Breathing manoeuvre-dependent changes in myocardial oxygenation in healthy humans.

AIMS CO₂ is an intrinsic vasodilator for cerebral and myocardial blood vessels. Myocardial vasodilation without a parallel increase of the oxygen demand leads to changes in myocardial oxygenation. Because apnoea and hyperventilation modify blood CO₂, we hypothesized that voluntary breathing manoeuvres induce changes in myocardial oxygenation that can be measured by oxygenation-sensitive cardiovascular magnetic resonance (CMR). METHODS AND RESULTS Fourteen healthy volunteers were studied. Eight performed free long breath-hold as well as a 1- and 2-min hyperventilation, whereas six aquatic athletes were studied during a 60-s breath-hold and a free long breath-hold. Signal intensity (SI) changes in T₂*-weighted, steady-state free precession, gradient echo images at 1.5 T were monitored during breathing manoeuvres and compared with changes in capillary blood gases. Breath-holds lasted for 35, 58 and 117 s, and hyperventilation for 60 and 120 s. As expected, capillary pCO₂ decreased significantly during hyperventilation. Capillary pO₂ decreased significantly during the 117-s breath-hold. The breath-holds led to a SI decrease (deoxygenation) in the left ventricular blood pool, while the SI of the myocardium increased by 8.2% (P = 0.04), consistent with an increase in myocardial oxygenation. In contrast, hyperventilation for 120 s, however, resulted in a significant 7.5% decrease in myocardial SI/oxygenation (P = 0.02). Change in capillary pCO₂ was the only independently correlated variable predicting myocardial oxygenation changes during breathing manoeuvres (r = 0.58, P < 0.01). CONCLUSION In healthy individuals, breathing manoeuvres lead to changes in myocardial oxygenation, which appear to be mediated by CO₂. These changes can be monitored in vivo by oxygenation-sensitive CMR and thus, may have value as a diagnostic tool.

Pollen dispersal properties of Poaceae and Cyperaceae: First estimates of their absolute pollen productivities

Pollen-trap results from the Swiss Alps 1996–2009 were used to assess the pollen dispersal–deposition properties of Poaceae (grasses) and Cyperaceae (sedges). Dispersal parameter values were investigated for a modified version of the Prentice–Sugita pollen dispersal–deposition model. Appropriate values (i.e. realistic in the field and allowing realistic modelling results) for wind speed are suggested to be in the range of 3–7 m s− 1 and for pollen an injection height of 0.03–0.1 m above the ground. The appropriate range of pollen injection height values for grasses and sedges differs from that of trees in the same area, suggesting different pollen dispersal properties between herbs and trees. In addition, logarithmic weighting of the vegetation was tested as an alternative to the modified Prentice–Sugita model. This yielded very similar results, suggesting that the use of such much simpler approximations of the pollen–vegetation relationship is a plausible alternative. Based on the modified Prentice–Sugita model, absolute pollen productivity for Poaceae was estimated to 7300 ± 400 grains cm− 2 year− 1 (1 SE). The data basis for Cyperaceae is smaller than for Poaceae, but the dispersal parameter values determined as appropriate for Poaceae yield good results. Absolute pollen productivity for Cyperaceae was estimated to 6300 ± 1100 grains cm− 2 year− 1 (1 SE).

Is dosing of therapeutic immunoglobulins optimal? A review of a three-decade long debate in europe.

The consumption of immunoglobulins (Ig) is increasing due to better recognition of antibody deficiencies, an aging population, and new indications. This review aims to examine the various dosing regimens and research developments in the established and in some of the relevant off-label indications in Europe. The background to the current regulatory settings in Europe is provided as a backdrop for the latest developments in primary and secondary immunodeficiencies and in immunomodulatory indications. In these heterogeneous areas, clinical trials encompassing different routes of administration, varying intervals, and infusion rates are paving the way toward more individualized therapy regimens. In primary antibody deficiencies, adjustments in dosing and intervals will depend on the clinical presentation, effective IgG trough levels and IgG metabolism. Ideally, individual pharmacokinetic profiles in conjunction with the clinical phenotype could lead to highly tailored treatment. In practice, incremental dosage increases are necessary to titrate the optimal dose for more severely ill patients. Higher intravenous doses in these patients also have beneficial immunomodulatory effects beyond mere IgG replacement. Better understanding of the pharmacokinetics of Ig therapy is leading to a move away from simplistic "per kg" dosing. Defective antibody production is common in many secondary immunodeficiencies irrespective of whether the causative factor was lymphoid malignancies (established indications), certain autoimmune disorders, immunosuppressive agents, or biologics. This antibody failure, as shown by test immunization, may be amenable to treatment with replacement Ig therapy. In certain immunomodulatory settings [e.g., idiopathic thrombocytopenic purpura (ITP)], selection of patients for Ig therapy may be enhanced by relevant biomarkers in order to exclude non-responders and thus obtain higher response rates. In this review, the developments in dosing of therapeutic immunoglobulins have been limited to high and some medium priority indications such as ITP, Kawasaki' disease, Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, myasthenia gravis, multifocal motor neuropathy, fetal alloimmune thrombocytopenia, fetal hemolytic anemia, and dermatological diseases.

Long-term live imaging reveals cytosolic immune responses of host hepatocytes against Plasmodium infection and parasite escape mechanisms

Plasmodium parasites are transmitted by Anopheles mosquitoes to the mammalian host and actively infect hepatocytes after passive transport in the bloodstream to the liver. In their target host hepatocyte, parasites reside within a parasitophorous vacuole (PV). In the present study it was shown that the parasitophorous vacuole membrane (PVM) can be targeted by autophagy marker proteins LC3, ubiquitin, and SQSTM1/p62 as well as by lysosomes in a process resembling selective autophagy. The dynamics of autophagy marker proteins in individual Plasmodium berghei-infected hepatocytes were followed by live imaging throughout the entire development of the parasite in the liver. Although the host cell very efficiently recognized the invading parasite in its vacuole, the majority of parasites survived this initial attack. Successful parasite development correlated with the gradual loss of all analyzed autophagy marker proteins and associated lysosomes from the PVM. However, other autophagic events like nonselective canonical autophagy in the host cell continued. This was indicated as LC3, although not labeling the PVM anymore, still localized to autophagosomes in the infected host cell. It appears that growing parasites even benefit from this form of nonselective host cell autophagy as an additional source of nutrients, as in host cells deficient for autophagy, parasite growth was retarded and could partly be rescued by the supply of additional amino acid in the medium. Importantly, mouse infections with P. berghei sporozoites confirmed LC3 dynamics, the positive effect of autophagy activation on parasite growth, and negative effects upon autophagy inhibition.

Migration and population expansion of Abies, Fagus, Picea, and Quercus since 15000 years in and across the Alps, based on pollen-percentage threshold values

Aims: The aim of this study is to explore the migration (colonization of new areas) and subsequent population expansion (within an area) since 15 ka cal BP of Abies, Fagus, Picea, and Quercus into and through the Alps solely on the basis of high-quality pollen data. Methods: Chronologies of 101 pollen sequences are improved or created. Data from the area delimited by 45.5–48.1°N and 6–14°E are summarized in three ways: (1) in a selection of pollen-percentage threshold maps (thresholds 0.5%, 1%, 2%, 4%, 8%, 16%, and 32% of land pollen); (2) in graphic summaries of 250-year time slices and geographic segments (lengthwise and transverse in relation to the main axis of the Alps) as pollen-percentage curves, pollen-percentage difference curves, and pollen-percentage threshold ages cal BP graphed against both the length and the transverse Alpine axes; and (3) in tables showing statistical relationships of either pollen-percentage threshold ages cal BP or pollen expansion durations (=time lapse between different pollen-percentage threshold ages cal BP) with latitude, longitude, and elevation; to establish these relationships we used both simple linear regression and multiple linear regression after stepwise-forward selection. Results: The statistical results indicate that (a) the use of pollen-percentage thresholds between 0.5% and 8% yield mostly similar directions of tree migration, so the method is fairly robust, (b) Abies migrated northward, Fagus southward, Picea westward, and Quercus northward; more detail does not emerge due to an extreme scarcity of high-quality data especially along the southern foothills of the Alps and in the eastern Alps. This scarcity allows the reconstruction of one immigration route only of Abies into the southern Alps. The speed of population expansion (following arrival) of Abies increased and of Picea decreased during the Holocene, of Fagus it decreased especially during the later Holocene, and of Quercus it increased especially at the start of the Holocene.

Holocene vegetation development in the catchment of Sagistalsee (1935 m asl), a small lake in the Swiss Alps

Pollen and plant macrofossils were analysed at Sägistalsee (1935 m asl), a small lake near timber-line in the Swiss Northern Alps. Open forests with Pinus cembra and Abies alba covered the catchment during the early Holocene (9000–6300 cal. BP), suggesting subcontinental climate conditions. After the expansion of Picea abies between 6300 and 6000 cal. BP the subalpine forest became denser and the tree-line reached its maximum elevation at around 2260 m asl. Charcoal fragments in the macrofossil record indicate the beginning of Late-Neolithic human impact at ca. 4400 cal. BP, followed by a extensive deforestation and lowering of the forest-limit in the catchment of Sägistalsee at 3700 cal. BP (Bronze Age). Continuous human activity, combined with a more oceanic climate during the later Holocene, led to the local extinction of Pinus cembra and Abies alba and favoured the mass expansion of Picea and Alnus viridis in the subalpine area of the Northern Alps. The periods before 6300 and after 3700 cal. BP are characterised by high erosion activity in the lake's catchment, whereas during the phase of dense Picea-Pinus cembra-Abies forests (6300–3700 cal. BP) soils were stable and sediment-accumulation rates in the lake were low. Due to decreasing land-use at higher altitudes during the Roman occupation and the Migration period, forests spread beween ca. 2000 and 1500 cal. BP, before human impact increased again in the early Middle Ages. Recent reforestation due to land-use changes in the 20th century is recorded in the top sediments. Pollen-inferred July temperature and annual precipitation suggest a trend to cooler and more oceanic climate starting at about 5500 cal. BP.

Middle to Late Holocene vegetation history of the Upper Engadine (Swiss Alps): the role of man and fire

o reconstruct the vegetation and fire history of the Upper Engadine, two continuous sediment cores from Lej da Champfèr and Lej da San Murezzan (Upper Engadine Valley, southeastern Switzerland) were analysed for pollen, plant macrofossils, charcoal and kerogen. The chronologies of the cores are based on 38 radiocarbon dates. Pollen and macrofossil data suggest a rapid afforestation with Betula, Pinus sylvestris, Pinus cembra, and Larix decidua after the retreat of the glaciers from the lake catchments 11,000 cal years ago. This vegetation type persisted until ca. 7300 cal b.p. (5350 b.c.) when Picea replaced Pinus cembra. Pollen indicative of human impact suggests that in this high-mountain region of the central Alps strong anthropogenic activities began during the Early Bronze Age (3900 cal b.p., 1950 b.c.). Local human settlements led to vegetational changes, promoting the expansion of Larix decidua and Alnus viridis. In the case of Larix, continuing land use and especially grazing after fire led to the formation of Larix meadows. The expansion of Alnus viridis was directly induced by fire, as evidenced by time-series analysis. Subsequently, the process of forest conversion into open landscapes continued for millennia and reached its maximum at the end of the Middle Ages at around 500 cal b.p. (a.d. 1450).

Climate-pollen relationships AD 1901-1996 in two small mires near the forest limit in the northern and central Swiss Alps

Climatic relationships were established in two 210Pb dated pollen sequences from small mires closely surrounded by forest just below actual forest limits (but about 300 m below potential climatic forest limits) in the northern Swiss Alps (suboceanic in climate; mainly with Picea) and the central Swiss Alps (subcontinental; mainly Pinus cembra and Larix) at annual or near-annual resolution from ad 1901 to 1996. Effects of vegetational succession were removed by splitting the time series into early and late periods and by linear detrending. Both pollen concentrations detrended by the depth-age model and modified percentages (in which counts of dominant pollen types are down-weighted) are correlated by simple linear regression with smoothed climatic parameters with one-and two-year timelags, including average monthly and April/September daylight air temperatures and with seasonal and annual precipitation sums. Results from detrended pollen concentrations suggest that peat accumulation is favoured in the northern-Alpine mire either by early snowmelt or by summer precipitation, but in the central-Alpine mire by increased precipitation and cooler summers, suggesting a position of the northern-Alpine mire near the upper altitudinal limit of peat formation, but of the central-Alpine mire near the lower limit. Results from modified pollen percentages indicate that pollen pro duction by plants growing near their upper altitudinal limit is limited by insufficient warmth in summer, and pollen production by plants growing near their lower altitudinal limit is limited by too-high temperatures. Only weakly significant pollen/climate relationships were found for Pinus cembra and Larix, probably because they experience little climatic stress growing 300 m below the potential climatic forest limit.

Climatic change and contemporaneous land-use phases north and south of the Alps 2300 BC to 800 AD

Fluctuations in the Δ14C curve and subsequent gaps of archaeological findings at 800–650 and 400–100 BC in western and central Europe may indicate major climate-driven land-abandonment phases. To address this hypothesis radiocarbon-dated sediments from four lakes in Switzerland were studied palynologically. Pollen analysis indicates contemporaneous phases of forest clearances and of intensified land-use at 1450–1250 BC, 650–450 BC, 50 BC–100 AD and around 700 AD. These land-use expansions coincided with periods of warm climate as recorded by the Alpine dendroclimatic and Greenland oxygen isotope records. Our results suggest that harvest yields would have increased synchronously over wide areas of central and southern Europe during periods of warm and dry climate. Combined interpretation of palaeoecological and archaeological findings suggests that higher food production led to increased human populations. Positive long-term trends in pollen values of Cerealia and Plantago lanceolata indicate that technical innovations during the Bronze and Iron Age (e.g. metal ploughs, scythes, hay production, fertilising methods) gradually increased agricultural productivity. The successful adoption of yield-increasing advances cannot be explained by climatic determinism alone. Combined with archaeological evidence, our results suggest that despite considerable cycles of spatial and demographic reorganisation (repeated land abandonments and expansions, as well as large-scale migrations and population decreases), human societies were able to shift to lower subsistence levels without dramatic ruptures in material culture. However, our data imply that human societies were not able to compensate rapidly for harvest failures when climate deteriorated. Agriculture in marginal areas was abandoned, and spontaneous reforestations took place on abandoned land south and north of the Alps. Only when the climate changed again to drier and warmer conditions did a new wide-spread phase of forest clearances and field extensions occur, allowing the reoccupation of previously abandoned areas. Spatial distribution of cereal cultivation and growth requirements of Cerealia species suggest that increases in precipitation were far more decisive in driving crop failures over central and southern Europe than temperature decreases.

Interactions of climate and land use documented in the varved sediments of Seebergsee in the Swiss Alps

This paper presents a multiproxy high-resolution study of the past 2600 years for Seebergsee, a small Swiss lake with varved sediments at the present tree-line ecotone. The laminae were identified as varves by a numerical analysis of diatom counts in the thin-sections. The hypothesis of two diatom blooms per year was corroborated by the 210Pb and 137Cs chronology. A period of intensive pasturing during the ‘Little Ice Age’ between ad 1346 and ad 1595 is suggested by coprophilous fungal spores, as well as by pollen indicators of grazing, by the diatom-inferred total phosphorus, by geochemistry and by documentary data. The subsequent re-oligotrophication of the lake took about 88 years, as determined by the timelag between the decline of coprophile fungal spores and the restoration of pre-eutrophic nutrient conditions. According to previous studies of latewood densities from the same region, cold summers around ad 1600 limited the pasturing at this altitude. This demonstrated the socio-economic impact of a single climatic event. However, the variance partitioning between the effects of land use and climate, which was applied for the whole core, revealed that climate independent of land use and time explained only 1.32% of the diatom data, while land use independent of climate and time explained 15.7%. Clearly land use in‘ uenced the lake, but land use was not always driven by climate. Other factors beside climate, such as politics or the introduction of fertilizers in the seventeenth and eighteenth centuries also in‘ uenced the development of Alpine pasturing.

A Late-glacial and Holocene record of climatic change from a Swiss peat humification profile

Colorimetric measurements of alkaline extracts from two Swiss peat cores have provided a complete 14500-year-long record of peat humification, a proxy of effective precipitation. Peat from the cold Younger Dryas (11050–9550 cal. bc) was well preserved despite low levels of precipitation. A particularly dry period, peaking at c. 7100 cal. bc, is indicated by well-decomposed peat. Peat from c. 6750–4250 cal. bc shows a low degree of decomposition, indicating a wet bog surface despite relatively warm temperatures and therefore indicating high levels of precipitation. A sharp transition to higher levels of decomposition c. 4450–3750 cal. bc indicates a major transition to a drier bog surface. Subsequently, peat humification generally decreases towards the end of the deeper profile (c. cal. ad 1050), indicating a gradual return to wetter conditions. This gradual decrease is punctuated by periods of particularly low humification which appear to be due to shifts to higher levels of effective precipitation from c. 2500 to 1350 cal. bc, c. 1050 to 550 cal. bc, centered around 150 cal. bc, and from c. cal. ad 550 onwards. Anthropogenic influences appear to have affected peat humification at the site at least since the Middle Ages. This study indicates that humification in colder regions/time periods could be more affected by temperature than precipitation and vice versa.

Long-term man–environment interactions in the Bolivian Amazon: 8000 years of vegetation dynamics

Only few studies documenting the vegetation history of the Llanos de Moxos, one of the largest seasonally flooded wetland areas in South America, are available and little is known about the environmental impact of pre-Columbian settlements. We use radiocarbon-dated terrestrial plant macrofossils to establish a sound chronology and palynological analyses to reconstruct the vegetation and fire history of the Lago Rogaguado area. The sedimentary pollen and spore record suggests that wetland and wooded savannah (Cerrado) environments occurred around the lake between 8100 and 5800 cal BP. Fire activity was high during this period and was probably connected to the dry Cerrado environments. The pollen evidence suggests early plant cultivation (Zea mays, Annonaceae and Cucurbitaceae) from 6500 cal BP onwards, which is significantly earlier than hitherto assumed for Amazonia. Gallery forests expanded after 5800 cal BP, when fire activity strongly declined. Forest expansion intensified around 2800 cal BP and continued until 2000 cal BP, when forest cover reached its maximum and fire activity its minimum. The late-Holocene forest expansion to the south and the decrease of fire activity may have resulted from a climatic shift to moister conditions (possibly a shorter dry season). New crops (e.g. Avena-type) or adventive plants (e.g. Rumex acetosella-type) document the impact of European economies after ca. 500 cal BP. Land use intensity remained rather stable over the most recent centuries, arguing against a collapse of settlements in response to the arrival of Europeans, as reconstructed from other Amazonian pollen records.

Morphological Brain Changes after Climbing to Extreme Altitudes-A Prospective Cohort Study.

BACKGROUND Findings of cerebral cortical atrophy, white matter lesions and microhemorrhages have been reported in high-altitude climbers. The aim of this study was to evaluate structural cerebral changes in a large cohort of climbers after an ascent to extreme altitudes and to correlate these findings with the severity of hypoxia and neurological signs during the climb. METHODS Magnetic resonance imaging (MRI) studies were performed in 38 mountaineers before and after participating in a high altitude (7126m) climbing expedition. The imaging studies were assessed for occurrence of new WM hyperintensities and microhemorrhages. Changes of partial volume estimates of cerebrospinal fluid, grey matter, and white matter were evaluated by voxel-based morphometry. Arterial oxygen saturation and acute mountain sickness scores were recorded daily during the climb. RESULTS On post-expedition imaging no new white matter hyperintensities were observed. Compared to baseline testing, we observed a significant cerebrospinal fluid fraction increase (0.34% [95% CI 0.10-0.58], p = 0.006) and a white matter fraction reduction (-0.18% [95% CI -0.32--0.04], p = 0.012), whereas the grey matter fraction remained stable (0.16% [95% CI -0.46-0.13], p = 0.278). Post-expedition imaging revealed new microhemorrhages in 3 of 15 climbers reaching an altitude of over 7000m. Affected climbers had significantly lower oxygen saturation values but not higher acute mountain sickness scores than climbers without microhemorrhages. CONCLUSIONS A single sojourn to extreme altitudes is not associated with development of focal white matter hyperintensities and grey matter atrophy but leads to a decrease in brain white matter fraction. Microhemorrhages indicative of substantial blood-brain barrier disruption occur in a significant number of climbers attaining extreme altitudes.