Cyclic Reductions Research Articles

Au (III) cross-linked hollow organosilica capsules from 3-aminopropyltriethoxysilane

Hollow organosilica capsules have received extensive interest due to their application potentials in catalyst, sensor, drug delivery etc. In this work, we demonstrate a novel strategy to fabricate hollow organosilica capsules based on coordination interaction, by using 3-aminopropyltriethoxysilane (APTES) as precursor and Au (III) as cross-linker. In this approach, stable APTES droplets are first formed in water with the presence of Au (III) due to the coordination effect between Au (III) and the amino groups of APTES located on the surface of the droplets. Subsequently, the self-catalyzed hydrolysis/condensation of APTES allows for the formation of hollow organosilica capsules, in which the droplets of APTES themselves act as soft template and the Au (III) as cross-linker. The formation mechanism of the capsules was investigated, and potential of the as-prepared Au (III) cross-linked hollow organosilica capsules as glutathione (GSH) sensitive drug carriers was evaluated. In addition, Au particle embedded hollow capsules are further obtained by in-situ reduction of the Au (III) in the shell, which showed excellent stability towards the cyclic catalytic reductions of p-nitroaniline.

Germany and the United States in coronavirus distress: internal versus external labour market flexibility

Germany and the United States pursued different economic strategies to minimise the impact of the Coronavirus Crisis on the labour market. Germany focused on safeguarding existing jobs through the use of internal flexibility measures, especially short-time work (STW). The United States relied on a mix of external flexibility and income protection. On this basis, we use macroeconomic time series to examine the German strategy of securing employment through internal flexibility by contrasting it with the chosen strategy in the United States. In Germany, temporary cyclical reductions in working hours are mainly driven via STW. US unemployment rose at an unprecedented rate, but unlike in previous recessions, it was mostly driven by temporary layoffs. However, a closer look at the blind spots of the chosen strategies in both countries showed that despite the different approaches, people in weaker labour market positions were less well protected by the chosen strategies.

Roots of Characteristic Polynomial Sequences in Iterative Block Cyclic Reductions

The block cyclic reduction method is a finite-step direct method used for solving linear systems with block tridiagonal coefficient matrices. It iteratively uses transformations to reduce the number of non-zero blocks in coefficient matrices. With repeated block cyclic reductions, non-zero off-diagonal blocks in coefficient matrices incrementally leave the diagonal blocks and eventually vanish after a finite number of block cyclic reductions. In this paper, we focus on the roots of characteristic polynomials of coefficient matrices that are repeatedly transformed by block cyclic reductions. We regard each block cyclic reduction as a composition of two types of matrix transformations, and then attempt to examine changes in the existence range of roots. This is a block extension of the idea presented in our previous papers on simple cyclic reductions. The property that the roots are not very scattered is a key to accurately solve linear systems in floating-point arithmetic. We clarify that block cyclic reductions do not disperse roots, but rather narrow their distribution, if the original coefficient matrix is symmetric positive or negative definite.

Why do developed economies become vulnerable to economic cycles

The possible reasons for the intensification of cyclical fluctuations of the economies of the developed countries in the last decade are analyzed in the article. At the same time, the countries with risky markets (emerging markets and developing economies) are experiencing lower GDP losses during cyclical reductions of the economy. This is particularly paradoxical in view of the fact that developed economies are generally considered to be more stable and competitive. Besides, during the twentieth century, mankind has accumulated considerable experience in counteracting the cyclical nature of national economies and learned to smooth the amplitude of cyclical fluctuations. The authors of the article put forward and substantiate the assumption that the reason for the increase in the amplitude of cyclical fluctuations, increase of the depth of cyclical fluctuations of economies of the developed countries compared to the countries with emerging markets and developing economies, is the significant difference in the structure of these economies. The significant predominance of the tertiary sector in the developed economies makes them more vulnerable to cyclical fluctuations due to the greater multiplier effect that is inherent in the tertiary sector industries compared to other sectors of the economy. The conducted correlation analysis showed the presence of the strong relationship between such parameters of the economy as the share of the tertiary sector in the economy and the percentage value of the predicted economic recession in 2020 in the developed economies and emerging markets and developing economies. But it is necessary to keep in mind that the autonomous cost multiplier works in the opposite direction, accelerating the economic decline during the economic cycle. That is why, in our opinion, measures of state regulation of the economy today should be increasingly aimed at regulating the tertiary sector to prevent the increasing cyclicality of the modern global economy, as the leading economic leaders themselves are often becoming generators of the business cycle due to economic financialization and tertiary sector growth in general.

CARDIAC chronotropic effects of sleep-disordered breathing in patients with heart failure.

It is still not known whether the oscillation in heart rate (HR) induced by sleep-disordered breathing (SDB) in patients with heart failure entails significant chronotropic effects. We hypothesised that since cyclical changes in ventilation and arterial blood gases during SDB affect HR through multiple and complexly interacting mechanisms characterised by large inter-subject variability, chronotropic effects may change from patient to patient. A total of 42 patients with moderate-to-severe chronic heart failure with systolic dysfunction underwent an in-hospital sleep study. Chronotropic effects of SDB were quantified by comparing the distribution of instantaneous HR during SDB with that during periods without SDB (noSDB) within the same night in each patient. Based on distribution changes from noSDB to SDB, 12, nine, 11, and 10 patients showed a significant tachycardic, bradycardic, tachycardic and bradycardic, and neither significant tachycardic nor significant bradycardic effect, respectively. Tachycardic and bradycardic effects were primarily due to an increase in the rate rather than in the magnitude of cyclical HR elevations and reductions, and were more prevalent and severe in patients with dominant obstructive and central events, respectively. The apnea-hypopnea index did not differ between groups. Conversely, the time spent with an oxygen saturation of <90% was greater in the tachycardic and tachycardic-bradycardic groups compared to the bradycardic group. These findings indicate that HR distribution changes induced by SDB can vary from patient to patient revealing four distinct and well-characterised chronotropic effects. These effects are related to the degree of hypoxic burden brought about by SDB and are affected by the type of sleep apnea (central/obstructive).

The mode of anesthesia influences outcome in mouse models of arterial thrombosis

BackgroundArterial thrombosis models are important for preclinical evaluation of antithrombotics but how anesthetic protocol can influence experimental results is not studied. ObjectivesWe studied how three most commonly used rodent anesthetics affect the induction of thrombosis and thrombus resolution with antiplatelet agent integrilin (Eptifibatide). MethodsThe Folts, electrolytic, and FeCl3 models of carotid artery thrombosis were evaluated. The extent of blood flow reduction required to elicit cyclic flow reductions (CFR) was examined in the Folts model. The occlusion time and stability following electrolytic or FeCl3 injury was assessed. The efficacy of Eptifibatide was studied in each cohort and clot composition following FeCl3 application was assessed histologically. ResultsIsoflurane and ketamine‐xylazine (ket‐x) elicited higher basal blood flow velocities. For reliable CFR in the Folts model, a higher degree of blood flow reduction was required under ket‐x and isoflurane. For the FeCl3 and electrolytic models, injury severity had to be increased in mice under ket‐x anesthesia to achieve rapid occlusion. FeCl3‐injured artery sections from ket‐x and isoflurane‐treated mice showed vessel dilatation and clots that were more fibrin/red‐cell rich compared to pentobarbitone. Integrilin led to cycle abolishment for all three Folts‐injury cohorts but for the electrolytic model a 2.5‐fold higher dose was required to restore blood flow under pentobarbitone. Integrilin after FeCl3 arterial injury was partially ineffective in isoflurane‐treated mice. ConclusionsAnesthesia impacts rodent carotid artery occlusion experiments and alters integrilin efficacy. It is important to consider anesthetic protocols in animal experiments involving pharmacological agents for treatment of atherothrombosis.

Evaluation of recombinant factor VIIa, tranexamic acid and desmopressin to reduce prasugrel-related bleeding: A randomised, placebo-controlled study in a rabbit model.

Prasugrel is a thienopyridine that inhibits platelet aggregation more rapidly and effectively than clopidogrel, with an increased bleeding risk. The current study aimed to evaluate the efficacy of three nonspecific haemostatic drugs - recombinant activated factor VII (rFVIIa), tranexamic acid and desmopressin (DDAVP) - to limit blood loss after administration of prasugrel in a rabbit model of bleeding while also evaluating any prothrombotic effects. Randomised, placebo-controlled study. Faculty of Medicine, University of Geneva, Switzerland, in 2013. Anaesthetised and artificially ventilated rabbits (n=56). Animals were randomly allocated to one of five groups: control (placebo-placebo), prasugrel-placebo, rFVIIa (prasugrel-rFVIIa 150 μg kg), tranexamic acid (prasugrel-tranexamic acid 20 mg kg) or DDAVP (prasugrel-DDAVP 1 μg kg). Two hours after an oral prasugrel loading dose (4 mg kg), a stenosis and an injury were inflicted on the carotid artery to induce cyclic flow reductions (CFRs) due to thrombosis. Haemostatic drugs were administered during the ensuing observation period. Standardised hepatosplenic sections were performed to evaluate the primary endpoint of blood loss, monitored for 15 min. Ear-immersion bleeding time and incidence of CFRs were secondary endpoints. Prasugrel decreased ADP-induced platelet aggregation (light transmission method) from 66 ± 4% (mean ± SD) to 41 ± 7% (P < 0.001) and doubled blood loss: 10.7 g (10.1 to12.7) [median (interquartile range)] vs. 20.0 g (17.0 to 24.4), P = 0.003 in the control and prasugrel-placebo groups, respectively. rFVIIa, tranexamic acid and DDAVP reduced neither hepatosplenic blood loss [19.7 g (14.0 to 27.6), 25.2 g (22.6 to 28.7) and 22.9 g (16.8 to 28.8), respectively] nor bleeding time compared with placebo. Regarding safety, rVIIa induced three or more CFRs in 5/12 rabbits, vs. 0/12 in the prasugrel-placebo group (P = 0.037), whereas tranexamic acid and DDAVP did not increase them. The three studied haemostatic drugs rFVIIa, tranexamic acid and DDAVP failed to reduce prasugrel-related bleeding in this model. rFVIIa-treated rabbits were more prone to arterial thrombotic events. NA.

The German employment miracle in the Great Recession: the significance and institutional foundations of temporary working-time reductions

We analyse the robust performance of the German labour market in the Great Recession, and investigate to what extent cyclical reductions in productivity and working time cushioned employment losses. We present stylized facts and apply time-series techniques to estimate counterfactual developments. Our results show that the magnitude of temporary working-time reductions was extraordinarily pronounced, whereas cyclical reductions in hourly productivity were in line with historical evidence. Using detailed information on instruments for the adjustment of working time, we uncover the institutional mechanisms behind this strong reduction. While short-time work played a significant role, even more important were working-time accounts and discretionary variations in regular working time, two new instruments which gained widespread use in the decade before the Great Recession.

Literature review: Why do we continue to lose our nurses?

Objective: To decrypt what determining factors contribute to nurses leaving the clinical facet of the profession. Primary argument: Nurses encompass the largest professional constituent of the health care workforce in most countries, resulting in the impact of a shortage of these professionals, as immense. A projection in the shortage of nurses is upon us, and the margin in the reduction of these health professionals is thought to be worse than any of the preceding cyclical reductions. More than half of the nursing profession feel they are underpaid and overworked, resulting in the likelihood of patient’s needs not being met, significantly increasing. Lengthy hours, quality of working environments, lack of leadership and the ageing population and workforce, can all be seen as influential factors, in which have the potential to leave this profession in a situation of calamity. Conclusion: In light of the predicted global demand for nurses over the next decade, the departure and retirement of the existing nursing workforce will potentially result in the loss of significant and treasured experience and organisational knowledge, weakening the capacity and capability of the nursing profession.

The chimeric monoclonal antibody MHCSZ-123 against human von Willebrand factor A3 domain inhibits high-shear arterial thrombosis in a Rhesus monkey model

BackgroundSZ-123, a murine monoclonal antibody that targets the human von Willebrand factor (VWF) A3 domain and blocks the binding of collagen, is a powerful antithrombotic. In a Rhesus monkey model of thrombosis, SZ-123 had no side effects, such as bleeding or thrombocytopenia.MethodsThe mouse/human chimeric version of SZ-123, MHCSZ-123, was developed and maintained inhibitory capacities in vitro and ex vivo after injection into monkeys. CHO-S cells were selected for stable expression of MHCSZ-123. Cell clones with high levels of MHCSZ-123 expression were screened with G418 then adapted to serum-free suspension culture. The antithrombotic effect of MHCSZ-123 on acute platelet-mediated thrombosis was studied in monkeys where thrombus formation was induced by injury and stenosis of the femoral artery, which allowed for cyclic flow reductions (CFRs). CFRs were measured in the femoral artery of anesthetized Rhesus monkeys before and after intravenous administration of MHCSZ-123. Ex vivo VWF binding to collagen, platelet aggregation, platelet counts, and template bleeding time were used as measurements of antithrombotic activity. In addition, plasma VWF and VWF occupancy were measured by ELISA.ResultsInjection of 0.1, 0.3, and 0.6 mg/kg MHCSZ-123 significantly reduced CFRs by 29.4%, 57.9%, and 73.1%, respectively. When 0.3 and 0.6 mg/kg MHCSZ-123 were administered, 46.6%–65.8% inhibition of ristocetin-induced platelet aggregation was observed between 15 and 30 min after injection. We observed minimal effects on bleeding time, minimal blood loss, and no spontaneous bleeding or thrombocytopenia.ConclusionsThe VWF-A3 inhibitor MHCSZ-123 significantly reduced thrombosis in Rhesus monkeys and appeared to be safe and well tolerated.

A cohort perspective of the effect of unemployment on fertility

This work offers an explanation for the apparent contradiction between empirical work that finds a negative relationship between unemployment and fertility, and theoretical work that emphasizes the lower opportunity cost of childbearing while unemployed. I reconcile these perspectives by distinguishing between two forms of unemployment. The first form is structural unemployment, while the second form is cyclical unemployment, a less permanent component of unemployment that is linked to the economic cycle. I apply a cohort-based model to study both effects over the life cycle using panel data methods applied to a sample of developed countries. My results show that higher levels of structural unemployment decrease fertility, but that the effects of cyclical variations in unemployment depend to a large extent on the age at which they are experienced. Cyclical reductions in the unemployment level mostly result in increases in fertility rates. However, for some age groups, positive variations in the cyclical component of unemployment can also have a positive impact on fertility.

Optimal Design of New Generation Fiscal Rules: Coping with the Business Cycle and Discretionary Tax Reductions

While business cycles are crucial for determining the dynamics of government budget deficits, it is rare to find an analysis of optimal fiscal rules that are designed to cope with the asymmetric behavior of fiscal variables during the cycle. In this paper I characterize the dynamics of budget deficits along the cycle: i) in recessions marginal propensity to spend is higher than the coefficient of marginal tax revenues, causing an increase of the deficit over GDP; ii) in expansions tax revenues soar allowing for a deficit reduction; however, marginal spending is still high and consequently a full cycle implies an increase in the deficit. Then, I present a model in which fiscal rules are designed to cope with a political bias that is based on two components: the cyclical bias and discretionary tax reductions. According to my analysis, the new generation fiscal rules should be based on a combination of expenditure and revenue rules, which are newer than budget deficit rules and are becoming widespread. According to my empirically calibrated simulation, this combination of rules succeeds on avoiding the political bias and is more cycle-friendly than a budget deficit rule.

Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis

As all anticoagulants, apixaban exposes to a bleeding risk, thus an effective way to reverse its effects is needed. Objectives were to study efficacy and safety of recombinant activated factor VII (rFVIIa), prothrombin complex concentrate (PCC), and fibrinogen concentrate (Fib) to reverse apixaban in a rabbit model of bleeding and thrombosis. After a dose-ranging study to assess the minimal amount of apixaban increasing bleeding, 63 anaesthetized rabbits were randomized into 5 groups: control (saline), apixaban (apixaban and saline), rFVIIa (apixaban and rFVIIa), PCC (apixaban and PCC) and fibrinogen (apixaban and Fib). The Folts model was applied: a stenosis and an injury were carried out on the carotid artery, inducing thrombosis detected as cyclic flow reductions (CFRs) within 20 min. A number of parameters were recorded through ear immersion bleeding time (BT), clotting times (CT), thrombelastography, and thrombin generation time (TGT). Ultimately, a hepatosplenic section was performed to evaluate as primary endpoint the blood loss in 15 min. Apixaban increased blood loss (11.6 ± 3 g vs. 8.3 ± 3 g for control, p < 0.0003), lengthened BT, the prothrombin time (PT), thrombelastographic CT and decreased thrombin generation. Only rFVIIa reduced BT yet failed to improve blood loss. PCC and rFVIIa both shortened the PT, CT in thrombelastographic, and lag time in TGT. Fib improved clot firmness, enhanced thrombin generation but increased bleeding. Regarding safety, neither rFVIIa, PCC, nor Fib increased CFRs. rFVIIa, PCC, and Fib failed to reverse apixaban-induced bleeding. They only improved several laboratory parameters.

Antithrombotic effect of Z4A5 on coronary thrombosis in a canine model of acute unstable angina

The glycoprotein IIb/IIIa receptor is the final common pathway of platelet aggregation, regardless of the agonist, and thus represents an ideal therapeutic target for blocking coronary thrombosis. In this study, the anti-platelet and antithrombotic actions of Z4A5, a new glycoprotein IIb/IIIa receptor inhibitor, were evaluated in a canine model of acute unstable angina. Z4A5 was given i.v. as a bolus followed by 60 min of continuous infusion at doses of 30 μg·kg⁻¹ + 1 μg·kg⁻¹·min⁻¹, 30 μg·kg⁻¹ + 5 μg·kg⁻¹·min⁻¹ or 300 μg·kg⁻¹ + 5 μg·kg⁻¹·min⁻¹. Its antithrombotic effect was evaluated in a model of coronary thrombosis, the injured, stenosed left circumflex coronary artery, in which platelet-dependent cyclic flow reductions (CFRs) were induced by vascular compression and constriction to simulate clinical acute unstable angina. Platelet aggregation and coagulation parameters were determined in platelet-rich plasma and platelet poor plasma respectively. The Z4A5 infusion induced a dose-dependent reduction in CFR frequency, which returned to baseline levels after the termination of the infusion at low doses. At medium dose that inhibited most part of platelet aggregation, it increased tongue bleeding time marginally with no dramatic changes in haemodynamic and coagulation parameters. Furthermore, the inhibition of ADP-induced platelet aggregation and prolonged bleeding time observed during Z4A5 infusion reverted to baseline levels after the termination of the infusion. Z4A5 is an effective antithrombotic agent for coronary artery thrombosis with a rapid-on and rapid-off pharmacological profile, and could be used as an alternative treatment of coronary artery ischaemic syndromes.

Anti-human VWF monoclonal antibody SZ-123 prevents arterial thrombus formation by inhibiting VWF–collagen and VWF–platelet interactions in Rhesus monkeys

The interactions between collagen, von Willebrand factor (VWF), and glycoprotein Ib (GPIb) are crucial for hemostasis and thrombosis. This axis represents a promising target for the development of new antithrombotic agents. In this study, we investigate the in vivo antithrombotic efficacy of an anti-VWF monoclonal antibody SZ-123 and its potential underlying mechanisms. Cyclic flow reductions (CFRs), an indicator of arterial thrombosis, were measured in the femoral artery of anesthetized Rhesus monkeys before and after intravenous administration of SZ-123. Ex vivo VWF binding to collagen, platelet agglutination, platelet count, and template bleeding time were used as measurements of antithrombotic activity. In addition, plasma VWF and SZ-123 levels, and VWF occupancy were measured by ELISA. Administration of 0.1, 0.3, and 0.6mg/kg SZ-123 resulted in 45.3%, 78.2%, and 100% reductions in CFRs, respectively. When 0.3 and 0.6mg/kg SZ-123 were administered, 100% of VWF was occupied by the antibody. Moreover, 100% ex vivo inhibition of VWF–collagen binding and 60–95% inhibition of platelet agglutination were observed from 15min to 1h. None of the doses resulted in significant prolongation of bleeding time. In vitro experiments revealed that SZ-123 not only blocks the collagen–VWF A3 interaction but also indirectly inhibits VWF A1 binding to GPIbα induced by ristocetin. Thus, we demonstrate that SZ-123 prevents in vivo arterial thrombus formation under high shear conditions by inhibiting VWF A3–collagen and VWF A1–platelet interactions and does not significantly prolong bleeding time.

Production performance of Atlantic salmon (Salmo salarL.) postsmolts in cyclic hypoxia, and following compensatory growth

This study investigated the production performance of the Atlantic salmon postsmolt (Salmo salar L.) subjected to cyclic oxygen reductions (hypoxia) of varying severity. Triplicate groups (N = 955) were kept at constant 80% O2 (control) or subjected to 1 h and 45 min of hypoxia (50, 60 or 70% O2, termed 80:70, 80:60 and 80:50 groups) every 6 h at 16°C for 69 days. Feed was provided in normoxia. One third of the fish were kept further for 30 days in normoxia to study possible compensatory growth. Cyclic hypoxia did not alter the oxygen uptake rates of fish, measured in night-time. Fish subjected to 50% and 60% O2 reduced feeding by 13% and 6% compared with the controls, respectively, with corresponding reductions in specific growth rates. Feed utilization was not reduced. Compensatory growth was observed in fish from the 80:50 group, but full compensation was not achieved. The main conclusions were that feeding in normoxia does not fully alleviate negative effects of cyclic hypoxia on feeding and growth, when oxygen is reduced to 60% or below in hypoxic periods, that feed utilization is maintained, and that compensatory growth may lessen negative effects.

Anti-Human VWF Monoclonal Antibody SZ-123 Prevents Arterial Thrombus Formation by Inhibiting VWF–collagen and VWF-Platelet Interactions in Rhesus Monkeys

Abstract 5194 Objective:To investigate the in vivo antithrombotic efficacy of an anti-VWF monoclonal antibody SZ-123, and its potential underlying mechanism. Methods and Results:Cyclic flow reductions (CFRs) were measured in the femoral artery of monkeys before and after intravenous administration of SZ-123. Ex vivo VWF binding to collagen, platelet aggregation, platelet count and template bleeding time were performed as measurements of antithrombotic activity. In addition, plasma VWF, SZ-123 levels, and VWF occupancy were measured by ELISA. Administration of 0. 1, 0. 3, and 0. 6 mg/kg SZ-123 resulted in 45. 3%, 78. 2%, and 100% reduction in CFRs, respectively. When 0. 3 and 0. 6 mg/kg SZ-123 were administrated, 100% of VWF was occupied by the antibody. Moreover, 100% ex vivo inhibition of VWF-collagen binding and 60–95% inhibition of platelet aggregation were observed from 15 min to 1h. None of the doses resulted in significant prolongation of bleeding time. In vitro experiment also revealed that SZ-123 not only blocks collagen-VWF A3 interaction but also inhibits indirectly VWF A1 binding to GPIba induced by ristocetin. Conclusions:SZ-123 prevents in vivo arterial thrombus formation under high shear conditions by inhibiting VWF A3–collagen and VWF A1-platelet interactions and does not prolong bleeding time. Disclosures:No relevant conflicts of interest to declare.

Proinflammatory cytokine regulation of cyclic AMP‐phosphodiesterase 4 signaling in microglia in vitro and following CNS injury

Cyclic AMP suppresses immune cell activation and inflammation. The positive feedback loop of proinflammatory cytokine production and immune activation implies that cytokines may not only be regulated by cyclic AMP but also conversely regulate cyclic AMP. This study examined the effects of tumor necrosis factor (TNF)-α and interleukin (IL)-1β on cyclic AMP-phosphodiesterase (PDE) signaling in microglia in vitro and after spinal cord injury (SCI) or traumatic brain injury (TBI). TNF-α or IL-1β stimulation produced a profound reduction (>90%) of cyclic AMP within EOC2 microglia from 30 min that then recovered after IL-1β but remained suppressed with TNF-α through 24 h. Cyclic AMP was also reduced in TNF-α-stimulated primary microglia, albeit to a lesser extent. Accompanying TNF-α-induced cyclic AMP reductions, but not IL-1β, was increased cyclic AMP-PDE activity. The role of PDE4 activity in cyclic AMP reductions was confirmed by using Rolipram. Examination of pde4 mRNA revealed an immediate, persistent increase in pde4b with TNF-α; IL-1β increased all pde4 mRNAs. Immunoblotting for PDE4 showed that both cytokines increased PDE4A1, but only TNF-α increased PDE4B2. Immunocytochemistry revealed PDE4B nuclear translocation with TNF-α but not IL-1β. Acutely after SCI/TBI, where cyclic AMP levels are reduced, PDE4B was localized to activated OX-42(+) microglia; PDE4B was absent in OX-42(+) cells in uninjured spinal cord/cortex or inactive microglia. Immunoblotting showed PDE4B2 up-regulation from 24 h to 1 wk post-SCI, the peak of microglia activation. These studies show that TNF-α and IL-1β differentially affect cyclic AMP-PDE signaling in microglia. Targeting PDE4B2 may be a putative therapeutic direction for reducing microglia activation in CNS injury and neurodegenerative diseases.

Recombinant activated factor VII and prothrombin complex concentrates have different effects on bleeding and arterial thrombosis in the haemodiluted rabbit

Recombinant activated factor VII (rFVIIa) is indicated in bleeding patients when a life-threatening haemorrhage occurs. Prothrombin complex concentrates (PCCs) are also used for this indication in several countries, without any evidence-based rationale. Our objective was to compare the efficacy and safety of PCC and rFVIIa in a model of bleeding and thrombosis in haemodiluted rabbits. Forty-eight rabbits were randomly allocated into four groups: a control group and three treatment groups, in which animals were haemodiluted with hydroxyethyl starch 130/0.4 then administered either placebo, 160 µg kg(-1) rFVIIa, or 25 IU FIX kg(-1) PCC. The primary endpoint was hepatosplenic (HS) blood loss. Secondary endpoints were: (i) ear immersion bleeding time (IBT); (ii) thrombosis risk assessed by cyclic flow reductions (CFRs) of the carotid artery; and (iii) activated partial thromboplastin time (aPTT), and progress of thrombin activity. Haemodilution increased HS blood loss by 80% from 8 g (5-16) (control group) to 14 g (8-45) (placebo group) (P<0.01). HS blood loss was not different in animals receiving either rFVIIa [10 g (7-22)] or PCC [15 g (4-33)] (P<0.05) compared with the placebo group. Ear IBT was reduced with both rFVIIa and PCC. CFRs disappeared after haemodilution and were not restored with any treatment. Although PCC nearly doubled the total amount of thrombin generated, no significant change in the total amount of thrombin was seen in animals treated with rFVIIa. Neither rVIIa nor PCC reduced HS blood loss, whereas they both controlled the bleeding time, without increasing the thrombosis risk.

Whence the Little Ice Age?

Climate Science In the second half of the past millennium, glaciers advanced and temperatures fell in many regions around the world, although the timings and durations of the cold spells differed widely between regions. Numerous causes for this Little Ice Age have been proposed, including cyclical reductions in solar irradiance, changes in ocean circulation, and increases in volcanic activity, but the direct radiative effects of these processes are either weak or short-lived and require substantial feedbacks within the climate system. Miller et al. now exploit the fact that small ice caps in Arctic Canada are retreating, exposing vegetation that was entombed when the ice caps were advancing. By radiocarbon-dating these plants, the authors can accurately determine the time of glacial advance. They identify abrupt summer temperature decreases in the late 13th century and between 1430 and 1455 CE; subsequently, most ice caps remained in an expanded state until the 20th century. Comparison with varved sediments recording ice-cap growth from Iceland provides support for these dates, which coincide with periods of enhanced volcanic activity. Climate model results suggest that short-lived volcanic eruptions, reinforced by weak solar irradiance changes, can cause a sea-ice/ocean feedback that yields a centuries-long reduction in summer air temperature across the Arctic. Geophys. Res. Lett. 10.1029/2011GL050168 (2012).