Is fast track management after elective cranial surgery safe and can it replace routine early postoperative computed tomography?

Aims: Patient management following elective cranial surgery varies between different neurosurgical institutions. Early routine postoperative cranial computed tomography (CT) is often performed while keeping patients sedated and ventilated for several hours. We hypothesize that fast track management without routine CT scanning, i.e., early extubation within one hour allowing neurological monitoring, is safe and does not increase the rate of return to OR compared with published data. Methods: We prospectively screened 1118 patients with cranial procedures performed at our department over a period of two years. 420 patients with elective brain surgery older than 18 years with no history of prior cranial surgery were included. Routine neurosurgical practice as it is performed at our department was not altered for this observational study. Fast track management was aimed for all cases, extubated and awake patients were further monitored. CT scanning within 48 hours after surgery was not performed except for unexpected neurological deterioration. This study was registered at ClinicalTrials.gov (NCT01987648). Results: 420 elective craniotomies were performed for 310 supra- and 110 infratentorial lesions. 398 patients (94.8%) were able to be extubated within 1 hour, 21 (5%) within 6 hours, and 1 patient (0.2%) was extubated 9 hours after surgery. Emergency CT within 48 hours was performed for 36 patients (8.6%, 26 supra- and 10 infratentorial cases) due to unexpected neurological worsening. Of these 36 patients 5 had to return to the OR (hemorrhage in 3, swelling in 2 cases). Return to OR rate of all included cases was 1.2%. This rate compares favorably with 1-4% as quoted in the current literature. No patient returned to the OR without prior CT imaging. Of 398 patients extubated within one hour 2 (0.5%) returned to the OR. Patients who couldn’t be extubated within the first hour had a higher risk of returning to the OR (3 of 22, i.e., 14%). Overall 30-day mortality was 0.2% (1 patient). Conclusions: Early extubation and CT imaging performed only for patients with unexpected neurological worsening after elective craniotomy procedures is safe and does not increase patient mortality or the return to OR rate. With this fast track approach early postoperative cranial CT for detection of postoperative complications in the absence of an unexpected neurological finding is not justified. Acknowledgments The authors thank Nicole Söll, study nurse, Department of Neurosurgery, Bern University Hospital, Switzerland for crucial support in data collection and managing the database.

Early co-occurrence of a neurologic-psychiatric disease pattern in Niemann-Pick type C disease: a retrospective Swiss cohort study

BackgroundNiemann-Pick disease type C (NP-C) is a rare autosomal recessive disorder of lysosomal cholesterol transport. The objective of this retrospective cohort study was to critically analyze the onset and time course of symptoms, and the clinical diagnostic work-up in the Swiss NP-C cohort.MethodsClinical, biochemical and genetic data were assessed for 14 patients derived from 9 families diagnosed with NP-C between 1994 and 2013. We retrospectively evaluated diagnostic delays and period prevalence rates for neurological, psychiatric and visceral symptoms associated with NP-C disease. The NP-C suspicion index was calculated for the time of neurological disease onset and the time of diagnosis.ResultsThe shortest median diagnostic delay was noted for vertical supranuclear gaze palsy (2y). Ataxia, dysarthria, dysphagia, spasticity, cataplexy, seizures and cognitive decline displayed similar median diagnostic delays (4¿5y). The longest median diagnostic delay was associated with hepatosplenomegaly (15y). Highest period prevalence rates were noted for ataxia, dysarthria, vertical supranuclear gaze palsy and cognitive decline. The NP-C suspicion index revealed a median score of 81 points in nine patients at the time of neurological disease onset which is highly suspicious for NP-C disease. At the time of diagnosis, the score increased to 206 points.ConclusionA neurologic-psychiatric disease pattern represents the most characteristic clinical manifestation of NP-C and occurs early in the disease course. Visceral manifestation such as isolated hepatosplenomegaly often fails recognition and thus highlights the importance of a work-up for lysosomal storage disorders. The NP-C suspicion index emphasizes the importance of a multisystem evaluation, but seems to be weak in monosymptomatic and infantile NP-C patients.

Early adolescents’ enjoyment experienced in learning situations at school and its relation to student achievement

While many studies confirm that positive emotions, including enjoyment, lead to better student achievement, less empirical evidence exists about possible mediator variables that link achievement to enjoyment. It is proposed that achievement and enjoyment form a circular dependency; enjoyment in learning leads to higher achievement but a degree of achievement is required to enjoy learning. This study provides insight into the reverse of the much studied enjoyment to achievement link and provides practical recommendations on how to use these findings. Founded in Control-value theory, which suggests that control and value cognitions are important variables that mediate the connection between enjoyment and achievement, this study explores the reciprocal achievement-cognition-enjoyment link. The reciprocal link was investigated by applying a one year longitudinal design to students of grade 6 and 7 (N = 356). This age group was chosen because early adolescence represents a critical period during which a strong decrease in positive learning emotions is observed. Part of the work involved identifying factors that might be responsible for this negative development. Results of cross-lagged path analysis identified reciprocal effects between student achievement and enjoyment with control and value cognitions functioning as partial mediators. High achievement goes with high control and value cognitions, which in turn positively affect enjoyment. However, cross-lagged correlations could only be partly confirmed. The results are discussed in terms of theoretical and practical implications

Clinical importance of risk variants in the dihydropyrimidine dehydrogenase gene for the prediction of early-onset fluoropyrimidine toxicity.

We investigated the clinical relevance of dihydropyrimidine dehydrogenase gene (DPYD) variants to predict severe early-onset fluoropyrimidine (FP) toxicity, in particular of a recently discovered haplotype hapB3 and a linked deep intronic splice site mutation c.1129-5923C>G. Selected regions of DPYD were sequenced in prospectively collected germline DNA of 500 patients receiving FP-based chemotherapy. Associations of DPYD variants and haplotypes with hematologic, gastrointestinal, infectious, and dermatologic toxicity in therapy cycles 1-2 and resulting FP-dose interventions (dose reduction, therapy delay or cessation) were analyzed accounting for clinical and demographic covariates. Fifteen additional cases with toxicity-related therapy delay or cessation were retrospectively examined for risk variants. The association of c.1129-5923C>G/hapB3 (4.6% carrier frequency) with severe toxicity was replicated in an independent prospective cohort. Overall, c.1129-5923G/hapB3 carriers showed a relative risk of 3.74 (RR, 95% CI = 2.30-6.09, p = 2 × 10(-5)) for severe toxicity (grades 3-5). Of 31 risk variant carriers (c.1129-5923C>G/hapB3, c.1679T>G, c.1905+1G>A or c.2846A>T), 11 (all with c.1129-5923C>G/hapB3) experienced severe toxicity (15% of 72 cases, RR = 2.73, 95% CI = 1.61-4.63, p = 5 × 10(-6)), and 16 carriers (55%) required FP-dose interventions. Seven of the 15 (47%) retrospective cases carried a risk variant. The c.1129-5923C>G/hapB3 variant is a major contributor to severe early-onset FP toxicity in Caucasian patients. This variant may substantially improve the identification of patients at risk of FP toxicity compared to established DPYD risk variants (c.1905+1G>A, c.1679T>G and c.2846A>T). Pre-therapeutic DPYD testing may prevent 20-30% of life-threatening or lethal episodes of FP toxicity in Caucasian patients.

Milk fatty acids as possible biomarkers to early diagnose elevated concentrations of blood plasma nonesterified fatty acids in dairy cows

Most cows encounter a state of negative energy balance during the periparturient period, which may lead to metabolic disorders and impaired fertility. The aim of this study was to assess the potential of milk fatty acids as diagnostic tools of detrimental levels of blood plasma nonesterified fatty acids (NEFA), defined as NEFA concentrations beyond 0.6 mmol/L, in a data set of 92 early lactating cows fed a glucogenic or lipogenic diet and subjected to 0-, 30-, or 60-d dry period before parturition. Milk was collected in wk 2, 3, 4, and 8 (n = 368) and blood was sampled weekly from wk 2 to 8 after parturition. Milk was analyzed for milk fatty acids and blood plasma for NEFA. Data were classified as "at risk of detrimental blood plasma NEFA" (NEFA ≥ 0.6 mmol/L) and "not at risk of detrimental blood plasma NEFA" (NEFA <0.6 mmol/L). Concentrations of 45 milk fatty acids and milk fat C18:1 cis-9-to-C15:0 ratio were subjected to a discriminant analysis. Milk fat C18:1 cis-9 revealed the most discriminating variable to identify detrimental blood plasma NEFA. A false positive rate of 10% allowed us to diagnose 46% of the detrimental blood plasma NEFA cases based on a milk fat C18:1 cis-9 concentration of at least 230 g/kg of milk fatty acids. Additionally, it was assessed whether the milk fat C18:1 cis-9 concentrations of wk 2 could be used as an early warning for detrimental blood plasma NEFA risk during the first 8 wk in lactation. Cows with at least 240 g/kg of C18:1 cis-9 in milk fat had about 50% chance to encounter blood plasma NEFA values of 0.6 mmol/L or more during the first 8 wk of lactation, with a false positive rate of 11.4%. Profit simulations were based on costs for cows suffering from detrimental blood plasma NEFA, and costs for preventive treatment based on daily dosing of propylene glycol for 3 wk. Given the relatively low incidence rate (8% of all observations), continuous monitoring of milk fatty acids during the first 8 wk of lactation to diagnose detrimental blood plasma NEFA does not seem cost effective. On the contrary, milk fat C18:1 cis-9 of the second lactation week could be an early warning of cows at risk of detrimental blood NEFA. In this case, selective treatment may be cost effective.

Milk production during the colostral period is not related to the later lactational performance in dairy cows

In dairy cows, milk yield increases rapidly after parturition until a peak at around wk 6 of lactation. However, the description of the shape of the lactation curve is commonly based on weekly average milk yields. For a more detailed analysis of the milk production curve from the very beginning of lactation including the colostral period and the effect of colostrum yield on further lactational performance, the first 10 milkings after parturition, daily milk yields from d 1 to 28 of lactation, and the cumulative milk production on d 100 to 305 of lactation were investigated in 17 primiparous and 39 multiparous cows milked twice daily. Milk yield at the first milking after parturition (colostrum) ranged from 1.3 to 20.7kg (Δ=19.4kg) in multiparous and from 1.8 to 10.9kg in primiparous animals (Δ=9.1kg). At the tenth milking, milk production ranged from 9.2 to 21.5kg (Δ=12.3kg) in multiparous and from 7.0 to 15.2kg (Δ=8.2kg) in primiparous animals. Immediately after parturition, daily milk production increased rapidly, but after approximately 1wk in lactation, the slope of the daily milk production curve flattened and continued more linear. A nonlinear regression equation was used to determine this timely change, which occurred earlier in primiparous (d 6.9±0.3) than in multiparous cows (d 8.2±0.2). The correlation between the amount of first colostrum and milk production during further lactation decreased already from 0.47 on d 5 to 0.32 on d 14. In multiparous cows, the correlation between total milk production of the previous 305d standard lactation and the amount of first colostrum was not significant (correlation=0.29), whereas the correlation with the daily production increased from 0.45 on d 5 to 0.69 on d 14. However, in primiparous animals, correlations between first-colostrum yield and daily milk yields up to d 28 of lactation were not significant, possibly due to the smaller sample size compared with multiparous animals. First-colostrum yield and cumulative milk production of 100, 200, and 305 lactation days were not significantly correlated in multiparous and primiparous cows. In conclusion, the milk production during the first few milkings is widely independent from the overall production level of a cow. Potentially, genetic selection toward lower milk yield during the very first days after parturition at a simultaneously high lactational performance may be a tool to ensure sufficient colostrum quality and to reduce the metabolic load around parturition.

Short communication: Circulating and milk adiponectin change differently during energy deficiency at different stages of lactation in dairy cows

Adiponectin, one of the most abundant adipokines in circulation, is known for its role in regulation of body metabolism. The aim of this study was to evaluate the effects of a negative energy balance (NEB) at 2 stages of lactation (lactational NEB at the onset of lactation and an induced NEB by feed restriction near 100 d of lactation) on circulating adiponectin concentrations. We also investigated the effect of feed restriction on adiponectin concentrations in milk and the relationships of blood and milk adiponectin with selected plasma or milk variables and with measures of body condition. Plasma adiponectin was measured in 50 multiparous Holstein dairy cows throughout 3 experimental periods [i.e., period 1=3 wk antepartum up to 12 wk postpartum, period 2=3 wk of feed restriction starting at around 100 d in milk with a control (n=25) and feed-restricted group (50% of energy requirements; n=25), and period 3=subsequent realimentation period for 8 wk]. Milk adiponectin was investigated among 21 multiparous cows at wk 2 and wk 12 of period 1 and wk 2 of period 2. Adiponectin concentrations in plasma and skim milk were measured using an in-house ELISA specific for bovine adiponectin. Major changes in circulating adiponectin concentrations were observed during the periparturient period, whereas energy deficiency during established lactation at around 100 d in milk and subsequent refeeding did not affect plasma adiponectin. Together with lower adiponectin concentrations in milk (µg/mL), the reduction in milk yield led to decreased adiponectin secretion via milk (mg/d) at the second week of feed restriction. Irrespective of time and treatment, milk adiponectin represented about 0.002% of total milk protein. Mean adiponectin concentrations in milk (0.61 ± 0.03 µg/mL) were about 92% lower than the mean plasma adiponectin concentrations (32.1 ± 1.0 µg/mL). The proportion of the steady-state plasma adiponectin pool secreted daily via milk was 2.7%. In view of the similar extent of NEB in both periods of energy deficiency, decreasing adiponectin concentrations seems important for accomplishing the adaptation to the rapidly increasing metabolic rates in early lactation, whereas the lipolytic reaction toward feed restriction-induced NEB during established lactation seems to occur largely independent of changes in circulating adiponectin.

Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV.

Tyrosine kinase inhibitors (TKI) have changed the natural course of chronic myeloid leukemia (CML). With the advent of second-generation TKI safety and efficacy issues have gained interest. The randomized CML - Study IV was used for a long-term evaluation of imatinib (IM). 1503 patients have received IM, 1379 IM monotherapy. After a median observation of 7.1 years, 965 patients (64%) still received IM. At 10 years, progression-free survival was 82%, overall survival 84%, 59% achieved MR(5), 72% MR(4.5), 81% MR(4), 89% major molecular remission and 92% MR(2) (molecular equivalent to complete cytogenetic remission). All response levels were reached faster with IM800 mg except MR(5). Eight-year probabilities of adverse drug reactions (ADR) were 76%, of grades 3-4 22%, of non-hematologic 73%, and of hematologic 28%. More ADR were observed with IM800 mg and IM400 mg plus interferon α (IFN). Most patients had their first ADR early with decreasing frequency later on. No new late toxicity was observed. ADR to IM are frequent, but mostly mild and manageable, also with IM 800 mg and IM 400 mg+IFN. The deep molecular response rates indicate that most patients are candidates for IM discontinuation. After 10 years, IM continues to be an excellent initial choice for most patients with CML.Leukemia advance online publication, 13 March 2015; doi:10.1038/leu.2015.36.

Cholesterol metabolism, transport, and hepatic regulation in dairy cows during transition and early lactation

The transition from the nonlactating to the lactating state represents a critical period for dairy cow lipid metabolism because body reserves have to be mobilized to meet the increasing energy requirements for the initiation of milk production. The purpose of this study was to provide a comprehensive overview on cholesterol homeostasis in transition dairy cows by assessing in parallel plasma, milk, and hepatic tissue for key factors of cholesterol metabolism, transport, and regulation. Blood samples and liver biopsies were taken from 50 multiparous Holstein dairy cows in wk 3 antepartum (a.p.), wk 1 postpartum (p.p.), wk 4 p.p., and wk 14 p.p. Milk sampling was performed in wk 1, 4, and 14 p.p. Blood and milk lipid concentrations [triglycerides (TG), cholesterol, and lipoproteins], enzyme activities (phospholipid transfer protein and lecithin:cholesterol acyltransferase) were analyzed using enzymatic assays. Hepatic gene expression patterns of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGC) synthase 1 (HMGCS1) and HMGC reductase (HMGCR), sterol regulatory element-binding factor (SREBF)-1 and -2, microsomal triglyceride transfer protein (MTTP), ATP-binding cassette transporter (ABC) A1 and ABCG1, liver X receptor (LXR) α and peroxisome proliferator activated receptor (PPAR) α and γ were measured using quantitative RT-PCR. Plasma TG, cholesterol, and lipoprotein concentrations decreased from wk 3 a.p. to a minimum in wk 1 p.p., and then gradually increased until wk 14 p.p. Compared with wk 4 p.p., phospholipid transfer protein activity was increased in wk 1 p.p., whereas lecithin:cholesterol acyltransferase activity was lowest at this period. Total cholesterol concentration and mass, and cholesterol concentration in the milk fat fraction decreased from wk 1 p.p. to wk 4 p.p. Both total and milk fat cholesterol concentration were decreased in wk 4 p.p. compared with wk 1 and 14 p.p. The mRNA abundance of genes involved in cholesterol synthesis (SREBF-2, HMGCS1, and HMGCR) markedly increased from wk 3 a.p. to wk 1 p.p., whereas SREBF-1 was downregulated. The expression of ABCA1 increased from wk 3 a.p. to wk 1 p.p., whereas ABCG1 was increased in wk 14 p.p. compared with other time points. In conclusion, hepatic expression of genes involved in the biosynthesis of cholesterol as well as the ABCA1 transporter were upregulated at the onset of lactation, whereas plasma concentrations of total cholesterol, phospholipids, lipoprotein-cholesterol, and TG were at a minimum. Thus, at the gene expression level, the liver seems to react to the increased demand for cholesterol after parturition. Whether the low plasma cholesterol and TG levels are due to impaired hepatic export mechanisms or reflect an enhanced transfer of these compounds into the milk to provide essential nutrients for the newborn remains to be elucidated.

‘Idolatry’ and Religious Diversity: Thinking about the Other in Early Modern Europe

Idolatry is a key concept in the history of Western thinking about religion, as an all-encompassing category in which all religions more or less alien to the Christian tradition could be subsumed. From Late Antiquity to the Modern period, we can follow how the notion was put to work within Christian discourse to think about the religious “other. ” In fact, the word is almost ubiquitous in pre-modern debates on religion and the origins of religion. Theories on the nature and causes of “idolatry” framed much of the issue of “Religion” vs. the “religions,” and largely provided the conceptual space, in early modern Europe, in which religious anthropology would emerge. The present paper will investigate some aspects of the early modern discourse on idolatry, and its place in early modern discussions on the “diversity” of religions.

Antipredator defences of young are independently determined by genetic inheritance, maternal effects and own early experience in mouthbrooding cichlids.

1. Predation is a prime force of natural selection. Vulnerability to predation is typically highest early in life, hence effective antipredator defences should work already shortly after birth. Such early defences may be innate, transmitted through non-genetic parental effects or acquired by own early experience. 2. To understand potential joint effects of these sources of antipredator defences on pheno- typic expression, they should be manipulated within the same experiment. We investigated innate, parental and individual experience effects within a single experiment. Females of the African cichlid Simochromis pleurospilus were exposed to the offspring predator Ctenochromis horei or a benign species until spawning. Eggs and larvae were hand-reared, and larvae were then exposed to odour cues signalling the presence or absence of predators in a split-brood design. 3. Shortly after independence of maternal care, S. pleurospilus undergo a habitat shift from a deeper, adult habitat to a shallow juvenile habitat, a phase where young are thought to be par- ticularly exposed to predation risk. Thus, maternal effects induced by offspring predators pres- ent in the adult habitat should take effect mainly shortly after independence, whereas own experience and innate antipredator responses should shape behaviour and life history of S. pleurospilus during the later juvenile period. 4. We found that the manipulated environmental components independently affected different offspring traits. (i) Offspring of predator-exposed mothers grew faster during the first month of life and were thus larger at termination of maternal care, when the young migrate from the adult to the juvenile habitat. (ii) The offspring’s own experience shortly after hatching exerted lasting effects on predator avoidance behaviour. (iii) Finally, our results suggest that S. pleuro- spilus possess a genetically inherited ability to distinguish dangerous from benign species. 5. In S. pleurospilus, maternal effects were limited to a short but critical time window, when young undergo a niche shift. Instead, own environmental sampling of predation risk combined with an innate predisposition to correctly identify predators appears to prepare the young best for the environment, in which they grow up as juveniles.

Microbe sampling by mucosal dendritic cells is a discrete, MyD88-independent step in DeltainvG S. Typhimurium colitis.

Intestinal dendritic cells (DCs) are believed to sample and present commensal bacteria to the gut-associated immune system to maintain immune homeostasis. How antigen sampling pathways handle intestinal pathogens remains elusive. We present a murine colitogenic Salmonella infection model that is highly dependent on DCs. Conditional DC depletion experiments revealed that intestinal virulence of S. Typhimurium SL1344 DeltainvG mutant lacking a functional type 3 secretion system-1 (DeltainvG)critically required DCs for invasion across the epithelium. The DC-dependency was limited to the early phase of infection when bacteria colocalized with CD11c(+)CX3CR1(+) mucosal DCs. At later stages, the bacteria became associated with other (CD11c(-)CX3CR1(-)) lamina propria cells, DC depletion no longer attenuated the pathology, and a MyD88-dependent mucosal inflammation was initiated. Using bone marrow chimeric mice, we showed that the MyD88 signaling within hematopoietic cells, which are distinct from DCs, was required and sufficient for induction of the colitis. Moreover, MyD88-deficient DCs supported transepithelial uptake of the bacteria and the induction of MyD88-dependent colitis. These results establish that pathogen sampling by DCs is a discrete, and MyD88-independent, step during the initiation of a mucosal innate immune response to bacterial infection in vivo.

Cryptococcal Antigenemia in Immunocompromised Human Immunodeficiency Virus Patients in Rural Tanzania: A Preventable Cause of Early Mortality

Background.  Cryptococcal meningitis is a leading cause of death in people living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome. The World Health Organizations recommends pre-antiretroviral treatment (ART) cryptococcal antigen (CRAG) screening in persons with CD4 below 100 cells/µL. We assessed the prevalence and outcome of cryptococcal antigenemia in rural southern Tanzania. Methods.  We conducted a retrospective study including all ART-naive adults with CD4 <150 cells/µL prospectively enrolled in the Kilombero and Ulanga Antiretroviral Cohort between 2008 and 2012. Cryptococcal antigen was assessed in cryopreserved pre-ART plasma. Cox regression estimated the composite outcome of death or loss to follow-up (LFU) by CRAG status and fluconazole use. Results.  Of 750 ART-naive adults, 28 (3.7%) were CRAG-positive, corresponding to a prevalence of 4.4% (23 of 520) in CD4 <100 and 2.2% (5 of 230) in CD4 100-150 cells/µL. Within 1 year, 75% (21 of 28) of CRAG-positive and 42% (302 of 722) of CRAG-negative patients were dead or LFU (P<.001), with no differences across CD4 strata. Cryptococcal antigen positivity was an independent predictor of death or LFU after adjusting for relevant confounders (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.29-4.83; P = .006). Cryptococcal meningitis occurred in 39% (11 of 28) of CRAG-positive patients, with similar retention-in-care regardless of meningitis diagnosis (P = .8). Cryptococcal antigen titer >1:160 was associated with meningitis development (odds ratio, 4.83; 95% CI, 1.24-8.41; P = .008). Fluconazole receipt decreased death or LFU in CRAG-positive patients (HR, 0.18; 95% CI, .04-.78; P = .022). Conclusions.  Cryptococcal antigenemia predicted mortality or LFU among ART-naive HIV-infected persons with CD4 <150 cells/µL, and fluconazole increased survival or retention-in-care, suggesting that targeted pre-ART CRAG screening may decrease early mortality or LFU. A CRAG screening threshold of CD4 <100 cells/µL missed 18% of CRAG-positive patients, suggesting guidelines should consider a higher threshold.

A regional climate palaeosimulation for Europe in the period 1500–1990 – Part 2: Shortcomings and strengths of models and reconstructions

This study compares gridded European seasonal series of surface air temperature (SAT) and precipitation (PRE) reconstructions with a regional climate simulation over the period 1500–1990. The area is analysed separately for nine subareas that represent the majority of the climate diversity in the European sector. In their spatial structure, an overall good agreement is found between the reconstructed and simulated climate features across Europe, supporting consistency in both products. Systematic biases between both data sets can be explained by a priori known deficiencies in the simulation. Simulations and reconstructions, however, largely differ in the temporal evolution of past climate for European subregions. In particular, the simulated anomalies during the Maunder and Dalton minima show stronger response to changes in the external forcings than recorded in the reconstructions. Although this disagreement is to some extent expected given the prominent role of internal variability in the evolution of regional temperature and precipitation, a certain degree of agreement is a priori expected in variables directly affected by external forcings. In this sense, the inability of the model to reproduce a warm period similar to that recorded for the winters during the first decades of the 18th century in the reconstructions is indicative of fundamental limitations in the simulation that preclude reproducing exceptionally anomalous conditions. Despite these limitations, the simulated climate is a physically consistent data set, which can be used as a benchmark to analyse the consistency and limitations of gridded reconstructions of different variables. A comparison of the leading modes of SAT and PRE variability indicates that reconstructions are too simplistic, especially for precipitation, which is associated with the linear statistical techniques used to generate the reconstructions. The analysis of the co-variability between sea level pressure (SLP) and SAT and PRE in the simulation yields a result which resembles the canonical co-variability recorded in the observations for the 20th century. However, the same analysis for reconstructions exhibits anomalously low correlations, which points towards a lack of dynamical consistency between independent reconstructions.

Early-Holocene afforestation processes in the lower subalpine belt of the Central Swiss Alps as inferred from macrofossil and pollen records

To reconstruct the vegetation history of the Upper Engadine, continuous sediment cores covering the past 11 800 years from Lej da Champfer and Lej da San Murezzan (Upper Engadine Valley, c. 1800 m a.s.l., southeastern Switzerland) have been analysed for pollen and plant macrofossils. The chronologies of the cores are based on 16 and 22 radiocarbon dates, respectively. The palaeobotanical records of both lakes are in agreement for the Holocene, but remarkable differences exist between the sites during the period 11 100 to 10 500 cal. BP, when Lej da Champfer was affected by re-sedimentation processes. Macrofossil data suggest that Holocene afforestation began at around 11400 cal. BP. A climatic deterioration, the Preboreal Oscillation, stopped and subsequently delayed the establishment of trees until c. 11000 cal. BP, when first Betula, then Pinus sylvestrislmugo, then Larix 300 years later, and finally Pinus cembra expanded within the lake catchment. Treeline was at c. 1500 m during the Younger Dryas (12 542- 11 550 cal. BP) in the Central Alps. Our results, along with other macrofossil studies from the Alps, suggest a nearly simultaneous afforestation (e.g., by Pinus sylvestris in the lower subalpine belt) between 1500 and 2340 m a.s.l. at around 11 400 to 11 300 cal. BP. We suggest that forest-limit species (e.g., Pinus cembra, Larix decidua) could expand faster at today's treeline (c. 2350 m a.s.l.), than 550 m lower. Earlier expansions at higher altitudes probably resulted from reduced competition with low-altitude trees (e.g. Pinus sylvestris) and herbaceous species. Comparison with other proxies such as oxygen isotopes, residual A14C, glacier fluctuations, and alpine climatic cooling phases suggests climatic sensitivity of vegetation during the early Holocene.