Scanning for Mutations of the Ryanodine Receptor (RYR1) Gene by Denaturing HPLC: Detection of Three Novel Malignant Hyperthermia Alleles

AbstractBackground: Malignant hyperthermia (MH) is a fatal autosomal dominant pharmacogenetic disorder characterized by skeletal muscle hypertonicity that causes a sudden increase in body temperature after exposure to common anesthetic agents. The disease is genetically heterogeneous, with mutations in the gene encoding the skeletal muscle ryanodine receptor (RYR1) at 19q13.1 accounting for up to 80% of the cases. To date, at least 42 RYR1 mutations have been described that cause MH and/or central core disease. Because the RYR1 gene is huge, containing 106 exons, molecular tests have focused on the regions that are more frequently mutated. Thus the causative defect has been identified in only a fraction of families as linked to chromosome 19q, whereas in others it remains undetected.Methods: We used denaturing HPLC (DHPLC) to analyze the RYR1 gene. We set up conditions to scan the 27 exons to identify both known and unknown mutations in critical regions of the protein. For each exon, we analyzed members from 52 families with positive in vitro contracture test results, but without preliminary selection by linkage analysis.Results: We identified seven different mutations in 11 MH families. Among them, three were novel MH alleles: Arg44Cys, Arg533Cys, and Val2117Leu.Conclusion: Because of its sensitivity and speed, DHPLC could be the method of choice for the detection of unknown mutations in the RYR1 gene

Biliverdin Protects against Liver Ischemia Reperfusion Injury in Swine

Ischemia reperfusion injury (IRI) in organ transplantation remains a serious and unsolved problem. Organs that undergo significant damage during IRI, function less well immediately after reperfusion and tend to have more problems at later times when rejection can occur. Biliverdin has emerged as an agent that potently suppress IRI in rodent models. Since the use of biliverdin is being developed as a potential therapeutic modality for humans, we tested the efficacy for its effects on IRI of the liver in swine, an accepted and relevant pre-clinical animal model. Administration of biliverdin resulted in rapid appearance of bilirubin in the serum and significantly suppressed IRI-induced liver dysfunction as measured by multiple parameters including urea and ammonia clearance, neutrophil infiltration and tissue histopathology including hepatocyte cell death. Taken together, our findings, in a large animal model, provide strong support for the continued evaluation of biliverdin as a potential therapeutic in the clinical setting of transplantation of the liver and perhaps other organs

Five Years of Observations of the Circumpolar Cyclones of Jupiter

The regular polygons of circumpolar cyclones, discovered by Juno in 2017, are one of the most puzzling features of Jupiter. Here we show new recent global pictures of the North polar cyclones' structure. These are the first simultaneous images of the whole structure since 2017, and we find that it remained almost unperturbed, just like the South one. The observation of these long-lasting structures poses questions regarding the formation mechanism of cyclones, and on their vertical structure. Data by Juno/JIRAM infrared camera collected over the last 5 years show that cyclones migrate around what may seem like equilibrium positions, with timescales of a few months but, aside from that, the cyclones systems are very stable. Our analysis of the observations shows that the motion of cyclones around their equilibrium position is uncorrelated with their position if a barotropic approximation (β-drift) is assumed. Thus, a different dynamical explanation than the barotropic β-drift is needed to explain the stability of the observed features. Each cyclone has a peculiar morphology, which differs from the others and is stable over the observed lapse of time in most cases

Transitions to food democracy through multilevel governance

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High Frequency of Endothelial Colony Forming Cells Marks a Non-Active Myeloproliferative Neoplasm with High Risk of Splanchnic Vein Thrombosis

Increased mobilization of circulating endothelial progenitor cells may represent a new biological hallmark of myeloproliferative neoplasms. We measured circulating endothelial colony forming cells (ECFCs) in 106 patients with primary myelofibrosis, fibrotic stage, 49 with prefibrotic myelofibrosis, 59 with essential thrombocythemia or polycythemia vera, and 43 normal controls. Levels of ECFC frequency for patient's characteristics were estimated by using logistic regression in univariate and multivariate setting. The sensitivity, specificity, likelihood ratios, and positive predictive value of increased ECFC frequency were calculated for the significantly associated characteristics. Increased frequency of ECFCs resulted independently associated with history of splanchnic vein thrombosis (adjusted odds ratio = 6.61, 95% CI = 2.54–17.16), and a summary measure of non-active disease, i.e. hemoglobin of 13.8 g/dL or lower, white blood cells count of 7.8×109/L or lower, and platelet count of 400×109/L or lower (adjusted odds ratio = 4.43, 95% CI = 1.45–13.49) Thirteen patients with splanchnic vein thrombosis non associated with myeloproliferative neoplasms were recruited as controls. We excluded a causal role of splanchnic vein thrombosis in ECFCs increase, since no control had elevated ECFCs. We concluded that increased frequency of ECFCs represents the biological hallmark of a non-active myeloproliferative neoplasm with high risk of splanchnic vein thrombosis. The recognition of this disease category copes with the phenotypic mimicry of myeloproliferative neoplasms. Due to inherent performance limitations of ECFCs assay, there is an urgent need to arrive to an acceptable standardization of ECFC assessment

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Operationalizing mild cognitive impairment criteria in small vessel disease: The VMCI-Tuscany Study

Introduction Mild cognitive impairment (MCI) prodromic of vascular dementia is expected to have a multidomain profile. Methods In a sample of cerebral small vessel disease (SVD) patients, we assessed MCI subtypes distributions according to different operationalization of Winblad criteria and compared the neuroimaging features of single versus multidomain MCI. We applied three MCI diagnostic scenarios in which the cutoffs for objective impairment and the number of considered neuropsychological tests varied. Results Passing from a liberal to more conservative diagnostic scenarios, of 153 patients, 5% were no longer classified as MCI, amnestic multidomain frequency decreased, and nonamnestic single domain increased. Considering neuroimaging features, severe medial temporal lobe atrophy was more frequent in multidomain compared with single domain. Discussion Operationalizing MCI criteria changes the relative frequency of MCI subtypes. Nonamnestic single domain MCI may be a previously nonrecognized type of MCI associated with SVD

Large-Scale Land Acquisitions in Sub-Saharan Africa and Corporate Social Responsibility (CSR): Insights from Italian Investments

Since the mid-2000s, there has been a large interest in agriculture-based private and public\u2013private investments in many parts of Sub-Saharan Africa (SSA). A major driver of this land rush has been the increasing demand for biofuels in the European Union, especially due to the EU 2009 (EU RED, Directive 2009/28/EC of the European Parliament and of the Council of 23 April 2009 on the Promotion of the Use of Energy from Renewable Sources), Renewable Energy Directive (EU RED), which stipulates that by 2020 at least 10% of the energy used in the transport sector in every Member-State must be from renewable energy sources. However, large-scale land acquisitions (LSLAs) can have very diverse sustainability impacts in SSA. This chapter analyses the intersection between corporate social responsibility (CSR) strategies and LSLAs in SSA, focusing on Italian investors. We initially identify the characteristics of these LSLAs during the last decade, especially in the context of EU RED. The results suggest that Italian investors have acquired large tracts of land, especially for bioenergy crops. However, the analysis of CSR strategies suggests that most investors do not show responsible behaviour for issues related to land acquisitions. Practically none of these investors has adopted voluntary standard or certification and labelling (SCL) schemes that properly consider the main sustainability impacts of LSLAs

Assessing the Contribution of Bioeconomy to the Total Economy: A Review of National Frameworks

Developments in technology have enabled envisioning the derivation of materials and products from renewable biomass as an alternative to finite fossil-based resource consumption. Therefore, bioeconomy is regarded as an opportunity for sustainable economic growth. Countries are formulating strategies in accordance with their goals to attain a bioeconomy. Proper measurement, monitoring, and reporting of the outcomes of these strategies are crucial for long-term success. This study aims to critically evaluate the national methods used for the measurement, monitoring, and reporting of bioeconomy contribution to the total economy. For this purpose, research and surveys have been conducted on selected countries (Argentina, Germany, Malaysia, the Netherlands, South Africa, and the United States). The results reveal that the bioeconomy targets set up in the strategies often reflect the country’s priorities and comparative advantages. However, comprehensive approaches to measure and monitor bioeconomy progress are frequently lacking. Most countries only measure the contribution to gross domestic product (GDP), turnover, and employment of the sectors included in their bioeconomy definition, which may provide an incomplete picture. In addition, this study identifies the mismatch between the targets and measurement methods, as the environmental and social impacts of bioeconomy are often foreseen, but not measured. It is concluded that existing global efforts towards sustainable bioeconomy monitoring can be strengthened and leveraged to measure progress towards sustainable goals