Virtual flow-diverter treatment planning: The effect of device placement on bifurcation aneurysm haemodynamics

Bifurcation aneurysms account for a large fraction of cerebral aneurysms and often present morphologies that render traditional endovascular treatments, such as coiling, challenging and problematic. Flow-diverter stents offer a potentially elegant treatment option for such aneurysms, but clinical use of these devices remains controversial. Specifically, the deployment of a flow-diverter device in a bifurcation entails jailing one or more potentially vital vessels with a low-porosity mesh designed to restrict the flow. When multiple device placement configurations exist, the most appropriate clinical decision becomes increasingly opaque. In this study, three bifurcation aneurysm geometries were virtually treated by flow-diverter device. Each aneurysm was selected to offer two possible device deployment positions. Flow-diverters similar to commercially available designs were deployed with a fast-deployment algorithm before transient and steady state computational fluid dynamics simulations were performed. Reductions in aneurysm inflow, mean wall shear stress and maximum wall shear stress, all factors often linked with aneurysm treatment outcome, were compared for different device configurations in each aneurysm. In each of the three aneurysms modelled, a particular preferential device placement was shown to offer superior performance with the greatest reduction in the flow metrics considered. In all the three aneurysm geometries, substantial variations in inflow reduction (up to 25.3%), mean wall shear stress reduction (up to 14.6%) and maximum wall shear stress reduction (up to 12.1%) were seen, which were all attributed to device placement alone. Optimal device placement was found to be non-trivial and highly aneurysm specific; in only one-third of the simulated geometries, the best overall performance was achieved by deploying a device in the daughter vessel with the highest flow rate. Good correspondence was seen between transient results and steady state computations that offered a significant reduction in simulation run time. If accurate steady state computations are combined with the fast-deployment algorithm used, the modest run time and corresponding hardware make a virtual treatment pipeline in the clinical setting a meaningful possibility

Global assessment of nitrogen deposition effects on terrestrial plant diversity : a synthesis

Atmospheric nitrogen (N) deposition is it recognized threat to plant diversity ill temperate and northern parts of Europe and North America. This paper assesses evidence from field experiments for N deposition effects and thresholds for terrestrial plant diversity protection across a latitudinal range of main categories of ecosystems. from arctic and boreal systems to tropical forests. Current thinking on the mechanisms of N deposition effects on plant diversity, the global distribution of G200 ecoregions, and current and future (2030) estimates of atmospheric N-deposition rates are then used to identify the risks to plant diversity in all major ecosystem types now and in the future. This synthesis paper clearly shows that N accumulation is the main driver of changes to species composition across the whole range of different ecosystem types by driving the competitive interactions that lead to composition change and/or making conditions unfavorable for some species. Other effects such its direct toxicity of nitrogen gases and aerosols long-term negative effects of increased ammonium and ammonia availability, soil-mediated effects of acidification, and secondary stress and disturbance are more ecosystem, and site-specific and often play a supporting role. N deposition effects in mediterranean ecosystems have now been identified, leading to a first estimate of an effect threshold. Importantly, ecosystems thought of as not N limited, such as tropical and subtropical systems, may be more vulnerable in the regeneration phase. in situations where heterogeneity in N availability is reduced by atmospheric N deposition, on sandy soils, or in montane areas. Critical loads are effect thresholds for N deposition. and the critical load concept has helped European governments make progress toward reducing N loads on sensitive ecosystems. More needs to be done in Europe and North America. especially for the more sensitive ecosystem types. including several ecosystems of high conservation importance. The results of this assessment Show that the Vulnerable regions outside Europe and North America which have not received enough attention are ecoregions in eastern and Southern Asia (China, India), an important part of the mediterranean ecoregion (California, southern Europe). and in the coming decades several subtropical and tropical parts of Latin America and Africa. Reductions in plant diversity by increased atmospheric N deposition may be more widespread than first thought, and more targeted Studies are required in low background areas, especially in the G200 ecoregions

Palliative treatment of uncontrollable hypercalcemia due to parathyrotoxicosis: denosumab as rescue therapy

Parathyroid carcinoma is a rare disease leading to severe hypercalcemia due to hyperparathyroidism. Surgery is the primary treatment option. A more progressive form of the disease is characterized by parathyrotoxicosis, and subsequent hypercalcemia is the most common cause of death. We report a case presenting with severe hypercalcemia due to parathyrotoxicosis from parathyroid carcinoma treated for the first time using the monoclonal antibody denosumab as a rescue therapy and present long-term follow-up data. The 71-year-old patient presented with severe hypercalcemia due to metastatic parathyroid carcinoma. Despite undergoing treatment with bisphosphonates, cinacalcet hydrochloride, and forced diuresis, the patient's condition deteriorated rapidly due to resistant hypercalcemia. Surgery performed because of spinal metastasis and forced diuresis lowered calcium levels, albeit they remained in the hypercalcemic range and significantly increased when forced diuresis was stopped. Considering a palliative situation to overcome hypercalcemia, we decided to administer denosumab, a monoclonal antibody that binds to the receptor activator of nuclear factor-kappa B ligand. After a single subcutaneous administration of 60 mg denosumab, calcium levels normalized within one day. Subsequent denosumab injections led to permanent control of serum calcium for more than 2 years despite rising parathyroid hormone levels and repeated surgeries. Together with recent cases in the literature supporting our observation, we believe that denosumab is relevant for future trials and represents an effective tool to control hypercalcemia in patients with advanced stages of parathyroid cancer

Renal function is independently associated with circulating betatrophin

OBJECTIVE: Betatrophin has been identified as a marker linking liver with beta cell function and lipid metabolism in murine models. Until now, the regulation of circulating betatrophin in humans is not entirely clear. We here analyzed the relation of betatrophin levels to phenotypes of the metabolic syndrome and speculated that renal function might influence circulating betatrophin levels and explain age-dependent changes of betatrophin. SUBJECTS: We analyzed blood samples from 535 individuals participating in the Metabolic Syndrome Berlin Potsdam study. RESULTS: In a crude analysis we found a positive correlation between betatrophin levels and HbA1c (r = 0.24; p < 0.001), fasting glucose (r = 0.20; p < 0.001) and triglycerides (r = 0.12; p = 0.007). Furthermore betatrophin was positively correlated with age (r = 0.47; p <0.001), systolic blood pressure (r = 0.17; p < 0.001), intima media thickness (r = 0.26; p < 0.001) and negatively correlated with CKD-EPI eGFR (r = -0.33; p < 0.001) as an estimate of renal function. Notably, eGFR remained highly associated with betatrophin after adjustment for age, waist circumference, gender, HbA1c and lipid parameters in a multivariate linear regression model ({beta} = -0.197, p< 0.001). CONCLUSIONS: Our data suggest that circulating levels of betatrophin depend on age, gender, waist circumference, total/HDL cholesterol ratio and renal function. Especially the association to eGFR highlights the importance for future studies to address renal function as possible influence on betatrophin regulation and consider eGFR as potential confounder when analyzing the role of betatrophin in humans

Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21

OBJECTIVE—Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator–activator receptor (PPAR) –dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPAR, might modify FGF-21 levels. RESEARCH DESIGN AND METHODS—The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPAR activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks. RESULTS—Oleate and linoleate increased FGF-21 expression and secretion in a PPAR-dependent fashion, as demonstrated by small-interfering RNA–induced PPAR knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect. CONCLUSIONS—The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity

Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene

<p>Abstract</p> <p>Background</p> <p>Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.</p> <p>Methods</p> <p>Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the <it>EVC/EVC2 </it>locus. The results did not exclude linkage, so samples were sequenced for mutations.</p> <p>Results</p> <p>We identified a c.1868T>C mutation in <it>EVC</it>, which predicts p.L623P, and was homozygous in affected individuals.</p> <p>Conclusion</p> <p>We conclude that this <it>EVC </it>mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. <it>EVC </it>mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.</p

Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene

<p>Abstract</p> <p>Background</p> <p>Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.</p> <p>Methods</p> <p>Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the <it>EVC/EVC2 </it>locus. The results did not exclude linkage, so samples were sequenced for mutations.</p> <p>Results</p> <p>We identified a c.1868T>C mutation in <it>EVC</it>, which predicts p.L623P, and was homozygous in affected individuals.</p> <p>Conclusion</p> <p>We conclude that this <it>EVC </it>mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. <it>EVC </it>mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.</p

Nitrogen in Current European Policies

Europe, and especially the European Union (EU), has many governmental policy ¿ measures aimed at decreasing unwanted reactivenitrogen (N r ) emissions from combustion, agriculture and urban wastes. Many of these policy measures have an ¿eff ects-basedapproach¿, and focus on single N r compounds, single sectors and either on air or waters.¿ Th is chapter addresses the origin, objectives and targets of EU policy measures related to Nr emissions, considers which instrumentsare being used to implement the policies and briefl y discusses the eff ects of the policy measures.Approaches¿ Th e chapter starts with a brief description of the basic elements of governmental policy measures.¿ A review of the main international conventions and EU policies related to emissions of Nr to air and water is then provided.¿ Finally the chapter provides a semi-quantitative assessment of the eff ectiveness and effi ciency of European policy measures.Key fi ndings/state of knowledge¿ International conventions and other treaties have played a key role in raising awareness and establishing policy measures for Nr emissionsabatement in EU through so-called Directives and Regulations.¿ Th ere are many diff erent EU Directives, oft en addressing individual Nr compounds from individual sectors (e.g. NOx emissions fromcombustion; NH 3 emissions from agriculture, pollution of groundwater and surface water by nitrates from agriculture, discharge oftotal nitrogen from urban sewage to surface waters).¿ Many EU Directives have been revised following review and evaluation. Th ere are increasing eff orts to cluster single EU Directives intolarger Framework Directives.¿ Compliance with, and eff ectiveness of, the Directives diff ers between sectors; it decreases in the order (i) reducing NO x emissions fromcombustion sources, (ii) reducing nitrogen (and especially Phosphorus) discharges to waters from industries and households, and (iii)reducing NH 3 emissions and NO 3 leaching from agriculture.¿ Th ere is not much literature on the diff erences in the eff ectiveness and effi ciencies of Directives; a number of factors seem to be involvedin eff ectiveness and effi ciency, but these have not yet been analysed in a coherent manner.Major uncertainties/challenges¿ Th ere is a huge diversity in N r emission sources and pathways, while the number of policy instruments is limited. Th ere is need to fi ndthe optimal mix of policy instruments targeted to the emission sources as well as the stakeholders involved.¿ It has been indicated that some EU Directives addressing emissions of nitrogen compounds from specifi c sources have antagonisticeff ects. Th e magnitude of these eff ects is not yet well known.¿ Th ere is a delay in the environmental and ecological responses following the introduction of Directives; these are due to legislativedelays, lack of enforcement and control, constraints in practice and because of biogeochemical hysteresis eff ects; these eff ects are notyet well understood quantitatively.¿ In general, only modest reductions in Nr emissions from agriculture have been achieved to date; this refl ects the need for more eff ectiveand effi cient policy measures and/or greater enforcement of current policies.Recommendations¿ To examine further the diff erences between sectors of the factors that contribute to the eff ectiveness and effi ciency of policy measuresfor the abatement of N r emissions.¿ T o explore further the eff ectiveness and effi ciency of more integrated N management and integrated policy measures for the abatementof adverse impacts of N r emissions.JRC.DDG.H.2-Climate change and air qualit

Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity

The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity