversity. Results: Our results show that from c. 5500 cal. yr bc, slash-and-burn activities created a more open landscape for agriculture, at the expense of Pinus and Betula forests. Land clearance by slash-and-burn promoted diverse grassland ecosystems, while on the long term it reduced woodland and forest diversity, affecting important tree species such as Ulmus and Tilia. Main conclusions: Understanding the resilience of Alpine ecosystems to past disturbance variability is relevant for future nature conservation plans. Our study suggests that forecasted land abandonment in the Alps will lead to pre-Neolithic conditions, with significant biodiversity losses in abandoned grassland ecosystems. Thus, management measures for biodiversity, such as ecological compensation areas, are needed in agricultural landscapes with a millennial history of human impact, such as the non-boreal European lowlands. Our study supports the hypothesis that species coexistence is maximized at an intermediate level of disturbances. For instance, species richness decreased when fire exceeded the quasi-natural variability observed during the Mesolithic times. Under a more natural disturbance regime, rather closed Pinus sylvestris and mixed oak forests would prevail.

Climatic and human impacts on mountain vegetation at Lauenensee (Bernese Alps, Switzerland) during the last 14,000 years

Lake sediments from Lauenensee (1381 m a.s.l.), a small lake in the Bernese Alps, were analysed to reconstruct the vegetation and fire history. The chronology is based on 11 calibrated radiocarbon dates on terrestrial plant macrofossils suggesting a basal age of 14,200 cal. BP. Pollen and macrofossil data imply that treeline never reached the lake catchment during the Bølling–Allerød interstadial. Treeline north of the Alps was depressed by c. 300 altitudinal meters, if compared with southern locations. We attribute this difference to colder temperatures and to unbuffered cold air excursions from the ice masses in northern Europe. Afforestation started after the Younger Dryas at 11,600 cal. BP. Early-Holocene tree-Betula and Pinus sylvestris forests were replaced by Abies alba forests around 7500 cal. BP. Continuous high-resolution pollen and macrofossil series allow quantitative assessments of vegetation dynamics at 5900–5200 cal. BP (first expansion of Picea abies, decline of Abies alba) and 4100–2900 cal. BP (first collapse of Abies alba). The first signs of human activity became noticeable during the late Neolithic c. 5700–5200 cal. BP. Cross-correlation analysis shows that the expansion of Alnus viridis and the replacement of Abies alba by Picea abies after c. 5500 cal. BP was most likely a consequence of human disturbance. Abies alba responded very sensitively to a combination of fire and grazing disturbance. Our results imply that the current dominance of Picea abies in the upper montane and subalpine belts is a consequence of anthropogenic activities through the millennia.

1200 years of decadal-scale variability of Mediterranean vegetation and climate at Pantelleria Island, Italy

A new sedimentary sequence from Lago di Venere on Pantelleria Island, located in the Strait of Sicily between Tunisia and Sicily was recovered. The lake is located in the coastal infra-Mediterranean vegetation belt at 2 m a.s.l. Pollen, charcoal and sedimentological analyses are used to explore linkages among vegetation, fire and climate at a decadal scale over the past 1200 years. A dry period from ad 800 to 1000 that corresponds to the ‘Medieval Warm Period’ (WMP) is inferred from sedimentological analysis. The high content of carbonate recorded in this period suggests a dry phase, when the ratio of evaporation/precipitation was high. During this period the island was dominated by thermophilous and drought-tolerant taxa, such as Quercus ilex, Olea, Pistacia and Juniperus. A marked shift in the sediment properties is recorded at ad 1000, when carbonate content became very low suggesting wetter conditions until ad 1850–1900. Broadly, this period coincides with the ‘Little Ice Age’ (LIA), which was characterized by wetter and colder conditions in Europe. During this time rather mesic conifers (i.e. Pinus pinaster), shrubs and herbs (e.g. Erica arborea and Selaginella denticulata) expanded, whereas more drought-adapted species (e.g. Q. ilex) declined. Charcoal data suggest enhanced fire activity during the LIA probably as a consequence of anthropogenic burning and/or more flammable fuel (e.g. resinous Pinus biomass). The last century was characterized by a shift to high carbonate content, indicating a change towards drier conditions, and re-expansion of Q. ilex and Olea. The post-LIA warming is in agreement with historical documents and meteorological time series. Vegetation dynamics were co-determined by agricultural activities on the island. Anthropogenic indicators (e.g. Cerealia-type, Sporormiella) reveal the importance of crops and grazing on the island. Our pollen data suggest that extensive logging caused the local extinction of deciduous Quercus pubescens around ad1750.