Extensive retreat and re-advance of the West Antarctic Ice Sheet during the Holocene.

To predict the future contributions of the Antarctic ice sheets to sea-level rise, numerical models use reconstructions of past ice-sheet retreat after the Last Glacial Maximum to tune model parameters 1 . Reconstructions of the West Antarctic Ice Sheet have assumed that it retreated progressively throughout the Holocene epoch (the past 11,500 years or so)2-4. Here we show, however, that over this period the grounding line of the West Antarctic Ice Sheet (which marks the point at which it is no longer in contact with the ground and becomes a floating ice shelf) retreated several hundred kilometres inland of today's grounding line, before isostatic rebound caused it to re-advance to its present position. Our evidence includes, first, radiocarbon dating of sediment cores recovered from beneath the ice streams of the Ross Sea sector, indicating widespread Holocene marine exposure; and second, ice-penetrating radar observations of englacial structure in the Weddell Sea sector, indicating ice-shelf grounding. We explore the implications of these findings with an ice-sheet model. Modelled re-advance of the grounding line in the Holocene requires ice-shelf grounding caused by isostatic rebound. Our findings overturn the assumption of progressive retreat of the grounding line during the Holocene in West Antarctica, and corroborate previous suggestions of ice-sheet re-advance 5 . Rebound-driven stabilizing processes were apparently able to halt and reverse climate-initiated ice loss. Whether these processes can reverse present-day ice loss 6 on millennial timescales will depend on bedrock topography and mantle viscosity-parameters that are difficult to measure and to incorporate into ice-sheet models.

Hemispheric specialization for nonverbal gestures depicting motion and space.

INTRODUCTION: The right hemispheric specialisation for mental rotation suggests a left hand preference for nonverbal gestures that depict spatial information. We therefore hypothesized that nonverbal depictions of spatial information are preferentially demonstrated by the left hand, i.e., are grounded in right hemispheric functions. METHODS: Right-handed participants were asked in two experiments to nonverbally demonstrate how to move tachistoscopically presented (in the left or right visual hemifields) geometric objects of different rotations into an identical final position. Two independent blind raters evaluated the videotaped hand gestures employing the Neuropsychological Gesture (NEUROGES) Coding System. RESULTS: Pantomime gestures increase in order to rotate gravitationally unstable objects whereas spatial relation presentation gestures increase when to nonverbally demonstrate a gravitationally stable object. Individuals preferred the right hand for pantomime gestures but the left hand for spatial relation presentation gestures. DISCUSSION: Individuals increase their pantomime gestures to nonverbally depict motion particularly with the right hand, i.e. the left hemisphere. In contrast, increased left hand spatial relation presentations gestures indicate that those gestures are of right hemispheric origin. Thus, the hemispherical lateralization of nonverbal gestures seems to depend on the hands' functional depiction.

The pantomime of mental rotation: Left-handers are less lateralized.

INTRODUCTION: The conceptualization of skilled hand movements (praxis) may be grounded in hemispherically specialized functions. However, a left-hemispherical advantage of (tool-use) pantomime gestures and a right-hemispherical advantage of spatial gestures may be more prominent in right-handed than left-handed individuals. We therefore investigated the hypothesis that right-handed but not left-handed individuals show a superiority of the left hemisphere (/right-hand preference) for the execution of pantomime (rotation of an object) gestures as well as a right-hemispherical superiority (/left-hand preference) for gestures that depict spatial information (/positioning of an object). METHODS: 20 right- and 20 left-handed participants were asked in two experiments to demonstrate with their two hands how to move tachistoscopically (in the left (LVF) or right visual hemifields (RVF)) presented geometric objects of different rotations into an identical final position. Two independent blind raters evaluated the videotaped hand gestures employing the Neuropsychological Gesture (NEUROGES) Coding System. RESULTS: In contrast to left-handed individuals, right-handed individuals present increased pantomime - rotation gestures with the right hand and pantomime - position gestures with the left hand during stimuli presentation in either visual field. Left-handers showed significantly increased left-hand pantomime - rotation gestures during stimulus presentation within the LVF (only). DISCUSSION: Right-handed individuals increase their pantomime - rotation gestures with the right hand to depict motion but use their left hand for pantomime - position gestures to describe spatial relations of the objects. Left-handers do not show a clear lateralization of the right and left hand with regards to either handedness or hemispherically lateralized motor functions. The hemispherical lateralization of praxis functions is therefore more pronounced in right-handed than left-handed individuals.

Persistent influence of precession on northern ice sheet variability since the early Pleistocene.

Prior to ~1 million years ago (Ma), variations in global ice volume were dominated by changes in obliquity; however, the role of precession remains unresolved. Using a record of North Atlantic ice rafting spanning the past 1.7 million years, we find that the onset of ice rafting within a given glacial cycle (reflecting ice sheet expansion) consistently occurred during times of decreasing obliquity whereas mass ice wasting (ablation) events were consistently tied to minima in precession. Furthermore, our results suggest that the ubiquitous association between precession-driven mass wasting events and glacial termination is a distinct feature of the mid to late Pleistocene. Before then (increasing), obliquity alone was sufficient to end a glacial cycle, before losing its dominant grip on deglaciation with the southward extension of Northern Hemisphere ice sheets since ~1 Ma.

The effects of new life-prolonging drugs for metastatic castration-resistant prostate cancer (mCRPC) patients in a real-world population.

BACKGROUND: In 2004 docetaxel was the first life-prolonging drug (LPD) registered for metastatic castration-resistant prostate cancer (mCRPC) patients. Between 2011 and 2014 new LPDs for mCRPC (cabazitaxel, abiraterone, enzalutamide, and radium-223) were introduced in the Netherlands. The objective of this study is to assess the impact of the introduction of new LPDs on treatment patterns and overall survival (OS) over time. PATIENTS AND METHODS: CRPC patients diagnosed in the years 2010-2016 in the observational, retrospective CAPRI registry (20 hospitals) were included and followed up to 2018. Two subgroups were analyzed: treatment-naïve patients (subgroup 1, n = 3600) and post-docetaxel patients (subgroup 2, n = 1355). RESULTS: In both subgroups, the use of any LPD increased: from 57% (2010-2011) to 69% (2014-2015) in subgroup 1 and from 65% (2011-2012) to 79% (2015-2016) in subgroup 2. Chemotherapy as first mCRPC-treatment (i.e., docetaxel) and first post-docetaxel treatment (i.e., cabazitaxel or docetaxel rechallenge) decreased (46-29% and 20-9% in subgroup 1 and 2, respectively), while the use of androgen-receptor targeting treatments (ART) increased from 11% to 39% and 46% to 64% in subgroup 1 and 2, respectively. In subgroup 1, median OS (mOS) from diagnosis CRPC increased from 28.5 months to 31.0 months (p = 0.196). In subgroup 2, mOS from progression on docetaxel increased from 7.9 months to 12.5 months (p < 0.001). After multiple imputations of missing values, in multivariable cox-regression analysis with known prognostic parameters, the treatment period was independent significant for OS in subgroup 1 (2014-2015 vs. 2010-2011 with HR 0.749, p < 0.001) and subgroup 2 (2015-2016 vs. 2011-2012 with HR 0.811, p = 0.037). CONCLUSION: Since 2010, a larger proportion of mCRPC patients was treated with LPDs, which was related to an increased mOS.

Reduced frontopolar brain activation characterizes concussed athletes with balance deficits.

OBJECTIVES: Athletes with sport-related concussions (SRC) often demonstrate deficits in postural stability. Lower cerebral blood flow in frontal cortices has been documented in athletes with symptoms after SRC, however, it is unclear if functional brain oxygenation during postural control tasks is reduced in symptomatic athletes after SRC in the same manner. We therefore compared brain oxygenation patterns in frontal cortices of symptomatic and asymptomatic athletes with SRC during postural control tasks with the hypothesis that symptomatic athletes are characterized by reduced functional brain oxygenation during postural control. METHODS: 62 concussed athletes (n = 31 symptomatic, n = 31 asymptomatic) were investigated during four postural control tasks with eyes closed versus eyes opened conditions and stable vs. unstable surface conditions. Brain oxygenation was assessed using functional NearInfraRed Spectroscopy (fNIRS) on frontopolar cortices of each hemisphere. Postural sway was measured by the analysis of ground reaction forces. RESULTS: Symptomatic athletes showed greater postural sway when compared to asymptomatic athletes during postural control, particularly during closed eyes and/or unstable surface conditions. Changes of oxygenated hemoglobin (∆HbO2) within the left hemispheric frontopolar cortex were significantly reduced in symptomatic athletes when compared to asymptomatic athletes during the eyes closed condition. A stepwise linear regression analysis revealed that self-reported post-concussion symptoms such as headaches and sadness predict decreased brain oxygenation during postural control with closed eyes. CONCLUSION: Symptomatic athletes with increased postural sway are characterized by decreased frontopolar brain oxygenation during postural control tasks, particularly during conditions with closed eyes. Because the frontopolar cortex showed to be involved in redistributing executive functions to novel task situations, we conclude that athletes with post-concussion symptoms suffer from a deficit in coordinating postural adjustments to balance control tasks with reduced sensory input.

Extrapulmonary lymphangioleiomyomatosis: an unusual cause of biliary tract obstruction.

We present a patient who was diagnosed with retroperitoneal lymphangioleiomyomatosis (LAM) and who developed biliary tract obstruction caused by LAM in the papilla of Vater. After endoscopic retrograde cholangiopancreatography (ERCP) and papillotomy, the patient's liver enzymes normalised. Disease progression was slowed down with gosereline and interferon alpha 2b (IF N-alpha 2b). In patients with LAM and signs of biliary tract obstruction, disseminated LAM should be considered. IFN alpha 2b can be a useful treatment in patients with widespread LAM.

Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+ CD25+ FoxP3+ T cells.

Graft-versus-host-disease (GVHD) is the most common cause of poor outcome after allogeneic stem cell transplantation (SCT). Of late, exploitation of FOXP3(+) regulatory T-cell (T(REG)) function is emerging as a promising strategy in suppression of GVHD, while preserving graft-versus-leukemia (GVL). Cyclosporine and rapamycin reduce the expansion of effector T cells by blocking interleukin (IL)-2, but signaling by IL-2 is pivotal for T(REG) homeostasis. The resolution of GVHD is critically dependent on thymus-dependent reconstitution of the immunoregulatory system. Thus, there has been concern about the impact of blocking IL-2 signaling by immunosuppressive agents on T(REG) homeostasis. Here we demonstrate in a mouse model that in contrast to rapamycin, cyclosporine compromises not only the thymic generation of CD4(+)CD25(+)FoxP3(+) T cells but also their homeostatic behavior in peripheral immune compartments. Treatment with cyclosporine resulted in a sharp reduction of peripheral CD25(+)FoxP3(+) T cells in all immune compartments studied. Prolonged rapamycin treatment allowed for thymic generation of CD4(+)FoxP3(+) T cells, whereas treatment with cyclosporine led to a reduced generation of these cells. In conclusion, cyclosporine and rapamycin differentially affect homeostasis of CD4(+)FoxP3(+) T(REG) in vivo. As peripheral tolerance induction is a prerequisite for successful treatment outcome after allogeneic SCT, these findings are of potential clinical relevance.

Subglacial Lake Whillans microbial biogeochemistry: a synthesis of current knowledge.

Liquid water occurs below glaciers and ice sheets globally, enabling the existence of an array of aquatic microbial ecosystems. In Antarctica, large subglacial lakes are present beneath hundreds to thousands of metres of ice, and scientific interest in exploring these environments has escalated over the past decade. After years of planning, the first team of scientists and engineers cleanly accessed and retrieved pristine samples from a West Antarctic subglacial lake ecosystem in January 2013. This paper reviews the findings to date on Subglacial Lake Whillans and presents new supporting data on the carbon and energy metabolism of resident microbes. The analysis of water and sediments from the lake revealed a diverse microbial community composed of bacteria and archaea that are close relatives of species known to use reduced N, S or Fe and CH4 as energy sources. The water chemistry of Subglacial Lake Whillans was dominated by weathering products from silicate minerals with a minor influence from seawater. Contributions to water chemistry from microbial sulfide oxidation and carbonation reactions were supported by genomic data. Collectively, these results provide unequivocal evidence that subglacial environments in this region of West Antarctica host active microbial ecosystems that participate in subglacial biogeochemical cycling.

Sauvagine regulates Ca2+ oscillations and electrical membrane activity of melanotrope cells of Xenopus laevis.

Ca2+ oscillations regulate secretion of the hormone alpha-melanphore-stimulating hormone (alpha-MSH) by the neuroendocrine pituitary melanotrope cells of the amphibian Xenopus laevis. These Ca2+ oscillations are built up by discrete increments in the intracellular Ca2+ concentration, the Ca2+ steps, which are generated by electrical membrane bursting firing activity. It has been demonstrated that the patterns of Ca2+ oscillations and kinetics of the Ca2+ steps can be modulated by changing the degree of intracellular Ca2+ buffering. We hypothesized that neurotransmitters known to regulate alpha-MSH secretion also modulate the pattern of Ca2+ oscillations and related electrical membrane activity. In this study, we tested this hypothesis for the secretagogue sauvagine. Using high temporal-resolution Ca2+ imaging, we show that sauvagine modulated the pattern of Ca2+ signalling by increasing the frequency of Ca2+ oscillations and inducing a broadening of the oscillations through its effect on various Ca2+ step parameters. Second, we demonstrate that sauvagine caused a small but significant decrease in K+ currents measured in the whole-cell voltage-clamp, whereas Ca2+ currents remained unchanged. Third, in the cell-attached patch-clamp mode, a stimulatory effect of sauvagine on action current firing was observed. Moreover, sauvagine changed the shape of individual action currents. These results support the hypothesis that the secretagogue sauvagine stimulates the frequency of Ca2+ oscillations in Xenopus melanotropes by altering Ca2+ step parameters, an action that likely is evoked by an inhibition of K+ currents.

Risk factors determining chemotherapeutic toxicity in patients with advanced colorectal cancer.

Antitumour therapy in advanced colorectal cancer has limited efficacy. For decades, fluorouracil has been the main anticancer drug for the treatment of colorectal cancer. Recently, however, new agents have been introduced: raltitrexed, irinotecan and oxaliplatin. Currently, the dosage for an individual patient is calculated from the estimated body surface area of the patient. Toxicity, however, frequently necessitates decreasing the dosage, extending the dose interval or even discontinuing treatment. Risk factors with predictive value for toxicity have been identified in several studies. These risk factors are often determined by the pharmacokinetic and pharmacodynamic properties of the drug. In this review, the risk factors for toxicity of the cytotoxic agents used in the treatment of advanced colorectal cancer are considered. For fluorouracil, age, gender, performance status, genetic polymorphism of dihydropyridine dehydrogenase, drug administration schedule, circadian rhythm of plasma concentrations, history of previous chemotherapy-related diarrhoea, xerostomia, low neutrophil levels, and drug-drug interactions have been identified as affecting chemotherapeutic toxicity. For raltitrexed, gender and renal and hepatic impairment, and for oxaliplatin, renal impairment and circadian rhythm of plasma concentrations, respectively, can be considered as risk factors for toxicity. In addition, age, performance status, bilirubinaemia, genetic polymorphism of uridine 5'-diphosphate-glucuronyltransferase-1A1 and drug administration schedule have been shown to be related to irinotecan toxicity. The available literature suggests that dose adjustment based on these risk factors can be used to individualise the dose in order to decrease toxicity and to improve the therapeutic index. This also applies to therapeutic drug monitoring, which has been shown to be effective controlling the toxicity of fluorouracil in some studies. Future research is warranted to assess the potential advantage of dose individualisation of chemotherapy founded on risk factors, over direct dose calculation from the estimated body surface area, with regard to toxicity, therapeutic index, and quality of life, in patients with advanced colorectal cancer.

Management of chemotherapy-induced adverse effects in the treatment of colorectal cancer.

The anticancer agents fluorouracil, raltitrexed, irinotecan and oxaliplatin show limited efficacy in the treatment of colorectal cancer and may be associated with substantial toxicity. Therefore, the prevention and reduction of chemotherapy-induced adverse effects is of major significance, in accordance with the increasing concern for the quality of life of patients with cancer. Therapeutic drug monitoring of fluorouracil and chronomodulation of fluorouracil and oxaliplatin, have been effective in reducing the incidence and gravity of adverse effects in several clinical trials. However, these concepts have not been implemented in clinical practice yet. At the present time, dose adaptation and supportive measures are the main tools for toxicity control in the treatment of colorectal cancer. In this review, supportive measures for alleviation of the adverse effects of fluorouracil, raltitrexed, irinotecan and oxaliplatin, respectively, are described, based on study results. The main adverse effects of these agents are myelosuppression, oral mucositis, diarrhoea, acute cholinergic syndrome, nausea and emesis, neurotoxicity, hand-foot syndrome and other cutaneous adverse effects, ocular toxicity, cardiotoxicity, small bowel toxicity, asthenia, elevated liver transaminase levels and alopecia. The incidence and gravity of these adverse effects are more or less related to the agent and administration schedule involved. The supportive measures and recommendations include the use of specific drugs, alterations of administration schedule and several nonpharmacological methods. In addition, guidelines for dosage adjustments when toxicity occurs are presented. For optimal management of adverse effects, patients should be considered individually, while patients, nurses and physicians should cooperate to identify and treat adverse effects in an early stage of their development.

A breakthrough in cryosurgery.

Liver cryosurgery is one of the treatment options for unresectable liver metastases. Indications for the use of this treatment instead of classic surgery are bilobar disease, location of the tumor at an irresectable anatomic site, and comorbid conditions of the patient. Possible complications of cryosurgery are hemorrhage, coagulopathy, pneumonia, pleural effusion, abdominal abscess, and bile fistula. We describe a patient in whom a hepatobronchial fistula developed after cryosurgery. The patient had cryosurgery because of an unresectable liver metastasis in a Dukes' C rectal carcinoma. More details are given in the case report. To our knowledge, a hepatobronchial fistula as a complication of cryosurgery has never been reported. It therefore should be added to the list of possible cryosurgery complications.

A patient with probable systemic lupus erythematosus, lupus anticoagulant and myocardial infarction.

The case history of a 31-year-old woman is described. She had a history of thrombosis; in the past there had been an arterial embolus of the left superficial femoral artery and venous thrombosis of the right leg. The patient was admitted to hospital because of fever of unknown origin. During the hospital stay the diagnosis of probable SLE was made. She died of myocardial infarction. At autopsy, thrombosis of the small arterioles of the heart was found without sclerosis of the coronary arteries. A lupus anticoagulant could be demonstrated in her blood and seems to have been the cause of this rare complication. Treatment with anticoagulants is advised for patients with LAC and a history of thrombosis.

Successful homografting in an elderly patient with extensive burns using his identical twin brother as skin donor.

A 60-year-old patient with 50 per cent body surface area (BSA) flame burns (of which 46 per cent were full skin thickness loss) was treated successfully with skin grafts taken from his identical twin brother to cover 20 per cent of the wounds. On theoretical grounds, it can be assumed that the period in hospital was reduced by 28 days. Blood for tissue and blood group typing should be taken at an early stage, before the patient is given a blood transfusion.

Poly(ether urethane) wound covering with high water vapour permeability compared with conventional tulle gras on split-skin donor sites.

The experimental poly(ether urethane) (PEU) wound covering with a high water vapour permeance was compared with tulle gras treatment on adjacent areas of the same 20 split-skin donor sites. All patients experienced little or no pain from the PEU-covered areas, while 70 per cent of the patients complained of more pain from the tulle gras-covered areas. The PEU covering did not absorb the wound exudate underneath, neither did it retain wound fluid, but turned the wound exudate into a jelly-like clot layer by allowing a high evaporative water loss from the wound. Tulle gras treatment also prevented wound desiccation, but the exudate was absorbed into the overlaying cotton pads, where it became dry at the outer surface. Microscopy revealed that re-epithelialization occurred at a similar rate under the PEU covering as under tulle gras. In conclusion, the high water vapour permeable PEU wound covering prevents fluid retention, induces clotting of the wound exudate and reduces pain in split-skin donor sites. Tulle gras dressed with gauzes and crêpe bandage prevents wound desiccation, but causes more pain.

Use of the focusing multi-slit ion optical system at RUssian Diagnostic Injector (RUDI).

The upgrade of the diagnostic neutral beam injector RUDI in 2010 was performed to increase the beam density at the focal plane in accordance with the requirements of charge-exchange recombination spectroscopy diagnostics. A new focusing ion-optical system (IOS) with slit beamlets and an enlarged aperture was optimized for 50% higher nominal beam current and reduced angular divergence with respect to the previous multi-aperture IOS version. The upgraded injector provides the beam current up to 3 A, the measured beam divergence in the direction along the slits is 0.35°. Additionally, the plasma generator was modified to extend the beam pulse to 8 s.

Randomised phase II/III study of docetaxel with or without risedronate in patients with metastatic Castration Resistant Prostate Cancer (CRPC), the Netherlands Prostate Study (NePro).

BACKGROUND: This multicentre, randomised, open label, phase II/III study aimed to investigate the potential benefit of adding risedronate (R) to docetaxel (D) in patients with metastatic Castration Resistant Prostate Cancer (CRPC). PATIENTS AND METHODS: CRPC patients with bone metastasis were randomly assigned to receive D 75 mg/m(2) every 3 weeks and prednisone as first line chemotherapy, with or without R 30 mg oral once daily. The primary end-point was time to progression (TTP). A composite end-point of objective progression by RECIST criteria, PSA progression, or pain progression, whichever occurred first, was applied. The study had 80% power to detect an improvement of 30% in median TTP in the DR group (two-sided α=0.05). RESULTS: Five hundred and ninety-two men (301 D versus 291 DR) were randomised. TTP was 7.4 [D] versus 6.5 [DR] months (p=0.75). PSA and pain response rates were similar, 66.3% [D] versus 65.9% [DR] and 27.9% [D] versus 31.2% [DR], respectively. Median overall survival (OS) was 18.4 [D] versus 19.2 [DR] months (p=0.33). There were no differences in toxicity. CONCLUSION: The addition of the third generation bisphosphonate, risedronate, in the setting of effective first line docetaxel based chemotherapy did not increase efficacy, as indicated by the lack of improvement in TTP, OS, PSA- and pain response.

Prognostic factors and outcome in relapsed multiple myeloma after nonmyeloablative allo-SCT: a single center experience.

For relapsed multiple myeloma (MM) patients, allo-SCT is a possible treatment option, but recent data obtained using a nonmyeloablative (NMA) conditioning regimen are scarce. We retrospectively collected data from 38 relapsed MM patients who received a NMA allo-SCT from October 2001 to January 2008. In total, 18 patients (48%) were transplanted using a matched unrelated donor. The median follow-up is 2.3 years. In 16 patients (42%) the response improved and eight patients (21%) were rapidly progressive within 6 months after allo-SCT. In total, 15 patients (39%) were in CR after allo-SCT. The median PFS was 1.4 years (range, 0.1-4.9), and having a CR after allo-SCT or having chronic GVHD resulted in longer PFS. Median OS was 3.1 years (range, 0.2-7.2) and again having a CR after allo-SCT or chronic GVHD was associated with a better OS. Six patients (16%) have died from treatment-related diseases. These results indicate that NMA allo-SCT is a treatment option in relapsed MM patients and that results may be improved by strategies that enhance the CR rate after allo-SCT.

Operation and upgrade of diagnostic neutral beam injector RUDI at TEXTOR tokamak.

The status and the executing modernization of RUssian Diagnostic Injector (RUDI) are described. The ion source consists of arc plasma emitter and multiaperture four-electrode ion optical system. The present ion optical system with round beamlets is to be replaced by new slit apertures system for the reducing beam angular divergence in one direction. Due to enlarged dimensions and transparency of new ion optical system the extracted ion beam current will be by 50% increased. For the extension of beam pulse duration from 4 s to 8-10 s an optimized metal-ceramic arc-discharge channel is introduced. In the paper, the optical measurements results of beam parameters, including the profile of species distribution, scanned by custom-built multichannel spectroscope, are also presented.